Natural products as a source of Coronavirus entry inhibitors.

The COVID-19 pandemic has had a significant and lasting impact on the world. Four years on, despite the existence of effective vaccines, the continuous emergence of new SARS-CoV-2 variants remains a challenge for long-term immunity. Additionally, there remain few purpose-built antivirals to protect individuals at risk of severe disease in the event of future coronavirus outbreaks. A promising mechanism of action for novel coronavirus antivirals is the inhibition of viral entry. To facilitate entry, the coronavirus spike glycoprotein interacts with angiotensin converting enzyme 2 (ACE2) on respiratory epithelial cells. Blocking this interaction and consequently viral replication may be an effective strategy for treating infection, however further research is needed to better characterize candidate molecules with antiviral activity before progressing to animal studies and clinical trials. In general, antiviral drugs are developed from purely synthetic compounds or synthetic derivatives of natural products such as plant secondary metabolites. While the former is often favored due to the higher specificity afforded by rational drug design, natural products offer several unique advantages that make them worthy of further study including diverse bioactivity and the ability to work synergistically with other drugs. Accordingly, there has recently been a renewed interest in natural product-derived antivirals in the wake of the COVID-19 pandemic. This review provides a summary of recent research into coronavirus entry inhibitors, with a focus on natural compounds derived from plants, honey, and marine sponges.

The causal impacts of empty stadiums on women's sports activities: Evidence from European football leagues.

This paper examines the effect of spectators on women's football games. COVID-19 and related restrictions provide a unique opportunity with an adequate sample size to test the effect of lockdown on sports activities. Studies have recently exploited this opportunity for men's football to better understand the potential causes of home advantage and, more specifically, assess the psychological consequences when matches are played without supporters. Despite the increased scientific interest, there was only one paper that focused on women's football. Therefore, we aim to contribute to this research field by considering matches from four major European women's football leagues. The findings suggest that for three of these leagues, lockdown has a statistically significant effect on the sanctioned yellow cards by either reducing the number of yellow cards sanctioned to the away teams or increasing the number of yellow cards sanctioned to the home teams. Nonetheless, lockdown does not affect any final match outcomes; therefore, it does not significantly affect the magnitude of home advantage for women's games.

Ultrasonographic Appearance of Gallbladder Neoplasia in 14 Dogs and 1 Cat.

Ultrasonography is the most commonly used diagnostic imaging tool for gallbladder disease in veterinary medicine. Primary gallbladder neoplasia is an uncommon finding with variable prognosis for which no studies have been published describing their ultrasonographic appearance and diagnosis. This retrospective, multicenter, case series study examines the ultrasonographic appearance of gallbladder neoplasia with histologically or cytologically confirmed diagnoses. A total of 14 dogs and 1 cat were analyzed. All discrete masses were sessile in shape and varied in size, echogenicity, location, and gallbladder wall thickening. All studies with images showing Doppler interrogation exhibited vascularity. Cholecystoliths were an uncommon finding, being present in only one case in this study, unlike in humans. The final diagnosis of the gallbladder neoplasia was neuroendocrine carcinoma (8), leiomyoma (3), lymphoma (1), gastrointestinal stromal tumor (1), extrahepatic cholangiocellular carcinoma (1), and adenoma (1). Findings from this study indicate that primary gallbladder neoplasms have variable sonographic appearances and cytologic and histologic diagnoses.

Distributed Thermal Monitoring of High-Voltage Power Lines.

The purpose of this paper is to present the sensor placement strategies that currently determine the thermal monitoring of the phase conductors of high-voltage power lines. In addition to reviewing the international literature, a new sensor placement concept is presented based on a strategy centered on the following question: What are the chances of thermal overload if devices are only placed in certain tension sections? In this new concept, the number and installation location of the sensors are determined in three steps, and a new type of tension-section-ranking constant is introduced that is universal in space and time. The simulations based on this new concept show that the data-sampling frequency and the type of thermal constraint influence the number of sensors. The paper's main finding is that there are cases when only a distributed sensor placement strategy can result in safe and reliable operation. However, due to requiring a large number of sensors, this solution means additional expenses. In the last section, the paper presents different possibilities to reduce costs and introduces the concept of low-cost sensor applications. These devices can result in more flexible network operation and more reliable systems in the future.

Interlaboratory Study to Evaluate a Testing Protocol for the Safety of Food Packaging Coatings.

