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Objective The aim of this study was to evaluate oncological outcome for patients with and without anastomotic leakage after colon or rectal cancer surgery. Summary of background data The role of anastomotic leakage in oncological outcome after colorectal cancer surgery is still topic of debate and impact on follow-up and consideration for further treatment remains unclear. Methods Patients included in the international, multicenter, non-inferior, open label, randomized, controlled trials COLOR and COLOR II, comparing laparoscopic surgery for curable colon (COLOR) and rectal (COLOR II) cancer with open surgery, were analyzed. Patients operated by abdominoperineal excision were excluded. Both univariate and multivariate analyses were performed to investigate the impact of leakage on overall survival, disease-free survival, local and distant recurrences, adjusted for possible confounders. Primary endpoints in the COLOR and COLOR II trial were disease-free survival and local recurrence at 3-year follow-up, respectively, and secondary endpoints included anastomotic leakage rate. Results For colon cancer, anastomotic leakage was not associated with increased percentage of local recurrence or decreased disease-free-survival. For rectal cancer, an increase of local recurrences (13.3% vs 4.6%; hazard ratio 2.96; 95% confidence interval 1.38-6.34; P = 0.005) and a decrease of disease-free survival (53.6% vs 70.9%; hazard ratio 1.67; 95% confidence interval 1.16-2.41; P = 0.006) at 5-year follow-up were found in patients with anastomotic leakage. Conclusion Short-term morbidity, mortality, and long-term oncological outcomes are negatively influenced by the occurrence of anastomotic leakage after rectal cancer surgery. For colon cancer, no significant effect was observed; however, due to low power, no conclusions on the influence of anastomotic leakage on outcomes after colon surgery could be reached. Clinical awareness of increased risk of local recurrence after anastomotic leakage throughout the follow-up is mandatory. Trial registration Registered with ClinicalTrials.gov, number NCT00387842 and NCT00297791.

Many disorders affect the equine foot, and many hoof problems have multiple predisposing causes. Surgery may be necessary after conservative management has failed. Diseases of the hoof capsule may seem simple, but their effect on performance can be long-lasting and healing is often prolonged. Diagnosis of problems within the hoof capsule is enhanced with the use of computed tomography and MRI. The prognosis of fractures has improved with strategic placement of lag screws across fracture planes using aiming devices and advanced intraoperative imaging techniques. Collaboration between the clinician and a skilled farrier is important for successful management of hoof disorders.

Artificial Intelligence (AI) has rapidly developed over the past several decades. Several related AI approaches, such as Machine Learning (ML), have been applied to research on landscape patterns and ecological processes. Our goal was to review the methods of AI, particularly ML, used in studies related to landscape ecology and the main topics addressed. We aimed to assess the trend in the number of ML papers and the methods used therein, and provide a synopsis and prospectus of current use and future applications of ML in landscape ecology. We conducted a systematic literature search and selected 125 papers for review. These were examined and scored according to multiple criteria regarding methods and topic. We applied quantitative statistical methods, including cluster analysis based on titles, abstracts, and keywords and a non-metric multidimensional scaling based on attributes assigned during the review. We used Random Forests machine learning to describe the differences between identified clusters in terms of the topics and methods they included. The most frequent method found was Random Forests, but it is noteworthy to mention the increasing popularity of tools related to Deep Learning. The topics cover both ecologically oriented issues and the landscape-human interface. There has been a rapid increase in ML and AI methods in landscape ecology research, with Deep Learning and complex multi-step pipeline AI methods emerging in the last several years. The rapid increase in the number of ML papers in landscape ecology research, and the range of methods employed in them, suggest explosive growth in application of these methods in landscape ecology. The increase of Deep Learning approaches in the most recent years suggest a major change in analytical paradigms and methodologies that we feel may transform the field and enable analyses of more complex pattern process relationships across vaster data sets than has been possible previously.

Background Even when palliative care is an integrated part of the healthcare system, the quality is still substandard for many patients and often initiated too late. There is a lack of structured guidelines for identifying and caring for patients; in particular for those with early palliative care needs. A care guide can act as a compass for best practice and support the care of patients throughout their palliative trajectory. Such a guide should both meet the needs of health care professionals and patients and families, facilitating discussion around end-of-life decision-making and enabling them to plan for the remaining time in life. The aim of this article is to describe the development and pilot testing of a novel Swedish palliative care guide. Methods The Swedish Palliative Care Guide (S-PCG) was developed according to the Medical Research Council framework and based on national and international guidelines for good palliative care. An interdisciplinary national advisory committee of over 90 health care professionals together with patient, family and public representatives were engaged in the process. The feasibility was tested in three pilot studies in different care settings. Results After extensive multi-unit and interprofessional testing and evaluation, the S-PCG contains three parts that can be used independently to identify, assess, address, follow up, and document the individual symptoms and care-needs throughout the whole palliative care trajectory. The S-PCG can provide a comprehensive overview and shared understanding of the patients’ needs and possibilities for ensuring optimal quality of life, the family included. Conclusions Based on broad professional cooperation, patients and family participation and clinical testing, the S-PCG provides unique interprofessional guidance for assessment and holistic care of patients with palliative care needs, promotes support to the family, and when properly used supports high-quality personalised palliative care throughout the palliative trajectory. Future steps for the S-PCG, entails scientific evaluation of the clinical impact and effect of S-PCG in different care settings – including implementation, patient and family outcomes, and experiences of patient, family and personnel.

Background Despite being a common overuse entity in youth soccer, scientific data on risk factors, rehabilitation and return to play for long-standing pubic-related groin pain is still rare. The current prospective cohort study aims to evaluate potential risk-factors, propose a criteria-based conservative rehabilitation protocol and assess return-to-play outcomes among professional youth soccer players suffering from long-standing pubic-related groin pain. Methods Male soccer players with long-standing (> 6 weeks) pubic-related groin pain from a professional soccer club’s youth academy were analyzed for possible risk factors such as age, team (U12 - U23), younger/older age group within the team, position and preinjury Functional movement score. All injured players received a conservative, standardized, supervised, criteria-based, 6-level rehabilitation program. Outcome measures included time to return to play, recurrent groin pain in the follow-up period and clinical results at final follow-up two years after their return to play. Results A total of 14 out of 189 players developed long-standing pubic-related groin pain in the 2017/2018 season (incidence 7.4%). The average age of the players at the time of the injury was 16.1 ± 1.9 years. Risk factor analysis revealed a significant influence of the age group within the team (p = .007). Only players in the younger age group were affected by long-standing pubic-related groin pain, mainly in the first part of the season. Injured players successfully returned to play after an average period of 135.3 ± 83.9 days. Only one player experienced a recurrence of nonspecific symptoms (7.1%) within the follow-up period. The outcome at the 24-month follow-up was excellent for all 14 players. Conclusions Long-standing pubic-related groin pain is an overuse entity with a markedly high prevalence in youth soccer players, resulting in a relevant loss of time in training and match play. In particular, the youngest players in each team are at an elevated risk. Applying a criteria-based rehabilitation protocol resulted in an excellent return-to-play rate, with a very low probability of recurrence. Trial registration The trial was retrospectively registered under DRKS00016510 in the German Clinical Trials Register on 19.04.2021.

