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Bakgrund: Sepsis är en livshotande organdysfunktion som orsakas av ett stört systematiskt svar på en infektion och drabbar årligen 48,9 miljoner människor globalt. Sepsis är en diagnos som globalt sett är associerad med hög morbiditet och ökad mortalitet, detta eftersom sepsis är ett tillstånd som kan bli livshotande om inte effektiv behandling snabbt sätts in. Diagnosen har uppmärksammats nationellt såväl som internationell som ett område inom sjukvården med stor förbättringspotential. För att möta denna utmaning är det nödvändigt att förstå hur sepsis utvecklas och vilka åtgärder som krävs för att känna igen sepsissymtom på ett effektivt sätt. Syfte: Syftet med litteraturstudien är att beskriva sjuksköterskors upplevelser av att känna igen sepsissymtom hos patienter. Metod: En litteraturstudie med kvalitativ metod genomfördes med 10 vetenskapliga artiklar av kvalitativ ansats. Databaserna CINAHL och PubMed användes för databassökning. Analysen genomfördes som en stegvis process inspirerad av innehållsanalys. Resultat: Sjuksköterskors upplevelser av att känna igen sepsissymtom hos patienter visade sig bero på olika faktorer som delades in i tre kategorier; ́Organisation ́, ́Samverkan i vårdteam ́ och ́Påverkan av sjuksköterskors individuella faktorer ́. Konklusion: Inom omvårdnadsområdet är samarbete med läkare en avgörande faktor som antingen underlättar eller hindrar sjuksköterskan att känna igen sepsissymtom. Bristande kunskap utgör ett hinder för sjuksköterskans förmåga att känna igen sepsissymtom, särskilt när dessa är diffusa. Men det är också en komplex process där hög arbetsbelastning, samverkan, dokumentation, riktlinjer, kunskap, erfarenhet, klinisk blick och kritiskt tänkande vävs samman och påverkar sjuksköterskors förmåga att effektivt känna igen sepsissymtom., Background: Sepsis is a life-threatening organ dysfunction caused by a disrupted systemic response to an infection and annually affects 48.9 million people globally each year. It is a diagnosis that globally is associated with high morbidity and increased mortality because sepsis is a condition that can become life- threatening if not effective treatment immediately is used. It has become a subject of national and international attention as an area within healthcare with significant improvement potential. To address this challenge, it is necessary to understand how sepsis develops and what measures are required for its effective detection. Aim: The aim of this study is to explore nurses' experiences in recognizing sepsis symptoms in patients. Method: A literature review using a qualitative approach was conducted, analyzing 10 scientific articles with a qualitative approach. The databases CINAHL and PubMed were utilized for the literature search. The analysis followed a stepwise process inspired by content analysis. Results: Nurses' experience of recognizing sepsis symptoms in patients was found to be influenced by various factors categorized into three main groups: 'Organization', 'Collaboration in the healthcare team', and 'Impact of individual factors on nurses'. Conclusion: In the field of nursing, collaboration with physicians is a crucial factor that either facilitates or prevents nurses from recognizing sepsis symptoms. Insufficient knowledge poses a barrier to nurses' ability to recognize sepsis symptoms, especially when symptoms are vague. In summary, it is a complex process where high workload, collaboration, documentation, guidelines, knowledge, experience, clinical intuition, and critical thinking are interwoven to affect nurses' ability to effectively recognize sepsis symptoms.

Bakgrund: Sepsis är en livshotande organdysfunktion som orsakas av ett stört systematiskt svar på en infektion och drabbar årligen 48,9 miljoner människor globalt. Sepsis är en diagnos som globalt sett är associerad med hög morbiditet och ökad mortalitet, detta eftersom sepsis är ett tillstånd som kan bli livshotande om inte effektiv behandling snabbt sätts in. Diagnosen har uppmärksammats nationellt såväl som internationell som ett område inom sjukvården med stor förbättringspotential. För att möta denna utmaning är det nödvändigt att förstå hur sepsis utvecklas och vilka åtgärder som krävs för att känna igen sepsissymtom på ett effektivt sätt. Syfte: Syftet med litteraturstudien är att beskriva sjuksköterskors upplevelser av att känna igen sepsissymtom hos patienter. Metod: En litteraturstudie med kvalitativ metod genomfördes med 10 vetenskapliga artiklar av kvalitativ ansats. Databaserna CINAHL och PubMed användes för databassökning. Analysen genomfördes som en stegvis process inspirerad av innehållsanalys. Resultat: Sjuksköterskors upplevelser av att känna igen sepsissymtom hos patienter visade sig bero på olika faktorer som delades in i tre kategorier; ́Organisation ́, ́Samverkan i vårdteam ́ och ́Påverkan av sjuksköterskors individuella faktorer ́. Konklusion: Inom omvårdnadsområdet är samarbete med läkare en avgörande faktor som antingen underlättar eller hindrar sjuksköterskan att känna igen sepsissymtom. Bristande kunskap utgör ett hinder för sjuksköterskans förmåga att känna igen sepsissymtom, särskilt när dessa är diffusa. Men det är också en komplex process där hög arbetsbelastning, samverkan, dokumentation, riktlinjer, kunskap, erfarenhet, klinisk blick och kritiskt tänkande vävs samman och påverkar sjuksköterskors förmåga att effektivt känna igen sepsissymtom., Background: Sepsis is a life-threatening organ dysfunction caused by a disrupted systemic response to an infection and annually affects 48.9 million people globally each year. It is a diagnosis that globally is associated with high morbidity and increased mortality because sepsis is a condition that can become life- threatening if not effective treatment immediately is used. It has become a subject of national and international attention as an area within healthcare with significant improvement potential. To address this challenge, it is necessary to understand how sepsis develops and what measures are required for its effective detection. Aim: The aim of this study is to explore nurses' experiences in recognizing sepsis symptoms in patients. Method: A literature review using a qualitative approach was conducted, analyzing 10 scientific articles with a qualitative approach. The databases CINAHL and PubMed were utilized for the literature search. The analysis followed a stepwise process inspired by content analysis. Results: Nurses' experience of recognizing sepsis symptoms in patients was found to be influenced by various factors categorized into three main groups: 'Organization', 'Collaboration in the healthcare team', and 'Impact of individual factors on nurses'. Conclusion: In the field of nursing, collaboration with physicians is a crucial factor that either facilitates or prevents nurses from recognizing sepsis symptoms. Insufficient knowledge poses a barrier to nurses' ability to recognize sepsis symptoms, especially when symptoms are vague. In summary, it is a complex process where high workload, collaboration, documentation, guidelines, knowledge, experience, clinical intuition, and critical thinking are interwoven to affect nurses' ability to effectively recognize sepsis symptoms.

