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Abstract Background Primary aromatic amines (PAAs) present significant challenges in the prediction of mutagenicity using current standard quantitative structure activity relationship (QSAR) systems, which are knowledge-based and statistics-based, because of their low positive prediction values (PPVs). Previous studies have suggested that PAAs are metabolized into genotoxic nitrenium ions. Moreover, ddE, a relative-energy based index derived from quantum chemistry calculations that measures the stability nitrenium ions, has been correlated with mutagenicity. This study aims to further examine the ability of the ddE-based approach in improving QSAR mutagenicity predictions for PAAs and to develop a refined method to decrease false positive predictions. Results Information on 1,177 PAAs was collected, of which 420 were from public databases and 757 were from in-house databases across 16 laboratories. The total dataset included 465 Ames test-positive and 712 test-negative chemicals. For internal PAAs, detailed Ames test data were scrutinized and final decisions were made using common evaluation criteria. In this study, ddE calculations were performed using a convenient and consistent protocol. An optimal ddE cutoff value of -5 kcal/mol, combined with a molecular weight ≤ 500 and ortho substitution groups yielded well-balanced prediction scores: sensitivity of 72.0%, specificity of 75.9%, PPV of 65.6%, negative predictive value of 80.9% and a balanced accuracy of 74.0%. The PPV of the ddE-based approach was greatly reduced by the presence of two ortho substituent groups of ethyl or larger, as because almost all of them were negative in the Ames test regardless of their ddE values, probably due to steric hindrance affecting interactions between the PAA and metabolic enzymes. The great majority of the PAAs whose molecular weights were greater than 500 were also negative in Ames test, despite ddE predictions indicating positive mutagenicity. Conclusions This study proposes a refined approach to enhance the accuracy of QSAR mutagenicity predictions for PAAs by minimizing false positives. This integrative approach incorporating molecular weight, ortho substitution patterns, and ddE values, substantially can provide a more reliable basis for evaluating the genotoxic potential of PAAs.

Abstract Pembrolizumab-containing regimens are the standard first-line treatment for recurrent/metastatic squamous cell carcinoma of the head and neck (R/M HNSCC). The neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein-to-albumin ratio (CAR) have been reported to be important prognostic factors in a variety of carcinomas, but none have been investigated in combination with pembrolizumab and chemotherapy or in first-line treatment. Seventy-four patients with R/M HNSCC received pembrolizumab-containing regimens at Tohoku University Hospital, Sendai, Japan, from April 2020 to March 2023. Patient characteristics, tumor response, overall survival (OS), progression-free survival (PFS), and laboratory findings were reviewed. Associations between NLR, CAR, and survival outcomes were analyzed. The 1-year OS and 1-year PFS rates were 60.4% and 18.1%, respectively. The disease control rate was 66.2%. In multivariate analysis, low NLR (

Ureteral obstruction after urinary diversion is not a rare complication, and the treatment is generally the ureteral stent placement via antegrade approach via the nephrostomy. We present a case of 64-year-old man with history of total pelvic resection and urinary diversion for local recurrence of rectal cancer who presented bilateral ureteral obstruction due to postoperative adhesion. First, bilateral nephrostomies were performed. The antegrade approach via nephrostomy could not break through the obstruction in the left side. Therefore, antegrade and retrograde approaches were attempted, and the internal-external drainage catheter could be placed by the rendezvous technique using bilateral microcatheters and microguidewires. The patient was able to avoid a permanent nephrostomy and continues to undergo regular internal drainage catheter exchange. Permanent nephrostomy considerably reduces the patient's quality of life, and in cases of tight obstruction, rendezvous techniques can be used.

Objectives: To investigate the significance of lateral pelvic lymph node dissection (LPLND) in resectable stage IV low rectal cancers, reviewing the treatment outcomes from a single cancer center dedicated to LPLND. Methods: Consecutive 56 patients with stage IV low rectal cancers who underwent primary tumor resection (PTR) between 2007 and 2022 were identified. Sixteen patients with non-curative PTR were excluded, and 40 with curative PTR were analyzed. Results: The dominant metastatic organ was the liver in 30 (75.0%) patients, followed by the lung in 9 (22.5%). Seven (17.5%) patients had multiple organ metastasis. Five of 40 patients had cT1bN0 or cT2N0 disease, 8 did not receive LPLND for other reasons, and accordingly, 27 (67.5%) finally received LPLND. A total of 15 patients (37.5% of all 40 cases and 55.5% of 27 LPLND cases) had LPLN metastasis. Six (15.0%) patients had bilateral metastasis, and 6 (15.0%) had LD3 metastasis. Eight (20.0%) patients developed local recurrence (LR), and the 5Y-LR rate was 22.3%. Twelve (30.0%) patients underwent preceding chemotherapy before PTR, 26 (65.0%) received chemotherapy after PTR, and 23 (57.5%) achieved complete resection. Twelve (52.2%) of 23 patients developed distant recurrence after complete resection. 5Y-overall survival for all patients was 42.4%. Conclusions: A high rate of LPLN metastasis implies the significance of management for LPLN metastasis; meanwhile, an unsatisfactory complete resection rate and overall survival implies that LPLN metastasis in this cohort should be dealt with as a systemic disease.

Abstract Background Cutis laxa constitutes a diverse group of connective tissue diseases, both inherited and acquired, characterized by loose skin and varying systemic involvement, including pulmonary lesions. While cutis laxa has been linked to conditions like emphysema, asthma, and bronchiectasis, the specific pathological and radiological characteristics underlying pulmonary complications related to cutis laxa remain unclear. Case presentation A 36-year-old woman, diagnosed with cutis laxa at birth, presented to our outpatient clinic with severe obstructive ventilatory impairment, evident in pulmonary function tests (expiratory volume in one second (FEV1)/forced vital capacity (FVC): 34.85%; %residual volume [RV]: 186.5%; %total lung capacity [TLC]: 129.2%). Pulmonary function tests also indicated small airway disease (%FEF50%, 7.9%; %FEF75%, 5.7%; and %FEF25–75%, 6.8%). Computed tomography (CT) revealed the lack of normal increase in lung attenuation on expiratory CT scan, with no discernible emphysematous changes. Exome sequencing was performed to confirm the association between the pulmonary lesions and cutis laxa, revealing a frameshift variant in exon 30 of the elastin gene (ELN). Further analysis employing a parametric response map revealed a longitudinal increase in the percentage of functional small airway disease (fSAD) from 37.84% to 46.61% over the 8-year follow-up, despite the absence of overt changes in CT findings, specifically the lack of normal increase in lung attenuation on expiratory CT scan. Over the same follow-up interval, there was a modest reduction of 25.6 mL/year in FEV1 coupled with a significant increase in %RV. Pulmonary function test metrics, reflective of small airway disease, exhibited a continual decline; specifically, %FEF50%, %FEF75%, and %FEF25–75% diminished from 7.9% to 7.0%, 5.7% to 4.6%, and 6.8% to 5.4%, respectively. Conclusions This case highlighted an instance of autosomal dominant cutis laxa arising from a frameshift variant in exon 30 of ELN, accompanied by small airway disease. Comprehensive investigation, utilizing quantitative CT analysis, revealed a longitudinal increase in fSAD percentage with a mild reduction in FEV1. These findings indicate that elastin deficiency may not only diminish elastic fibers in the skin but also be implicated in small airway disease by impacting components of the extracellular matrix in the lungs.

Abstract Chronic fibrotic tissue disrupts various organ functions. Despite significant advances in therapies, mortality and morbidity due to heart failure remain high, resulting in poor quality of life. Beyond the cardiomyocyte-centric view of heart failure, it is now accepted that alterations in the interstitial extracellular matrix (ECM) also play a major role in the development of heart failure. Here, we show that protein kinase N (PKN) is expressed in cardiac fibroblasts. Furthermore, PKN mediates the conversion of fibroblasts into myofibroblasts, which plays a central role in secreting large amounts of ECM proteins via p38 phosphorylation signaling. Fibroblast-specific deletion of PKN led to a reduction of myocardial fibrotic changes and cardiac dysfunction in mice models of ischemia-reperfusion or heart failure with preserved ejection fraction. Our results indicate that PKN is a therapeutic target for cardiac fibrosis in heart failure.