According to European regulations, migration from food packaging must be safe. However, currently, there is no consensus on how to evaluate its safety, especially for non-intentionally added substances (NIAS). The intensive and laborious approach, involving identification and then quantification of all migrating substances followed by a toxicological evaluation, is not practical or feasible. In alignment with the International Life Sciences Institute (ILSI) and the European Union (EU) guidelines on packaging materials, efforts are focused on combining data from analytics, bioassays and in silico toxicology approaches for the risk assessment of packaging materials. Advancement of non-targeted screening approaches using both analytical methods and in vitro bioassays is key. A protocol was developed for the chemical and biological screening of migrants from coated metal packaging materials. This protocol includes guidance on sample preparation, migrant simulation, chemical analysis using liquid chromatography (LC-MS) and validated bioassays covering endocrine activity, genotoxicity and metabolism-related targets. An inter-laboratory study was set-up to evaluate the consistency in biological activity and analytical results generated between three independent laboratories applying the developed protocol and guidance. Coated packaging metal panels were used in this case study. In general, the inter-laboratory chemical analysis and bioassay results displayed acceptable consistency between laboratories, but technical differences led to different data interpretations (e.g., cytotoxicity, cell passages, chemical analysis). The study observations with the greatest impact on the quality of the data and ultimately resulting in discrepancies in the results are given and suggestions for improvement of the protocol are made (e.g., sample preparation, chemical analysis approaches). Finally, there was agreement on the need for an aligned protocol to be utilized by qualified laboratories for chemical and biological analyses, following best practices and guidance for packaging safety assessment of intentionally added substances (IAS) and NIAS to avoid inconsistency in data and the final interpretation.

Demonstration of a Transportable Fabry-Pérot Refractometer by a Ring-Type Comparison of Dead-Weight Pressure Balances at Four European National Metrology Institutes.

Fabry-Pérot-based refractometry has demonstrated the ability to assess gas pressure with high accuracy and has been prophesized to be able to realize the SI unit for pressure, the pascal, based on quantum calculations of the molar polarizabilities of gases. So far, the technology has mostly been limited to well-controlled laboratories. However, recently, an easy-to-use transportable refractometer has been constructed. Although its performance has previously been assessed under well-controlled laboratory conditions, to assess its ability to serve as an actually transportable system, a ring-type comparison addressing various well-characterized pressure balances in the 10-90 kPa range at several European national metrology institutes is presented in this work. It was found that the transportable refractometer is capable of being transported and swiftly set up to be operational with retained performance in a variety of environments. The system could also verify that the pressure balances used within the ring-type comparison agree with each other. These results constitute an important step toward broadening the application areas of FP-based refractometry technology and bringing it within reach of various types of stakeholders, not least within industry.

Current status and future directions for a neurotoxicity hazard assessment framework that integrates in silico approaches.

Neurotoxicology is the study of adverse effects on the structure or function of the developing or mature adult nervous system following exposure to chemical, biological, or physical agents. The development of more informative alternative methods to assess developmental (DNT) and adult (NT) neurotoxicity induced by xenobiotics is critically needed. The use of such alternative methods including in silico approaches that predict DNT or NT from chemical structure (e.g., statistical-based and expert rule-based systems) is ideally based on a comprehensive understanding of the relevant biological mechanisms. This paper discusses known mechanisms alongside the current state of the art in DNT/NT testing. In silico approaches available today that support the assessment of neurotoxicity based on knowledge of chemical structure are reviewed, and a conceptual framework for the integration of in silico methods with experimental information is presented. Establishing this framework is essential for the development of protocols, namely standardized approaches, to ensure that assessments of NT and DNT based on chemical structures are generated in a transparent, consistent, and defendable manner.

What Is Your Diagnosis?

In collaboration with the American College of Veterinary Radiology.

Principles and Procedures for Assessment of Acute Toxicity Incorporating In Silico Methods.

