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Abstract Neuromuscular blocking agents are used commonly to induce skeletal muscle relaxation during surgery. While muscle relaxation facilitates surgical procedures and tracheal intubation, adequate recovery of muscle function after surgery is required to support pulmonary function, and even mild residual neuromuscular block increases the risk of severe postoperative pulmonary complications. While recovery of muscle function after surgery involving neuromuscular blocking agents can be monitored and, in addition, be accelerated by use of current antagonists (reversal agents), there is a clear clinical need for a safe drug to antagonize all types of neuromuscular blocking agents. Here, we show that inhibition of the skeletal muscle-specific chloride ion (Cl-) channel, the ClC-1 channel, markedly accelerates recovery of both single contraction (twitch) and, important physiologically, sustained (tetanic) contractions in a rat model mimicking neuromuscular blocking agent-induced muscle block used during surgery. This suggests ClC-1 inhibition as a mechanism for fast and efficacious recovery of neuromuscular function induced by any neuromuscular blocking agents.

Significant research has been carried out in the last decade to describe the CO2 system dynamics in the Baltic Sea. However, there is a lack of knowledge in this field in the NE Baltic Sea, which is the main focus of the present study. We analysed the physical forcing and hydrographic background in the study year (2018) and tried to elucidate the observed patterns of surface water CO2 partial pressure (pCO2) and methane concentrations (cCH4). Surface water pCO2 and cCH4 were continuously measured during six monitoring cruises onboard R/V Salme, covering the Northern Baltic Proper (NBP), the Gulf of Finland (GoF), and the Gulf of Riga (GoR) and all seasons in 2018. The general seasonal pCO2 pattern showed oversaturation in autumn–winter (average relative CO2 saturation 1.2) and undersaturation in spring–summer (average relative CO2 saturation 0.5), but it locally reached the saturation level during the cruises in April, May, and August in the GoR and in August in the GoF. The cCH4 was oversaturated during the entire study period, and the seasonal course was not well exposed on the background of high variability. Surface water pCO2 and cCH4 distributions showed larger spatial variability in the GoR and GoF than in the NBP for all six cruises. We linked the observed local maxima to river bulges, coastal upwelling events, fronts, and occasions when vertical mixing reached the seabed in shallow areas. Seasonal averaging over the CO2 flux suggests a weak sink for atmospheric CO2 for all basins, but high variability and the long periods between cruises (temporal gaps in observation) preclude a clear statement.

Abstract In many countries, hormone receptor status assessment of ductal carcinoma in situ (DCIS) is routinely performed, as hormone receptor-positive DCIS patients are eligible for adjuvant anti-hormonal treatment, aiming to reduce the ipsilateral and contralateral breast cancer risk. Although HER2 gene amplification and its associated HER2 protein overexpression constitute a major prognostic and predictive marker in invasive breast carcinoma, its use in the diagnosis and treatment of DCIS is less straightforward. HER2 immunohistochemistry is not routinely performed yet, as the role of HER2-positivity in DCIS biology is unclear. Nonetheless, recent data challenge this practice. Here, we discuss the value of routine HER2 assessment for DCIS. HER2-positivity correlates strongly with DCIS grade: around four in five HER2-positive DCIS show high grade atypia. As morphological DCIS grading is prone to interobserver variability, HER2 immunohistochemistry could render grading more robust. Several studies showed an association between HER2-positive DCIS and ipsilateral recurrence risk, albeit currently unclear whether this is for overall, in situ or invasive recurrence. HER2-positive DCIS tends to be larger, with a higher risk of involved surgical margins. HER2-positive DCIS patients benefit more from adjuvant radiotherapy: it substantially decreases the local recurrence risk after lumpectomy, without impact on overall survival. HER2-positivity in pure biopsy-diagnosed DCIS is associated with increased upstaging to invasive carcinoma after surgery. HER2 immunohistochemistry on preoperative biopsies might therefore provide useful information to surgeons, favoring wider excisions. The time seems right to consider DCIS subtype-dependent treatment, comprising appropriate local treatment for HER2-positive DCIS patients and de-escalation for hormone receptor-positive, HER2-negative DCIS patients.

