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Abstract Embryo implantation failures are a major challenge in reproductive medicine, but the underlying mechanism remains poorly understood. Successful implantation requires dynamic remodeling of the endometrium through integrated proliferation and differentiation of endometrial cells including luminal epithelial, glandular epithelial, and stromal cells. Conversely, their disruption causes infertility. Spatiotemporal control of transcription is required for these processes; however, the underlying epigenetic regulation is largely unknown. In this study, we examined expression data from the human endometrium during implantation and discovered that expression of the histone lysine methyltransferase KMT2D was significantly suppressed in patients with recurrent implantation failure. Further study revealed that uterine deletion of Kmt2d in mice caused infertility due to implantation failure. Morphological analysis discovered a reduction in the number of uterine glands and aberrant differentiation of the luminal and glandular epithelium into stratified phenotypes in Kmt2d knockout uteri. Administration of leukemia inhibitory factor protein, which is expressed in uterine glands and is essential for implantation, did not rescue implantation failure in Kmt2d knockout mice, suggesting that infertility was not solely due to uterine gland dysfunction. RNA sequencing analysis revealed that Kmt2d knockout uteri displayed suppressed expression of genes involved in ion homeostasis, which may affect the uterine luminal morphology. Our study suggests that KMT2D plays an essential role in facilitating successful embryo implantation by regulating the coordinated differentiation of endometrial cells, providing valuable insights into unexplained implantation failures in women.

Abstract The combination of trifluridine/tipiracil hydrochloride (FTD/TPI) plus ramucirumab has demonstrated clinical activity in patients with advanced gastric cancer (AGC). We evaluated the efficacy and safety of this combination compared with those of FTD/TPI monotherapy in patients with AGC. We retrospectively reviewed data of patients with AGC who received FTD/TPI plus ramucirumab or FTD/TPI monotherapy as third- or later-line treatment. This study included 36 patients treated with FTD/TPI plus ramucirumab and 70 patients receiving FTD/TPI monotherapy. The objective response rate (ORR) and disease control rate (DCR) were 25.8% and 58.1%, respectively, in the FTD/TPI plus ramucirumab group and 5.0% and 38.3%, respectively, in the FTD/TPI group (ORR, P = 0.007; DCR, P = 0.081). The median progression-free survival (PFS) was significantly longer in the FTD/TPI plus ramucirumab group (median PFS, 2.9 vs. 1.8 months; hazard ratio [HR]: 0.52; P = 0.001). A numerical survival benefit was also observed (median overall survival, 7.9 months vs. 5.0 months; HR: 0.68, P = 0.089). In the multivariate analysis, PFS was significantly longer in the FTD/TPI plus ramucirumab group than in the FTD/TPI monotherapy group (HR: 0.61, P = 0.030). The incidence of febrile neutropenia was higher in the FTD/TPI plus ramucirumab group than in the FTD/TPI group (13.8% vs. 2.9%); however, no new safety signals were identified. Compared with FTD/TPI monotherapy, FTD/TPI plus ramucirumab offers clinical benefits with acceptable toxicity in heavily pretreated patients with AGC. Further investigation via randomized trials is warranted to confirm these findings.

We established a protocol for assessing the areal bone mineral density (BMD) of the proximal humerus using dual-energy X-ray absorptiometry (DXA). We also investigated the correlation between the BMD of the proximal humerus and that of the lumbar spine and proximal femur to predict the BMD of the proximal humerus. We included female patients aged >60 years who underwent bone density evaluation using DXA. The BMD of the proximal humerus was calculated at seven regions of interest (ROIs): the head of the humerus, lesser tubercle, greater tubercle in two locations, and proximal metaphysis in three locations. The intra- and inter-examiner reliabilities in the setting of the ROIs were examined using intraclass correlation coefficients (ICCs) (1.1) and (2.1), respectively, and the intra-examiner reliability in DXA was examined using ICCs (1.1). The intra- and inter-examiner reliabilities in the setting of ROIs and the intra-examiner reliability in DXA were high in all regions. The BMD of the lumbar spine and proximal femur correlated weakly with that of the humeral head and diaphysis. Our method for measuring the BMD of the proximal humerus was found to be reliable and may be applied in future studies.

