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Abstract The count of mitotic figures (MFs) observed in hematoxylin and eosin (H&E)-stained slides is an important prognostic marker, as it is a measure for tumor cell proliferation. However, the identification of MFs has a known low inter-rater agreement. In a computer-aided setting, deep learning algorithms can help to mitigate this, but they require large amounts of annotated data for training and validation. Furthermore, label noise introduced during the annotation process may impede the algorithms’ performance. Unlike H&E, where identification of MFs is based mainly on morphological features, the mitosis-specific antibody phospho-histone H3 (PHH3) specifically highlights MFs. Counting MFs on slides stained against PHH3 leads to higher agreement among raters and has therefore recently been used as a ground truth for the annotation of MFs in H&E. However, as PHH3 facilitates the recognition of cells indistinguishable from H&E staining alone, the use of this ground truth could potentially introduce an interpretation shift and even label noise into the H&E-related dataset, impacting model performance. This study analyzes the impact of PHH3-assisted MF annotation on inter-rater reliability and object level agreement through an extensive multi-rater experiment. Subsequently, MF detectors, including a novel dual-stain detector, were evaluated on the resulting datasets to investigate the influence of PHH3-assisted labeling on the models’ performance. We found that the annotators’ object-level agreement significantly increased when using PHH3-assisted labeling (F1: 0.53 to 0.74). However, this enhancement in label consistency did not translate to improved performance for H&E-based detectors, neither during the training phase nor the evaluation phase. Conversely, the dual-stain detector was able to benefit from the higher consistency. This reveals an information mismatch between the H&E and PHH3-stained images as the cause of this effect, which renders PHH3-assisted annotations not well-aligned for use with H&E-based detectors. Based on our findings, we propose an improved PHH3-assisted labeling procedure.

The present study contributes to the morphogenesis of the Miresii Cave, located in Cheia Mare of Dâmbovița in the area of the Bran—Dragoslavele Corridor, an important tourist axis in Romania. The main aim of the research is the proposal to the Scientific Council of Piatra Craiului National Park to bring to the attention of the national decision-making commissions that the cave be declared a natural monument. The inventory of this speleological geomorphosite suggested its inclusion in a thematic geotouristic circuit integrated into national and EU-protected natural areas. The novelty of the present research lies in the fact that the cave has never been studied before, being difficult to access. This cave, spatially found in the strict protection zone of the national park, is not included in its management plan. When being integrated into other nature protection areas, it is necessary to exclude any form of recreational tourism so that the cave can be exploited as a geotouristic resource strictly for research and educational purposes. The morphogenetic analysis of the cave, based on the information synthesized from geomorphological and geological literature, allowed us to decipher the morphological individualization of Miresii Cave in the local and regional geocronomorphological context, in accordance with the chronological separation of the karstification phenomenon manifested first in phreatic and later in vadose karst. The diversified typology of speleothems has been rendered according to the geomorphologic generating processes. The identification of the Rhinolophus ferrumequinum chiropteran colony and observations of its biotope highlighted the ecological significance of the cave. The inventory of the individuals of the colony led to the conclusion that the cave harbors one of the first two largest bat communities of this species in the national park and the adjacent depressional corridor. The present study may allow the documentation of the photographs and description of the geomorphosite integrated into the proposed thematic circuit to be included on billboards and in promotional brochures. Thus, it could also be useful for the decision-making authorities of Rucar and Podu Dâmboviței villages, which are interested in making decisions related to the promotion of geotourism, especially due to the existence of numerous geological and geomorphological tourist resources in the administrative territories.

Abstract Background Premenopausal, high-risk, hormone receptor-positive breast cancer patients are often treated with ovarian suppression in combination with aromatase inhibitors (AI). This combination has important adverse effects, particularly in sexual function, such as vaginal dryness and loss of libido. There is no effective therapy for reduced sexual function in this setting. Our study aimed to determine the efficacy and safety, particularly regarding sexual function, of a low-dose, topical testosterone gel administration. Methods This is a pilot, single-center study, designed to evaluate the efficacy of topical testosterone gel (3 mg/day) in improving sexual function in 29 premenopausal patients on ovarian suppression in combination with an AI. The primary safety endpoint was to assess serum estradiol elevation. The primary efficacy endpoint was sexual function improvement, assessed by the Female Sexual Function Index questionnaire. Results We report the results on 29 patients. Twenty-two patients (75%) completed the 3-month treatment, and seven discontinued treatment before completion, mostly due to logistical difficulties related to the COVID-19 pandemic. All patients maintained the value of baseline mass spectrometry assay for estradiol of less than 2.7 pg/mL during the undertaken measurements. We observed a significant improvement in Female Sexual Function Index measures over the visits, with an increase from a mean of 11.7 at baseline to 19.1 in the third month (p