Metabolic homeostasis and the ability to link energy supply to demand are essential requirements for all living cells to grow and proliferate. Key to metabolic homeostasis in all eukaryotes are AMPK and mTORC1, two kinases that sense nutrient levels and function as counteracting regulators of catabolism (AMPK) and anabolism (mTORC1) to control cell survival, growth and proliferation. Discoveries beginning in the early 2000s revealed that AMPK and mTORC1 communicate, or cross-talk, through direct and indirect phosphorylation events to regulate the activities of each other and their shared protein substrate ULK1, the master initiator of autophagy, thereby allowing cellular metabolism to rapidly adapt to energy and nutritional state. More recent reports describe divergent mechanisms of AMPK/mTORC1 cross-talk and the elaborate means by which AMPK and mTORC1 are activated at the lysosome. Here, we provide a comprehensive overview of current understanding in this exciting area and comment on new evidence showing mTORC1 feedback extends to the level of the AMPK isoform, which is particularly pertinent for some cancers where specific AMPK isoforms are implicated in disease pathogenesis.

The use of mechanistic population models as research and decision-support tools in ecology and ecological risk assessment is increasing. This growth has been facilitated by advances in technology, allowing the simulation of more complex systems, as well as by standardized approaches for model development, documentation, and evaluation. Mechanistic population models are particularly useful for simulating complex systems, but the required model complexity can make them challenging to communicate. Conceptual diagrams that summarize key model elements, as well as elements that were considered but not included, can facilitate communication and understanding of models and increase their acceptance as decision-support tools. Currently, however, there are no consistent standards for creating or presenting conceptual model diagrams, and both terminology and content vary widely. Here we argue that greater consistency in conceptual model diagram development and presentation is an important component of good modeling practice, and we provide recommendations, examples, and a free web app (pop-cmd.com) for achieving this for population models used for decision support in ecological risk assessments.

The present paper focuses on teacher’s role in social justice and explores how teachers perceive and react upon diversity and inequality in their classrooms. Through a literature review, we aimed to answer three research questions: 1) what are diversity awareness and critical consciousness in education; 2) why are diversity awareness and critical consciousness important; and 3) how can diversity awareness and critical consciousness be supported in teachers. The literature review has revealed that most papers on teachers’ diversity awareness and critical consciousness have been published within the last few years and that the importance of the two concepts has been recognized for a wide range of educators. There seems to be a growing interest in this topic due to the increase of the diversity in classrooms and the recognition of the teachers’ role in addressing diversity and inequality. However, large-scale studies would be a needed contribution to the field, as most of the existing studies are small-scale. Based on this review, we argue that both diversity awareness and critical consciousness need to be supported through preservice and in-service teacher professional development programs, if we are to make education systems more inclusive for all., Artikeln finns publicerad både på kroatiska och engelska, länkar till båda versionerna finns i denna post.The article is published in both Croatian and English, links to both versions can be found in this record.

This deliverable contains the 12 demonstrator area restoration workplans. The restoration workplans describe restoration sites, restoration goals and restoration activities for each demo area. The restoration measures will be integrated into the forest and landscape as much as possible. Additionally, the connections with other WPs such as WP2 – Stakeholders engagement and WP6 – Biodiversity monitoring are made within these restoration workplans.These workplans serve as a handbook, now for the demos themselves and later on for others who also work on the forest restoration. This deliverable includes the restoration workplans for the following demonstrator areas: Po Valley (Italy), southern Netherlands, North Moravia(Czech Republic), North Rhine Westphalia (Germany), Vindelälven-Juhttátahkka BiosphereReserve (Sweden), Queen Elizabeth Forest Park (Scotland), Biosphere Reserve BačkoPodunavlje (Croatia/Serbia cross-border), Făgăraș mountains (Romania), Thy andNordsjælland (Denmark), Castilla y Leon (Spain), Nouvelle-Aquitaine (France) and coppiceforests in Serbia.

Background and aim: Obstructive sleep apnea (OSA) is an independent risk factor for dyslipidemia. The current study examined the effects of positive airway pressure (PAP) treatment on lipid status in the European Sleep Apnea Database (ESADA). Methods: The prospective cohort study enrolled 1564 OSA subjects (74% male, mean age 54 ± 11y, body mass index (BMI) 32.7 ± 6.6 kg/m2 and apnea-hypopnea index (AHI) 40.3 ± 24.4 n/h) undergoing PAP therapy for at least three months (mean 377.6 ± 419.5 days). Baseline and follow-up total cholesterol (TC) from nine centers were analyzed. Repeated measures and logistic regression tests (adjusted for age, sex, weight changes, lipid lowering medication, PAP compliance, and treatment duration) were used to compare changes in TC concentration. Incident risk for a coronary heart disease event (CHD) was used to compute a Framingham CHD risk score (estimated from age, BMI, blood pressure, and TC). Results: Adjusted means of TC decreased from 194.2 mg/dl to 189.3 mg/dl during follow-up (p = 0.019). A clinically significant (10%) reduction of TC at PAP follow-up was observed in 422 patients (27%). Duration of PAP therapy was identified as independent predictor for TC reduction, which implies an approximately 10% risk reduction for incident CHD events (from 26.7% to 24.1% in men and from 11.2% to 10.1% in women, p < 0.001 respectively). Conclusion: This observational study demonstrates a reduction of TC after long-term PAP treatment. The close association between TC concentration and cardiovascular (CV) mortality suggests that identification and treatment of OSA may have a beneficial effect on overall CV risk due to this mechanism. This possibility needs to be evaluated in prospective randomized studies.