Abstract Background Previous systematic reviews suggest that nurse-led interventions improve short-term blood pressure (BP) control for people with hypertension. However, the long-term effects, adverse events, and appropriate target BP level are unclear. This study aimed to evaluate the long-term efficacy and safety of nurse-led interventions. Methods We conducted a systematic review and meta-analysis. We searched the Cochrane Central Register of Controlled Trials, PubMed, and CINAHL, as well as three Japanese article databases, as relevant randomized controlled trials from the oldest possible to March 2021. This search was conducted on 17 April 2021. We did an update search on 17 October 2023. We included studies on adults aged 18 years or older with hypertension. The treatments of interest were community-based nurse-led BP control interventions in addition to primary physician-provided care as usual. The comparator was usual care only. Primary outcomes were long-term achievement of BP control goals and serious adverse events (range: 27 weeks to 3 years). Secondary outcomes were short-term achievement of BP control goals and serious adverse events (range: 4 to 26 weeks), change of systolic and diastolic BP from baseline, medication adherence, incidence of hypertensive complications, and total mortality. Results We included 35 studies. Nurse-led interventions improved long-term BP control (RR 1.10, 95%CI 1.03 to 1.18). However, no significant differences were found in the short-term effects of nurse-led intervention compared to usual care about BP targets. Little information on serious adverse events was available. There was no difference in mortality at both terms between the two groups. Establishing the appropriate target BP from the extant trials was impossible. Conclusions Nurse-led interventions may be more effective than usual care for achieving BP control at long-term follow-up. It is important to continue lifestyle modification for people with hypertension. We must pay attention to adverse events, and more studies examining appropriate BP targets are needed. Nurse-led care represents an important complement to primary physician-led usual care.

BackgroundHigher-level functional capacity (HLFC) is crucial for the independent living of older adults. While internet use positively impacts the health of older adults, its effect on HLFC and how this effect varies with educational attainment remains uncertain. ObjectiveThis longitudinal study aimed to investigate whether internet use could mitigate the risk of HLFC decline and if this benefit extends to older adults with lower levels of education. MethodsThe data were sourced from the Japan Gerontological Evaluation Study (JAGES), encompassing 8050 community-dwelling adults aged 65 years and older from 2016 to 2019. The study focused on those who remained self-sufficient from 2016 to 2019, identifying participants with independent HLFC in 2016. The Tokyo Metropolitan Institute of Gerontology Index of Competence defined HLFC operationally, consisting of 3 subscales, namely instrumental activities of daily living, intellectual activity, and social role. The primary variable was the frequency of internet use in 2016; participants who reported using the internet were classified as internet users, while those who answered “No” were identified as nonusers. The study compared the effects of internet use on HLFC decline across educational levels of ≤9 years, 10-12 years, and ≥13 years using Poisson regression analysis adjusted for robust SE to calculate the risk ratio (RR) and 95% CI for HLFC decline in 2019. ResultsAfter adjusting for demographic and health condition risk factors, internet use was significantly linked to a decreased risk of HLFC decline in older adults over 3 years, including those with lower educational levels. Internet users with ≤9 years of educational attainment experienced a suppressed decline in the total score (RR 0.57, 95% CI 0.43-0.76; P

Abstract BackgroundInternet-based cognitive behavioral therapy (iCBT) shows promise in the prevention of depression. However, the specific iCBT components that contribute to its effectiveness remain unclear. ObjectiveWe aim to evaluate the effects of iCBT components in preventing depression among university students. MethodsUsing a smartphone cognitive behavioral therapy (CBT) app, we randomly allocated university students to the presence or absence of 5 different iCBT components: self-monitoring, behavioral activation, cognitive restructuring, assertiveness training, and problem-solving. The active intervention lasted 8 weeks but the app remained accessible through the follow-up. The primary outcome was the onset of a major depressive episode (MDE) between baseline and the follow-up after 52 weeks, as assessed with the computerized World Health Organization Composite International Diagnostic Interview. Secondary outcomes included changes in the 9-item Patient Health Questionnaire, 7-item General Anxiety Disorder, and CBT Skills Scale. ResultsDuring the 12-month follow-up, 133 of 1301 (10) participants reported the onset of an MDE. There were no significant differences in the incidence of MDEs between the groups with or without each component (hazard ratios ranged from 0.85, 95% CI 0.60‐1.20, for assertiveness training to 1.26, 95% CI 0.88‐1.79, for self-monitoring). Furthermore, there were no significant differences in the changes on the 9-item Patient Health Questionnaire, 7-item General Anxiety Disorder, or for CBT Skills Scale between component allocation groups. However, significant reductions in depression and anxiety symptoms were observed among all participants at the 52-week follow-up. ConclusionsIn this study, we could not identify any specific iCBT components that were effective in preventing depression or the acquisition of CBT skills over the 12-month follow-up period, but all participants with and without intervention of each iCBT component demonstrated significant improvements in depressive and anxiety symptoms. Further research is needed to explore the potential impact of frequency of psychological assessments, nonspecific intervention effects, natural change in the mental state, and the baseline depression level.

Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) is the established therapy for refractory metastatic colorectal cancer, but there are concerns regarding the regimen’s complexity and hematotoxic effects, especially for patients with organ dysfunction, comorbidities, or a reduced performance status—groups often excluded from conventional clinical trials. Preliminary studies demonstrated that bi-weekly FTD/TPI + BEV may mitigate these hematotoxic effects compared with the conventional schedule without compromising efficacy. No clinical trials, however, have directly compared these two regimens. Therefore, we initiated the PRABITAS trial, a multicenter, randomized, phase III non-inferiority trial, to evaluate the efficacy and safety of bi-weekly FTD/TPI + BEV compared with conventional FTD/TPI + BEV. This was designed as a pragmatic trial, a novel approach in clinical trials aiming to aid decision-making in daily practice by mimicking real-world clinical settings. The PRABITAS trial incorporates minimal eligibility criteria to include a more representative patient population, allows flexibility in intervention adherence and assessment, and employs streamlined data collection to reduce the burden on both patients and healthcare providers. The primary endpoint is overall survival in the intention-to-treat population. Launched in December 2023, the trial aimed to enroll a total of 890 patients.

Abstract Background Based on the JCOG1109 trial, it is suggested that the combination of docetaxel, cisplatin, and 5‐fluorouracil (DCF) could potentially become a standard neoadjuvant chemotherapy regimen, alongside the conventional 5‐fluorouracil and cisplatin (CF) therapy, for esophageal cancer. However, there are few reports on the impact of body composition changes associated with neoadjuvant chemotherapy on prognosis. Aim Our study aimed to explore the effect of different neoadjuvant chemotherapy regimens on body composition during treatment and the impacts of body composition changes on their prognosis. Methods and results This is a retrospective study of 215 patients with advanced thoracic esophageal cancer who had surgery after neoadjuvant chemotherapy from 2013 to 2019. Computed tomography scans were performed before and after neoadjuvant chemotherapy to assess body composition. Skeletal muscle mass index (SMI) was calculated by dividing total skeletal muscle mass at the 3rd lumbar level by the square of height, while visceral and subcutaneous fat masses were measured at the level of umbilicus. Patients in the lowest 25% of both sexes were classified into the low visceral fat and low subcutaneous fat groups, respectively. Of the patients enrolled, 178 were male and 37 were female. Among them, 91 had clinical Stage II disease, and 124 had clinical Stage III disease. Additionally, 146 patients received neoadjuvant chemotherapy CF, and 69 received neoadjuvant chemotherapy DCF. Comparing the DCF and CF groups, the DCF group consisted of significantly younger patients (p

Abstract A recent meta-epidemiological study did not reveal major differences between the results of blinded and open randomised-controlled trials (RCTs). Fewer patients may consent to double-blind RCTs than to open RCTs, compromising generalisability, making this question very important. However, the issue has not been addressed in schizophrenia. We used a database of randomised, acute-phase antipsychotic drug trials. Whenever at least one open and one blinded RCT was available for a comparison of two drugs, we contrasted the results by random-effects meta-analysis with subgroup tests. The primary outcome was overall symptoms as measured by the Positive and Negative Syndrome Scale, supplemented by seven secondary efficacy and side-effect outcomes. We also examined whether open RCTs were biased in favour of more recently introduced antipsychotics, less efficacious or more prone to side-effects antipsychotics, and pharmaceutical sponsors. 183 RCTs (155 blinded and 28 open) with 34715 participants comparing two active drugs were available. The results did not suggest general differences between open and blinded RCTs, which examined two active drugs. Only 12 out of 122 subgroup tests had a p-value below 0.1, four below 0.05, and if a Bonferroni correction for multiple tests had been applied, only one would have been significant. There were some exceptions which, however, did not always confirm the originally hypothesized direction of bias. Due to the relatively small number of open RCTs, our analysis is exploratory, but this fundamental question should be given more scientific attention. Currently, open RCTs should be excluded from meta-analyses, at least in sensitivity analyses.

