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During the first years of Covid, 2020–2023, a group of seven colleagues across three continents—working outside of institutional contexts—prepared a Practice Note on naturecultures. The Practice Note draws together the long-time work, experience, and thinking of the authors, all of whom work in the field of heritage conservation. It gives focus to the improved integration of nature and culture, and cultural heritage and natural heritage, in the work of caring for and safeguarding important places. By promoting awareness of diversity and mutual respect for multiple views and understandings, the Practice Note is concerned with working together, fostering dialogue, and creating long-lasting and equitable approaches to conservation. In this introduction, we outline the purpose, origins, and the making of the Practice Note.

Abstract Embryo implantation is crucial for successful pregnancy, requiring appropriate uterine responses to implantation-competent blastocysts. Molecular communication at the maternal–fetal junction governs this process. Leukemia inhibitory factor (Lif) plays a pivotal role in implantation across species. Lif is abundantly expressed in the glandular epithelium during blastocyst-receptive phase and is induced in the stroma surrounding attached blastocysts. While diminished Lif expression leads to infertility, its influence on peri-implantation uteri remains unclear. Therefore, we investigated the role of Lif in uterine physiology using its uterine-specific knockout (uKO) and uterine epithelial-specific KO (eKO) in mice. Lif eKO and uKO mice displayed infertility owing to failed embryo attachment. Recombinant Lif supplementation rescued the reproductive phenotype of Lif eKO mice, but not Lif uKO mice; however, recombinant Lif injection rescued embryo attachment in Lif uKO mice. RNA-seq analysis indicated that Lif governs uterine epithelial genes, but not embryonic genes, to facilitate embryo attachment via activating nuclear Stat3. Concordantly, three-dimensional imaging of the uterine epithelium revealed that luminal closure and crypt formation are regulated by the uterine Lif–Stat3 axis as well as the presence of blastocysts. Collectively, our findings shed light on previously unknown mechanism on how Lif influences uterine functions molecularly and physiologically during early pregnancy.

Abstract Estimating accurate oil and gas methane emissions has been a global challenge, highlighted by a twofold discrepancy between atmospheric measurement-based estimates and emission inventories. The principle of continuous improvement in Canada’s National Inventory Report has led to an unstable baseline in recent years for tracking emission reduction progress. The gaps between previous inventory estimates and inversions exceeded 60%. Here we show that incorporating new source-resolved information derived from low-altitude aerial survey data has narrowed this gap by 80%, reducing the discrepancy to 10% for the 2010–2014 baseline. This study proposes a hybrid emission reporting framework, complemented by an ensemble inversion top-down method using continuous tower-based atmospheric measurements, to establish a stable baseline and provide independent verification. As the 2030 target year for emission reduction approaches, we report a significant 27% decline (19%–34%) in inverse oil and gas methane emissions from 2010 to 2022 in Alberta and Saskatchewan, Canada, and a 41% decline (26%–56%) as calculated using the 2024 official inventory.

Abstract Background Understanding the roles and competencies of professions outside of one’s specialty is essential for providing efficient healthcare. However, it is difficult for medical professionals to understand the roles and competencies of other related professions while performing their duties. This study examined the impact of clinical practice-based interprofessional education (IPE) on pharmacy students, who are future medical professionals. Methods Sixty-eight pharmaceutical students undergoing clinical practice were divided into non-IPE or IPE groups, with the IPE group attending an educational program with medical students conducted by doctors, pharmacists, and teachers during the clinical practice period. The effect was evaluated through a group survey using self-administered questionnaires focusing on contributing to multidisciplinary team medicine based on the Readiness for Interprofessional Learning Scale. The survey included specific behavioral objectives (SBOs), the Readiness for Interpersonal Learning Scale (RIPLS), and Kikuchi’s Scale of Social Skills (KiSS-18). Results Regardless of group, SBOs [non-IPE: 3.2, 95% CI (2.6–3.8), p

A radial correlation ECE radiometer diagnostic has been developed for electron temperature fluctuation measurements in the helical-axis heliotron device, Heliotron J. The radiometer consists of two heterodyne detection systems. One system scans the frequency of a local oscillator from 52 to 64 GHz with a single intermediate frequency filter, and the second system has a fixed frequency, 56 GHz local oscillator with four intermediate frequency filters. This frequency range covers measurement positions spanning from the plasma core to the half radius. Laboratory tests indicate that each system has narrow intermediate frequency bandwidth and high-sensitivity over a large dynamic range. During plasma experiments with NBI heating, radiation temperature fluctuation measured by the CECE radiometer decrease with increasing ECCD commensurate with previous measurements of energetic particle driven modes on Heliotron J.