Abstract Background People with dementia and severe challenging behavior in the Netherlands can be temporarily admitted to highly specialized units when their behavior is not manageable in regular dementia special care units (DSCUs). With scarce evidence available for the treatment of these patients, treatment in these units is in a pioneering phase. To gain more insight into these units, this study investigated organizational characteristics, i.e. admission and discharge characteristics, staffing, the physical environment, and the management of severe challenging behavior. Methods Three data collection methods were used: 1) a digital questionnaire to be completed by the unit manager, 2) an interview with the physician responsible for medical care and often another practitioner, and 3) an observation of the physical environment for which the OAZIS-dementia questionnaire was used. Descriptive analysis was used for quantitative data and thematic analysis for qualitative data, after which data was interpreted together. Thirteen units participated, with their sizes ranging from 10 to 28 places. Results Patients were mainly admitted from regular DSCUs, home or mental health care, and discharged to regular DSCUs. A multidisciplinary team comprising at least an elderly care physician or geriatrician, psychologist, and nursing staff member and other therapists as needed provided the treatment. Nursing staff hours per patient considerably differed among units. Nursing staff played a central role in the treatment. Competences such as reflectiveness on one’s own behavior, and being able to cope with stressful situations were described as relevant for nursing staff. Investing in a stable nursing staff team was described as important. The units varied in whether their work-up was more intuitive or methodological. In the diagnostic phase, observation together with an extensive analysis of the patient’s biography was essential. The units used a broad variety of interventions, and all paid attention to sensory stimuli. In the observation of the physical environment, the safety scored well and domesticity relatively low. Conclusion Highly specialized units show strong heterogeneity in organizational characteristics and management, which can be understood in the light of the pioneering phase. Despite this, similarities were found in nursing staff roles, frequent multidisciplinary evaluation, and attention to sensory stimuli.

Animal models are an important tool in the research of chronic autoimmune diseases, like systemic lupus erythematosus (SLE). MRL-Faslpr mice are one of different lupus models that develop spontaneously an SLE-like disease with autoantibodies and immune complex deposition that leads into damage of different organs. In contrast to human SLE, both sexes of MRL-Faslpr mice develop a similar autoimmune disease. Due to the sex bias in human and the delayed disease progression in male MRL-Faslpr mice, the majority of studies have been performed in female mice. To determine the suitability of male MRL-Faslpr mice for SLE research, especially with regard to the 3 R-principle and animal welfare, analyses of phenotype, inflammation and damage with focus on kidney and spleen were performed in mice of both sexes. Female mice developed lymphadenopathy and skin lesions earlier as males. At an age of 3.5 month, more immune cells infiltrated kidney and spleen in females compared to males. At the age of 5 months, however, substantially less sex-specific differences were detected. Since other studies have shown differences between both sexes on other manifestations like autoimmune pancreatitis and Sjögren syndrome in MRL-Faslpr mice, the use of male mice as part of 3 R-principle and animal welfare must be carefully considered.

The EU funded project EuroSea brought together key actors of the European ocean observing and forecasting communities with key users of the ocean observing products and services in order to better integrate existing ocean observation systems and tools, and to improve the delivery of ocean information to users. EuroSea was constructed around the ocean observing value chain that connects observations to users of ocean information, and, just as intended, the value chain concept was a useful prism to improve the system. In this article, we summarize some of the main take-home messages from EuroSea on the needs for developing the European Ocean Observing System and its links with modeling and forecasting systems. During the project, the challenges and gaps in the design and coordination of the European ocean observing and forecasting system were identified and mapped. Many gaps and challenges related to the observations of physical, chemical and biological Essential Ocean Variables were identified. Some of these gaps are related to technological developments, while others are caused by insufficient and short-term funding leading to a not sustainable system, management, and cooperation between different entities, as well as limitations in foresight activities, policies and decisions. This article represents a compilation of the broader needs for advancing the observing and forecasting system, and is meant as a guide for the community, and to funders and investors to advance ocean observing and the delivery of ocean information in Europe. To enhance the sustainability of ocean observations, which is paramount for a reliable provision of quality oceanographic data and services, several recommendations were compiled for ocean observing networks, frameworks, initiatives, as well as the ocean observing funders within the European nations, and the European Commission.

Background: Ductal carcinoma in situ (DCIS) can progress to invasive breast cancer (IBC), but often never will. As we cannot predict accurately which DCIS-lesions will or will not progress to IBC, almost all women with DCIS undergo breast-conserving surgery supplemented with radiotherapy, or even mastectomy. In some countries, endocrine treatment is prescribed as well. This implies many women with non-progressive DCIS undergo overtreatment. To reduce this, the LORD patient preference trial (LORD-PPT) tests whether mammographic active surveillance (AS) is safe by giving women with low-risk DCIS a choice between treatment and AS. For this, sufficient knowledge about DCIS is crucial. Therefore, we assessed women's DCIS knowledge in association with socio-demographic and clinical characteristics. Methods: LORD-PPT participants (N = 376) completed a questionnaire assessing socio-demographic and clinical characteristics, risk perception, treatment choice and DCIS knowledge after being informed about their diagnosis and treatment options. Results: 66 % of participants had poor knowledge (i.e., answered ≤3 out of 7 knowledge items correctly). Most incorrect answers involved overestimating the safety of AS and misunderstanding of DCIS prognostic risks. Overall, women with higher DCIS knowledge score perceived their risk of developing IBC as being somewhat higher than women with poorer knowledge (p = 0.049). Women with better DCIS knowledge more often chose surgery whilst most women with poorer knowledge chose active surveillance (p = 0.049). Discussion: Our findings show that there is room for improvement of information provision to patients. Decision support tools for patients and clinicians could help to stimulate effective shared decision-making about DCIS management.