Acute toxicity in silico models are being used to support an increasing number of application areas including (1) product research and development, (2) product approval and registration as well as (3) the transport, storage and handling of chemicals. The adoption of such models is being hindered, in part, because of a lack of guidance describing how to perform and document an in silico analysis. To address this issue, a framework for an acute toxicity hazard assessment is proposed. This framework combines results from different sources including in silico methods and in vitro or in vivo experiments. In silico methods that can assist the prediction of in vivo outcomes (i.e., LD50) are analyzed concluding that predictions obtained using in silico approaches are now well-suited for reliably supporting assessment of LD50-based acute toxicity for the purpose of GHS classification. A general overview is provided of the endpoints from in vitro studies commonly evaluated for predicting acute toxicity (e.g., cytotoxicity/cytolethality as well as assays targeting specific mechanisms). The increased understanding of pathways and key triggering mechanisms underlying toxicity and the increased availability of in vitro data allow for a shift away from assessments solely based on endpoints such as LD50, to mechanism-based endpoints that can be accurately assessed in vitro or by using in silico prediction models. This paper also highlights the importance of an expert review of all available information using weight-of-evidence considerations and illustrates, using a series of diverse practical use cases, how in silico approaches support the assessment of acute toxicity.

SEVTAR-A multicenter randomized controlled trial to investigate the impact of prophylactic endoluminal placed vacuum sponge for prevention of anastomotic leakage after low rectal resections.

Background: Low anterior resection for rectal cancer is commonly associated with a diverting stoma. In general, the stoma is closed 3 months after the initial operation. The diverting stoma reduces the rate of anastomotic leakage as well as the severeness of a potential leakage itself. Nevertheless, anastomotic leakage is still a life-threatening complication and might reduce the quality of life in the short and long term. In case of leakage, the construction can be converted into a Hartmann situation or it could be treated by endoscopic vacuum therapy or by leaving the drains. In recent years, endoscopic vacuum therapy has become the treatment of choice in many institutions. In this study, the hypothesis is to be evaluated, if a prophylactic endoscopic vacuum therapy reduces the rate of anastomotic leakage after rectal resections. Methods: A multicenter parallel group randomized controlled trial is planned in as many as possible centers in Europe. The study aims to recruit 362 analyzable patients with a resection of the rectum combined with a diverting ileostoma. The anastomosis has to be between 2 and 8 cm off the anal verge. Half of these patients receive a sponge for 5 days, and the control group is treated as usual in the participating hospitals. There will be a check for anastomotic leakage after 30 days. Primary end point is the rate of anastomotic leakages. The study will have 60% power to detect a difference of 10%, at a one-sided alpha significance level of 5%, assuming an anastomosis leakage rate of 10%-15%. Discussion: If the hypothesis proves to be true, anastomosis leakage could be reduced significantly by placing a vacuum sponge over the anastomosis for 5 days. Trial registration: The trial is registered at DRKS: DRKS00023436. It has been accredited by Onkocert of the German Society of Cancer: ST-D483. The leading Ethics Committee is the Ethics Committee of Rostock University with the registration ID A 2019-0203.

Prognostic value of sternal lymphadenopathy on malignancy and survival in dogs undergoing splenectomy.

The purpose of this retrospective cohort study was to determine prevalence of sternal lymphadenopathy in a population of dogs undergoing splenectomy, and to evaluate if the prevalence was associated with splenic malignancy. In addition, the study investigated if survival in dogs diagnosed with hemangiosarcoma (HSA) differed between those with or without sternal lymphadenopathy at the time of surgery. Digital radiographs and medical records for dogs who underwent splenectomy from 2013 to 2016 where retrospectively reviewed. One hundred ninety-five dogs underwent splenectomy during the study period. The overall prevalence of sternal lymphadenopathy was 12.8%. The prevalence of sternal lymphadenopathy in dogs with hemangiosarcoma was 16.2% (12/74), other malignancy was 15.8% (3/19), and with a benign process 9.8% (10/102). There was no significant association between sternal lymphadenopathy with hemoperitoneum (p = .20) or between sternal lymphadenopathy and presence of neoplasia (p = .37). There was no significant difference in survival probability in all dogs with or without sternal lymphadenopathy (p = .073). However, sternal lymphadenopathy was associated with lower survival in 74 dogs with HSA (p = .036) and 19 with other splenic malignancies (p = .039). The presence of sternal lymphadenopathy should not be considered a negative prognostic indicator if present in dogs presenting with a hemoperitoneum. Although the presence of sternal lymphadenopathy at the time of initial presentation was not significantly associated with survival time in all dogs with splenic disease, it may have predictive value related to survival of dogs with splenic malignancy.

In silico approaches in organ toxicity hazard assessment: Current status and future needs for predicting heart, kidney and lung toxicities.