Objective: The purpose of the study was to examine associations between self-esteem and symptoms of anxiety and depression among young adults who lost a parent to cancer. Methods: Older adolescents and young adults, aged 16 to 28 years, who had lost their parent to cancer and had accepted an invitation to join a support group, completed a questionnaire 5 to 8 months after the loss and a similar questionnaire about 10 months later (follow-up). Of a total of 77 young adults who participated in the study, 56 completed both questionnaires. Self-esteem was measured with the Rosenberg Self-Esteem Scale. Symptoms of anxiety and depression were measured with the Hospital Anxiety and Depression Scale. Univariate and multiple linear regression models were used to analyze the associations. Result: Self-esteem was significantly associated with symptoms of anxiety and depression at baseline and at follow-up. Conclusion: This study reveals that self-esteem is a valuable explanatory variable, and that it is associated with both symptoms of anxiety and depression in bereavement. This new knowledge could be used to guide future support to parentally bereaved young adults. This work was supported by the Erling Persson Family Foundation and the Clas Groschinsky's Memorial Fund.

Background Efficiency and transparency of pricing and reimbursement (P&R) rules and procedures as well as their implementation in South-eastern Europe (SEE) lag substantially behind Western European practice. Nevertheless, P&R systems in SEE are rarely critically assessed, warranting a detailed and wider-encompassing exploration. Objective Our study provides a comparative assessment of P&R processes for patent-protected medicines in ten SEE countries—EU member states: Croatia, Slovenia, Hungary, Romania and Bulgaria ; and non-EU countries: Albania, Montenegro, Serbia, North Maceodina, Bosnia and Herzegovina. P&R systems are compared and evaluated through a research framework that focuses on: (1) public financing of patent-protected medicines, (2) definition of benefit packages, (3) requirements for the submission of reimbursement dossiers, (4) assessment and appraisal processes, (5) reimbursement decision making, (6) processes that occur post reimbursement, and (7) pricing. The study aims to contribute to the discussion on improving the efficiency and quality of P&R of patent-protected medicines in the region. Methods We conducted a non-systematic literature review of published literature, as well as policy briefs and reports on healthcare systems in the SEE region along with legal documents framing the P&R procedures in local languages. The information gathered from these various sources was then discussed and clarified through structured telephone interviews with relevant national experts from each SEE country, mainly current and former senior officials and/or executives of the funding and assessment/ appraisal bodies (total of 20 interviews conducted in late 2019). Results Capacity building through sharing knowledge and information on successful reforms across borders is an opportunity for SEE countries to further develop their P&R policies and increase (equitable) access to patent-protected medicines (especially expensive medicines), increasing affordability and containing costs. Simple yet robust and systematic decision-making frameworks that rely on international health technology assessment (HTA) procedures and are based on the pursuit of transparency seem to be the most cost- effective approach to strengthening P&R systems in SEE. Conclusions Further reforms aiming to develop transparent and robust national decision-making frameworks (including oversight) and build institutional HTA- related and decision-making capacity are awaited in most of SEE countries, especially the non-EU members. In non-EU SEE countries, these efforts could increase access to patent-protected medicines, which is—at the moment —very limited. The EU-member SEE countries operate more developed P&R systems but could further benefit from developing their procedures, oversight and value- for-money assessment toolbox and capacity, hence further improving the transparency and efficiency of procedures that regulate access to patent- protected medicines.

Cultural ecosystem services (CES) in Southwestern Ghana evoke a strong sense of attachment of local land users to the landscape. Hence, their supply is necessary for a balanced socio-ecological system. This study explored the potential supply of cultural ecosystem services (science/education, spiritual, tourism, health and recreation benefits) under different land use planning (LUP) scenarios in Southwestern Ghana. Future LUP scenarios were developed and articulated with a diverse group of land-use planning actors (LUPAs) such as regional land use planners, environmental experts, researchers, farmers and landowners. The scenarios covered business-as-usual, mangrove ecosystem restoration, market-driven growth, and the establishment of an “eco-corridor” as green network. A spatially explicit modeling platform, GISCAME, which combines Geographic Information System and Cellular Automaton modules and multicriteria evaluation was used to evaluate the developed scenarios. Outcomes of the study revealed that in the coastal landscape of Southwestern Ghana, values, perceptions and preferences of LUPAs underpin socio-ecological interactions aimed at maintaining and enhancing CES supply. In addition, it indicated that future supply of CES is characterized by an interplay between multiple and diverse perspectives about plausible land-use futures. Perceptions of, and preferences for, CES align with land-use visions related to afforestation, infrastructure development, agriculture expansion and tourism. In the study area and similar contexts where an array and diversity of individual and societal values exist, effective negotiation and facilitation are essential for harnessing and optimizing land-use planning for CES supply.

Objective The aim of this study was to evaluate the effect of reducing the bone to cast distance on the resistance of the pin to cyclic loading in equine transfixation pin casts. Study Design Eleven pairs of cadaveric equine third metacarpal bones were prepared and one 6.3/8.0 mm transfixation pin was placed in standard fashion 10 mm proximal to the distal physeal scar into each bone. One metacarpus of each pair was tested with a distance of 10 mm (10 mm group) and the contralateral metacarpus with a distance of 20 mm (20 mm group) between the outer cortex of the bone and the fixation of the pin. Eight pairs were tested using a simplified test set-up in which the pins were fastened at both ends to polyoxymethylene-copolymer sleeves. The pins of the remaining three pairs of bones were incorporated into a fibreglass cast. All specimens were tested under cyclic loading until failure of the pin in axial compression. Results All pins failed uni- or bilaterally at clinically relevant load levels. Pins of the 10 mm group endured significantly (p Conclusion The distance between the bone surface and the cast at the location of pin insertion has a significant effect on resistance of the pins to cyclic loading. Therefore, the amount of padding applied underneath an equine transfixation pin cast can have an influence on the overall stability and durability of the construct.

The theory-practice gap (TPG) is well known in the environmental realm, referring to disconnects between knowledge generated through scientific research and the needs, expectations, and practices of knowledge users for environmental decision-making and practice. While the presence of the TPG is well established, we have yet to fully implement mechanisms for overcoming its challenges. Thus, our goal is to characterize the TPG and identify practical recommendations for minimizing it. Here, a diverse group of experts in the environmental realm (spanning landscape planning, conservation science, environmental sociology, resource management, political science, and anthropology, among others) present our perspectives on the TPG. More specifically, we share an organized framework for understanding the TPG and suggest recommendations that can help make progress in one or more dimension(s). Conceptual topics discussed are the implications of the gap and its persistence. Organizational/institutional topics include the implications of the overabundance, inaccessibility, and uncertainty of scientific information, and a need for mainstreaming boundary spanning activities. Lastly, cultural topics include differences in culture and epistemologies across knowledge generators and users, shifting cultures through co-production, and changes in educational curricula. Recommendations for minimizing the TPG include conceptually recasting what is considered ‘success,’ institutional reform, enhanced information delivery, leveraging knowledge brokers and boundary organizations, leveraging ‘champions’ in policy, using co-production and/or integrative research, confronting the contemporary ‘fake news’ phenomenon, and rethinking researcher and practitioner training and development. By sharing our framework and recommendations, we provide insight, as well as a starting point for those looking to narrow the TPG and improve knowledge generator-user relationships.