Abstract Understanding the oceanic phosphate concentration is critical for understanding marine productivity and oxygen evolution throughout Earth history. During the Archean, estimates of marine phosphate levels range from scarce to enriched conditions. However, biogeochemical conditions required for sustaining high phosphate concentrations while retaining an anoxic atmosphere during the Archean remain ambiguous. Here, we employ a biogeochemical model of the marine phosphate cycle to determine the conditions under which oceanic phosphate levels could have been higher than present‐day values during the Archean after the emergence of oxygenic photoautotrophs (OP). We show that, under the presence of OP, phosphate‐rich oceans require the limitation by factors other than phosphate, or a high outgassing rate of reducing gases. If these conditions were not met, the occurrence of oceanic phosphate levels higher than present‐day values during the Archean would require the absence of OP.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic was reported to have increased depression among university students which was associated with impairments in their campus lives. This study examined changes in depressive states among Japanese university students during the COVID-19 pandemic. Methods A secondary data analysis from a factorial randomized controlled trial involving smartphone-based cognitive-behavioral therapy was performed. Six cohorts (N = 1626) underwent an 8-week intervention during the spring or autumn of 2019–2021, with a 9-month follow-up. We evaluated participants’ depressive states weekly using the Patient Health Questionnaire-9 (PHQ-9) during the intervention, with monthly evaluations thereafter. The follow-up periods included Japan’s four states of emergency (SOEs) to control COVID-19. Hypothesizing that SOEs caused a sudden worsening of depressive states, Study 1 compared the cohorts’ PHQ-9 scores, and Study 2 employed time series analysis with a mixed-effects model to estimate identified changes in PHQ-9 scores. Results Although no changes in depressive states were observed in relation to the SOEs, Study 1 identified sudden increases in PHQ-9 scores at the 28-week evaluation point, which corresponded to the beginning of the new academic year for the three autumn cohorts. In contrast, the three spring cohorts did not exhibit similar changes. Study 2 showed that, for all three autumn cohorts (n = 522), the 0.60-point change was significant (95% CI 0.42–0.78; p

Background: Recent trials have reported a median overall survival (OS) of 11–17 months in patients with advanced gastric cancer (AGC). However, it is unclear how recently approved drugs contribute to patient prognosis. Objectives: We aimed to evaluate the characteristics and survival in patients with AGC over the past 15 years. Design: Retrospective study. Methods: We evaluated data of 1355 patients with AGC who received first-line chemotherapy between January 2005 and March 2019 at a single institution. We compared the characteristics and survival rates across four periods: January 2005–December 2007 (period A), January 2008–February 2011 (period B), March 2011–May 2015 (period C), and June 2015–March 2019 (period D). The median follow-up duration was 13.1 months, with 312, 333, 393, and 317 patients in periods A, B, C, and D, respectively. Results: There were no significant differences in patient characteristics between the four periods, except for the proportion of patients who underwent prior gastrectomy and human epidermal growth factor receptor 2 (HER2) testing. Patients in period D had significantly longer OS than those in period A [median: 15.7 versus 12.4 months; adjusted hazard ratio (aHR): 0.79; p = 0.02]. The mean OS in patients with liver metastasis (LM) in period D was remarkably longer than that in patients in period A (median: 19.3 versus 12.4 months; aHR: 0.61; p < 0.01), while that in patients with peritoneal metastasis showed limited improvement. Conclusion: Clinical strategy changes, including gastrectomy, HER2 testing, and approval of new drugs, may be associated with improved OS in patients with AGC. In the last 4 years, a remarkable improvement has been observed in patients with LM.

Abstract Background The increasing number of patients with chronic pain in Japan has become a major issue in terms of the patient's quality of life, medical costs, and related social problems. Pain is a multi-dimensional experience with physiological, affective, cognitive, behavioral and social components, and recommended to be managed via a combination of bio-psycho-social aspects. However, a biomedical approach is still the dominant method of pain treatment in Japan. The current study aimed to evaluate comprehensive psychological functions and processes in Japanese chronic pain patients. Methods The Rorschach Comprehensive System was administered to 49 in-patients with non-malignant chronic pain. Major variables and frequencies from the test were then compared to normative data from non-patient Japanese adults by way of the t-test and chi-square test. Results Patients exhibited high levels of emotional distress with a sense of helplessness with regard to situational stress, confusion, and ambivalent feelings. These emotions were managed by the patients in an inappropriate manner. Cognitive functions resulted in moderate dysfunction in all stages. Information processing tended to focus upon minute features in an inflexible manner. Mediational dysfunction was likely to occur with unstable affective conditions. Ideation was marked by pessimistic and less effective thinking. Since patients exhibited negative self-perception, their interpersonal relationship skills tended to be ineffective. Originally, our patients displayed average psychological resources for control, stress tolerance, and social skills for interpersonal relationships. However, patient coping styles were either situation- or emotion-dependent, and patients were more likely to exhibit emotional instability influenced by external stimuli, resulting in increased vulnerability to pain. Conclusions Data gathered from the Rorschach test suggested psychological approaches to support chronic pain patients that are likely to be highly beneficial, and we thus recommend their incorporation into the course of current pain treatments.