Abstract Paleoclimate model simulations provide reference data to help interpret the geological record and offer a unique opportunity to evaluate the performance of current models under diverse boundary conditions. Here, we present a dataset of 35 climate model simulations of the warm early Eocene Climatic Optimum (EECO; ~ 50 million years ago) and corresponding preindustrial reference experiments. To streamline the use of the data, we apply standardised naming conventions and quality checks across eight modelling groups that have carried out coordinated simulations as part of the Deep-Time Model Intercomparison Project (DeepMIP). Gridded model fields can be downloaded from an online repository or accessed through a new web application that provides interactive data exploration. Local model data can be extracted in CSV format or visualised online for streamlined model-data comparisons. Additionally, processing and visualisation code templates may serve as a starting point for advanced analysis. The dataset and online platform aim to simplify accessing and handling complex data, prevent common processing issues, and facilitate the sharing of climate model data across disciplines.

Abstract Background Polypharmacy is an escalating public health concern across various healthcare settings worldwide. We aimed to comprehensively investigate postoperative complications after laparoscopic surgery for colorectal cancer and explore their association with polypharmacy. As laparoscopic surgery is widespread, clarifying the association between polypharmacy and postoperative complications is clinically important. Methods We retrospectively surveyed the medical charts of adult inpatients who underwent laparoscopic surgery for colorectal cancer at Tohoku Medical and Pharmaceutical University Hospital between April 2019 and March 2023. Postoperative complications were determined using the Clavien–Dindo classification. We explored the factors related to postoperative complications and calculated the cut-off values for the number of medication ingredients. Results Among the 236 patients, 32 (13.6%) developed postoperative complications. On multivariable logistic regression analysis, the number of regularly used medication ingredients (odds ratio = 1.160, 95% confidence interval 1.050–1.270, p = 0.002) was identified as a factor related to postoperative complications. The identified cut-off value for complications was 10 ingredients. Patients using 10 or more ingredients had approximately 3.5 times higher occurrence of postoperative complications than those using fewer than 10 ingredients (33.3% vs. 9.3%, p

Abstract Particles containing alpha (α) nuclides were identified from sediment in stagnant water in the Unit 3 reactor building of the Fukushima Daiichi Nuclear Power Station (FDiNPS). We analyzed different concentrations of α-nuclide samples collected at two sampling sites, the torus room and the main steam isolation valve (MSIV) room. The solids in the stagnant water samples were classified, and the uranium (U) and total alpha concentrations of each fraction were measured by dissolution followed by inductively coupled plasma mass spectrometry and α-spectrometry. Most of the α-nuclides in the stagnant water samples from the torus and MSIV rooms were in particle fractions larger than 10 μm. We detected uranium-bearing particles ranging from sub-µm to 10 µm in size by scanning electron microscopy–energy-dispersive X-ray (SEM–EDX) observations. The chemical forms of U particles were determined in U–Zr oxides, oxidized UO2, and U3O8 with micro-Raman spectroscopy. Other short-lived α-nuclides (plutonium [Pu], americium [Am], and curium [Cm]) were detected by alpha track detection, and the particles with α-nuclides was characterized by SEM–EDX analysis. α-nuclide-containing particles with several tens to several 100 µm in size mainly comprised iron (Fe) oxyhydroxides. In addition, we detected adsorbed U onto Fe oxyhydroxide particles in the MSIV room sample, which indicated nuclear fuel dissolution and secondary U accumulation. This study clarifies the major characteristics of U and other α-nuclides in sediment in stagnant water in the FDiNPS Unit 3 reactor building, which significantly contribute to the consideration of removal methods for particles containing α-nuclides in the stagnant water.

Abstract The underlying mechanisms of atherosclerosis, the second leading cause of death among Werner syndrome (WS) patients, are not fully understood. Here, we establish an in vitro co-culture system using macrophages (iMφs), vascular endothelial cells (iVECs), and vascular smooth muscle cells (iVSMCs) derived from induced pluripotent stem cells. In co-culture, WS-iMφs induces endothelial dysfunction in WS-iVECs and characteristics of the synthetic phenotype in WS-iVSMCs. Transcriptomics and open chromatin analysis reveal accelerated activation of type I interferon signaling and reduced chromatin accessibility of several transcriptional binding sites required for cellular homeostasis in WS-iMφs. Furthermore, the H3K9me3 levels show an inverse correlation with retrotransposable elements, and retrotransposable element-derived double-stranded RNA activates the DExH-box helicase 58 (DHX58)-dependent cytoplasmic RNA sensing pathway in WS-iMφs. Conversely, silencing type I interferon signaling in WS-iMφs rescues cell proliferation and suppresses cellular senescence and inflammation. These findings suggest that Mφ-specific inhibition of type I interferon signaling could be targeted to treat atherosclerosis in WS patients.

Abstract Titanium (Ti) is an attractive material, abundant in nature and possessing superior mechanical and chemical properties. However, its widespread use is significantly hampered by the strong affinity between titanium and oxygen (O), resulting in elevated manufacturing costs during the refining, melting, and casting processes. The current work introduces a high-throughput technique that effectively reduces the oxygen content in molten titanium to a level suitable for structural material applications (1000 mass ppm, equivalent to 0.1 mass%). This technique aspires to streamline the mass production of titanium by seamlessly integrating the refining, melting, and casting processes. The developed method leverages the high affinity of rare-earth metals, such as yttrium (Y), for oxygen. This method utilizes the formation reaction of their oxyhalides (YOF) to directly remove oxygen from liquid titanium, resulting in titanium with a significantly reduced oxygen content of 200 mass ppm. This technique enables the direct conversion of titanium oxide feeds into low-oxygen titanium without requiring conversion into intermediate compounds. Additionally, this process offers a pathway for the upgrade recycling of high-oxygen-content titanium scrap directly into low-oxygen titanium. Consequently, this technology holds the potential to dramatically lower titanium production costs, thereby facilitating its more widespread utilization.

Abstract The mid-Piacenzian warm period (MPWP, ~3.264–3.025 Ma) has gained widespread interest due to its partial analogy with future climate. However, quantitative data–model comparison of East Asian Summer Monsoon (EASM) precipitation during the MPWP is relatively rare, especially due to problems in decoding the imprint of physical processes to climate signals in the records. In this study, pollen-based precipitation records are reconstructed and compared to the multi-model ensemble mean of the Pliocene Model Intercomparison Project Phase 2 (PlioMIP2). We find spatially consistent precipitation increase in most simulations but a spatially divergent change in MPWP records. We reconcile proxy data and simulation by decomposing physical processes that control precipitation. Our results 1) reveal thermodynamic control of an overall enhancement of EASM precipitation and 2) highlight a distinct control of thermodynamic and dynamical processes on increases of tropical and subtropical EASM precipitation, reflecting the two pathways of water vapor supply that enhance EASM precipitation, respectively.

Macaques are representative animal models in translational research. However, the distinct shape and location of the brain regions between macaques and humans prevents us from comparing the brain structure directly. Here, we calculated structural connectivity (SC) with multi-scale hierarchical regions of interest (ROIs) to parcel out human and macaque brain into 8 (level 1 ROIs), 28 (level 2 ROIs), or 46 (level 3 ROIs) regions, which consist of anatomically and functionally defined level 4 ROIs (around 100 parcellation of the brain). The SC with the level 1 ROIs showed lower individual and interspecies variation in macaques and humans. SC with level 2 and 3 ROIs shows that the several regions in frontal, temporal and parietal lobe show distinct connectivity between macaques and humans. Lateral frontal cortex, motor cortex and auditory cortex were shown to be important areas for interspecies differences. These results provide insights to use macaques as animal models for translational study.