OBJECTIVES: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. METHODS: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe-/-/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe-/- and Apoe-/-/Hmgcr KI mice. RESULTS: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe-/-/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe-/-/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe-/-/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. CONCLUSIONS: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O-3O4 and PXL 770 for reducing ather

Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe−/−/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe−/− and Apoe−/−/Hmgcr KI mice. Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe−/−/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe−/−/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe−/−/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O–3O4 and PXL 770 for reducing ather

Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe−/−/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe−/− and Apoe−/−/Hmgcr KI mice. Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe−/−/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe−/−/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe−/−/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O–3O4 and PXL 770 for reducing ather

Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe−/−/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe−/− and Apoe−/−/Hmgcr KI mice. Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe−/−/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe−/−/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe−/−/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O–3O4 and PXL 770 for reducing ather

Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe−/−/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe−/− and Apoe−/−/Hmgcr KI mice. Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe−/−/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe−/−/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe−/−/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O–3O4 and PXL 770 for reducing ather

Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis. Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe−/−/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe−/− and Apoe−/−/Hmgcr KI mice. Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe−/−/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe−/−/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe−/−/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs. Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O–3O4 and PXL 770 for reducing ather

Background: According to the neurodevelopmental theory, brain structuring early markers could be seen in different body parts as minor physical anomalies. Alongside minor physical anomalies, handedness and index to ring finger ratio are brain development indicators, specifically brain lateralization. Studies are consentient about the association of these findings with schizophrenia, though there is inconsistency about individual anatomical regions' contribution. We proposed that handedness in combination with morphological indicators of early brain development could be sensitive and specific in predicting schizophrenia status. Subjects and methods: Within the list for the assessment of schizophrenia patients and normal controls of the Caucasian race were seven categorical minor physical anomalies of hand and feet, handedness, and index to ring finger ratio. In this cross-sectional study the examinees were recruited from January 2012 to December 2015. Results: Forced-entry binary logistic regression model correctly classified 86.5% of patients and 99.2% of the comparison subjects with a 92.8% overall accuracy. Mixed-handedness, hyperconvex fingernails, big gap between 1st and 2nd toe, and partial syndactyly of 2nd and 3rd toe made a significant independent contribution to the patient-control prediction group status. Furthermore, these items showed a significant correlation with the predictors of the head from the previous study. Conclusion: Briefly, the limb components, assessed independently of other body regions, proved to be worthy as schizophrenia predictors.

Deep learning has a great potential to alleviate diagnosis and prognosis for various clinical procedures. However, the lack of a sufficient number of medical images is the most common obstacle in conducting image-based analysis using deep learning. Due to the annotations scarcity, semi-supervised techniques in the automatic medical analysis are getting high attention. Artificial data augmentation and generation techniques such as generative adversarial networks (GANs) may help overcome this obstacle. In this work, we present an image generation approach that uses generative adversarial networks with a conditional discriminator where segmentation masks are used as conditions for image generation. We validate the feasibility of GAN-enhanced medical image generation on whole heart computed tomography (CT) images and its seven substructures, namely: left ventricle, right ventricle, left atrium, right atrium, myocardium, pulmonary arteries, and aorta. Obtained results demonstrate the suitability of the proposed adversarial approach for the accurate generation of high-quality CT images. The presented method shows great potential to facilitate further research in the domain of artificial medical image generation., Comment: Proceedings of the 7th International Conference on Smart and Sustainable Technologies (SpliTech 2022)

Objective/Background: The Clinical Global Impression scale (CGI) reflects the clinician's assessment of the disease impact on patient's global functioning. We assessed predictors of CGI scale rating in patients with obstructive sleep apnea (OSA). Patients/Methods: Consecutive patients with suspected OSA (n = 7581) were identified in the European Sleep Apnea Database (ESADA). Anthropometrics, comorbidities, apnea severity obtained by polygraphy or polysomnography, and daytime sleepiness [Epworth Sleepiness Scale (ESS)] were assessed. The CGI 7-point scale was completed at the end of the diagnostic process (CGI-severity, ie, CGI-S) and, in a subpopulation, at treatment follow-up (CGI-Improvement). Results: CGI-S was rated mild to moderate in 44% of patients. CGI rating at any given apnea intensity was worse in women than in men (p < 0.01). Patients undergoing polygraphy (n = 5075) were more frequently rated as severely ill compared to those studied with polysomnography (19.0% vs 13.0%, p < 0.001). In patients aged ≤65 years, CGI scoring was generally better than in the elderly despite a similar degree of OSA (eg, ‘normal, not ill’ 24.2% vs 15.3%, p < 0.01, respectively). Independent predictors of CGI rating included age, BMI, AHI, ESS, cardio-metabolic comorbidities, and diagnosis based on polygraphy. CGI-improvement rating (Beta = −0.406, p < 0.01) was superior to sleep apnea severity or ESS-score (Beta = 0.052 and −0.021, p = 0.154 and 0.538 respectively) at baseline for prediction of good CPAP compliance at follow-up. Conclusions: CGI rating is confounded by gender, age class and the type of sleep diagnostic method. As OSA phenotypes differ, CGI may contribute as a clinical tool to reflect the significance of clinical disease.