Due to their compactness and power density, planetary gearboxes are used for a wide range of high-performance applications in the automotive, aviation and marine sector. Aerospace applications in particular benefit from a full use of the load capacity potential to meet the requirements for lightweight construction and efficiency. Against this background, the load sharing between the individual planetary gears plays a decisive role. A uniform load sharing enables the design of the single tooth meshes without load increases and oversizing. However, due to manufacturing and assembly deviations, a perfect load sharing is technically not feasible. These load increases are taken into account in the standard calculation of the load capacity of planetary gearboxes by the mesh load factor Kγ. The load sharing in planetary gearboxes is influenced by a number of factors, such as the rigidity of shafts, housing and bearings, the number of planets, the quality of the gear wheels and the operating conditions. Detailed simulations or extensive experimental measurements are required to determine the exact load sharing. For new designs of planetary gearboxes, there are only simplified assumptions available, based on the number of planets and a rough estimation of the operating range. Especially additional dynamic forces, due to operation in high-speed ranges or near resonance frequencies, can lead to a considerable change of the dynamic load sharing compared to the static load sharing and cause an uncertainty in the design. Thus, in this paper the dynamic load sharing behaviour is investigated from 0 to 6800 rpm sun speed for different loads. Based on the experimental data recommendations for the design of planetary gearboxes under consideration of the operating conditions are derived.

According to ASCO guidelines, cancer-directed treatment should be avoided in the last month of life. However, Mattsson et al. (this issue) demonstrate that 16% of Danish patients receive such treat...

Aim. Our aim was to examine the contribution of shear wave elastography to ultrasonographic assessment in diffuse thyroid disease, specifically to evaluate the stiffness of the thyroid gland in diffuse thyroid disease and compare it with healthy controls. Methods. A total of 46 patients with diffuse thyroid disease were examined clinically, by conventional ultrasound, and shear wave elastography. The conventional ultrasound parameters followed were: volume, margin quality, presence of nodules, and vascularisation. We measured the mean, minimum, and maximum stiffnesses by shear wave elastography. Results were correlated with values in 128 healthy subjects. Results. Patients with diffuse thyroid disease had significantly higher mean and maximal stiffnesses of the thyroid gland: 12.5 ± 5 kPa and 35.3 ± 12.8 kPa, respectively, and lower minimal stiffness: 0.5 ± 0.6 kPa than the healthy control group with mean, maximal, and minimal values of 9.5 ± 3.6 kPa, 22.5 ± 7.3 kPa, and 2.2 ± 2.1 kPa (P

BackgroundDespite the severe symptoms experienced by dying COPD patients, specialized palliative care (SPC) services focus mainly on cancer patients. We aimed to study the access to SPC that COPD and lung cancer (LC) patients receive and how that access affects the need for acute hospital care.MethodsA descriptive regional registry study using data acquired through VAL, the Stockholm Regional Council’s central data warehouse, which covers nearly all healthcare use in the county of Stockholm. All the patients who died of COPD or LC from 2015 to 2019 were included. T-tests, chi-2 tests, and univariable and multivariable logistic regression analyses were performed on the accumulated data.ResultsIn total, 6479 patients, (2917 with COPD and 3562 with LC) were studied. The patients with LC had more access to SPC during the last three months of life than did those with COPD (77% vs. 18%, respectively; p 2 = 287, p ConclusionsCompared to dying COPD patients, LC patients have more access to SPC. Access to SPC reduces the need for emergency room visits and admissions to acute hospitals.

The EFSA Panel on Food Additives and Flavourings (FAF) was requested to evaluate the safety of the substance 2‐hydroxy‐4‐methoxybenzaldehyde [FL‐no: 05.229] as a new flavouring substance, in accordance with Regulation (EC) No 1331/2008. 2‐Hydroxy‐4‐methoxybenzaldehyde belongs to chemical group 23 (Commission Regulation (EC) No 1565/2000) and is structurally related to the hydroxy‐ and alkoxy‐ring substituted benzyl derivatives evaluated in FGE.52 and in FGE.20Rev4. The Panel considered the structural/metabolic similarity sufficient to evaluate the candidate substance following a group‐based approach according to the EFSA Guidance on the data required for the risk assessment of flavourings to be used in or on foods. The information provided on the manufacturing process, the composition and the stability of [FL‐no: 05.229] was considered sufficient. From studies carried out with this substance, the Panel concluded that there is no concern with respect to genotoxicity. Based on QSAR evaluation of possible metabolism, and based on information from structurally related substances, various metabolic routes can be anticipated, which only result in the formation of innocuous metabolites. The exposure estimates for [FL‐no: 05.229] (24 and 60 μg/person per day for children and adults, respectively) were below the Threshold of Toxicological Concern (TTC) for its structural class (I). Accordingly, toxicity studies are not required and the Panel concluded at step A3 of the Procedure that 2‐hydroxy‐4‐methoxybenzaldehyde is not of safety concern when used as a flavouring substance at the intended uses and use levels. Cumulative exposure estimates for 2‐hydroxy‐4‐methoxybenzaldehyde and three structurally related substances (2.4 and 6.2 mg/kg body weight (bw) per day for adults and children, respectively) are above the TTC for structural class I, but below the ADI (acceptable daily intake) of 0‐10 mg/kg bw per day for vanillin, which is one of these structurally related substances. Therefore, the cumulative exposure to these four substances [FL‐no: 05.015, 05.018, 05.229 and 09.749] also does not raise a safety concern.

Mono- and diglycerides of fatty acids (E 471) was re-evaluated in 2017 by the former EFSA Panel on Food Additives and Nutrient sources added to Food (ANS). As a follow-up to this assessment, the Panel on Food Additives and Flavouring was requested to assess mono- and diglycerides of fatty acids (E 471) for its use as food additive in food for infants below 16 weeks of age belonging to food categories 13.1.1 (Infant formulae) and 13.1.5.1 (Dietary foods for infants for special medical purposes and special formulae for infants). In addition, the FAF Panel was requested to address the issues already identified during the re-evaluation of the food additive in 2017 when used in food for the general population. The Panel considered that there is no indication of adverse effects from the available animal studies at the highest dose tested and from the post marketing data. A comparison was made between the daily exposure to the sum of mono- and di-acylglycerols from breast milk and that resulting from the use of E 471 in the infant formula. The Panel noted that the resulting exposures are in the same order of magnitude. Overall, the Panel concluded that there is no reason for a safety concern when E 471 used as food additive in FC 13.1.1 and 13.1.5.1 and according to the Annex III to Regulation (EC) No 1333/2008. The risk assessment for toxic elements and impurities clearly indicated the need to lower the current maximum limits for arsenic, lead, cadmium and mercury and to include limits for glycidyl esters, 3-monochloropropane diol and erucic acid in the EU specifications of E 471. © 2021 European Food Safety Authority. EFSA Journal published by John Wiley and Sons Ltd on behalf of European Food Safety Authority