Abstract The Ice Sheet Model Intercomparison Project for CMIP6 (ISMIP6) is the primary effort of CMIP6 (Coupled Model Intercomparison Project–Phase 6) focusing on ice sheets, designed to provide an ensemble of process‐based projections of the ice‐sheet contribution to sea‐level rise over the twenty‐first century. However, the behavior of the Antarctic Ice Sheet beyond 2100 remains largely unknown: several instability mechanisms can develop on longer time scales, potentially destabilizing large parts of Antarctica. Projections of Antarctic Ice Sheet evolution until 2300 are presented here, using an ensemble of 16 ice‐flow models and forcing from global climate models. Under high‐emission scenarios, the Antarctic sea‐level contribution is limited to less than 30 cm sea‐level equivalent (SLE) by 2100, but increases rapidly thereafter to reach up to 4.4 m SLE by 2300. Simulations including ice‐shelf collapse lead to an additional 1.1 m SLE on average by 2300, and can reach 6.9 m SLE. Widespread retreat is observed on that timescale in most West Antarctic basins, leading to a collapse of large sectors of West Antarctica by 2300 in 30%–40% of the ensemble. While the onset date of retreat varies among ice models, the rate of upstream propagation is highly consistent once retreat begins. Calculations of sea‐level contribution including water density corrections lead to an additional ∼10% sea level and up to 50% for contributions accounting for bedrock uplift in response to ice loading. Overall, these results highlight large sea‐level contributions from Antarctica and suggest that the choice of ice sheet model remains the leading source of uncertainty in multi‐century projections.

Abstract Background As a third of all community dwellers aged 65+ fall each year, falls are common reasons for older adults to present to an Emergency Department (ED). Although EDs should assess patients’ multifactorial fall risks to prevent future fall-related injuries, this frequently does not occur. We describe our protocol to determine the feasibility, acceptability, and safety of a pilot ED Virtual Observation Unit (VOU) Falls program. Methods To ensure standardized conduct and reporting, the Standard Protocol Items for Intervention Trials (SPIRIT) guidelines will be used. The VOU is a program where patients are sent home from the ED but are part of a virtual observation unit in that they can call on-call ED physicians while they are being treated for conditions such as cellulitis, congestive heart failure, or pneumonia. A paramedic conducts daily visits with the patient and facilitates a telemedicine consult with an ED physician. VOU nursing staff conduct daily assessments of patients via telemedicine. The ED VOU Falls program is one of the VOU pathways and is a multi-component fall prevention program for fall patients who present after an ED visit. The paramedic conducts a home safety evaluation, a Timed Up and Go Test (TUG). During the VOU visit, the ED physician conducts a telemedicine visit, while the paramedic is visiting the home, to review patients' fall-risk-increasing drugs and their TUG test. We will determine feasibility by calculating rates of patient enrollment refusal, and adherence to fall-risk prevention recommendations using information from 3-month follow-up telephone calls, as well as qualitative interviews with the paramedics. We will determine the acceptability of the ED VOU Falls program based on patient and provider surveys using a Likert scale. We will ask VOU nursing staff to report any safety issues encountered while the patient is in the ED VOU Falls program (e.g., tripping hazards). We will use the chi-square test or Fisher’s exact test for categorical variables, Student’s t-test for continuous variables, and Mann-Whitney for nonparametric data. We will review interview transcripts and generate codes. Codes will then be extracted and organized into concepts to generate an overall theme following grounded theory methods. This is a pilot study; hence, results cannot be extrapolated. However, a definite trial would be the next step in the future to determine if such a program could be implemented as part of fall prevention interventions. Discussion This study will provide insights into the feasibility and acceptability of a novel ED VOU Falls program with the aim of ultimately decreasing falls. In the future, such a program could be implemented as part of fall prevention interventions.

During the mid-Pliocene warm period (mPWP; 3.264–3.025 Ma), atmospheric CO2 concentrations were approximately 400 ppm, and the Antarctic Ice Sheet was substantially reduced compared to today. Antarctica is surrounded by the Southern Ocean, which plays a crucial role in the global oceanic circulation and climate regulation. Using results from the Pliocene Model Intercomparison Project (PlioMIP2), we investigate Southern Ocean conditions during the mPWP with respect to the pre-industrial period. We find that the mean sea surface temperature (SST) warming in the Southern Ocean is 2.8 °C, while global mean SST warming is 2.4 °C. The enhanced warming is strongly tied to a dramatic decrease in sea ice cover over the mPWP Southern Ocean. We also see a freshening of the ocean (sub)surface, driven by an increase in precipitation over the Southern Ocean and Antarctica. The warmer and fresher surface leads to a highly stratified Southern Ocean that can be related to weakening of the deep abyssal overturning circulation. Sensitivity simulations show that the decrease in sea ice cover and enhanced warming is largely a consequence of the reduction in the Antarctic Ice Sheet. In addition, the mPWP geographic boundary conditions are responsible for approximately half of the increase in mPWP SST warming, sea ice loss, precipitation, and stratification increase over the Southern Ocean. From these results, we conclude that a strongly reduced Antarctic Ice Sheet during the mPWP has a substantial influence on the state of the Southern Ocean and exacerbates the changes that are induced by a higher CO2 concentration alone. This is relevant for the long-term future of the Southern Ocean, as we expect melting of the western Antarctic Ice Sheet in the future, an effect that is not currently taken into account in future projections by Coupled Model Intercomparison Project (CMIP) ensembles.

Abstract BCR::ABL1 fusion is found in

The last deglaciation (∼20–11 ka BP) is a period of a major, long-term climate transition from a glacial to interglacial state that features multiple centennial- to decadal-scale abrupt climate variations whose root cause is still not fully understood. To better understand this time period, the Paleoclimate Modelling Intercomparison Project (PMIP) has provided a framework for an internationally coordinated endeavour in simulating the last deglaciation whilst encompassing a broad range of models. Here, we present a multi-model intercomparison of 17 transient simulations of the early part of the last deglaciation (∼20–15 ka BP) from nine different climate models spanning a range of model complexities and uncertain boundary conditions and forcings. The numerous simulations available provide the opportunity to better understand the chain of events and mechanisms of climate changes between 20 and 15 ka BP and our collective ability to simulate them. We conclude that the amount of freshwater forcing and whether it follows the ice sheet reconstruction or induces an inferred Atlantic meridional overturning circulation (AMOC) history, heavily impacts the deglacial climate evolution for each simulation rather than differences in the model physics. The course of the deglaciation is consistent between simulations except when the freshwater forcing is above 0.1 Sv – at least 70 % of the simulations agree that there is warming by 15 ka BP in most places excluding the location of meltwater input. For simulations with freshwater forcings that exceed 0.1 Sv from 18 ka BP, warming is delayed in the North Atlantic and surface air temperature correlations with AMOC strength are much higher. However, we find that the state of the AMOC coming out of the Last Glacial Maximum (LGM) also plays a key role in the AMOC sensitivity to model forcings. In addition, we show that the response of each model to the chosen meltwater scenario depends largely on the sensitivity of the model to the freshwater forcing and other aspects of the experimental design (e.g. CO2 forcing or ice sheet reconstruction). The results provide insight into the ability of our models to simulate the first part of the deglaciation and how choices between uncertain boundary conditions and forcings, with a focus on freshwater fluxes, can impact model outputs. We can use these findings as helpful insight in the design of future simulations of this time period.

Atmospheric carbon dioxide concentration (pCO2) has increased by approximately 80 ppm from the Last Glacial Maximum (LGM) to the early Holocene. The change in this atmospheric greenhouse gas is recognized as a climate system response to gradual change in insolation. Previous modeling studies suggested that the deglacial increase in atmospheric pCO2 is primarily attributed to the release of CO2 from the ocean. Additionally, it has been suggested that abrupt change in the Atlantic meridional overturning circulation (AMOC) and associated interhemispheric climate changes are involved in the release of CO2. However, understanding remains limited regarding oceanic circulation changes and the factors responsible for changes in chemical tracers in the ocean during the last deglaciation and their impact on atmospheric pCO2. In this study, we investigate the evolution of the ocean carbon cycle during the last deglaciation (21 to 11 ka BP) using three-dimensional ocean fields from the transient simulation of the MIROC 4m climate model, which exhibits abrupt AMOC changes similar to those observed in reconstructions. We investigate the reliability of simulated changes in the ocean carbon cycle by comparing the simulated carbon isotope ratios with sediment core data, and we examine potential biases and overlooked or underestimated processes in the model. Qualitatively, the modeled changes in atmospheric pCO2 are consistent with ice core records. For example, during Heinrich Stadial 1 (HS1), atmospheric pCO2 increases by 10.2 ppm, followed by a reduction of 7.0 ppm during the Bølling–Allerød (BA) period and then by an increase of 6.8 ppm during the Younger Dryas (YD) period. However, the model underestimates the changes in atmospheric pCO2 during these events compared to values derived from ice core data. Radiocarbon and stable isotope signatures (Δ14C and δ13C) indicate that the model underestimates both the activated deep-ocean ventilation and reduced efficiency of biological carbon export in the Southern Ocean and the active ventilation in the North Pacific Intermediate Water (NPIW) during HS1. The relatively small changes in simulated atmospheric pCO2 during HS1 might be attributable to these underestimations of ocean circulation variation. The changes in Δ14C associated with strengthening and weakening of the AMOC during the BA and YD periods are generally consistent with values derived from sediment core records. However, although the data indicate continuous increase in δ13C in the deep ocean throughout the YD period, the model shows the opposite trend. It suggests that the model either simulates excessive weakening of the AMOC during the YD period or has limited representation of geochemical processes, including marine ecosystem response and terrestrial carbon storage. Decomposing the factors behind the changes in ocean pCO2 reveals that variations in temperature and alkalinity have the greatest impact on change in atmospheric pCO2. Compensation for the effects of temperature and alkalinity suggests that the AMOC changes and the associated bipolar climate changes contribute to the decrease in atmospheric pCO2 during the BA and the increase in atmospheric pCO2 during the YD period.