Background and objective: Obstructive sleep apnoea (OSA) and hyperlipidaemia are independent risk factors for cardiovascular disease. This study investigates the association between OSA and prevalence of hyperlipidaemia in patients of the European Sleep Apnea Database (ESADA) cohort. Methods: The cross-sectional analysis included 11 892 patients (age 51.9 ± 12.5 years, 70% male, body mass index (BMI) 31.3 ± 6.6 kg/m2, mean oxygen desaturation index (ODI) 23.7 ± 25.5 events/h) investigated for OSA. The independent odds ratio (OR) for hyperlipidaemia in relation to measures of OSA (ODI, apnoea-hypopnoea index, mean and lowest oxygen saturation) was determined by means of general linear model analysis with adjustment for important confounders such as age, BMI, comorbidities and study site. Results: Hyperlipidaemia prevalence increased from 15.1% in subjects without OSA to 26.1% in those with severe OSA, P < 0.001. Corresponding numbers in patients with diabetes were 8.5% and 41.5%, P < 0.001. Compared with ODI quartile I, patients in ODI quartiles II-IV had an adjusted OR (95% CI) of 1.33 (1.15–1.55), 1.37 (1.17–1.61) and 1.33 (1.12–1.58) (P < 0.001), respectively, for hyperlipidaemia. Obesity was defined as a significant risk factor for hyperlipidaemia. Subgroups of OSA patients with cardio-metabolic comorbidities demonstrated higher prevalence of HL. In addition, differences in hyperlipidaemia prevalence were reported in European geographical regions with the highest prevalence in Central Europe. Conclusion: Obstructive sleep apnoea, in particular intermittent hypoxia, was independently associated with the prevalence of hyperlipidaemia diagnosis.

Background: Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. In this study, we evaluated the long-term efficacy, safety, and tolerability of monthly and quarterly fremanezumab. Methods: Episodic migraine and chronic migraine patients completing the 12-week double-blind period of the FOCUS trial entered the 12-week open-label extension and received 3 monthly doses of fremanezumab (225 mg). Changes from baseline in monthly migraine days, monthly headache days of at least moderate severity, days of acute headache medication use, days with photophobia/phonophobia, days with nausea or vomiting, disability scores, and proportion of patients achieving a ≥50% or ≥75% reduction in monthly migraine days were evaluated. Results: Of the 807 patients who completed the 12-week double-blind treatment period and entered the open-label extension, 772 patients completed the study. In the placebo, quarterly fremanezumab, and monthly fremanezumab dosing regimens, respectively, patients had fewer average monthly migraine days (mean [standard deviation] change from baseline: − 4.7 [5.4]; − 5.1 [4.7]; − 5.5 [5.0]), monthly headache days of at least moderate severity (− 4.5 [5.0]; − 4.8 [4.5]; − 5.2 [4.9]), days per month of acute headache medication use (− 4.3 [5.2]; − 4.9 [4.6]; − 4.8 [4.9]), days with photophobia/phonophobia (− 3.1 [5.3]; − 3.4 [5.3]; − 4.0 [5.2]), and days with nausea or vomiting (− 2.3 [4.6]; − 3.1 [4.5]; − 3.0 [4.4]). During the 12-week open-label extension, 38%, 45%, and 46% of patients, respectively, achieved a ≥50% reduction and 16%, 15%, and 20%, respectively, achieved a ≥75% reduction in monthly migraine days. Disability scores were substantially improved in all 3 treatment groups. There were low rates of adverse events leading to discontinuation (<1%). Conclusion: Fremanezumab demonstrated sustained efficacy up to 6 months

Introduction/Objective Calcium hydroxide (CH) is the medicament of choice in endodontic treatment of internal root resorptions. The aim of the study was to compare the effectiveness of three different techniques for CH removal from simulated internal root resorptions. Methods Twenty-nine extracted single-root teeth were prepared using NiTi rotary files of BioRaCe system (40/.04) following irrigation. A round diamond drill was used in the making of a symmetrical standardized internal resorptions 6 mm from the apex. Three techniques for CH removal from internal resorptions were tested: modified conventional syringe irrigation (CSI), passive ultrasonic irrigation (PUI), XP-endo Finisher (XP). Resorptive cavities and apical thirds were observed under a stereomicroscope (x45) and scored (from 1 to 5), while representative samples were analysed by a scanning electron microscope. Obtained results were statistically processed by Kruskal-Wallis and Mann-Whitney U-test (p lt 0.05). Results The most efficient system was PUI, with 66.7% of samples rated 1 and 33.3% rated 2. The next one was XP, and the least efficient was CSI, with 33.3% of samples rated 1 (resorptive defect without medicament). There was a statistically significant difference between the PUI and CSI systems (p lt 0.05), while there was no difference between the PUI and XP systems. Conclusion No system completely removed the CH from the simulated internal root resorption cavities. PUI was the most effective system for removing CH. The combination of techniques provides better performance in removing CH paste residues from the canal walls.