The kidneys, heart and lungs are vital organ systems evaluated as part of acute or chronic toxicity assessments. New methodologies are being developed to predict these adverse effects based on in vitro and in silico approaches. This paper reviews the current state of the art in predicting these organ toxicities. It outlines the biological basis, processes and endpoints for kidney toxicity, pulmonary toxicity, respiratory irritation and sensitization as well as functional and structural cardiac toxicities. The review also covers current experimental approaches, including off-target panels from secondary pharmacology batteries. Current in silico approaches for prediction of these effects and mechanisms are described as well as obstacles to the use of in silico methods. Ultimately, a commonly accepted protocol for performing such assessment would be a valuable resource to expand the use of such approaches across different regulatory and industrial applications. However, a number of factors impede their widespread deployment including a lack of a comprehensive mechanistic understanding, limited in vitro testing approaches and limited in vivo databases suitable for modeling, a limited understanding of how to incorporate absorption, distribution, metabolism, and excretion (ADME) considerations into the overall process, a lack of in silico models designed to predict a safe dose and an accepted framework for organizing the key characteristics of these organ toxicants.

In silico approaches in organ toxicity hazard assessment: current status and future needs in predicting liver toxicity.

Hepatotoxicity is one of the most frequently observed adverse effects resulting from exposure to a xenobiotic. For example, in pharmaceutical research and development it is one of the major reasons for drug withdrawals, clinical failures, and discontinuation of drug candidates. The development of faster and cheaper methods to assess hepatotoxicity that are both more sustainable and more informative is critically needed. The biological mechanisms and processes underpinning hepatotoxicity are summarized and experimental approaches to support the prediction of hepatotoxicity are described, including toxicokinetic considerations. The paper describes the increasingly important role of in silico approaches and highlights challenges to the adoption of these methods including the lack of a commonly agreed upon protocol for performing such an assessment and the need for in silico solutions that take dose into consideration. A proposed framework for the integration of in silico and experimental information is provided along with a case study describing how computational methods have been used to successfully respond to a regulatory question concerning non-genotoxic impurities in chemically synthesized pharmaceuticals.

Skin sensitization in silico protocol.

The assessment of skin sensitization has evolved over the past few years to include in vitro assessments of key events along the adverse outcome pathway and opportunistically capitalize on the strengths of in silico methods to support a weight of evidence assessment without conducting a test in animals. While in silico methods vary greatly in their purpose and format; there is a need to standardize the underlying principles on which such models are developed and to make transparent the implications for the uncertainty in the overall assessment. In this contribution, the relationship between skin sensitization relevant effects, mechanisms, and endpoints are built into a hazard assessment framework. Based on the relevance of the mechanisms and effects as well as the strengths and limitations of the experimental systems used to identify them, rules and principles are defined for deriving skin sensitization in silico assessments. Further, the assignments of reliability and confidence scores that reflect the overall strength of the assessment are discussed. This skin sensitization protocol supports the implementation and acceptance of in silico approaches for the prediction of skin sensitization.

Evaluation of Fluoroscopic-Guided Closed Reduction versus Open Reduction of Sacroiliac Fracture-Luxations Stabilized with a Lag Screw.

OBJECTIVE: The aim of this study was to compare radiographic outcomes of open reduction versus fluoroscopic-guided closed reduction (FGCR) of sacroiliac fracture-luxations stabilized with a lag screw, as well as peri- and postoperative complications. STUDY DESIGN: Medical records (2010-2015) and radiographs of dogs and cats diagnosed with sacroiliac fracture-luxation that underwent open reduction without fluoroscopic guidance (n = 24) or FGCR (n = 17) were retrospectively reviewed to assess sacroiliac fracture-luxation reduction and lag screw placement, and lag screw loosening on follow-up radiographs (range, 1-8 weeks postoperatively) when available. Peri- and postoperative complications were also recorded. RESULTS: Optimal screw depth to sacral body width ratio (>60%) was achieved in a significantly higher proportion of FGCR cases than openly reduced fracture-luxations. A significantly lower rate of lag screw loosening was found for FGCR cases. Few peri- and postoperative complications were noted across both groups. Four out of 17 FGCR cases requiring conversion to an open approach were excluded from data analysis; they had a longer duration from trauma to surgical repair than the median duration from trauma to surgical repair for cases successfully reduced in closed fashion. CONCLUSION: Fluoroscopic-guided closed reduction of sacroiliac fracture-luxations leads to consistently more optimal screw placement, as well as a lower incidence of lag screw loosening on follow-up radiographs. However, for cases with a longer duration from trauma to surgical repair, one should be prepared to convert to an open approach if a closed approach is not amenable to adequate reduction and lag screw placement.