This study explores the relationship between corporate sustainability, focusing on social performance and its impact on financial performance in the technology industry. Using secondary data from the Refinitiv Eikon database, covering 4,825 companies from 2019-2023, the research uses multiple regression models to analyze associations between sustainability variables and key financial indicators, mainly return on assets (ROA) and return on equity (ROE). Findings reveal a robust and statistically significant positive effect of social performance on ROE, complemented by positive impacts of workforce, human rights, community, and product responsibility in the models. In addition, company size consistently demonstrates a strong positive influence on ROE in all models. These results contribute valuable insights into the intersection of sustainability initiatives and financial performance in the technology sector.

Background We evaluated relationships of vital signs and laboratory-tested physiological parameters with in-hospital mortality, focusing on values that are unusual or extreme even in critical care settings. Methods We retrospectively studied Philips Healthcare–MIT eICU data (207 U.S. hospitals, 2014–2015), including 166,959 adult-patient critical care admissions. Analyzing most-deranged (worst) value measured in the first admission day, we investigated vital signs (body temperature, heart rate, mean arterial pressure, and respiratory rate) as well as albumin, bilirubin, blood pH via arterial blood gas (ABG), blood urea nitrogen, creatinine, FiO2 ABG, glucose, hematocrit, PaO2 ABG, PaCO2 ABG, sodium, 24-hour urine output, and white blood cell count (WBC). Results In-hospital mortality was ≥50% at extremes of low blood pH, low and high body temperature, low albumin, low glucose, and low heart rate. Near extremes of blood pH, temperature, glucose, heart rate, PaO2, and WBC, relatively small changes in measured values correlated with several-fold mortality rate increases. However, high mortality rates and abrupt mortality increases were often hidden by the common practice of thresholding or binning physiological parameters. The best predictors of in-hospital mortality were blood pH, temperature, and FiO2 (scaled Brier scores: 0.084, 0.063, and 0.049, respectively). Conclusions In-hospital mortality is high and sharply increasing at extremes of blood pH, body temperature, and other parameters. Common-practice thresholding obscures these associations. In practice, vital signs are sometimes treated more casually than laboratory-tested parameters. Yet, vitals are easier to obtain and we found they are often the best mortality predictors, supporting perspectives that vitals are undervalued.

The mechanism underlying ischaemic heart disease (IHD) has been primarily attributed to obstructive coronary artery disease (CAD). However, non-obstructive coronary arteries are identified in >50% of patients undergoing elective coronary angiography, recently leading to growing interest in the investigation and management of angina/ischaemia with non-obstructive coronary arteries (ANOCA/INOCA). INOCA is an umbrella term encompassing a multiple spectrum of possible pathogenetic entities, including coronary vasomotor disorders which consist of two major endotypes: coronary microvascular dysfunction (CMD) and vasospastic angina. Both conditions can coexist and be associated with concomitant obstructive CAD. Particularly, CMD refers to myocardial ischaemia due to reduced vasodilatory capacity of coronary microcirculation secondary to structural remodelling or impaired resting microvascular tone (functional) or a combination of both. CMD is not a benign condition and is more prevalent in women presenting with chronic coronary syndrome compared to men. In this setting, an impaired coronary flow reserve has been associated with increased risk of major adverse cardiovascular events. ANOCA/INOCA patients also experience impaired quality of life and associated increased healthcare costs. Therefore, research in this scenario has led to better definition, classification, and prognostic stratification based on the underlying pathophysiological mechanisms. The development and validation of non-invasive imaging modalities, invasive coronary vasomotor function testing and angiography-derived indices provide a comprehensive characterisation of CMD. The present narrative review aims to summarise current data relating to the diagnostic approach to CMD and provides details on the sequence that therapeutic management should follow.

COVID-19 struck the world and stretched the healthcare system and professionals. Medical students engaged in the pandemic effort, making personal and professional sacrifices. However, the impact of these sacrifices on students' professional development is still unknown. We applied constructivist grounded theory to individual audio diaries (total time = 5h38 min) and interviews (total time = 11h57min) performed with 18 last-year medical students during the first wave of COVID-19 pandemic in Brazil. The perspective of making sacrifices caused initial emotional distress in medical students, followed by a negotiation process revolving around three themes: predisposition to sacrifice, sense of competence, and sense of belonging. This negotiation process led to three response patterns: Pattern A: "No sense of duty"--the sacrifice was perceived as meaningless, and students showed intense anger and a desire to flee; Pattern B: "Sense of duty with hesitation to act"--the sacrifice was acknowledged as legitime, but students felt unprepared to contribute, leading to feelings of frustration and shame; and, Pattern C: "Sense of duty with readiness to act"--the engagement with the sacrifice was perceived as an opportunity to grow as a doctor, leading to fulfillment and proudness. Students ready to engage with the COVID-19 effort experienced identity consonance, reinforcing their professional identities. Students who felt incompetent or found the sacrifice meaningless experienced identity dissonance, which led to emotional suffering and the consideration of abandoning the course. Monitoring students' emotional reactions when facing professional challenges creates opportunities to problematize the role of sacrifice in the medical profession and scaffold professional identity development.