Chylous ascites is a rare form of ascites with high triglyceride content arising from the thoracoabdominal lymph nodes in the peritoneal cavity due to various benign or malignant etiologies, including pancreatic cancer. During cancer chemotherapy, the accumulation of ascites can lead to the deterioration of the patient’s general condition, making chemotherapy administration difficult, and resulting in a poor prognosis. We encountered a rare case of chylous ascites complicated by advanced pancreatic cancer. The patient presented with a discrepancy between the shrinkage of the pancreatic cancer and the accumulation of ascites. Therefore, we were able to promptly diagnose chylous ascites by performing biochemical tests. The patient was treated with octreotide, reportedly effective in treating chylous ascites, which rapidly improved the chylous ascites and general condition of the patient, allowing the patient to continue chemotherapy for pancreatic cancer. Therefore, physicians should consider the possibility of chylous ascites when clinically unexplained ascites are observed in patients with advanced cancer. The investigation and treatment of chylous ascites should be initiated as soon as possible.

Abstract Posterior tibial translation (PTT) after double-bundle posterior cruciate ligament (PCL) reconstruction has sometimes occurred. Purpose of this study is to identify the risk factors for postoperative PTT after double-bundle PCL reconstruction with a hamstring autograft. Comparing the results of bilateral gravity sag view (GSV) at 12 months after surgery, over 5-mm PTT was defined as ‘failure’ in this study. Of 26 isolated PCL reconstruction cases, over 5-mm PTT was seen in 7 cases (group F: 9.57 ± 1.28 mm), and 19 cases had less than 5 mm (group G: 2.84 ± 1.29 mm). Age, sex, body mass index (BMI), preoperative GSV, posterior slope angle of the tibia, anterolateral bundle (ALB) and posteromedial bundle (PMB) graft diameters, and tibial tunnel diameter were evaluated. The two groups were compared with the 2 × 2 chi-squared test, the Mann Whitney U-test, and Spearman’s rank correlation coefficient. Multivariate logistic regression analysis was also performed to determine the risk factor. Statistical significance was indicated as p

Abstract Deleterious germline variants in the BRCA1-associated ring domain (BARD1) gene moderately elevate breast cancer risk; however, their potential association with other neoplasms remains unclear. Here, we present the case of a 43-year-old female patient diagnosed with sigmoid colon adenocarcinoma whose maternal family members met the Amsterdam Criteria II for Lynch syndrome. Comprehensive multigene panel testing revealed a heterozygous BARD1 exon 3 deletion.

Purpose: We present a case of macular hole retinal detachment (MHRD) in a patient with Straatsma syndrome, a rare condition characterized by extensive unilateral myelinated retinal nerve fibers (MRNF), high myopia, and amblyopia. This study aimed to highlight the clinical presentations, diagnostic challenges, and success of surgical interventions. Observation: A 32-year-old Asian woman with a history of high myopia and poorly corrected vision in her right eye since childhood presented with a sudden loss of vision in the right eye. Examination revealed extensive MRNF and retinal detachment with a macular hole. A standard three-port pars plana vitrectomy was performed, and tight vitreous retinal adhesions were observed. PFCL-assisted inverted internal limiting membrane (ILM) flap technique was performed. Silicone oil was used owing to its tight vitreous retinal adhesion. Postoperatively, the macular hole was closed, the retina was reattached, and partial disappearance of the MRNF was observed. Conclusion and importance: This case report describes a successful surgical intervention for MHRD associated with Straatsma syndrome. The PFCL-assisted inverted ILM flap technique is effective for managing complicated cases of MHRD. The partial disappearance of MRNF after vitrectomy suggests potential nerve fiber layer damage, possibly due to retinal detachment or the use of silicone oil. This case highlights the unique features of MHRD, a rare disease associated with Straatsma syndrome.

Introduction: Space is a unique environment characterized by isolation from community life and exposure to circadian misalignment, microgravity, and space radiation. These multiple differences from those experienced on the earth may cause systemic and local tissue stress. Autonomic nerves, including sympathetic and parasympathetic nerves, regulate functions in multiple organs. Saliva is secreted from the salivary gland, which is regulated by autonomic nerves, and plays several important roles in the oral cavity and digestive processes. The balance of the autonomic nervous system in the seromucous glands, such as the submandibular glands, precisely controls serous and mucous saliva. Psychological stress, radiation damage, and other triggers can cause an imbalance in salivary secretion systems. A previous study reported that amylase is a stress marker in behavioral medicine and space flight crews; however, the detailed mechanisms underlying amylase regulation in the space environment are still unknown.Methods: In this study, we aimed to elucidate how lunar gravity (1/6 g) changes mRNA expression patterns in the salivary gland. Using a multiple artificial gravity research system during space flight in the International Space Station, we studied the effects of two different gravitational levels, lunar and Earth gravity, on the submandibular glands of mice. All mice survived, returned to Earth from space, and their submandibular glands were collected 2 days after landing.Results: We found that lunar gravity induced the expression of the salivary amylase gene Amy1; however, no increase in Aqp5 and Ano1, which regulate water secretion, was observed. In addition, genes involved in the exocrine system, such as vesicle-associated membrane protein 8 (Vamp8) and small G proteins, including Rap1 and Rab families, were upregulated under lunar gravity.Conclusion: These results imply that lunar gravity upregulates salivary amylase secretion via Rap/Rab signaling and exocytosis via Vamp8. Our study highlights Amy1 as a potential candidate marker for stress regulation in salivary glands in the lunar gravity environment.

Abstract Background Severe peripheral nerve damage always requires surgical treatment. Autologous nerve transplantation is a standard treatment, but it is not sufficient due to length limitations and extended surgical time. Even with the available artificial nerves, there is still large room for improvement in their therapeutic effects. Novel treatments for peripheral nerve injury are greatly expected. Methods Using a specialized microfluidic device, we generated artificial neurite bundles from human iPSC-derived motor and sensory nerve organoids. We developed a new technology to isolate cell-free neurite bundles from spheroids. Transplantation therapy was carried out for large nerve defects in rat sciatic nerve with novel artificial nerve conduit filled with lineally assembled sets of human neurite bundles. Quantitative comparisons were performed over time to search for the artificial nerve with the therapeutic effect, evaluating the recovery of motor and sensory functions and histological regeneration. In addition, a multidimensional unbiased gene expression profiling was carried out by using next-generation sequencing. Result After transplantation, the neurite bundle-derived artificial nerves exerted significant therapeutic effects, both functionally and histologically. Remarkably, therapeutic efficacy was achieved without immunosuppression, even in xenotransplantation. Transplanted neurite bundles fully dissolved after several weeks, with no tumor formation or cell proliferation, confirming their biosafety. Posttransplant gene expression analysis highlighted the immune system’s role in recovery. Conclusion The combination of newly developed microfluidic devices and iPSC technology enables the preparation of artificial nerves from organoid-derived neurite bundles in advance for future treatment of peripheral nerve injury patients. A promising, safe, and effective peripheral nerve treatment is now ready for clinical application.