ZusammenfassungInterstitielle Lungenerkrankungen (ILD) sind eine heterogene Gruppe von Pathologien, die zunehmend als relevanter Faktor pulmonaler Morbidität und Mortalität erkannt werden. Verschiedene ILD wie die idiopathische Lungenfibrose (IPF), aber auch durch Autoimmunprozesse oder durch exogene Noxen bedingte ILD können zu progredienter, meist irreversibler Lungenfibrose führen. Die antifibrotischen Substanzen Nintedanib und Pirfenidon können den Krankheitsverlauf bei IPF-Patienten günstig beeinflussen. Dagegen werden ILD, die auf entzündlichen Prozessen wie z. B. rheumatologischen Grunderkrankungen oder exogen-allergischer Alveolitis beruhen, bis dato klassischerweise immunsuppressiv therapiert. Immer wieder kommt es aber trotz einer solchen Behandlung zu progredienter Fibrosierung. Eine positive Wirkung antifibrotischer Medikation auf progredient fibrosierende (pf)ILD abseits der IPF konnte in rezenten Studien demonstriert werden, auch wenn der Stellenwert der Antifibrotika in solchen Situationen noch nicht vollständig geklärt ist. Dieses Consensus-Statement beruht auf einem virtuellen, multidisziplinären Expertenmeeting von Rheumatologen, Pneumologen und Radiologen und wurde durch die jeweiligen ILD-Arbeitskreise der Österreichischen Gesellschaften für Pneumologie sowie Rheumatologie (ÖGP und ÖGR) akkordiert. Ziel war es, den aktuellen Stand von klinischer Praxis und wissenschaftlicher Datenlage zu Definition, Evaluation und Therapie von pfILD darzustellen. Zusammenfassend sollen ILD-Patienten einer standardisierten Abklärung unterzogen, in einem multidisziplinären ILD-Board diskutiert und dementsprechend therapiert werden. Kern dieser Empfehlungen ist, auch Non-IPF-Patienten mit dokumentiert progredient fibrosierendem ILD-Verlauf antifibrotisch zu behandeln, insbesondere wenn Honigwabenzysten oder eine bereits ausgedehnte Erkrankung vorliegen. Patienten mit fibrotischer ILD, die auf Basis der ILD-Board-Empfehlung primär keiner oder ausschließlich einer immunsuppressiven Therapie unterzogen werden, sollten engmaschig hinsichtlich eines progredienten Verlaufes überwacht werden.

One of the varied tasks of the Large Animal Rescue Service Switzerland and Liechtenstein (GTRD CH/FL)® is the recovery of animals from manure and cesspools. The aim of the present retrospective study was the evaluation of the rescue protocols of the GTRD CH/FL from such operations and the documentation of a rescue procedure. In the past 25 years, a total of 176 animals have been rescued from manure and cesspools. These included 113 cattle, 51 horses and 12 pigs. All animals could be safely rescued with the animal rescue and transport net (TBTN) or the large animal vertical rescue set (GTVBS). The TBTN is used when the opening of the cesspool is large enough to recover the animal in a horizontal position. The GTVBS is particularly suitable for narrow openings, as the recovery in a -vertical position does not require any constructional modification or the enlargement of the cesspool opening. Both rescue harnesses are characterized by reliable handling and allow gentle recovery.Eine der vielfältigen Aufgaben des Grosstier-Rettungsdienstes Schweiz und Liechtenstein (GTRD CH/FL)® ist die Bergung von Tieren aus Mist- und Jauchegruben. Ziel der vorliegenden retrospektiven Studie war die Auswertung der Bergungsprotokolle des GTRD CH/FL aus solchen Einsätzen und die Dokumentation eines Bergungsablaufs. In den vergangenen 25 Jahren sind insgesamt 176 Tiere aus Mist- und Jauchegruben geborgen worden. Darunter befanden sich 113 Rinder, 51 Pferde und 12 Schweine. Alle Tiere konnten sicher mit dem Tier- Bergungs- und Transportnetz (TBTN) oder dem Grosstier- Vertikalbergungsset (GTVBS) geborgen werden. Das TBTN wird eingesetzt, wenn die Öffnung der Jauchegrube gross genug ist, um das Tier in horizontaler Position zu bergen. Bei engen Öffnungen eignet sich das GTVBS vorzüglich, da durch die Bergung in vertikaler Position die Öffnungen der Gruben nicht mehr vergrössert oder durch andere bauliche Massnahmen verändert werden müssen. Beide Bergungsgeschirre zeichnen sich durch eine zuverlässige Handhabung aus und erlauben eine schonende Bergung.L’une des multiples tâches du Service de sauvetage des grands animaux de Suisse et du Liechtenstein (GTRD CH/FL)® est de sortir des animaux de fosses à fumier ou à lisier. Le but de la présente étude rétrospective était l’évaluation des protocoles de sauvetage du GTRD CH/FL sur la base de ces opérations et la documentation d’un processus de sauvetage. Au cours des 25 dernières années, 176 animaux au total ont été tirés de fosses à fumier ou à lisier. Il s’agissait de 113 bovins, 51 chevaux et 12 porcs. Tous les animaux ont pu être secourus en toute sécurité grâce au filet de sauvetage et de transport des animaux (TBTN) ou à l’équipement de sauvetage vertical pour grands animaux (GTVBS). Le TBTN est utilisé lorsque l’ouverture de la fosse à lisier est suffisamment grande pour récupérer l’animal en position horizontale. Le GTVBS est particulièrement adapté aux ouvertures étroites, car la récupération en position verticale permet de ne pas devoir ou modifier modifiées par d’autres mesures structurelles les ouvertures des fosses. Les deux harnais de sauvetage se caractérisent par une manipulation fiable et permettent une récupération en douceur.Uno degli svariati compiti del Servizio di salvataggio di grandi animali di Svizzera e Liechtenstein (GTRD CH/FL)® è il soccorso di animali intrappolati nelle fosse di letame e liquame. Lo scopo di questo studio retrospettivo era di valutare i protocolli di salvataggio del GTRD CH/FL per tali missioni e di documentarne la procedura di salvataggio. Negli ultimi 25 anni, un totale di 176 animali sono stati recuperati dalle fosse di letame e liquami. Tra questi salvataggi si trovavano 113 bovini, 51 cavalli e 12 suini. Tutti gli animali sono stati salvati con sicurezza utilizzando la rete di salvataggio e trasporto animali (TBTN) o il set di recupero verticale per grandi animali (GTVBS). L’imbracatura TBTN viene utilizzata quando l’apertura della fossa di liquame è abbastanza grande per poter recuperare l’animale in posizione orizzontale. In caso di aperture strette, il GTVBS è molto meglio, perché il salvataggio in posizione verticale significa che le aperture delle fosse non devono essere allargate o modificate con altre misure strutturali. Entrambe le imbracature di recupero sono contraddistinte per la loro maneggevolezza e affidabilità che permette un salvataggio in modo gentile dell’animale.

In this communication article, we share our scenario ideas at the request of the journal editor. These are (1) a scenario for building sustainable suburbs; (2) a counterfactual scenario for coping with the super wicked COVID problem; (3) envisioning alternative futures of cultural ecosystem services supplies in Southwestern Ghana; and (4) a path toward writing successful scenarios. The ideas will be fully developed in due course into scholarly articles for the journal.