The present study analyzes the impact that the structure of the board of directors and its organization have on sustainability, especially on social and environmental pillar scores, in the European country in the period 2018-2022. The Refinitiv Eikon database is the main source, accumulating a number of 15,575 observations for the analyzed period. In order to analyze the structure of the board of directors and its way of organization, five independent variables were taken into account, represented by the number of directors in boards, how many of them are independent members and how many women are in board, the duality of the CEO and the total number of meetings in a year. Sustainability was analyzed using data collected for social and environmental performance and represented the dependent variables of the study. Using SPSS software, data were extracted from Refinitiv Eikon for 3,115 companies using econometric methods (multiple linear regression), as well as correlation matrix and descriptive statistics. The results indicate that boards with an increased proportion of independent and female directors, accompanied by a dual-role CEO, contribute to improved sustainability. Positive social and environmental performance effects associated with board size, degree of independence, gender diversity, and CEO duality were also observed. In contrast to previous hypotheses, no relationship was identified between the frequency of board meetings and social and environmental performance.

Abstract. The daily vertical migrations of fish and other metazoans actively transport organic carbon from the ocean surface to depth, contributing to the biological carbon pump. We use an oxygen-constrained, game-theoretic food-web model to simulate diel vertical migrations and estimate near-global (global ocean minus coastal areas and high latitudes) carbon fluxes and sequestration by fish and zooplankton due to respiration, fecal pellets, and deadfalls. Our model provides estimates of the carbon export and sequestration potential for a range of pelagic functional groups, despite uncertain biomass estimates of some functional groups.While the export production of metazoans and fish is modest (∼20 % of global total), we estimate that their contribution to carbon sequestered by the biological pump (∼800 PgC) is conservatively more than 50 % of the estimated global total (∼1300 PgC) and that they have a significantly longer sequestration timescale (∼250 years) than previously reported for other components of the biological pump. Fish and multicellular zooplankton contribute about equally to this sequestered carbon pool. This essential ecosystem service could be at risk from both unregulated fishing on the high seas and ocean deoxygenation due to climate change.

Abstract Background Lymphoma is a common neoplasm in horses but is reported much less commonly in donkeys. In this case report, we describe the macroscopic, microscopic and immunohistochemical features of a multicentric lymphoma with intestinal and bone marrow involvement. Case presentation A geriatric female donkey with history of chronic lameness was found dead. Post-mortem examination revealed advanced emaciation, periodontal disease, left front foot laminitis and multiple, soft, white to yellow tan intestinal transmural masses, up to 12 cm in diameter. Cytology suggested a round cell intestinal neoplasm. The femur of the left hint limb was double the size of the normal contralateral, with suspected neoplastic infiltration and replacement of bone marrow and bone. Histologically we diagnosed a lymphoma in the intestine and left femur. Immunohistochemically, the neoplastic cells showed CD3 immunolabelling, supporting a diagnosis of a multicentric T-cell lymphoma. Conclusions To the authors’ knowledge, this is the first time multicentric lymphoma is diagnosed in donkeys. Further studies of the genetic background, clinical, laboratory, histopathologic, and immunohistochemical, as well as the pathogenesis of lymphoma, is needed to better understand the uniquely low frequency of this neoplasm in donkeys.

The purpose of this article is to analyse at the micro- and macroeconomic level the energy industry in Romania, evaluating the economic efficiency of the company Nuclearelectrica SA in the period 2018-2022. Starting from a macroeconomic perspective, analysing electricity prices at the level of the European Union and Romania, a substantial increase in prices was observed that household and nonhousehold consumers have fully felt since 2022, corroborated, on the other hand, with the profits obtained in general by companies in the industry, and in particular by Nuclearelectrica SA in the period 2018-2022. In order to evaluate the economic efficiency of a company, level and structure indicators and performance indicators were calculated and interpreted. The results of the study show that the economic efficiency of companies in this industry is high, facing the difficult legislation on environmental pollution and the rules imposed by the European Union on the creation of clean energy. This study provides an overview to investors and stakeholders, which is a basis for substantiating subsequent investment decisions.