Abstract The progression of neuroinflammation after anti-parkinsonian therapy on the Parkinson’s disease (PD) brain and in vivo evidence of the therapy purporting neuroprotection remain unclear. To elucidate this, we examined changes in microglial activation, nigrostriatal degeneration, and clinical symptoms longitudinally after dopamine replacement therapy in early, optimally-controlled PD patients with and without zonisamide treatment using positron emission tomography (PET). We enrolled sixteen PD patients (Hoehn and Yahr stage 1–2), and age-matched normal subjects. PD patients were randomly divided into two groups: one (zonisamide+) that did and one (zonisamide−) that did not undergo zonisamide therapy. Annual changes in neuroinflammation ([11C]DPA713 PET), dopamine transporter availability ([11C]CFT PET) and clinical severity were examined. Voxelwise differentiations in the binding of [11C]DPA713 (BPND) and [11C]CFT (SUVR) were compared with normal data and between the zonisamide+ and zonisamide− PD groups. The cerebral [11C]DPA713 BPND increased with time predominantly over the parieto-occipital region in PD patients. Comparison of the zonisamide+ group with the zonisamide− group showed lower levels in the cerebral [11C]DPA713 BPND in the zonisamide+ group. While the striatal [11C]CFT SUVR decreased longitudinally, the [11C]CFT SUVR in the nucleus accumbens showed a higher binding in the zonisamide+ group. A significant annual increase in attention score were found in the zonisamide+ group. The current results indicate neuroinflammation proceeds to the whole brain even after anti-parkinsonian therapy, but zonisamide coadministration might have the potential to ameliorate proinflammatory responses, exerting a neuroprotective effect in more damaged nigrostriatal regions with enhanced attention in PD.

Abstract A simple screening test to identify the early stages of Alzheimer’s disease (AD) is urgently needed. We investigated whether odor identification impairment can be used to differentiate between stages of the A/T/N classification (amyloid, tau, neurodegeneration) in individuals with amnestic mild cognitive impairment or AD and in healthy controls. We collected data from 132 Japanese participants visiting the Toranomon Hospital dementia outpatient clinic. The odor identification scores correlated significantly with major neuropsychological scores, regardless of apolipoprotein E4 status, and with effective cerebrospinal fluid (CSF) biomarkers [amyloid β 42 (Aβ42) and the Aβ42/40 and phosphorylated Tau (p-Tau)/Aβ42 ratios] but not with ineffective biomarkers [Aβ40 and the p-Tau/total Tau ratio]. A weak positive correlation was observed between the corrected odor identification score (adjusted for age, sex, ApoE4 and MMSE), CSF Aβ42, and the Aβ42/40 ratio. The odor identification score demonstrated excellent discriminative power for the amyloidogenesis stage , according to the A/T/N classification, but was unsuitable for differentiating between the p-Tau accumulation and the neurodegeneration stages. After twelve odor species were analyzed, a version of the score comprising only four odors—India ink, wood, curry, and sweaty socks—proved highly effective in identifying AD amyloidogenesis, showing promise for the screening of preclinical AD.

Abstract Sulcus-to-sulcus vertical diameter is longer than the horizontal. However, the effect of vertical positioning of the implantable collamer lens (ICL) on the vault compared to preoperative prediction is unclear. This prospective consecutive case series aimed to examine postoperative and preoperative predicted vaults during vertical ICL fixation. This study assessed 180 right eyes in 180 patients with myopic astigmatism. For the 90 eyes in 90 patients who underwent horizontal fixation (horizontal group) and 90 eyes in 90 patients who underwent vertical fixation (vertical group), biometrics by three-dimensional tomography of the anterior segment optical coherence tomography (A-OCT) was performed before surgery and 2 h, 1 day, 1 week, 1 month and 3 months after surgery. The anterior chamber depth did not change over time in both groups, and there was no significant difference from preoperative values. The postoperative vault values were significantly lower in the vertical group than in horizontal group over time. The difference between vault measurements and preoperative predictions at all postoperative time points was significantly greater in the vertical group than in horizontal group. Vertical fixation of the ICL reduced the vault by > 100 μm compared with horizontal fixation, which was different from the A-OCT preoperative predicted value.

Abstract Background Schizophrenia is a psychiatric disorder characterized by hallucinations, delusions, and other symptoms. Although treatment guidelines for schizophrenia have been established in Japan, drugs are not recommended for pediatric schizophrenia. Additionally, the temporal trends in prescribing antipsychotics for pediatric patients with schizophrenia are unclear. Therefore, we aimed to clarify the trends in antipsychotic prescriptions for Japanese pediatric outpatients from 2015 to 2022. Methods Administrative data (as of November 2023) of Japanese pediatric outpatients with schizophrenia aged 0–18 years who visited acute-care diagnosis procedure combination hospitals between January 1, 2015, and December 31, 2022, were included in this study. The target drugs for schizophrenia were all indicated for treating schizophrenia and marketed in Japan as of December 2022. Annual prescription trends for antipsychotics during this period were calculated based on their proportions. The Cochran–Armitage trend test was used to evaluate the proportion of prescriptions for each antipsychotic. Results The main drugs prescribed for these patients were aripiprazole and risperidone. Among male patients, the proportion of prescriptions for aripiprazole increased significantly from 21.2% in 2015 to 35.9% in 2022, whereas that for risperidone decreased significantly from 47.9% in 2015 to 36.7% in 2022 (both P

Abstract Background As methadone can prevent the development of opioid resistance, it has application in alleviating cancer-related pain that proves challenging to manage with other opioids. QT interval prolongation is a serious side effect of methadone treatment, with some reported deaths. In particular, owing to the increased risk of QT interval prolongation, caution should be exercised when using it in combination with drugs that also prolong the QT interval. Case presentation This study presents a case in which methadone was introduced to a patient (a man in his 60s) already using levofloxacin, which could prolong the QT interval—a serious side effect of methadone treatment—and whose QTc value tended to increase. Given that levofloxacin can increase the risk of QT interval prolongation, we considered switching to other antibacterial agents before introducing methadone. However, because the neurosurgeon judged that controlling a brain abscess was a priority, low-dose methadone was introduced with continuing levofloxacin. Owing to the risks, we performed frequent electrocardiograms. Consequently, we responded before the QTc increased enough to meet the diagnostic criteria for QT interval prolongation. Consequently, we prevented the occurrence of drug-induced long QT syndrome. Conclusions When considering the use of methadone for intractable cancer pain, it is important to eliminate possible risk factors for QT interval prolongation. However, as it may be difficult to discontinue concomitant drugs owing to comorbidities, there could be cases in which the risk of QT interval prolongation could increase, even with the introduction of low-dose methadone. In such cases, frequent monitoring, even with simple measurements such as those used in this case, is likely to prevent progression to more serious conditions.

Abstract Objective This study investigated morphological changes in the composition of the pelvic floor muscles, degree of atrophy, and urethral function in a rat of simulated birth trauma induced by vaginal distension (VD) model. Methods Female Sprague–Dawley rats were classified into four groups: a sham group, and 1, 2, and 4 weeks post-VD (1 W, 2 W, and 4 W, respectively) groups. We measured the amplitude of urethral response to electrical stimulation (A-URE) to evaluate urethral function. After measuring the muscle wet weight of the pubococcygeus (Pcm) and iliococcygeus (Icm) muscles, histochemical staining was used to classify muscle fibers into Types I, IIa, and IIb, and the occupancy and cross-sectional area of each muscle fiber were determined. Results There were 24 Sprague–Dawley rats used. A-URE was significantly lower in the 1 W group versus the other groups. Muscle wet weight was significantly lower in the VD groups versus the sham group for Pcm. The cross-sectional area of Type I Pcm and Icm was significantly lower in the VD groups versus the sham group. Type I muscle fiber composition in Pcm was significantly lower in the VD groups versus the sham groupand lowest in the 2 W group. Type I muscle fiber composition in Icm was significantly lower in the 2 and 4 W groups versus the sham group. Conclusion Muscle atrophy and changes in muscle composition in the pelvic floor muscles were observed even after improvements in urethral function. These results may provide insight into the pathogenesis of stress urinary incontinence after VD.