Canada has major sources of atmospheric methane (CH4), with the world's second-largest boreal wetland and the world's fourth-largest natural gas production. However, Canada's CH4 emissions remain uncertain among estimates. Better quantification and characterization of Canada's CH4 emissions are critical for climate mitigation strategies. To improve our understanding of Canada's CH4 emissions, we performed an ensemble regional inversion for 2007–2017 constrained with the Environment and Climate Change Canada (ECCC) surface measurement network. The decadal CH4 estimates show no significant trend, unlike some studies that reported long-term trends. The total CH4 estimate is 17.4 (15.3–19.5) Tg CH4 yr−1, partitioned into natural and anthropogenic sources at 10.8 (7.5–13.2) and 6.6 (6.2–7.8) Tg CH4 yr−1, respectively. The estimated anthropogenic emission is higher than inventories, mainly in western Canada (with the fossil fuel industry). Furthermore, the results reveal notable spatiotemporal characteristics. First, the modelled differences in atmospheric CH4 among the sites show improvement after inversion when compared to observations, implying the CH4 observation differences could help in verifying the inversion results. Second, the seasonal variations show slow onset and a late-summer maximum, indicating wetland CH4 flux has hysteretic dependence on air temperature. Third, the boreal winter natural CH4 emissions, usually treated as negligible, appear quantifiable (≥ 20 % of annual emissions). Understanding winter emission is important for climate prediction, as the winter in Canada is warming faster than the summer. Fourth, the inter-annual variability in estimated CH4 emissions is positively correlated with summer air temperature anomalies. This could enhance Canada's natural CH4 emission in the warming climate.

Introduction: This study aimed to evaluate the association of obesity and diabetes mellitus (DM) comorbidity with hepatocellular carcinoma (HCC) recurrence and survival. Methods: We investigated 1,644 patients who underwent hepatic resection for solitary HCC without vascular invasion using computed tomography. Patients were categorized into four groups according to the combination of obesity and DM comorbidities: OB (+) or (−) and DM (+) or (−). Postoperative cumulative recurrence rates within and beyond 2 years and beyond 5 years were assessed. Results: Multivariate Cox proportional hazard regression analysis revealed that the adjusted hazard ratios (HRs) of reduced recurrence-free survival was 1.10 (95% confidence interval [CI]: 0.91–1.33; p = 0.31), 0.94 (95% CI: 0.78–1.12; p = 0.48), and 1.24 (95% CI: 1.01–1.54; p = 0.045) in the OB(+)DM(−), OB(−)DM(+), and OB(+)DM(+) groups compared with the OB(−)DM(−) group, respectively. Additionally, the corresponding adjusted HRs of reduced overall survival were 0.93 (p = 0.57), 0.97 (p = 0.76), and 1.38 (p = 0.013) for OB(+)DM(−), OB(−)DM(+), and OB(+)DM(+) groups, respectively. No significant difference in the early recurrence rate was determined among the four groups. The OB(+)DM(+) group demonstrated an increased risk for late recurrence beyond 2 years and 5 years postoperatively compared with the OB(−)DM(−) group (HR: 1.51; p = 0.024 and HR: 2.53; p = 0.046, respectively). The OB(+)DM(−) and OB(−)DM(+) groups demonstrated an increased risk for late recurrence beyond 5 years postoperatively (HR: 3.83; p < 0.001 and HR: 1.95; p = 0.037, respectively). Conclusions: Obesity and DM coexistence increased late recurrence and worsened prognosis in patients with HCC undergoing hepatic resection. The results help surgeons develop possible different surveillance protocol and need to focus on diabetes/obesity control during life-long surveillance for patients with HCC.