Background There is only limited clinical data on the benefit of intense immunosuppression in patients with severe interstitial pneumonia associated with autoimmune features or new-onset connective tissue disease. Case presentation We here report a series of three consecutive patients suffering from severe interstitial lung disease necessitating endotracheal intubation and mechanical ventilation. The first two patients fulfilled many diagnostic criteria for new-onset antisynthetase syndrome, the third patient for systemic lupus erythematosus. We decided to implement aggressive immunosuppressive strategies in these critically-ill patients including therapeutic plasma exchange, immunoadsorption, cyclophosphamide and rituximab. All three patients improved from respiratory failure, were successfully weaned from the respirator, and eventually dismissed from hospital with ongoing immunosuppressive therapy. Conclusion Patients suffering from severe connective tissue disease-associated interstitial lung disease and respiratory failure may benefit from an aggressive immunosuppressive regimen and extracorporeal blood purification with rapid reduction of circulating autoantibodies. The impressive clinical responses in this small case series warrant a controlled clinical trial.

Craniofacial sutures are fibrous connections between the flat bones in the skull, allowing a small amount of movement to absorb strain and load as long as they are patent. In the present study, we examined the histological appearance of facial suture lines in horses of different ages. The internasal, nasofrontal and maxillolacrimal sutures were macroscopically identified and extracted from the skulls of six horses aged 1 day (two horses), 5 days, 2, 6 and 9 years and prepared into histological samples. The suture lines were then examined for width, form, cell density and morphology, vascularisation and morphology of the surrounding tissue and compared based on the age of the horse. Although macroscopically the sutures became difficult to identify in the 6‐ and 9‐year‐old horses, histologically they were clearly visible in all samples, indicating that the sutures were patent and consisted of connective tissue in all analysed horses. The sutures became subjectively narrower with lower cell density in older horses as compared to young horses, and there was a noticeable maturation from woven to cancellous bone surrounding the sutures. Vascular structures were present in all sutures regardless of age or location. In conclusion, this study raises awareness of the histological suture conformation in neonatal and adult horses and their persistence into adulthood. A better understanding of the histological structure of facial sutures and their continued patency into adulthood can aide in the interpretation of radiographs and computed tomography images of the head and in improving treatment methods and outcomes for horses affected with suture exostosis. In addition, if biopsies are taken, clinicians will have a basis on which to determine which cells are related to the disease process and which are normally occurring.

We estimated the financial costs of different interventions against urogenital schistosomiasis, implemented by the Zanzibar Elimination of Schistosomiasis Transmission (ZEST) project, on Pemba and Unguja islands, Tanzania. We used available data on project activities, resources used, and costs reported in the accounting information systems of ZEST partners. The costs were estimated for all the activities related to snail control, behavior change interventions, the impact assessment surveys, and management of the whole program. Costs are presented in US$ for the full duration of the ZEST project from 2011/2012 to 2017. The total financial costs of implementing snail control activities over 5 years, excluding the costs for donated Bayluscide, were US$55,796 on Pemba and US$73,581 on Unguja, mainly driven by personnel costs. The total financial costs of implementing behavior change activities were US$109,165 on Pemba and US$155,828 on Unguja, with costs for personnel accounting for 47% on Pemba and 69% on Unguja. Costs of implementing biannual mass drug administration refer to the estimated 2.4 million treatments provided on Pemba over 4 years (2013–2016), and do not include the costs of donated praziquantel. The total cost per provided treatment was, on average, US$0.21. This study showed the value of exploiting administrative data to estimate costs of major global health interventions. It also provides an evidence base for financial costs and main cost drivers of implementing multiple combinations of intervention sets that inform decisions regarding the feasibility and affordability of implementing schistosomiasis control and elimination strategies.

Introduction Most of the approximately 60 genes that if mutated cause steroid-resistant nephrotic syndrome (SRNS) are highly expressed in the glomerular podocyte, rendering SRNS a “podocytopathy.” Methods We performed whole-exome sequencing (WES) in 1200 nephrotic syndrome (NS) patients. Results We discovered homozygous truncating and homozygous missense mutation in SYNPO2 (synaptopodin-2) (p.Lys1124∗ and p.Ala1134Thr) in 2 patients with childhood-onset NS. We found SYNPO2 expression in both podocytes and mesangial cells; however, notably, immunofluorescence staining of adult human and rat kidney cryosections indicated that SYNPO2 is localized mainly in mesangial cells. Subcellular localization studies reveal that in these cells SYNPO2 partially co-localizes with α-actinin and filamin A−containing F-actin filaments. Upon transfection in mesangial cells or podocytes, EGFP-SYNPO2 co-localized with α-actinin-4, which gene is mutated in autosomal dominant SRNS in humans. SYNPO2 overexpression increases mesangial cell migration rate (MMR), whereas shRNA knockdown reduces MMR. Decreased MMR was rescued by transfection of wild-type mouse Synpo2 cDNA but only partially by cDNA representing mutations from the NS patients. The increased mesangial cell migration rate (MMR) by SYNPO2 overexpression was inhibited by ARP complex inhibitor CK666. SYNPO2 shRNA knockdown in podocytes decreased active Rac1, which was rescued by transfection of wild-type SYNPO2 cDNA but not by cDNA representing any of the 2 mutant variants. Conclusion We show that SYNPO2 variants may lead to Rac1-ARP3 dysregulation, and may play a role in the pathogenesis of nephrotic syndrome.

Background The COVID-19 pandemic has affected the entire health care system, internationally as well as in Sweden. We aimed to study excess deaths (all death causes, but also COVID-19-related deaths) during the COVID-19 pandemic regarding age, socio-economic status, the situation in nursing homes, and place of death for nursing home residents. Design We performed a descriptive regional registry data study using VAL, the Stockholm Regional Council’s central data warehouse, which covers almost all health care use in the county of Stockholm. T tests and chi-square tests were used for comparisons. Results Compared with 2016–2019, there were excess deaths in March–May 2020 (p

The purpose of this study was to investigate variations in psychosocial well-being over time among young adults who participated in a support group after the death of a parent from cancer. Fifty-five young adults, aged 16-28 years, completed questionnaires that measured self-esteem, anxiety, depression, and life satisfaction at three time-points during the first year-and-one-half after the loss. Results indicated overall poor psychosocial well-being with few increases in psychological health over the study period, despite access to support and social networks. However, these resources may help to prevent major impairments in the participants' future lives.

Introduction: Obsessive-compulsive disorder (OCD) is associated with high chronicity and treatment resistance, indicating the need for early therapy response markers enabling fast and personalized treatment adaptations. Although epigenetic mechanisms such as DNA methylation of the oxytocin receptor (OXTR) gene have previously been linked to OCD pathogenesis, epigenetic markers as predictors of treatment success have not yet been investigated in OCD. Objective: For the first time, this therapyepigenetic study aimed to investigate the role of OXTR methylation as a treatment response marker in OCD. Methods: In total, 113 inpatients with OCD (57 females) were compared to 113 age- and sex-matched healthy controls. Patients were investigated over a 10-week course of standardized, OCD-specific cognitive-behavioral psychotherapy. Clinical response was measured using the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) at baseline, before in vivo exposure, and after therapy. OXTR exon III methylation was analyzed via direct sequencing of sodium bisulfite-treated DNA extracted from blood cells. Results: Relative OXTR hypermethylation was observed in OCD patients compared to healthy controls. In OCD, higher baseline OXTR methylation was found to predict impaired treatment response at both categorical (responders vs. nonresponders) and dimensional (relative Y-BOCS reduction) levels, whereas lower baseline methylation was related to treatment response and greater symptom improvements. Analysis of Y-BOCS subdimensions revealed that the association between OXTR hypermethylation with impaired treatment response applied especially to symptoms related to obsessions, but not compulsions. Conclusions: OXTR hypermethylation may constitute a predictive marker of impaired treatment response in OCD and thus carries great potential for future personalized treatment efforts in OCD.