Soil respiration is a significant contributor to the global emissions of CO2 and is governed by many soil factors. Reliable estimates of CO2 emission on different scales (e.g., field, regional level) are hard to obtain due to the expressed spatial and temporal variability of the CO2 flux. This study aims to investigate the spatial variability of CO2 flux and soil properties in soybean cropland on Fluvisols (Croatia). The field measurements and soil samples were taken in a regular sampling grid (2 × 2 m) with 44 points in total and the spatial variability was assessed using the kriging and cokriging techniques. The soil CO2 flux showed relatively high spatial heterogeneity, ranging from 0.03 mg/m2s to 0.40 mg/m2s. The soil organic matter content (SOM), soil water content (SWC), and soil temperature (ST) had the lower variability ranging from 2.09% to 2.52%, from 27.7% to 46.8%, and from 13.7 °C to 18.2 °C, respectively. The spatial dependence was high for CO2 flux and ST, moderate for SOM, and low for SWC. The incorporation of the auxiliary variables increased the precision of the estimations for CO2 flux, SOM, and SWC. Kriging was the most accurate method for the spatial prediction of ST. The SWC was associated as the most important factor of the CO2 fluxes, indicated by their significant negative correlation, and the highest increase of the prediction precision during spatial modeling. However, more robust co-variates should be incorporated in future models to further increase the precision., A talajlégzés, melyet számos talajtulajdonság befolyásol, jelentősen hozzájárul a globális CO2 emisszióhoz. A CO2 emisszió különböző léptékű, megbízható becslése nehéz, annak nagyfokú térbeli és időbeli változékonysága miatt. Kutatásunk célja a CO2 kibocsátás és különböző talajtulajdonságok térbeli változékonyságának vizsgálata egy horvátországi szója ültetvényben, Fluvisol talajon. Az in-situ méréseket, valamint a talajminták gyűjtését egy 2x2 méteres rácsháló 44 pontjában végeztük el, a térbeli változékonyság kimutatásához krigelést és kokrigelést használtunk. A talaj CO2 kibocsátása relatív nagy térbeli változékonyságot mutatott, az értékek 0.03 és 0.40 mg m-2 s-1 között alakultak. A talaj szerves anyag tartalmának (SOM), nedvesség tartalmának (SWC) és hőmérsékletének (ST) változékonysága kisebb volt, ezek értékei 2.09 és 2,52%, 27.7 és 46.8%, valamint 13.7 és 18.2 ºC között változtak. A talaj CO2 kibocsátását nagymértékben meghatározta a mérési pontok térbeli helyzete, a SOM közepes, az SWC pedig alacsony térbeli függést mutatott. A segédváltozók modellbe való beépítése növelte a CO2 kibocsátás, valamint a SOM és a SWC becslésének pontosságát. A SWC volt legnagyobb hatással a CO2 kibocsátás alakulására, e két változó között negatív szignifikáns összefüggést találtunk, valamint ez okozta a legnagyobb növekedést a becslés pontosságában a térbeli modellezés során. A továbbiakban robusztusabb segédváltozó adatsorok felvétele szükséges a pontosság növelése érdekében.

As life expectancy has increased, particularly in developed countries, due to medical advances and increased prosperity, age-related neurological diseases and mental health disorders have become more prevalent health issues, reducing the well-being and quality of life of sufferers and their families. In recent decades, due to reduced work-related levels of physical activity, and key research insights, prescribing adequate exercise has become an innovative strategy to prevent or delay the onset of these pathologies and has been demonstrated to have therapeutic benefits when used as a sole or combination treatment. Recent evidence suggests that the beneficial effects of exercise on the brain are related to several underlying mechanisms related to muscle-brain, liver-brain and gut-brain crosstalk. Therefore, this review aims to summarize the most relevant current knowledge of the impact of exercise on mood disorders and neurodegenerative diseases, and to highlight the established and potential underlying mechanisms involved in exercise-brain communication and their benefits for physiology and brain function.

The acceptance and usefulness of simulation models are often limited by the efficiency, transparency, reproducibility, and reliability of the modelling process. We address these issues by suggesting that modellers (1) “trace” the iterative modelling process by keeping a modelling notebook corresponding to the laboratory notebooks used by empirical researchers, (2) use a standardized notebook structure and terminology based on the existing TRACE documentation framework, and (3) use their notebooks to compile TRACE documents that supplement publications and reports. These practices have benefits for model developers, users, and stakeholders: improved and efficient model design, analysis, testing, and application; increased model acceptance and reuse; and replicability and reproducibility of the model and the simulation experiments. Using TRACE terminology and structure in modelling notebooks facilitates production of TRACE documents. We explain the rationale of TRACE, provide example TRACE documents, and suggest strategies for keeping “TRACE Modelling Notebooks.”

Background: Migraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18–45 years and > 45 years) and sex. Methods: In the FOCUS study, eligible participants were randomized (1:1:1) to 12 weeks of double-blind treatment with quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. In this post hoc analysis, we evaluated changes from baseline in monthly migraine days (primary endpoint of FOCUS) and other secondary and exploratory efficacy outcomes in prespecified age (18–45 and > 45 years) and sex subgroups. Results: The modified intention-to-treat population (received ≥ 1 dose of study drug and had ≥ 10 days of postbaseline efficacy assessments for the primary endpoint) totaled 837 participants (18–45 years, n = 373; > 45 years, n = 464; male, n = 138; female, n = 699). Consistent reductions in monthly average number of migraine days during 12 weeks were observed, regardless of age (18–45 years: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.7 days; placebo, − 0.9 days; P < 0.001; > 45 years: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.7 days; placebo, − 0.3 days; P < 0.001) and sex (male: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.6 days; placebo, − 0.3 days