Engineered photoproteins that give rise to photosynthetically-incompetent bacteria are effective as photovoltaic materials for biohybrid photoelectrochemical cells.

Reaction centre/light harvesting proteins such as the RCLH1X complex from Rhodobacter sphaeroides carry out highly quantum-efficient conversion of solar energy through ultrafast energy transfer and charge separation, and these pigment-proteins have been incorporated into biohybrid photoelectrochemical cells for a variety of applications. In this work we demonstrate that, despite not being able to support normal photosynthetic growth of Rhodobacter sphaeroides, an engineered variant of this RCLH1X complex lacking the PufX protein and with an enlarged light harvesting antenna is unimpaired in its capacity for photocurrent generation in two types of bio-photoelectrochemical cells. Removal of PufX also did not impair the ability of the RCLH1 complex to act as an acceptor of energy from synthetic light harvesting quantum dots. Unexpectedly, the removal of PufX led to a marked improvement in the overall stability of the RCLH1 complex under heat stress. We conclude that PufX-deficient RCLH1 complexes are fully functional in solar energy conversion in a device setting and that their enhanced structural stability could make them a preferred choice over their native PufX-containing counterpart. Our findings on the competence of RCLH1 complexes for light energy conversion in vitro are discussed with reference to the reason why these PufX-deficient proteins are not capable of light energy conversion in vivo.

Real option valuation of a decremental regulation service provided by electricity storage.

This paper is a quantitative study of a reserve contract for real-time balancing of a power system. Under this contract, the owner of a storage device, such as a battery, helps smooth fluctuations in electricity demand and supply by using the device to increase electricity consumption. The battery owner must be able to provide immediate physical cover, and should therefore have sufficient storage available in the battery before entering the contract. Accordingly, the following problem can be formulated for the battery owner: determine the optimal time to enter the contract and, if necessary, the optimal time to discharge electricity before entering the contract. This problem is formulated as one of optimal stopping, and is solved explicitly in terms of the model parameters and instantaneous values of the power system imbalance. The optimal operational strategies thus obtained ensure that the battery owner has positive expected economic profit from the contract. Furthermore, they provide explicit conditions under which the optimal discharge time is consistent with the overall objective of power system balancing. This paper also carries out a preliminary investigation of the 'lifetime value' aggregated from an infinite sequence of these balancing reserve contracts. This lifetime value, which can be viewed as a single project valuation of the battery, is shown to be positive and bounded. Therefore, in the long run such reserve contracts can be beneficial to commercial operators of electricity storage, while reducing some of the financial and operational risks in power system balancing.This article is part of the themed issue 'Energy management: flexibility, risk and optimization'.

COMPUTED TOMOGRAPHIC FINDINGS IN 24 DOGS WITH LIPOSARCOMA.

Computed tomography (CT) continues to become more widely available for assessment of tumors in dogs, yet there are no studies describing the CT appearance of canine liposarcomas. In this retrospective, multicenter study, CT images of dogs with histologically confirmed liposarcomas were reviewed for size, location, attenuation, contrast enhancement, border definition, internal homogeneity, local infiltration, and mineralization. A total of 24 dogs with 26 liposarcomas were sampled. Mean attenuation was +15.2 (SD = 22.3) Hounsfield units (HU) with a range of -36 to +47.5 HU based on representative regions of interest. Twenty tumors (77%) contained focal areas of fat attenuation. All masses enhanced with contrast medium administration, which is distinct from what has been reported previously in infiltrative lipomas. Other CT features associated with canine liposarcomas included heterogeneous internal attenuation (81%) and lack of a clearly defined capsule (38%) suggesting infiltration of local structures. Six tumors (23%) had foci of mineralization. Findings from the current study indicated that liposarcoma should be considered as a differential diagnosis for mixed-attenuation, contrast-enhancing masses in dogs that contain at least one focus of fat attenuation on precontrast images; however, presence of foci of fat attenuation was not a necessary finding for the diagnosis of canine liposarcoma.