Background To evaluate a new procedure in daily clinical practice, it might not be sufficient to rely exclusively on the findings of randomized clinical trials (RCTs). This is the first systematic review providing a synthesis of the most important RCTs and relevant retrospective cohort studies on short- and long-term outcomes of laparoscopic surgery in colon cancer patients. Materials and methods In a literature search, more than 1800 relevant publications on the topic were identified. Relevant RCTs and representative high-quality retrospective studies were selected based on the widely accepted Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) criteria. Finally, 9 RCTs and 14 retrospective cohort studies were included. Results Laparoscopic surgery for colon cancer is associated with a slightly longer duration of surgery, but a variety of studies show an association with a lower rate of postoperative complications and a shorter duration of hospital stay. Particularly in older patients with more frequent comorbidities, laparoscopy seems to contribute to decreasing postoperative mortality. Concerning long-term oncologic outcomes, the laparoscopic and open techniques were shown to be at least equivalent. Conclusion The findings of the existing relevant RCTs on laparoscopic surgery for colon cancer are mostly confirmed by representative retrospective cohort studies based on real-world data; therefore, its further implementation into clinical practice can be recommended.

Twenty percent of patients with high-tumor-burden (HTB) follicular lymphoma (FL) develop progression/relapse of disease (POD) within 24 months of frontline immunochemotherapy. Unfortunately, about 50% of these patients die within 5 years since POD event. Rituximab maintenance was proven to reduce relapse rate in responding FL, but its role on preventing POD was not defined. We analyzed 1360 HTB-FL patients from the Czech Lymphoma Study Group registry treated with frontline rituximab-containing regimen. Of those, 950 cases received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and achieved complete or partial remission: 712 patients received rituximab maintenance (MAINT) and 238 were a historical observational cohort (OBS). We have proposed a modified POD24 (mPOD24) endpoint for the chemosensitive patients calculated from the end-of-induction (EOI). Survival rates since EOI were as follows: 5-year overall survival (OS) 86.2% versus 94.5% in the OBS and MAINT groups, respectively (

The vitamin D receptor (VDR), primarily known as a crucial mediator of calcium homeostasis and metabolism, has been shown to play a significant role in various cancer entities. Previous studies have focused on vitamin D and its receptor in gynecological cancers, noting that the receptor is upregulated in epithelial ovarian cancer (EOC). The aim of this study is to analyze the prognostic impact of VDR and its functional significance in ovarian cancer. Through immunohistochemistry, VDR staining was examined in 156 ovarian cancer samples. Evaluation of VDR staining was conducted in the nucleus and the cytoplasm using the semi-quantitative immunoreactive score, and the scores were classified into high- and low-level expressions. Expression levels were correlated with clinical and pathological parameters as well as with overall survival to assess for prognostic impact. Differences in cytoplasmic VDR expression were identified between the histological subtypes (p = 0.001). Serous, clear cell, and endometrioid subtypes showed the highest staining, while the mucinous subtype showed the lowest. Cytoplasmic VDR correlated with higher FIGO stage (p = 0.013;Cc = 0.203), positive lymph node status (p = 0.023;Cc = 0.236), high-grade serous histology (p = 0.000;Cc = 0.298) and grading from the distinct histological subtypes (p = 0.006;Cc = − 0.225). Nuclear VDR did not correlate with clinicopathological data. High cytoplasmic expression of VDR was associated with impaired overall survival (HR 2.218, 32.5 months vs. median not reached;p

ObjectiveObesity is associated with worse survival and an increased risk of relapse in several malignancies. The influence of obesity on vulvar cancer recurrence has not been previously described. The primary objective of this study was to evaluate the association between obesity and tumor recurrence in patients with vulvar cancer.MethodsThis is an analysis of the AGO-CaRE-1 study. Patients diagnosed with squamous cell vulvar cancer (stage IB and higher), treated in 29 cancer centers between January 1998 and December 2008, were registered in a centralized database. The cohort was divided into two gropus depending on the body mass index (BMI) (ResultsIn 849 (52.4%) of 1618 patients in the database, the BMI was documented. Patients were grouped according to their BMI (ConclusionsIn this study a BMI ≥30 kg/m² was associated with a shorter time to recurrence in patients with vulvar cancer and this was mainly attributed to a higher risk of local recurrence.

To develop and validate a 3D registration approach by which double echo steady state (DESS) MR images with cartilage thickness segmentations are used to extract the cartilage transverse relaxation time (T2) from multi-echo-spin-echo (MESE) MR images, without direct segmentations for MESE. Manual DESS segmentations of 89 healthy reference knees (healthy) and 60 knees with early radiographic osteoarthritis (early ROA) from the Osteoarthritis Initiative were registered to corresponding MESE images that had independent direct T2 segmentations. For validation purposes, (a) regression analysis of deep and superficial cartilage T2 was performed and (b) between-group differences between healthy vs. early ROA knees were compared for registered vs. direct MESE analysis. Moderate to high correlations were observed for the deep (r = 0.80) and the superficial T2 (r = 0.81), with statistically significant between-group differences (ROA vs. healthy) of + 1.4 ms (p = 0.002) vs. + 1.3 ms (p

Background The implementation of quality of life (QoL) concepts in routine care, is still an open matter. We followed the Medical Research Council framework for complex interventions to implement a model of QoL diagnosis and therapeutic options, and investigated its effectiveness in patients with colorectal cancer. Methods This randomised, single-blind, multicentre, clinical trial enrolled patients diagnosed with primary colorectal cancer aged 18 years or older who were surgically treated in one of four recruiting hospitals in Germany. All patients received aftercare from one of 178 coordinating practitioners (CPs) who had access to 75 healthcare professionals providing tailored therapies. QoL was measured (EORTC QLQ-C30, QLQ-CR29) in all patients after surgery (baseline) and during aftercare (3, 6, 12, 18 months). Patients were randomised (1:1) into two groups: a care pathway, including QoL-profiles consisting of 13 QoL scales plus specific therapeutic recommendations forwarded to the patient’s CP or standard postoperative care adhering to the German national guideline for colorectal cancer (control). The primary endpoint was the proportion of patients in each group with a need for QoL therapy 12 months after surgery. Analyses were done in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT02321813 and closed to accrual. Findings Between Jan 13, 2014, and Oct 28, 2015, 220 patients were enrolled and randomly assigned (n = 110 per group). At baseline (in hospital after surgery), a need for QoL therapy was diagnosed in 92/103 (89%) of intervention and 86/104 (83%) of control group patients. At 12 months (primary endpoint) the proportion of patients with a need for QoL therapy was 35/83 (42%; 95% CI 31–54%) in the intervention group versus 50/87 (57%; 95% CI: 46–68%) in the control group (p = 0·046, number needed to treat = 7; 95% CI 3–225). Interpretation Patients profited from the diagnosis of QoL deficits and tailored therapeutic options in their treatment of colorectal cancer. This trial confirmed the results of a previous RCT in breast cancer patients. The implementation of QoL concepts should become standard in treatment guidelines on cancer care. Funding Federal Ministry of Education and Research (BMBF; grant no. 01GY1339). Clinical trial information NCT02321813.