Metal production in the Trans-Ural region in the Early Iron Age is known mainly from materials from the Itkul and Sargat cultures. The article introduces into scientific circulation the largest collection of objects (80 items) made of non-ferrous metal of the Baitovo culture of this period from the settlement of Isetskoye 3, located in the Lower Iset river area. The purpose of the study is to morphometrically characterize and determine the complex typology, as well as to conduct a comparative analysis with synchronous materials. The studied series of items includes weapons (arrowheads), labor tools (knives, a celt, an awl), elements of horse harness (a fragment of a bit), toilet items, jewelry (a mirror, rings, plaques), etc., as well as slags, ingots, and waste bronze foundry production. Preliminary conclusions on production technology were obtained, indicating that stone and clay molds were used for casting. The authors experimentally tested the hypothesis, which was not confirmed, on the possibility of using wooden knife models in the manufacture of clay casting molds. Signs of forging and abrasive casting processing were recorded on several metal objects. Based on their typology and the identified analogies, it was concluded that the complex is characteristic of the Scythian-Siberian cultures and can be dated back to the 7th – 6th/3rd centuries BC, which testifies to the contacts and connections of the Baitovo population with both the western (Itkul) and the eastern metallurgical centers. The presence of slag, a significant amount of bronze casting waste, and mold fragments confirms its local nature, which, however, does not exclude the import of some metal products from other territories.

Abstract Tumor-infiltrating lymphocytes (TILs) have been associated with outcomes in HER2-positive breast cancer patients treated with neoadjuvant chemotherapy and trastuzumab. However, it remains unclear if TILs could be a prognostic and/or predictive biomarker in the context of dual HER2-targeting treatment. In this study, we evaluated the association between TILs and pathological response (pCR) and invasive-disease free survival (IDFS) in 389 patients with stage II-III HER2 positive breast cancer who received neoadjuvant anthracycline-containing or anthracycline-free chemotherapy combined with trastuzumab and pertuzumab in the TRAIN-2 trial. Although no significant association was seen between TILs and pCR, patients with TIL scores ≥60% demonstrated an excellent 3-year IDFS of 100% (95% CI 100–100), regardless of hormone receptor status, nodal stage and attainment of pCR. Additionally, in patients with hormone receptor positive disease, TILs as a continuous variable showed a trend to a positive association with pCR (adjusted Odds Ratio per 10% increase in TILs 1.15, 95% CI 0.99–1.34, p = 0.070) and IDFS (adjusted Hazard Ratio per 10% increase in TILs 0.71, 95% CI 0.50–1.01, p = 0.058). We found no interactions between TILs and anthracycline treatment. Our results suggest that high TIL scores might be able to identify stage II-III HER2-positive breast cancer patients with a favorable prognosis.