Marine protected area (MPAs) networks can buffer marine ecosystems from the impacts of climate change by allowing species to redistribute as conditions change and by reducing other stressors. There are, however, few examples where climate change has been considered in MPA network design. In this paper, we assess how climate change considerations were integrated into the design of a newly released MPA network in the Northern Shelf Bioregion in British Columbia, Canada, and then evaluate the resulting network against projected physical and biogeochemical changes and biological responses. We found that representation, replication, and size and spacing recommendations integrated into the design phase were met in most cases. Furthermore, despite varying degrees of projected changes in temperature, dissolved oxygen, and aragonite saturation across the MPA network, suitable habitat for demersal fish species is projected to remain in the network despite some redistribution among sites. We also found that mid-depth MPAs are particularly important for persistence, as fish are projected to move deeper to avoid warming in shallower areas. Our results highlight that a representative MPA network with adequate replication, that incorporates areas of varying climate change trajectory, should buffer against the impacts of climate change.

Abstract Cough is known as a protective reflex to keep the airway free from harmful substances. Although brain activity during cough was previously examined mainly by functional magnetic resonance imaging (fMRI) with model analysis, this method does not capture real brain activity during cough. To obtain accurate measurements of brain activity during cough, we conducted whole-brain scans during different coughing tasks while correcting for head motion using a restraint-free positron emission tomography (PET) system. Twenty-four healthy right-handed males underwent multiple PET scans with [15O]H2O. Four tasks were performed during scans: “resting”; “voluntary cough (VC)”, which simply repeated spontaneous coughing; “induced cough (IC)”, where participants coughed in response to an acid stimulus in the cough‐inducing method with tartaric acid (CiTA); and “suppressed cough (SC)”, where coughing was suppressed against CiTA. The whole brain analyses of motion-corrected data revealed that VC chiefly activated the cerebellum extending to pons. In contrast, CiTA-related tasks (IC and SC) activated the higher sensory regions of the cerebral cortex and associated brain regions. The present results suggest that brain activity during simple cough is controlled chiefly by infratentorial areas, whereas manipulating cough predominantly requires the higher sensory brain regions to allow top-down control of information from the periphery.

The Antarctic Ice Sheet represents the largest source of uncertainty in future sea level rise projections, with a contribution to sea level by 2100 ranging from −5 to 43 cm of sea level equivalent under high carbon emission scenarios estimated by the recent Ice Sheet Model Intercomparison for CMIP6 (ISMIP6). ISMIP6 highlighted the different behaviors of the East and West Antarctic ice sheets, as well as the possible role of increased surface mass balance in offsetting the dynamic ice loss in response to changing oceanic conditions in ice shelf cavities. However, the detailed contribution of individual glaciers, as well as the partitioning of uncertainty associated with this ensemble, have not yet been investigated. Here, we analyze the ISMIP6 results for high carbon emission scenarios, focusing on key glaciers around the Antarctic Ice Sheet, and we quantify their projected dynamic mass loss, defined here as mass loss through increased ice discharge into the ocean in response to changing oceanic conditions. We highlight glaciers contributing the most to sea level rise, as well as their vulnerability to changes in oceanic conditions. We then investigate the different sources of uncertainty and their relative role in projections, for the entire continent and for key individual glaciers. We show that, in addition to Thwaites and Pine Island glaciers in West Antarctica, Totten and Moscow University glaciers in East Antarctica present comparable future dynamic mass loss and high sensitivity to ice shelf basal melt. The overall uncertainty in additional dynamic mass loss in response to changing oceanic conditions, compared to a scenario with constant oceanic conditions, is dominated by the choice of ice sheet model, accounting for 52 % of the total uncertainty of the Antarctic dynamic mass loss in 2100. Its relative role for the most dynamic glaciers varies between 14 % for MacAyeal and Whillans ice streams and 56 % for Pine Island Glacier at the end of the century. The uncertainty associated with the choice of climate model increases over time and reaches 13 % of the uncertainty by 2100 for the Antarctic Ice Sheet but varies between 4 % for Thwaites Glacier and 53 % for Whillans Ice Stream. The uncertainty associated with the ice–climate interaction, which captures different treatments of oceanic forcings such as the choice of melt parameterization, its calibration, and simulated ice shelf geometries, accounts for 22 % of the uncertainty at the ice sheet scale but reaches 36 % and 39 % for Institute Ice Stream and Thwaites Glacier, respectively, by 2100. Overall, this study helps inform future research by highlighting the sectors of the ice sheet most vulnerable to oceanic warming over the 21st century and by quantifying the main sources of uncertainty.

Abstract Here we studied the entire Atlantic Forest hotspot to investigate whether the effect of different environmental predictors depends on the phylogenetic extension and the biogeographical history of different Atlantic Forest sectors. We used occurrence data of 3,183 plant species with arboreal or arborescent habits. We reconstructed climatic stability across 120,000 years using the Random Forest method. Then, we compared the effect of biogeographical history, topographic, and climatic variables on species richness and phylogenetic diversity using Geographically Weighted Regression (GWR) models. Niche conservatism drives the strength and direction of environmental correlates with tree diversity, interacting with the biogeographical and phylogenetic extension considered. Low current climate seasonalities were the main drivers of species richness and phylogenetic diversity variation across the Atlantic Forest. Whereas in higher phylogenetic extension, topographic heterogeneity increased the number of tree species independent of the sector, deep-past climate stability favored phylogenetic diversity by increasing relict lineages of distant clades in all forests, but with anomalies in the southern sector. This investigation yields substantial evidence that the response of the northern and southern sectors of the Atlantic Forest to identical environmental conditions diverges significantly, providing compelling support for the imprint of phylogenetic heritage in generating non-linear diversity patterns.

Abstract A 70‐year‐old woman presented to our hospital with abdominal discomfort. Gastrointestinal endoscopy revealed an ampullary tumor, while a biopsy revealed a pathological diagnosis of adenocarcinoma. No distant metastases were observed and neoadjuvant chemotherapy and surgical resection were planned. Shortly thereafter, she developed obstructive jaundice due to the ampullary carcinoma. The patient underwent endoscopic retrograde cholangiopancreatography, during which a straight plastic stent was placed in the bile duct. The patient was discharged without complications. Neoadjuvant chemotherapy was initiated. Two months later, she was readmitted for surgery while asymptomatic. Endoscopic retrograde cholangiopancreatography was scheduled to replace the stent with a nasobiliary drainage tube for the surgery. Endoscopic imaging revealed that the proximal end of the stent had penetrated the duodenum on the oral side of the ampullary carcinoma. The distal end of the stent was grasped with forceps and the stent was successfully removed. A catheter was inserted into the bile duct orifice and cholangiography was performed, which revealed that the distal bile duct and the duodenum had formed a fistula. A guidewire was placed in the bile duct via the papilla and a nasobiliary drainage tube was placed. After endoscopic retrograde cholangiopancreatography, the patient exhibited smooth progress without issue. Pancreaticoduodenectomy was performed on the fourth day after the nasobiliary drainage tube placement, and the patient's postoperative course was uneventful. The proximal end of a biliary stent penetrating the duodenal wall is an infrequent phenomenon. This case report highlights a rare but noteworthy adverse event associated with straight biliary plastic stent placement.

Soup, including dried bonito broth, is customarily consumed as an umami taste during meals in Japan. Previous functional magnetic resonance imaging (fMRI) studies have investigated neuronal activation following human exposure to carbohydrates and umami substances. However, neuronal activity following ingestion of dried bonito soup has not been investigated. Additionally, recent progress in fMRI has enabled us to investigate the functional connectivity between two anatomically separated regions, such as the default mode network. In this study, we first investigated the altered functional connectivity after ingesting dried bonito soup in healthy volunteers. Functional connectivity in several brain regions, including the connection between the vermis, part of the cerebellum, and bilateral central opercular cortex, was markedly increased after ingesting dried bonito soup, compared to the ingestion of hot water. Physiological scaling showed that satiety was substantially increased by ingesting hot water rather than dried bonito soup. These results indicate that increased functional connectivity reflects the post-ingestive information pathway of dried bonito soup.