Thrombotic microangiopathy (TMA) is a rare but severe complication of tumors and their chemotherapeutic treatment. We report on two patients with chemotherapy-induced TMA who were successfully treated with a short course of the terminal complement inhibitor eculizumab. Both patients quickly achieved remission of microangiopathic hemolytic anemia and recovery of renal function. After withdrawal of eculizumab, remission was stable over an observation period of 47 months and 15 months, respectively. Our data show that eculizumab is effective in treating chemotherapy-induced TMA. Discontinuation of eculizumab is feasible once the complement-activating condition is controlled and the trigger is eliminated. Additional studies need to determine the optimal duration of complement-directed therapies and validate effective monitoring strategies after discontinuation of such therapy.

This paper investigates the flow past two variants of root section profile cascades for a last stage rotor considering three-dimensional flow structures in the near-wall region. Analyses were drawn based on RANS numerical simulations of both variants and on the experimental data obtained by the 3D traversing in the exit flow field of one of the variants. Extent of 3D structures at two different regimes and its influence on aerodynamic characteristics of the blade cascades was assessed. The distributions of Mach number along the profiles were compared with 2D optical measurements and its distortion due to the presence of the sidewall was explored. The interaction between main vortical structures was described and its influence on the loading of the blades, mechanical energy losses and exit flow angle was discussed. The results showed that for a front loaded blade the vortical structures appeared earlier and at a larger extent than for an aft loaded variant. However, due to different Mach number distribution, contribution of end wall flow to the energy losses was lower in the case of the aft loaded variant. The influence of the near wall flow on the loading was found to be rather weak while the deviation of the exit flow angle appeared to be comparable for both of the variants.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with aggressive behavior and poor prognosis. We present the first retrospective analysis mapping its incidence and therapeutic outcomes in patients diagnosed and treated from 2000 to 2017 in the Czech Republic. The cohort comprised 14 patients (10 males, 4 females) with a median age at diagnosis of 39 years (range, 5-68 years). Initially, skin involvement was noted in 10 (71%) patients and bone marrow infiltration was present in 9 (64%). The first complete remission was achieved in 6/14 (43%) patients after acute lymphoblastic leukemia/lymphoma induction therapy and in 3/14 (21%) patients after acute myeloid leukemia regimen. Nine patients underwent allogeneic hematopoietic cell transplantation, with two patients achieving the first complete remission only after allogeneic transplantation. Patients undergoing allogeneic hematopoietic cell transplantation had longer overall survival than those treated without transplantation (the median survival over the period 16.4 vs. 8.1 months). Relapse of the disease was a significant predictor of mortality (p=0.05). Over the study period, patients' survival ranged from 3.3 to 44.2 months, with a median overall survival of 13 months. Our results revealed an effectivity of allogeneic hematopoietic cell transplantation on complete remission achievement in refractory/relapsed disease. The study aimed to present the actual data from the Czech Republic and thus contribute to a global understanding of BPDCN.

The IceCube Neutrino Observatory will be upgraded with more than 700 additional optical sensor modules and new calibration devices. Improved calibration will enhance IceCube’s physics capabilities both at low and high neutrino energies. An important ingredient for good angular resolution of the observatory is precise calibration of the positions of optical sensors. Ten acoustic modules, which are capable of receiving and transmitting acoustic signals, will be attached to the strings. These signals can additionally be detected by compact acoustic sensors inside some of the optical sensor modules. With this system we aim for calibration of the detectors’ geometry with a precision better than 10 cm by means of trilateration of the propagation times of acoustic signals. This new method will allow for an improved and complementary geometry calibration with respect to previously used methods based on optical flashers and drill logging data. The longer attenuation length of sound compared to light makes the acoustic module a promising candidate for IceCube-Gen2, which may have optical sensors on strings with twice the current spacing. We present an overview of the technical design and tests of the system as well as analytical methods for determining the propagation times of the acoustic signals.

The field of deep learning has become increasingly important for particle physics experiments, yielding a multitude of advances, predominantly in event classification and reconstruction tasks. Many of these applications have been adopted from other domains. However, data in the field of physics are unique in the context of machine learning, insofar as their generation process and the laws and symmetries they abide by are usually well understood. Most commonly used deep learning architectures fail at utilizing this available information. In contrast, more traditional likelihood-based methods are capable of exploiting domain knowledge, but they are often limited by computational complexity. In this contribution, a hybrid approach is presented that utilizes generative neural networks to approximate the likelihood, which may then be used in a traditional maximum-likelihood setting. Domain knowledge, such as invariances and detector characteristics, can easily be incorporated in this approach. The hybrid approach is illustrated by the example of event reconstruction in IceCube., Comment: Presented at the 37th International Cosmic Ray Conference (ICRC 2021). See arXiv:2107.06966 for all IceCube contributions

37. International Cosmic Ray Conference, ICRC 2021, Berlin, Germany, 15 Jul 2021 - 22 Jul 2021; Proceedings of Science 395, 317 (2022). doi:10.22323/1.395.0317 special issue: "37th International Cosmic Ray Conference : ICRC2021 : 12-23 July 2021 : Berlin, Germany - Online / Editorial Board: Alexander Kappes, Institut für Kernphysik, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany ; Bianca Keilhauer, Karlsruhe Institute of Technology, Institute for Astroparticle Physics (IAP)", Published by SISSA, Trieste

Background. Diabetes mellitus rates and associated costs continue to rise across Europe enhancing health authority focus on its management. The risk of complications is enhanced by poor glycaemic control, with long-acting insulin analogues developed to reduce hypoglycaemia and improve patient convenience. There are concerns though with their considerably higher costs, but moderated by reductions in complications and associated costs. Biosimilars can help further reduce costs. However, to date, price reductions for biosimilar insulin glargine appear limited. In addition, the originator company has switched promotional efforts to more concentrated patented formulations to reduce the impact of biosimilars. There are also concerns with different devices between the manufacturers. As a result, there is a need to assess current utilisation rates for insulins, especially long-acting insulin analogues and biosimilars, and the rationale for patterns seen, among multiple European countries to provide future direction. Methodology. Health authority databases are examined to assess utilisation and expenditure patterns for insulins, including biosimilar insulin glargine. Explanations for patterns seen were provided by senior-level personnel. Results. Typically increasing use of long-acting insulin analogues across Europe including both Western and Central and Eastern European countries reflects perceived patient benefits despite higher prices. However, activities by the originator company to switch patients to more concentrated insulin glargine coupled with lowering prices towards biosimilars have limited biosimilar uptake, with biosimilars not currently launched in a minority of European countries. A number of activities were identified to address this. Enhancing the attractiveness of the biosimilar insulin market is essential to encourage other biosimilar manufacturers to enter the market as more long-acting insulin analogues lose their patents to benefit all key stakeholder groups. Conclusions. There are concerns with the availability and use of insulin glargine biosimilars among European countries despite lower costs. This can be addressed., peer-reviewed