Abstract Background Ductal Carcinoma In Situ (DCIS) can progress to invasive breast cancer, but most DCIS lesions never will. Therefore, four clinical trials (COMET, LORIS, LORETTA, AND LORD) test whether active surveillance for women with low-risk Ductal carcinoma In Situ is safe (E. S. Hwang et al., BMJ Open, 9: e026797, 2019, A. Francis et al., Eur J Cancer. 51: 2296–2303, 2015, Chizuko Kanbayashi et al. The international collaboration of active surveillance trials for low-risk DCIS (LORIS, LORD, COMET, LORETTA), L. E. Elshof et al., Eur J Cancer, 51, 1497–510, 2015). Low-risk is defined as grade I or II DCIS. Because DCIS grade is a major eligibility criteria in these trials, it would be very helpful to assess DCIS grade on mammography, informed by grade assessed on DCIS histopathology in pre-surgery biopsies, since surgery will not be performed on a significant number of patients participating in these trials. Objective To assess the performance and clinical utility of a convolutional neural network (CNN) in discriminating high-risk (grade III) DCIS and/or Invasive Breast Cancer (IBC) from low-risk (grade I/II) DCIS based on mammographic features. We explored whether the CNN could be used as a decision support tool, from excluding high-risk patients for active surveillance. Methods In this single centre retrospective study, 464 patients diagnosed with DCIS based on pre-surgery biopsy between 2000 and 2014 were included. The collection of mammography images was partitioned on a patient-level into two subsets, one for training containing 80% of cases (371 cases, 681 images) and 20% (93 cases, 173 images) for testing. A deep learning model based on the U-Net CNN was trained and validated on 681 two-dimensional mammograms. Classification performance was assessed with the Area Under the Curve (AUC) receiver operating characteristic and predictive values on the test set for predicting high risk DCIS-and high-risk DCIS and/ or IBC from low-risk DCIS. Results When classifying DCIS as high-risk, the deep learning network achieved a Positive Predictive Value (PPV) of 0.40, Negative Predictive Value (NPV) of 0.91 and an AUC of 0.72 on the test dataset. For distinguishing high-risk and/or upstaged DCIS (occult invasive breast cancer) from low-risk DCIS a PPV of 0.80, a NPV of 0.84 and an AUC of 0.76 were achieved. Conclusion For both scenarios (DCIS grade I/II vs. III, DCIS grade I/II vs. III and/or IBC) AUCs were high, 0.72 and 0.76, respectively, concluding that our convolutional neural network can discriminate low-grade from high-grade DCIS.

Introduction Postoperative pancreatic fistula (POPF) occurs in 25% of patients undergoing a high-risk pancreatoduodenectomy (PD) and is a driving cause of major morbidity, mortality, prolonged hospital stay and increased costs after PD. There is a need for perioperative methods to decrease these risks. In recent studies, preoperative chemoradiotherapy in patients with pancreatic ductal adenocarcinoma (PDAC) reduced the rate of POPF seemingly due to radiation-induced pancreatic fibrosis. However, patients with a high risk of POPF mostly have a non-pancreatic periampullary tumour and do not receive radiotherapy. Prospective studies using radiotherapy specifically to reduce the risk of POPF have not been performed. We aim to assess the safety, feasibility and preliminary efficacy of preoperative stereotactic radiotherapy on the future pancreatic neck transection margin to reduce the rate of POPF.Methods and analysis In this multicentre, single-arm, phase II trial, we aim to assess the feasibility and safety of a single fraction of preoperative stereotactic radiotherapy (12 Gy) to a 4 cm area around the future pancreatic neck transection margin in patients at high risk of developing POPF after PD aimed to reduce the risk of grade B/C POPF. Adult patients scheduled for PD for malignant and premalignant periampullary tumours, excluding PDAC, with a pancreatic duct diameter ≤3 mm will be included in centres participating in the Dutch Pancreatic Cancer Group. The primary outcome is the safety and feasibility of single-dose preoperative stereotactic radiotherapy before PD. The most relevant secondary outcomes are grade B/C POPF and the difference in the extent of fibrosis between the radiated and non-radiated (uncinate margin) pancreas. Evaluation of endpoints will be performed after inclusion of 33 eligible patients.Ethics and dissemination Ethical approval was obtained by the Amsterdam UMC’s accredited Medical Research Ethics Committee (METC). All included patients are required to have provided written informed consent. The results of this trial will be used to determine the need for a randomised controlled phase III trial and submitted to a high-impact peer-reviewed medical journal regardless of the study outcome.Trial registration number NL72913 (Central Committee on Research involving Human Subjects Registry) and NCT05641233 (ClinicalTrials).

The interdisciplinary community of ocean and coastal observers and modelers in Europe is driven by national observing needs for prediction and management of intricate processes shaping Europe’s Seas. Not all observing needs can be addressed by nations alone and various coordination activities exist to overcome fragmentation and create cross benefit within the European Ocean Observing Community (EOOC). This way critical insights into impacts of climate change on European Waters and cross border marine resources management can be achieved. Based on a large number of published material, this article is identifying and addressing the current state of activities of the EOOC and states gaps that potentially prevent efficacy. Key challenges include spatial and temporal coverage in observations, data integration, accessibility, uncertainties in projections, technological hurdles, and engagement and communication gaps. Detailed recommendations are provided for identified gaps, offering valuable insights for stakeholders, funders, and supporters of the EOOC. These recommendations, extending beyond academic interest, carry significant implications for climate change mitigation, marine resource management efficiency, ecosystem resilience, disaster preparedness, economic benefits, and the broader scientific advancements in European marine science, thereby benefiting society at large. As the world undergoes transformative changes impacting all facets of European life, substantial investment and support for the EOOC are crucial for precise information, accurate predictions, supporting sustained services that contribute to business growth and community resilience, and a sustainable ocean.