Abstract Anti-Cytotoxic T-Lymphocyte Associated protein 4 agents, such as ipilimumab, are widely applied to various cancers. However, they cause immune-related adverse effects throughout the body, including the eye. This study examined whether ipilimumab induces retinal and choroidal abnormalities in rodents, and investigated potential underlying mechanisms. Female wild-type mice were injected with ipilimumab three times/week for 5 weeks. The mice underwent optical coherence tomography (OCT) on the first day of the 6th week. Retinal function and morphology were evaluated by light microscopy, immunohistochemistry and electroretinography (ERG). On OCT, the lines indicating the ellipsoid and interdigitation were obscure in treated mice, suggesting outer retina destruction. Haematoxylin–eosin staining revealed destruction, shortening, and outer segment vacuolization. Treated mice exhibited weaker, fragmented rhodamine peanut agglutinin staining in outer photoreceptor structures. The choroid of treated mice showed severe infiltration of CD45-positive cells. In addition, CD8-positive cells invaded into the outer retina. On ERG, rod, maximum responses of combined rods and cones, and cone response wave amplitudes were significantly reduced in treated mice. Ipilimumab may induce impairments in outer photoreceptor architecture accompanied with CD8- positive infiltration in the retina and CD45-positive cell infiltration in the choroid, which may contribute to retinal function deterioration.

Total elbow arthroplasty is effective for pain relief and the functional improvement of severe symptomatic hemophilic osteoproliferative arthropathy. Nevertheless, high complication rates have been reported. This report describes clinical results obtained at 30-month follow-up of total elbow arthroplasty in a hemophilic patient with severe flexion contracture. A 50-year-old patient with advanced left elbow hemophilic arthropathy underwent unlinked total elbow arthroplasty. He had sustained an intraoperative fracture of the medial part of a supracondylar humerus complication. To control perioperative bleeding, strict factor VIII replacement therapy was performed under the guidance of hematologists. The total elbow range of motion was 35° preoperatively, but it had improved to 110° postoperatively. The Patient-Rated Elbow Evaluation Japanese version score, which was 53.7 preoperatively, improved to 10.7 postoperatively. During the 30 months after operation, no complication occurred. Good clinical results have been obtained under close collaboration with hematologists and close patient adherence following treatment.

The Miocene climatic optimum could have been triggered by coeval increase in magmatism, suggests global carbon cycle simulations constrained by seawater osmium isotope data from Pacific Ocean sediments.

Calcite particles (Source; CaCO3, ∼0.4 μm in size) were 3D-printed into cube honeycombs (honeycombs) with ∼0.7 mm thick struts and ∼0.6 mm cellular window opening. The sintered honeycombs, regardless of the presence of a sintering aid in the printing slurry, gave ∼3 MPa or more in the compressive stress, which exceeded that of trabecular bone. The conversion of calcite to hydroxyapatite (HAp) was assessed in 0.1 M K2HPO4 (pH: 7.0 or 7.4) at 20 °C–80 °C due to the X-ray diffraction intensity of the calcite and HAp peaks, surface microstructure, and P(V) accumulation on the honeycomb strut surface. Although a premature HAp layer yielded on all samples within 1 h soaking, further conversion depended on the samples. The conversion continued on Source until the volume fraction of the HAp shell layer reached ∼35% (37 °C). It was hardly detected on the grains of sintered honeycombs (from the slurry with the sintering aid) within the whole soaking period (≤24 h). In contrast, the conversion on the sintered honeycombs (from the slurry without the aid) became vigorous when soaked for 5 h, and, it reached at 24 h the highest level that the as-printed honeycombs achieved. The critical factors controlling the conversion were calcite dissolution, the equilibria among the carbonate and phosphate ions, and the rates of migration of Ca(II) and P(V) through the inter-granular channels of pores within the struts. A particle stacking model was proposed for the most plausible interpretation of the present results.