Abstract Background The lymph node metastasis rate in right‐sided colon cancer is unknown, and the optimal central vascular ligation level remains controversial. We aimed to determine the lymph node metastasis rate and short‐term results of radical surgery with extended lymph node dissection in right‐sided colon cancer. Methods This prospective multicenter observational study included patients with stage II/III right‐sided colon cancer from five cancer hospitals. The metastasis rate of each node station was analyzed according to tumor location and main feeding artery. Results Between April 2018 and August 2021, 208 patients underwent dissection around the superior mesenteric artery (SMA) and vein (SMV). In transverse colon cancer, 7.5% and 2.5% of metastases occurred around the SMV and SMA at the root of the middle colic artery (MCA), respectively; 6.7% and 6.7% at the root of the right colic artery. In caecal cancer, 1.9% of metastases occurred around the SMV and 1.9% around the SMA. In ascending colon cancer, the rate was 1.1% around the SMV. Of the tumors, 17% fed mainly by the ileocolic artery had node metastases along the middle or right colic artery, as did 66.7% fed mainly by the right colic artery and 41.2% fed by the MCA (p = 0.01). Postoperative complications occurred in 42 patients (20.2%). Conclusion Routine prophylactic extended lymphadenectomy around the SMA might not be necessary in caecum and ascending colon cancer. Dissection around the SMA may be necessary in cases of transverse colon cancer or when the feeding artery is the MCA.

Abstract Not all patients with ulcerative colitis (UC) respond initially to treatment with biologic agents, and predicting their efficacy prior to treatment is difficult. Vedolizumab, a humanized monoclonal antibody against alpha 4 beta 7 (α4β7) integrin, suppresses immune cell migration by blocking the interaction between α4β7 integrin and mucosal addressin cell adhesion molecule 1. Reports about histological features that predict vedolizumab efficacy are scarce. So, we examined the association between histological features and vedolizumab efficacy. This was a multicenter, retrospective study of patients with UC treated with vedolizumab. Biopsy specimens taken from the colonic mucosa prior to vedolizumab induction were used, and the areas positively stained for CD4, CD68, and CD45 were calculated. Clinical and histological features were compared between those with and without remission at week 22, and the factors associated with clinical outcomes were identified. We enrolled 42 patients. Patients with a high CD4+ infiltration showed a better response to vedolizumab [odds ratio (OR) = 1.44, P = 0.014]. The concomitant use of corticosteroids and high Mayo scores had a negative association with the vedolizumab response (OR = 0.11, P = 0.008 and OR = 0.50, P = 0.009, respectively). Histological evaluation for CD4+ cell infiltration may be helpful in selecting patients who can benefit from vedolizumab.

Abstract Providing standardized, high-quality rehabilitation for critically ill patients is a crucial issue. In 2017, the Japanese Society of Intensive Care Medicine (JSICM) promulgated the “Evidence-Based Expert Consensus for Early Rehabilitation in the Intensive Care Unit” to advocate for the early initiation of rehabilitations in Japanese intensive care settings. Building upon this seminal work, JSICM has recently conducted a rigorous systematic review utilizing the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. This endeavor resulted in the formulation of Clinical Practice Guidelines (CPGs), designed to elucidate best practices in early ICU rehabilitation. The primary objective of this guideline is to augment clinical understanding and thereby facilitate evidence-based decision-making, ultimately contributing to the enhancement of patient outcomes in critical care settings. No previous CPGs in the world has focused specifically on rehabilitation of critically ill patients, using the GRADE approach. Multidisciplinary collaboration is extremely important in rehabilitation. Thus, the CPGs were developed by 73 members of a Guideline Development Group consisting of a working group, a systematic review group, and an academic guideline promotion group, with the Committee for the Clinical Practice Guidelines of Early Mobilization and Rehabilitation in Intensive Care of the JSICM at its core. Many members contributed to the development of the guideline, including physicians and healthcare professionals with multiple and diverse specialties, as well as a person who had been patients in ICU. Based on discussions among the group members, eight important clinical areas of focus for this CPG were identified. Fourteen important clinical questions (CQs) were then developed for each area. The public was invited to comment twice, and the answers to the CQs were presented in the form of 10 GRADE recommendations and commentary on the four background questions. In addition, information for each CQ has been created as a visual clinical flow to ensure that the positioning of each CQ can be easily understood. We hope that the CPGs will be a useful tool in the rehabilitation of critically ill patients for multiple professions. Graphical Abstract

The Maritime Continent (MC) forms the western boundary of the tropical Pacific Ocean, and relatively small changes in this region can impact the climate locally and remotely. In the mid-Piacenzian warm period of the Pliocene (mPWP; 3.264 to 3.025 Ma) atmospheric CO2 concentrations were ∼ 400 ppm, and the subaerial Sunda and Sahul shelves made the land–sea distribution of the MC different to today. Topographic changes and elevated levels of CO2, combined with other forcings, are therefore expected to have driven a substantial climate signal in the MC region at this time. By using the results from the Pliocene Model Intercomparison Project Phase 2 (PlioMIP2), we study the mean climatic features of the MC in the mPWP and changes in Indonesian Throughflow (ITF) with respect to the preindustrial. Results show a warmer and wetter mPWP climate of the MC and lower sea surface salinity in the surrounding ocean compared with the preindustrial. Furthermore, we quantify the volume transfer through the ITF; although the ITF may be expected to be hindered by the subaerial shelves, 10 out of 15 models show an increased volume transport compared with the preindustrial. In order to avoid undue influence from closely related models that are present in the PlioMIP2 ensemble, we introduce a new metric, the multi-cluster mean (MCM), which is based on cluster analysis of the individual models. We study the effect that the choice of MCM versus the more traditional analysis of multi-model mean (MMM) and individual models has on the discrepancy between model results and data. We find that models, which reproduce modern MC climate well, are not always good at simulating the mPWP climate anomaly of the MC. By comparing with individual models, the MMM and MCM reproduce the preindustrial sea surface temperature (SST) of the reanalysis better than most individual models and produce less discrepancy with reconstructed sea surface temperature anomalies (SSTA) than most individual models in the MC. In addition, the clusters reveal spatial signals that are not captured by the MMM, so that the MCM provides us with a new way to explore the results from model ensembles that include similar models.

Abstract This randomized controlled trial aimed to investigate the effects of eight weeks of lactotripeptide (LTP) ingestion, physical activity (PA) intervention, and combined intervention on the fatigue status of middle-aged and older adults. A total of 78 middle-aged and older adults (63 ± 8 years of age) were randomly assigned to four groups: placebo, LTP, placebo with PA intervention (placebo + PA), and LTP with PA intervention (LTP + PA). All participants ingested the placebo or LTP tablets daily (three tablets/day). The placebo + PA and LTP + PA groups participated in a weekly supervised exercise class and were instructed to increase their moderate- to vigorous-intensity PA at home. The visual analog scale, Brief Fatigue Inventory, Profile of Mood States second edition (POMS2), and Beck Depression Inventory second edition (BDI-II) were administered before and after the intervention. No significant interactions or main effects were observed between LTP ingestion and PA intervention on any of the fatigue scales. The main-effect analyses revealed that the PA intervention improved the total mood disturbance score of the POMS2 (F = 5.22, P = 0.03) and BDI-II score (F = 4.81, P = 0.03). After the post hoc paired comparisons, the total mood disturbance and BDI-II scores improved more with the combined intervention than with the PA intervention alone (percentage difference between the effect of combined intervention and PA intervention alone was 3.7% for total mood disturbance score and 13.7% for BDI-II score). The present study suggests that eight weeks of LTP ingestion and PA intervention did not have a significant effect on fatigue status. However, the PA intervention improved mood status and depressive symptoms, and these effects were enhanced by LTP ingestion.

Encapsulated papillary carcinoma (EPC) is a relatively rare histologic type of breast cancer. It is sometimes difficult to obtain a definitive diagnosis by needle biopsy, reflecting its characteristics as an intracystic lesion. Herein, we report a case of EPC in an elderly male that was difficult to diagnose before surgery. A 70-year-old man visited our hospital after a mass just under his right nipple that gradually increased in size. Ultrasonography revealed a well-defined intracystic 50 mm-sized tumor and a papillary-shaped solid component arising from the cyst wall. Cytology revealed small clusters of atypical cells suggestive of malignancy, but we did not reach a definitive diagnosis with subsequent vacuum-assisted needle biopsy due to the small amount of specimen. Given the imaging findings strongly suggested a malignant tumor, a mastectomy was performed. Histologically, there was a thick fibrous capsule and mildly atypical cells showed papillary growth, and we diagnosed the case as EPC (pTisNXM0). Sometimes, EPC is difficult to discriminate from intracystic papilloma before surgery, but clinicians should always keep in mind that this histological type exists with a certain frequency in male patients.