Abstract Background Combination therapy can offer greater efficacy on medical treatments. However, the discovery of synergistic drug combinations is challenging. We propose a novel computational method, SyndrumNET, to predict synergistic drug combinations by network propagation with trans-omics analyses. Methods The prediction is based on the topological relationship, network-based proximity, and transcriptional correlation between diseases and drugs. SyndrumNET was applied to analyzing six diseases including asthma, diabetes, hypertension, colorectal cancer, acute myeloid leukemia (AML), and chronic myeloid leukemia (CML). Results Here we show that SyndrumNET outperforms the previous methods in terms of high accuracy. We perform in vitro cell survival assays to validate our prediction for CML. Of the top 17 predicted drug pairs, 14 drug pairs successfully exhibits synergistic anticancer effects. Our mode-of-action analysis also reveals that the drug synergy of the top predicted combination of capsaicin and mitoxantrone is due to the complementary regulation of 12 pathways, including the Rap1 signaling pathway. Conclusions The proposed method is expected to be useful for discovering synergistic drug combinations for various complex diseases.

Background: Ensitrelvir, a 3C-like protease inhibitor, received emergency approval in Japan in November 2022 for treating non-hospitalized patients with mild-to-moderate COVID-19. However, confirmation of its real-world clinical effectiveness is limited. Methods: This retrospective study evaluated 18 vaccinated outpatients (15 men; median age, 39.5 years; range, 26–56), treated with a 5-day oral ensitrelvir regimen (375 mg loading dose, followed by 125 mg daily) between December 1, 2022, and January 31, 2023. Nasal swabs were collected on days 0, 3, 6, and 9 for RT-qPCR to assess viral load. Variants were identified by Sanger sequencing, and outcomes were compared to historical controls. Patients were followed for 60 days to monitor for post-acute sequelae of COVID-19 (PASC). Results: Symptoms such as mild fever and sore throat improved rapidly after one day of ensitrelvir treatment, with 66 % of patients recovering within six days. All individuals were infected with the BA.5 Omicron variant. Viral loads, as measured by Ct values, increased significantly from 21.82 at symptom onset to 37.65 b y day 6, with SARS-CoV-2 RNA undetectable in most patients by day 9. Those treated within 48 h of symptom onset showed the viral load reduction. Compared to historical controls, where symptom resolution took 8.5 days, ensitrelvir shortened recovery time to as little as 1.4 days for over 66 % of patients. Conclusion: Ensitrelvir treatment resulted in rapid symptom relief and significant viral load reduction, with no adverse events, viral rebound, or PASC symptoms, demonstrating its potential efficacy and safety. Larger studies are needed for further confirmation.

Stalagmite is an important archive of paleoclimate especially in the region of the East Asian Monsoon. Despite the widespread use of radiocarbon (14C) dating to explore past environmental changes, the contribution of a14C-free carbon fraction leached from soil and/or host rocks during stalagmite formation, known as the dead carbon fraction (DCF), impedes its application to stalagmite chronology. Thus, uranium series dating is preferentially used to determine stalagmite ages. However, both U/Th and 14C dating can be applied to stalagmite samples, U/Th can be used to calibrate the radiocarbon ages by assuming a relatively constant DCF contribution over time. Studies exploring DCF changes from glacial to interglacial periods remain scarce, suggesting that temporal and speleothem-specific DCF studies are needed. Here, we present findings on DCF changes over the last 38 ka in speleothems obtained from southwestern Japan. Our analysis includes measurements of both 14C in drip water and speleothem calcite alongside U/Th dating of three stalagmites collected from Kyusendo Cave, located in southern Japan. The DCFs reconstructed from these stalagmites exhibited variations of 37.8%–73.9% between 4.2 and 38.3 ka, which exceeded the typical DCF values reported previously. Intra-test variations of the DCF values in Kyusendo Cave also revealed differences of up to 30%–40% among the three stalagmites. A higher drip water DCF and dripping rate showed a strong negative correlation, indicating that variations in DCF may reflect changes in local hydrology. The study findings suggest that speleothem-specific and temporally varied DCF should be considered in paleoclimate reconstructions using speleothems.