Soil respiration is a significant contributor to the global emissions of CO2 and is governed by many soil factors. Reliable estimates of CO2 emission on different scales (e.g., field, regional level) are hard to obtain due to the expressed spatial and temporal variability of the CO2 flux. This study aims to investigate the spatial variability of CO2 flux and soil properties in soybean cropland on Fluvisols (Croatia). The field measurements and soil samples were taken in a regular sampling grid (2 × 2 m) with 44 points in total and the spatial variability was assessed using the kriging and cokriging techniques. The soil CO2 flux showed relatively high spatial heterogeneity, ranging from 0.03 mg/m2s to 0.40 mg/m2s. The soil organic matter content (SOM), soil water content (SWC), and soil temperature (ST) had the lower variability ranging from 2.09% to 2.52%, from 27.7% to 46.8%, and from 13.7 °C to 18.2 °C, respectively. The spatial dependence was high for CO2 flux and ST, moderate for SOM, and low for SWC. The incorporation of the auxiliary variables increased the precision of the estimations for CO2 flux, SOM, and SWC. Kriging was the most accurate method for the spatial prediction of ST. The SWC was associated as the most important factor of the CO2 fluxes, indicated by their significant negative correlation, and the highest increase of the prediction precision during spatial modeling. However, more robust co-variates should be incorporated in future models to further increase the precision., A talajlégzés, melyet számos talajtulajdonság befolyásol, jelentősen hozzájárul a globális CO2 emisszióhoz. A CO2 emisszió különböző léptékű, megbízható becslése nehéz, annak nagyfokú térbeli és időbeli változékonysága miatt. Kutatásunk célja a CO2 kibocsátás és különböző talajtulajdonságok térbeli változékonyságának vizsgálata egy horvátországi szója ültetvényben, Fluvisol talajon. Az in-situ méréseket, valamint a talajminták gyűjtését egy 2x2 méteres rácsháló 44 pontjában végeztük el, a térbeli változékonyság kimutatásához krigelést és kokrigelést használtunk. A talaj CO2 kibocsátása relatív nagy térbeli változékonyságot mutatott, az értékek 0.03 és 0.40 mg m-2 s-1 között alakultak. A talaj szerves anyag tartalmának (SOM), nedvesség tartalmának (SWC) és hőmérsékletének (ST) változékonysága kisebb volt, ezek értékei 2.09 és 2,52%, 27.7 és 46.8%, valamint 13.7 és 18.2 ºC között változtak. A talaj CO2 kibocsátását nagymértékben meghatározta a mérési pontok térbeli helyzete, a SOM közepes, az SWC pedig alacsony térbeli függést mutatott. A segédváltozók modellbe való beépítése növelte a CO2 kibocsátás, valamint a SOM és a SWC becslésének pontosságát. A SWC volt legnagyobb hatással a CO2 kibocsátás alakulására, e két változó között negatív szignifikáns összefüggést találtunk, valamint ez okozta a legnagyobb növekedést a becslés pontosságában a térbeli modellezés során. A továbbiakban robusztusabb segédváltozó adatsorok felvétele szükséges a pontosság növelése érdekében.

Introduction/Objective Calcium hydroxide (CH) is the medicament of choice in endodontic treatment of internal root resorptions. The aim of the study was to compare the effectiveness of three different techniques for CH removal from simulated internal root resorptions. Methods Twenty-nine extracted single-root teeth were prepared using NiTi rotary files of BioRaCe system (40/.04) following irrigation. A round diamond drill was used in the making of a symmetrical standardized internal resorptions 6 mm from the apex. Three techniques for CH removal from internal resorptions were tested: modified conventional syringe irrigation (CSI), passive ultrasonic irrigation (PUI), XP-endo Finisher (XP). Resorptive cavities and apical thirds were observed under a stereomicroscope (x45) and scored (from 1 to 5), while representative samples were analysed by a scanning electron microscope. Obtained results were statistically processed by Kruskal-Wallis and Mann-Whitney U-test (p lt 0.05). Results The most efficient system was PUI, with 66.7% of samples rated 1 and 33.3% rated 2. The next one was XP, and the least efficient was CSI, with 33.3% of samples rated 1 (resorptive defect without medicament). There was a statistically significant difference between the PUI and CSI systems (p lt 0.05), while there was no difference between the PUI and XP systems. Conclusion No system completely removed the CH from the simulated internal root resorption cavities. PUI was the most effective system for removing CH. The combination of techniques provides better performance in removing CH paste residues from the canal walls.

Background: Migraine prevalence is age and sex dependent, predominating in women in early and middle adulthood; however, migraine also represents a substantial burden for men and adults of all ages. Thus, understanding this burden and the efficacy of migraine preventive medications in both sexes and across age groups is critical. The randomized, placebo-controlled, double-blind, phase 3b FOCUS study demonstrated the safety and efficacy of fremanezumab, a fully humanized monoclonal antibody (IgG2∆a) that selectively targets calcitonin gene-related peptide as a migraine preventive treatment for individuals with migraine and prior inadequate response to 2 to 4 migraine preventive medication classes. Here, we assessed the efficacy of fremanezumab in participants from FOCUS subgrouped by age (18–45 years and > 45 years) and sex. Methods: In the FOCUS study, eligible participants were randomized (1:1:1) to 12 weeks of double-blind treatment with quarterly fremanezumab, monthly fremanezumab, or matched monthly placebo. In this post hoc analysis, we evaluated changes from baseline in monthly migraine days (primary endpoint of FOCUS) and other secondary and exploratory efficacy outcomes in prespecified age (18–45 and > 45 years) and sex subgroups. Results: The modified intention-to-treat population (received ≥ 1 dose of study drug and had ≥ 10 days of postbaseline efficacy assessments for the primary endpoint) totaled 837 participants (18–45 years, n = 373; > 45 years, n = 464; male, n = 138; female, n = 699). Consistent reductions in monthly average number of migraine days during 12 weeks were observed, regardless of age (18–45 years: quarterly fremanezumab, − 4.1 days; monthly fremanezumab, − 4.7 days; placebo, − 0.9 days; P < 0.001; > 45 years: quarterly fremanezumab, − 3.6 days; monthly fremanezumab, − 3.7 days; placebo, − 0.3 days; P < 0.001) and sex (male: quarterly fremanezumab, − 4.1 days; mont

An ecosystem services (ES) approach to chemical risk assessment has many potential advantages, but there are also substantial challenges regarding its implementation. We report the findings of a multi-stakeholder workshop that evaluated the feasibility of adopting an ES approach to chemical risk assessment using currently available tools and data. Also evaluated is the added value such an approach would bring to environmental decision making. The aim was to build consensus across disparate stakeholders and to co-produce a common understanding of the regulatory benefits and feasibility of implementing an ES approach in European chemicals regulation. Workshop discussions were informed by proof of concept studies and resulted in the development of a novel tiered framework for assessing chemical risk to ES delivery. There was consensus on the substantial added value of adopting an ES-based approach for regulatory decision making. Ecosystem services provide a common currency and a ‘unifying approach’ across environmental compartments, stressors and regulatory frameworks. The ES approach informs prioritisation of risk and remedial action and aids risk communication and risk management. It facilitates a more holistic assessment, enables ES trade-offs to be compared across alternative interventions, and supports comparative risk assessments and a socio-economic analysis of management options and decisions. Key to realising this added value is a shift away from using a single threshold value to categorise risk, towards a consideration of the exposure-effect distribution for individual ES of interest. Also required is the development of an integrated systems-level approach across regulatory frameworks and agreement on specific protection goals and scenarios for framing environmental risk assessments. The need to further develop tools for extrapolating toxicity data to service providers and ES delivery, including logic chains and ecological production functions, was highlighte