Abstract To maintain and restore skeletal muscle mass and function is essential for healthy aging. We have found that myonectin acts as a cardioprotective myokine. Here, we investigate the effect of myonectin on skeletal muscle atrophy in various male mouse models of muscle dysfunction. Disruption of myonectin exacerbates skeletal muscle atrophy in age-associated, sciatic denervation-induced or dexamethasone (DEX)-induced muscle atrophy models. Myonectin deficiency also contributes to exacerbated mitochondrial dysfunction and reduces expression of mitochondrial biogenesis-associated genes including PGC1α in denervated muscle. Myonectin supplementation attenuates denervation-induced muscle atrophy via activation of AMPK. Myonectin also reverses DEX-induced atrophy of cultured myotubes through the AMPK/PGC1α signaling. Furthermore, myonectin treatment suppresses muscle atrophy in senescence-accelerated mouse prone (SAMP) 8 mouse model of accelerated aging or mdx mouse model of Duchenne muscular dystrophy. These data indicate that myonectin can ameliorate skeletal muscle dysfunction through AMPK/PGC1α-dependent mechanisms, suggesting that myonectin could represent a therapeutic target of muscle atrophy.

Purpose Follow-up reports of orthodontic treatment after one-stage repair until the completion of jaw development are scarce. We report a case of a child with unilateral incomplete cleft lip and palate who underwent presurgical orthopaedic treatment, one-stage repair (cheilo-palatoplasty with gingivoperiosteoplasty), and orthodontic treatment and was followed up until 19 years of age.Materials and methods The patient visited our orthodontic clinic at the age of 4 years with the chief complaint of crossbite. His facial profile was slightly concave and accompanied by an anterior crossbite. The ANB angle was −3.0° (maxillary growth deficiency). Treatment was initiated with a maxillary protraction appliance (MPA) to correct the overjet. Upon eruption of the permanent anterior teeth, an anterior crossbite was observed, which was treated with multi-bracket appliances to correct the overjet during phase I treatment. After the complete eruption of the permanent dentition, phase II treatment was initiated without dental extractions.Results Three years after treatment, slight maxillary growth deficiency remained. Although an anterior crossbite was observed at the initial visit, lateral expansion of the maxilla was unnecessary. Long-term stable occlusion was achieved through MPA, phase I, and phase II treatments, without requiring further surgical procedures, such as secondary alveolar bone grafting or jaw osteotomy.Conclusion In the present case, the one-stage repair was performed with minimal impact on jaw development, which greatly reduced the burden on the patient and family. One-stage repair followed by appropriate orthodontic treatment resulted in good outcomes and patient satisfaction.

Abstract Chromosome-level haplotype-resolved genome assembly is an important resource in molecular biology. However, current de novo haplotype assemblers require parental data or reference genomes and often fail to provide chromosome-level results. We present GreenHill, a novel scaffolding and phasing tool that considers various assemblers’ contigs as input to reconstruct chromosome-level haplotypes using Hi-C without parental or reference data. Its unique functions include new error correction based on Hi-C contacts and the simultaneous use of Hi-C and long reads. Benchmarks reveal that GreenHill outperforms other approaches in contiguity and phasing accuracy, and the majority of chromosome arms are entirely phased.

Abstract The Atlantic meridional overturning circulation is an important global-scale oceanic circulation, and its changes may be responsible for past abrupt climate change events. By using two versions of a coupled climate model, here we show that the stability of this circulation depends not only on the background climate, but also on the type of primary external forcing: freshwater vs. greenhouse gases. When freshwater forcing is dominant, hysteresis of this circulation (an abrupt collapse/reactivation) becomes possible only under simulated glacial conditions with closed Bering Strait. Under present day and future conditions, both freshwater and greenhouse gas forcings could collapse this circulation, but only greenhouse gas forcing produced a bi-stable equilibrium state comparable to abrupt climate change. Our results demonstrate that the Bering Strait status (open vs. closed) may facilitate or prohibit the existence of this circulation’s hysteresis, irrespective of the background climate conditions, but is directly related to the primary forcing.

AIM: To determine and evaluate the features of highly cited articles (HCAs) in the ophthalmology category in the Science Citation Index Expanded (SCI-EXPANDED) from 1991 to 2020. METHODS: The Web of Science Core Collection documents with at least 100 citations from their publication year until December 31, 2020, were evaluated as highly cited. The examined features were the distribution of yearly output and its average number of per publication, HCAs, authors, institutions, journals, and nations. The publication performance of nations and organizations was assessed using six publication indicators. The Y-index was employed to compare the research outputs of various authors. RESULTS: Publications that had cited the most references were highly published in high-impact factor journals. The United States of America came out on top across all six publication indicators, and it was home to eight of the top 10 most productive institutions. The articles written by Breivik et al (2006) and Farrar et al (2001) were highly cited and had a significant impact in 2020. The authors had a higher number of highly cited articles published as corresponding authors than as first authors. CONCLUSION: The findings of the present study highlight the current scope of global research in ophthalmology. The findings can help policy-makers and advisory groups of research centers to develop future policies. In addition, the findings can guide researchers in this field.

Abstract Background The duration and regimen of tuberculosis (TB) treatment is currently based predominantly on whether the M. tuberculosis (Mtb) strain is drug-sensitive (DS) or multidrug-resistant (MDR) with doses adjusted by patients’ weight only. The systematic stratification of patients for personalized treatment does not exist for TB. As each TB case is different, individualized treatment regimens should be applied to obtain better outcomes. In this scenario, novel therapeutic approaches are urgently needed to (1) improve outcomes and (2) shorten treatment duration, and host-directed therapies (HDT) might be the best solution. Within HDT, repurposed drugs represent a shortcut in drug development and can be implemented at the short term. As hyperinflammation is associated with worse outcomes, HDT with an anti-inflammatory effect might improve outcomes by reducing tissue damage and thus the risk of permanent sequelae. Methods SMA-TB is a multicentre randomized, phase IIB, placebo-controlled, three-arm, double-blinded clinical trial (CT) that has been designed in the context of the EC-funded SMA-TB Project ( www.smatb.eu ) in which we propose to use 2 common non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA) and ibuprofen (Ibu), as an HDT for use as adjunct therapy added to, and compared with, the standard of care (SoC) World Health Organization (WHO)-recommended TB regimen in TB patients. A total of 354 South African and Georgian adults diagnosed with confirmed pulmonary TB will be randomized into SoC TB treatment + placebo, SoC + acetylsalicylic acid or SoC + ibuprofen. Discussion SMA-TB will provide proof of concept of the HDT as a co-adjuvant treatment and identify the suitability of the intervention for different population groups (different epidemiological settings and drug susceptibility) in the reduction of tissue damage and risk of bad outcomes for TB patients. This regimen potentially will be more effective and targeted: organ saving, reducing tissue damage and thereby decreasing the length of treatment and sequelae, increasing cure rates and pathogen clearance and decreasing transmission rates. It will result in better clinical practice, care management and increased well-being of TB patients. Trial registration Clinicaltrials.gov NCT04575519. Registered on October 5, 2020.

The recovery of a new Antarctic ice core spanning the past ∼ 1.5 million years will advance our understanding of climate system dynamics during the Quaternary. Recently, glaciological field surveys have been conducted to select the most suitable core location near Dome Fuji (DF), Antarctica. Specifically, ground-based radar-echo soundings have been used to acquire highly detailed images of bedrock topography and internal ice layers. In this study, we use a one-dimensional (1-D) ice-flow model to compute the temporal evolutions of age and temperature, in which the ice flow is linked with not only transient climate forcing associated with past glacial–interglacial cycles but also transient basal melting diagnosed along the evolving temperature profile. We investigated the influence of ice thickness, accumulation rate, and geothermal heat flux on the age and temperature profiles. The model was constrained by the observed temperature and age profiles reconstructed from the DF ice-core analysis. The results of sensitivity experiments indicate that ice thickness is the most crucial parameter influencing the computed age of the ice because it is critical to the history of basal temperature and basal melting, which can eliminate old ice. The 1-D model was applied to a 54 km long transect in the vicinity of DF and compared with radargram data. We found that the basal age of the ice is mostly controlled by the local ice thickness, demonstrating the importance of high-spatial-resolution surveys of bedrock topography for selecting ice-core drilling sites.