ObjectivePreemptive thoracic endovascular aortic repair (TEVAR) has the potential to improve the prognosis of Stanford type B aortic dissection (TBAD), however it is important to determine whether it could be safely performed as a prophylactic treatment. This study aimed to determine the short- and long-term outcomes of preemptive TEVAR for uncomplicated TBAD with a small aortic aneurysm.DesignRetrospective multicenter analysis.MethodsWe analyzed 212 patients with medically treated uncomplicated subacute TBAD between July 2004 and October 2019 in two Japanese academic centers. The short- and long-term prognosis of patients who underwent preemptive TEVAR and the changes in aortic diameter over time after TEVAR were analyzed. Aorta-related complications, aortic-related death and postoperative complications were recorded and analyzed. Analysis was performed on an intension-to-treat basis.ResultsDuring follow-up, patients were divided into two groups: optimal medical treatment [OMT; n = 185 (87%)] and preemptive TEVAR [n = 27 (13%)]. In all cases, aortic enlargement was the reason for therapeutic intervention in the preemptive TEVAR group. Propensity score matching yielded a cohort of 27 control patients with OMT (group A) and 27 patients who underwent preemptive TEVAR (group B). Preoperative characteristics were similar between groups. In group B, only one patient developed type A dissection at a late stage and died from aortic rupture. Freedom from aortic-related death at 1/5/10 years was 100%/92%/92% in group B. Overall growth (mm/year) of max aorta was significantly smaller in the TEVAR group than in the control group (−3.7 ± 2.9 vs. 0.4 ± 5.6, p

BackgroundInflammatory bowel disease (IBD) is a refractory inflammatory disorder of the intestine, which is probably triggered by dysfunction of the intestinal epithelial barrier. Secretory leukocyte protease inhibitor (SLPI) secreted by colon epithelial cells protects against intestinal inflammation by exerting anti-protease and anti-microbial activities. Daikenchuto (DKT) is one of the most commonly prescribed Japanese traditional herbal medicines for various digestive diseases. Although several animal studies have revealed that DKT exerts anti-inflammatory effects, its detailed molecular mechanism is unclear. This study aimed to clarify the anti-inflammatory mechanism of DKT using a murine colitis model, and to evaluate its potential as a therapeutic agent for IBD.MethodsExperimental colitis was induced in wild-type (WT) mice and SLPI-deficient (KO) mice by dextran sulfate sodium (DSS) after oral administration of DKT. The resultant clinical symptoms, histological changes, and pro-inflammatory cytokine levels in the colon were assessed. Expression of SLPI in the colon was detected by Western blotting and immunohistochemistry. Composition of the gut microbiota was analyzed by 16S rRNA metagenome sequencing and intestinal metabolites were measured by gas chromatography-mass spectrometry analysis. Intestinal epithelial barrier function was assessed by oral administration of FITC-dextran and immunostaining of tight junction proteins (TJPs).ResultsOral administration of DKT increased the number of butyrate-producing bacteria, such as Parabacteroides, Allobaculum, and Akkermansia, enhanced the levels of short-chain fatty acids, including butyrate, in the colon, induced SLPI expression, and ameliorated DSS-induced colitis in WT mice. We found that mouse colon carcinoma cell line treatment with either DKT or butyrate significantly enhanced the expression of SLPI. Moreover, supplementation of DKT protected the intestinal epithelial barrier with augmented expression of TJPs in WT mice, but not in KO mice. Finally, the composition of the gut microbiota was changed by DKT in WT mice, but not in KO mice, suggesting that DKT alters the colonic bacterial community in an SLPI-dependent manner.ConclusionThese results indicate that DKT exerts anti-inflammatory effects on the intestinal epithelial barrier by SLPI induction, due, at least in part, to increased butyrate-producing bacteria and enhanced butyrate levels in the colon. These results provide insight into the mechanism of the therapeutic effects of DKT on IBD.