37. International Cosmic Ray Conference, ICRC 2021, Berlin, Germany, 15 Jul 2021 - 22 Jul 2021; Proceedings of Science 395, 1056 (2022). doi:10.22323/1.395.1056 special issue: "37th International Cosmic Ray Conference : ICRC2021 : 12-23 July 2021 : Berlin, Germany - Online / Editorial Board: Alexander Kappes, Institut für Kernphysik, Westfälische Wilhelms-Universität Münster, D-48149 Münster, Germany ; Bianca Keilhauer, Karlsruhe Institute of Technology, Institute for Astroparticle Physics (IAP)", Published by SISSA, Trieste

The Panel on Food Additives and Flavourings (FAF) was requested to consider the JECFA evaluations of 25 flavouring substances assigned to the Flavouring Group Evaluation 67 (FGE.67Rev3), using the Procedure as outlined in the Commission Regulation (EC) No 1565/2000. Eleven substances have already been considered in FGE.67 and its revisions (FGE.67Rev1 and FGE.67Rev2). During the current assessment, two substances were no longer supported by industry, therefore 12 candidate substances are evaluated in FGE.67Rev3. New genotoxicity and toxicity data are available for 2‐pentylfuran [FL‐no: 13.059] and 2‐acetylfuran [FL‐no: 13.054], which are representative substances of subgroup IV [FL‐no: 13.069, 13.106, 13.148] and VI‐B [FL‐no: 13.045, 13.070, 13.083, 13.101, 13.105, 13.138, 13.163], respectively. Based on these data, the Panel concluded that the concern for genotoxicity is ruled out for both [FL‐no: 13.054] and [FL‐no: 13.059] and consequently for the substances that they represent. Since the candidate substances cannot be anticipated to be metabolised to innocuous products only, they were evaluated along the B‐side of the Procedure. The Panel derived a NOAEL of 22.6 mg/kg bw per day and a BMDL of 8.51 mg/kg bw per day, for 2‐acetylfuran and 2‐pentylfuran, respectively. For all 12 substances sufficient margins of safety were calculated when based on the MSDI approach. Adequate specifications for the materials of commerce are available for all 23 flavouring substances. The Panel agrees with JECFA conclusions, for all 23 substances, ‘No safety concern at estimated levels of intake as flavouring substances’ based on the MSDI approach. For 18 substances [FL‐no: 13.021, 13.022, 13.023, 13.024, 13.031, 13.045, 13.047, 13.054, 13.059, 13.074, 13.083, 13.101, 13.105, 13.106, 13.138, 13.148, 13.163 and 13.190], the mTAMDI intake estimates are above the threshold of toxicological concern (TTC) for their structural classes and more reliable data on uses and use levels are required to finalise their evaluation.

In paediatrics, clinical study data are limited, especially on herbal medicinal products. To address this gap, 2063 datasets from the paediatric population were evaluated in the PhytoVIS data base. By screening for paediatric data, information on indication, gender, treatment, co-medication and tolerability were evaluated. The majority of patients was treated because of common cold, fever, digestive complaints, skin diseases, sleep disturbances and anxiety. The perceived effect of the therapy was rated in 84% of the patients as very good or good without adverse events. The data shed light on a still neglected field of phyto-pharmacotherapy by giving information on the use of herbal medicines in an unselected cohort of paediatric patients. The results confirm the good clinical effects and safety of herbal medicinal products in this patient population and show that they are widely used in Germany.What is Known:• In Germany, about 85% of children receive one or more herbal medicinal products per year.• Despite international initiatives to promote clinical research in paediatrics, there are still many gaps of knowledge in the use of drugs in paediatrics.What is New:• The PhytoVIS project evaluated 2063 data sets from the paediatric population using herbal medicinal products.• The majority of patients was treated because of common cold, fever, digestive complaints, skin diseases, sleep disturbances and anxiety, and 84% of the patients rated the therapy as very good or good without adverse events.

One of the most important parameters for economic growth is industrial development in many developing regions like Iran. The Markazi province in the center of Iran is one of the most important industrial areas in the country, where unplanned economic development in recent decades has led to many social and environmental problems. Accordingly, the main organizations involved in industrial development in this region are facing difficulties in the future development of industrial areas, which has become a complex problem. Therefore, the main purpose of this paper is to study the industrial development dispute in the Markazi province through a cooperative model of game theory in order to achieve conflict resolution through a comprehensive approach. In this research, the conflict has been analyzed through strategic analysis of stakeholders. For this purpose, a model of cooperative game theory and its bargaining analysis methods, including social choice rules (SCRs) and fallback bargaining (FB), and six available options were used. According to the six SCRs, the most likely option that can exist between the Department of the Environment (DOE) and the Industrial and Mining Organization (IMO) is compromise coordination (C). In addition, the results of the Fallback Bargaining (FB) rule in three different forms show that the most appropriate options for agreement between the IMO and DOE are the moderate version of construction through arbitration (TCa) and compromise coordination (C). In fact, the results indicate that if the actors involved in this conflict do not cooperate to resolve it, it can lead to more complex problems and the involvement of other groups who may not even have a proper perception of the conflict. In addition, the findings show that cooperation between the parties and understanding of their positions and views along with the policy coherence are necessary to strive for sustainable development and maintain economic growth and development.

This opinion deals with the re‐evaluation of polydextrose (E 1200) when used as a food additive. The Panel followed the conceptual framework for the risk assessment of certain additives and considered that: adequate exposure estimates were available; the margin of safety (MOS)/margin of exposure (MOE) for arsenic was between 0.5‐14 and 8.5 for lead; the exhaustions of the tolerable weekly intake (TWI) for cadmium would be 165%, 10% for mercury, whereas the exhaustion of the tolerable daily intake (TDI) for nickel would be 9%; the absorption is limited and part of polydextrose is fermented in the large intestine into short‐chain fatty acids (SCFA); adequate toxicity data were available; there is no concern with respect to genotoxicity; no adverse effects were reported in subchronic studies in rats, dogs or monkeys nor in chronic or carcinogenicity studies in mice and rats at the highest doses tested of up 12,500 mg/kg body weight (bw) per day and 15,000 mg/kg bw per day, respectively; the nephrocalcinosis in dogs given high doses of polydextrose was considered to be a treatment‐related but a secondary effect related to diarrhoea, and hence not relevant for the risk assessment; no adverse effects were reported in reproductive or developmental toxicity studies in rats administered up to 10,000 mg polydextrose/kg bw per day, or in a developmental toxicity study in rabbits up to 1,818 mg/kg bw per day (the highest dose tested). Therefore, the Panel concluded that there is no need for numerical acceptable daily intake (ADI) for polydextrose (E 1200), and that there is no safety concern for the reported uses and use levels of polydextrose as a food additive. The Panel recommended that European Commission considers to lower the maximum limit for lead and to introduce limits for arsenic, cadmium and mercury in the EU specifications for polydextrose (E 1200), and to verify that polydextrose‐N as a food additive (E 1200) is no longer marketed in the EU.