BACKGROUND Patients who are hospitalized for medical illness remain at risk for venous thromboembolism after discharge, but the role of extended thromboprophylaxis in the treatment of such patients is a subject of controversy. METHODS In this randomized, double-blind trial, medically ill patients who were at increased risk for venous thromboembolism on the basis of a modified International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) score of 4 or higher (scores range from 0 to 10, with higher scores indicating a higher risk of venous thromboembolism) or a score of 2 or 3 plus a plasma d-dimer level of more than twice the upper limit of the normal range (defined according to local laboratory criteria) were assigned at hospital discharge to either once-daily rivaroxaban at a dose of 10 mg (with the dose adjusted for renal insufficiency) or placebo for 45 days. The primary efficacy outcome was a composite of symptomatic venous thromboembolism or death due to venous thromboembolism. The principal safety outcome was major bleeding. RESULTS Of the 12,024 patients who underwent randomization, 12,019 were included in the intention-to-treat analysis. The primary efficacy outcome occurred in 50 of 6007 patients (0.83%) who were given rivaroxaban and in 66 of 6012 patients (1.10%) who were given placebo (hazard ratio, 0.76; 95% confidence interval [CI], 0.52 to 1.09; P = 0.14). The prespecified secondary outcome of symptomatic nonfatal venous thromboembolism occurred in 0.18% of patients in the rivaroxaban group and 0.42% of patients in the placebo group (hazard ratio, 0.44; 95% CI, 0.22 to 0.89). Major bleeding occurred in 17 of 5982 patients (0.28%) in the rivaroxaban group and in 9 of 5980 patients (0.15%) in the placebo group (hazard ratio, 1.88; 95% CI, 0.84 to 4.23). CONCLUSIONS Rivaroxaban, given to medical patients for 45 days after hospital discharge, was not associated with a significantly lower risk of symptomatic venous thromboembolism and death

The acceptance and usefulness of simulation models are often limited by the efficiency, transparency, reproducibility, and reliability of the modelling process. We address these issues by suggesting that modellers (1) “trace” the iterative modelling process by keeping a modelling notebook corresponding to the laboratory notebooks used by empirical researchers, (2) use a standardized notebook structure and terminology based on the existing TRACE documentation framework, and (3) use their notebooks to compile TRACE documents that supplement publications and reports. These practices have benefits for model developers, users, and stakeholders: improved and efficient model design, analysis, testing, and application; increased model acceptance and reuse; and replicability and reproducibility of the model and the simulation experiments. Using TRACE terminology and structure in modelling notebooks facilitates production of TRACE documents. We explain the rationale of TRACE, provide example TRACE documents, and suggest strategies for keeping “TRACE Modelling Notebooks.”, Ministerio de Economía y Competitividad (MINECO), Université de Lyon ((UdL)/Agence Nationale de la Recherche (ANR), Agence Nationale de la Recherche (ANR)-JCJC PEPPER, Scottish Government Rural Affairs Food and Environment Strategic Research Programme, Depto. de Biodiversidad, Ecología y Evolución, Fac. de Ciencias Biológicas, TRUE, pub

Objective: Glycogen is a major energy reserve in liver and skeletal muscle. The master metabolic regulator AMP-activated protein kinase (AMPK) associates with glycogen via its regulatory β subunit carbohydrate-binding module (CBM). However, the physiological role of AMPK-glycogen binding in energy homeostasis has not been investigated in vivo. This study aimed to determine the physiological consequences of disrupting AMPK-glycogen interactions. Methods: Glycogen binding was disrupted in mice via whole-body knock-in (KI) mutation of either the AMPK β1 (W100A) or β2 (W98A) isoform CBM. Systematic whole-body, tissue and molecular phenotyping was performed in KI and respective wild-type (WT) mice. Results: While β1 W100A KI did not affect whole-body metabolism or exercise capacity, β2 W98A KI mice displayed increased adiposity and impairments in whole-body glucose handling and maximal exercise capacity relative to WT. These KI mutations resulted in reduced total AMPK protein and kinase activity in liver and skeletal muscle of β1 W100A and β2 W98A, respectively, versus WT mice. β1 W100A mice also displayed loss of fasting-induced liver AMPK total and α-specific kinase activation relative to WT. Destabilisation of AMPK was associated with increased fat deposition in β1 W100A liver and β2 W98A skeletal muscle versus WT. Conclusions: These results demonstrate that glycogen binding plays critical roles in stabilising AMPK and maintaining cellular, tissue and whole-body energy homeostasis.