BackgroundThe field of mental health technology presently has significant gaps that need addressing, particularly in the domain of daily monitoring and personalized assessments. Current noninvasive devices such as wristbands and smartphones are capable of collecting a wide range of data, which has not yet been fully used for mental health monitoring. ObjectiveThis study aims to introduce a novel dataset for personalized daily mental health monitoring and a new macro-micro framework. This framework is designed to use multimodal and multitask learning strategies for improved personalization and prediction of emotional states in individuals. MethodsData were collected from 298 individuals using wristbands and smartphones, capturing physiological signals, speech data, and self-annotated emotional states. The proposed framework combines macro-level emotion transformer embeddings with micro-level personalization layers specific to each user. It also introduces a Dynamic Restrained Uncertainty Weighting method to effectively integrate various data types for a balanced representation of emotional states. Several fusion techniques, personalization strategies, and multitask learning approaches were explored. ResultsThe proposed framework was evaluated using the concordance correlation coefficient, resulting in a score of 0.503. This result demonstrates the framework’s efficacy in predicting emotional states. ConclusionsThe study concludes that the proposed multimodal and multitask learning framework, which leverages transformer-based techniques and dynamic task weighting strategies, is superior for the personalized monitoring of mental health. The study indicates the potential of transforming daily mental health monitoring into a more personalized app, opening up new avenues for technology-based mental health interventions.

Abstract In the treatment of chronic myeloid leukemia (CML), resistance to BCR‐ABL inhibitors makes it difficult to continue treatment and is directly related to life expectancy. Therefore, asciminib was introduced to the market as a useful drug for overcoming drug resistance. While combining molecular targeted drugs is useful to avoid drug resistance, the new BCR‐ABL inhibitor asciminib and conventional BCR‐ABL inhibitors should be used as monotherapy in principle. Therefore, we investigated the synergistic effect and mechanism of the combination of asciminib and imatinib. We generated imatinib‐resistant cells using the human CML cell line K562, examined the effects of imatinib and asciminib exposure on cell survival using the WST‐8 assay, and comprehensively analyzed genetic variation related to drug resistance using RNA‐seq and real‐time PCR. A synergistic effect was observed when imatinib and asciminib were combined with or without imatinib resistance. Three genes, GRRP1, ESPN, and NOXA1, were extracted as the sites of action of asciminib. Asciminib in combination with BCR‐ABL inhibitors may improve the therapeutic efficacy of conventional BCR‐ABL inhibitors and prevent the development of resistance. Its dosage may be effective even at minimal doses that do not cause side effects. Further verification of this mechanism of action is needed. Additionally, cross‐resistance between BCR‐ABL inhibitors and asciminib may occur, which needs to be clarified through further validation as soon as possible.

Abstract Background The concept of ablation index (AI) was introduced to evaluate radiofrequency (RF) ablation lesions. It is calculated from power, contact force (CF), and RF duration. However, other factors may also affect the quality of ablation lesions. To examine the difference in RF lesions made during sinus rhythm (SR) and atrial fibrillation (AF). Methods Sixty patients underwent index pulmonary vein isolation during SR (n = 30, SR group) or AF (n = 30, AF group). All ablations were performed with a power of 50 W, a targeted CF of 5–15 g, and AI of 400–450 using Thermocool Smarttouch SF. The CF, AI, RF duration, temperature rise (Δtemp), impedance drop (Δimp), and the CF stability of each ablation point quantified as the standard deviation of the CF (CF‐SD) were compared between the two groups. Results A total of 3579 ablation points were analyzed, which included 1618 and 1961 points in the SR and the AF groups, respectively. Power, average CF, RF duration per point, and the resultant AI (389 ± 59 vs. 388 ± 57) were similar for the two rhythms. However, differences were seen in the CF‐SD (3.5 ± 2.2 vs. 3.8 ± 2.1 g, p