This paper presents a detailed gross description of all anatomical elements of the humerus in the African green monkey and provides comparative and differential elements on monkey osteology. The osteometric investigation adds value to the gross morphological investigation, adjoining metric data to the gross descriptive data set. An in-depth investigation of the microstructural aspects of the humeral bone tissue is provided, with qualitative and quantitative details and potential for diagnostic applications. Of the gross morphological elements described, several unique features specific to this species include the humeral head shape that presents with distinctive low convexity and caudal placement, the shape of the intertubercular groove, the less developed greater tubercle, and the disposition of the rotator cuff muscle insertion. Furthermore, the overall cranio-lateral curvature of the bone shaft was found to have a distinctive 154–155 degree of angulation of the diaphysis, and the well-developed medial epicondyle was observed with its distinctive medio-caudal retroflexion. The histological investigation was more indicative of a typical non-primate organization of the bone tissue, with laminar vascular and avascular structures combined with the presence of the secondary Haversian system involving a mixture of scattered and dense unorganized secondary osteonal structures. The histomorphometric investigation yielded metrical data for the secondary osteonal structures in terms of area (20,331 ± 5105 µm2), perimeter, and vascular canal area (64,769 ± 257 µm2).

Production efficiency is used to determine the best conditions for manufacturing goods at the lowest possible unit cost. When achieved, production efficiency leads to increased revenues for the manufacturer, enhanced employee safety, and a satisfied customer base. Production efficiency not only measures the amount of resources that are needed for production but also considers the productivity levels and the state of the production lines. In this context, online anomaly detection (AD) is an important tool for maintaining the reliability of the production ecosystem. With advancements in artificial intelligence and the growing significance of identifying and mitigating anomalies across different fields, approaches based on artificial neural networks facilitate the recognition of intricate types of anomalies by taking into account both temporal and contextual attributes. In this paper, a lightweight framework based on the Echo State Network (ESN) model running at the edge is introduced for online AD. Compared to other AD methods, such as Long Short-Term Memory (LSTM), it achieves superior precision, accuracy, and recall metrics while reducing training time, CO2 emissions, and the need for high computational resources. The preliminary evaluation of the proposed solution was conducted using a low-resource computing device at the edge of the real production machine through an Industrial Internet of Things (IIoT) smart meter module. The machine used to test the proposed solution was provided by the Italian company SIFIM Srl, which manufactures filter mats for industrial kitchens. Experimental results demonstrate the feasibility of developing an AD method that achieves high accuracy, with the ESN-based framework reaching 85% compared to 80.88% for the LSTM-based model. Furthermore, this method requires minimal hardware resources, with a training time of 9.5 s compared to 2.100 s for the other model.

Optimizing energy consumption is an important aspect of industrial competitiveness, as it directly impacts operational efficiency, cost reduction, and sustainability goals. In this context, anomaly detection (AD) becomes a valuable methodology, as it supports maintenance activities in the manufacturing sector, allowing for early intervention to prevent energy waste and maintain optimal performance. Here, an AD-based method is proposed and studied to support energy-saving predictive maintenance of production lines using time series acquired directly from the field. This paper proposes a deep echo state network (DeepESN)-based method for anomaly detection by analyzing energy consumption data sets from production lines. Compared with traditional prediction methods, such as recurrent neural networks with long short-term memory (LSTM), although both models show similar time series trends, the DeepESN-based method studied here appears to have some advantages, such as timelier error detection and higher prediction accuracy. In addition, the DeepESN-based method has been shown to be more accurate in predicting the occurrence of failure. The proposed solution has been extensively tested in a real-world pilot case consisting of an automated metal filter production line equipped with industrial smart meters to acquire energy data during production phases; the time series, composed of 88 variables associated with energy parameters, was then processed using the techniques introduced earlier. The results show that our method enables earlier error detection and achieves higher prediction accuracy when running on an edge device.

NAD+-dependent deacetylase sirtuin-1 (Sirt1) belongs to the sirtuins family, known to be longevity regulators, and exerts a key role in the prevention of vascular aging. By aging, the expression levels of Sirt1 decline with a severe impact on vascular function, such as the rise of endothelial dysfunction, which in turn promotes the development of cardiovascular diseases. In this context, the impact of Sirt1 activity in preventing endothelial senescence is particularly important. Given the key role of Sirt1 in counteracting endothelial senescence, great efforts have been made to deepen the knowledge about the intricate cross-talks and interactions of Sirt1 with other molecules, in order to set up possible strategies to boost Sirt1 activity to prevent or treat vascular aging. The aim of this review is to provide a proper background on the regulation and function of Sirt1 in the vascular endothelium and to discuss the recent advances regarding the therapeutic strategies of targeting Sirt1 to counteract vascular aging.