Abstract Liver metastases from pancreatic ductal adenocarcinoma (PDAC) are highly fatal. A rat-based patient-derived tumor xenograft (PDX) model is available for transcatheter therapy. This study aimed to create an immunodeficient rat model with liver xenografts of patient-derived primary PDAC and evaluate efficacy of hepatic arterial infusion chemotherapy with cisplatin in this model. Three patient-derived PDACs were transplanted into the livers of 21 rats each (totally, 63 rats), randomly assigned into hepatic arterial infusion, systemic venous infusion, and control groups (n = 7 each) four weeks post-implantation. Computed tomography evaluated tumor volumes before and four weeks after treatment. Post-euthanasia, resected tumor specimens underwent histopathological examination. A liver-implanted PDAC PDX rat model was established in all 63 rats, with first CT identifying all tumors. Four weeks post-treatment, arterial infusion groups exhibited significantly smaller tumor volumes than controls for all three tumors on second CT. Xenograft tumors histologically maintained adenocarcinoma features compared to original patient tumors. Ki67 expression was significantly lower in arterial infusion groups than in the other two for the three tumors, indicating reduced tumor growth in PDX rats. A liver-implanted PDAC PDX rat model was established as a rat-based preclinical platform. Arterial cisplatin infusion chemotherapy represents a potential therapy for PDAC liver metastasis.

Indocyanine green (ICG) is one of the only clinically approved near-infrared (NIR) fluorophores used during fluorescence-guided surgery (FGS), but it lacks tumor specificity for pancreatic ductal adenocarcinoma (PDAC). Several tumor-targeted fluorescent probes have been evaluated in PDAC patients, yet no uniformity or consensus exists among the surgical community on the current and future needs of FGS during PDAC surgery. In this first-published consensus report on FGS for PDAC, expert opinions were gathered on current use and future recommendations from surgeons' perspectives. A Delphi survey was conducted among international FGS experts via Google Forms. Experts were asked to anonymously vote on 76 statements, with ≥70% agreement considered consensus and ≥80% participation/statement considered vote robustness. Consensus was reached for 61/76 statements. All statements were considered robust. All experts agreed that FGS is safe with few drawbacks during PDAC surgery, but that it should not yet be implemented routinely for tumor identification due to a lack of PDAC-specific NIR tracers and insufficient evidence proving FGS's benefit over standard methods. However, aside from tumor imaging, surgeons suggest they would benefit from visualizing vasculature and surrounding anatomy with ICG during PDAC surgery. Future research could also benefit from identifying neuroendocrine tumors. More research focusing on standardization and combining tumor identification and vital-structure imaging would greatly improve FGS's use during PDAC surgery.

Introduction:. This study aimed to identify research areas that demand attention in multimodal data-driven surgery for improving data management in minimally invasive surgery. Background:. New surgical procedures, high-tech equipment, and digital tools are increasingly being introduced, potentially benefiting patients and surgical teams. These innovations have resulted in operating rooms evolving into data-rich environments, which, in turn, requires a thorough understanding of the data pipeline for improved and more intelligent real-time data usage. As this new domain is vast, it is necessary to identify where efforts should be focused on developing seamless and practical data usage. Methods:. A modified electronic Delphi approach was used; 53 investigators were divided into the following groups: a research group (n=9) for problem identification and a narrative literature review, a medical and technical expert group (n=14) for validation, and an invited panel (n=30) for two electronic survey rounds. Round 1 focused on a consensus regarding bottlenecks in surgical data science areas and research gaps, while round 2 prioritized the statements from round 1, and a roadmap was created based on the identified essential and very important research gaps. Results:. Consensus panelists have identified key research areas, including digitizing operating room (OR) activities, improving data streaming through advanced technologies, uniform protocols for handling multimodal data, and integrating AI for efficiency and safety. The roadmap prioritizes standardizing OR data formats, integrating OR data with patient information, ensuring regulatory compliance, standardizing surgical AI models, and securing data transfers in the next generation of wireless networks. Conclusions:. This work is an international expert consensus regarding the current issues and key research targets in the promising field of data-driven surgery, highlighting the research needs of many operating room stakeholders with the aim of facilitating the implementation of novel patient care strategies in minimally invasive surgery.