Natural silicate weathering has always taken part in the geological CO2 sink that has helped stabilize atmospheric CO2 concentrations. Since this reaction is naturally slow, enhanced silicate weathering (ESW) is proposed to accelerate this process and potentially sequester higher amount of CO2. This method falls under negative carbon emission technologies (NETs), which is necessary to slow down anthropogenic climate change. The overall potential, however, depends on the availability of suitable rocks and proximity to the spreading locations. In this thesis research, the potential and environmental implications of enhanced weathering of olivine in arable lands of Europe were studied. The research objective is to mitigate 10% of EU’s 2017 total CO2 emissions by 2050, with the mineral sourced from the biggest olivine quarry in Norway. Dunite in this quarry has high purity (~92%) of olivine, which has high dissolution reactivity. Through the shrinking core model and detailed calculations, the potential amount of olivine weathered, the net CO2 sequestered, the CO2 penalty, and the accumulation of nickel in the topsoil were investigated. Scenarios were made for selected countries in Europe (northern and southern Europe) and most European countries. It was found that, for European scale, the current mining production in Norway needs to be increased 500-1000 times to achieve the target. Suitable pH soil for terrestrial ESW is 5-7, and 75 µm and 30 µm were chosen based on the shrinking core model. At soil pH of 7-8, weathering can still proceed, although it requires 10 µm grain size for a considerable weathering amount, e.g. 70-80% weathered in 25 years. This was proven to be highly inefficient, resulting to more CO2 being emitted than sequestered. Of all the mechanical processes involved to spread grounded olivine on arable land, transport contributed to the highest reduction of CO2 potential. However, fast weathering rates are found in countries with higher mean annual tem

OBJECTIVES: Loss-of-function mutations in the gene encoding the calcium-calmodulin (Ca2+ -CaM)-dependent protein kinase kinase-2 (CaMKK2) enzyme are linked to bipolar disorder. Recently, a de novo arginine to cysteine (R311C) mutation in CaMKK2 was identified from a whole exome sequencing study of bipolar patients and their unaffected parents. The aim of the present study was to determine the functional consequences of the R311C mutation on CaMKK2 activity and regulation by Ca2+ -CaM. METHODS: The effects of the R311C mutation on CaMKK2 activity and Ca2+ -CaM activation were examined using a radiolabeled adenosine triphosphate (ATP) kinase assay. We performed immunoblot analysis to determine whether the R311C mutation impacts threonine-85 (T85) autophosphorylation, an activating phosphorylation site on CaMKK2 that has also been implicated in bipolar disorder. We also expressed the R311C mutant in CaMKK2 knockout HAP1 cells and used immunoblot analysis and an MTS reduction assay to study its effects on Ca2+ -dependent downstream signaling and cell viability, respectively. RESULTS: The R311C mutation maps to the conserved HRD motif within the catalytic loop of CaMKK2 and caused a marked reduction in kinase activity and Ca2+ -CaM activation. The R311C mutation virtually abolished T85 autophosphorylation in response to Ca2+ -CaM and exerted a dominant-negative effect in cells as it impaired the ability of wild-type CaMKK2 to initiate downstream signaling and maintain cell viability. CONCLUSIONS: The highly disruptive, loss-of-function impact of the de novo R311C mutation in human CaMKK2 provides a compelling functional rationale for being considered a potential rare monogenic cause of bipolar disorder.

The anthropogenic emission of greenhouse gases including carbon dioxide, methane, and nitrous oxide is bringing about major changes to the global environment. Although most of the anthropogenic emissions originate from industrial processes, agriculture is responsible for a significant portion of the greenhouse gases produced by humans worldwide. The impact of agriculture has become a key issue, considering that the main greenhouse gases are those related to carbon and nitrogen global cycles. This paper presents a review of the scientific literature meant to provide the impact of human management through fertilizers use on CO2, CH4, and N2O emissions. The influence of organic and mineral fertilization on greenhouse gas emissions is analyzed, and usage of organic amendments showed a wise potential for protecting the environment and to mitigate greenhouse gas emissions.

The anthropogenic emission of greenhouse gases including carbon dioxide, methane, and nitrous oxide is bringing about major changes to the global environment. Although most of the anthropogenic emissions originate from industrial processes, agriculture is responsible for a significant portion of the greenhouse gases produced by humans worldwide. The impact of agriculture has become a key issue, considering that the main greenhouse gases are those related to carbon and nitrogen global cycles. This paper presents a review of the scientific literature meant to provide the impact of human management through fertilizers use on CO2, CH4, and N2O emissions. The influence of organic and mineral fertilization on greenhouse gas emissions is analyzed, and usage of organic amendments showed a wise potential for protecting the environment and to mitigate greenhouse gas emissions.

The acceptance and usefulness of simulation models are often limited by the efficiency, transparency, reproducibility, and reliability of the modelling process. We address these issues by suggesting that modellers (1) “trace” the iterative modelling process by keeping a modelling notebook corresponding to the laboratory notebooks used by empirical researchers, (2) use a standardized notebook structure and terminology based on the existing TRACE documentation framework, and (3) use their notebooks to compile TRACE documents that supplement publications and reports. These practices have benefits for model developers, users, and stakeholders: improved and efficient model design, analysis, testing, and application; increased model acceptance and reuse; and replicability and reproducibility of the model and the simulation experiments. Using TRACE terminology and structure in modelling notebooks facilitates production of TRACE documents. We explain the rationale of TRACE, provide example TRACE documents, and suggest strategies for keeping “TRACE Modelling Notebooks.”

Natural silicate weathering has always taken part in the geological CO2 sink that has helped stabilize atmospheric CO2 concentrations. Since this reaction is naturally slow, enhanced silicate weathering (ESW) is proposed to accelerate this process and potentially sequester higher amount of CO2. This method falls under negative carbon emission technologies (NETs), which is necessary to slow down anthropogenic climate change. The overall potential, however, depends on the availability of suitable rocks and proximity to the spreading locations. In this thesis research, the potential and environmental implications of enhanced weathering of olivine in arable lands of Europe were studied. The research objective is to mitigate 10% of EU’s 2017 total CO2 emissions by 2050, with the mineral sourced from the biggest olivine quarry in Norway. Dunite in this quarry has high purity (~92%) of olivine, which has high dissolution reactivity. Through the shrinking core model and detailed calculations, the potential amount of olivine weathered, the net CO2 sequestered, the CO2 penalty, and the accumulation of nickel in the topsoil were investigated. Scenarios were made for selected countries in Europe (northern and southern Europe) and most European countries. It was found that, for European scale, the current mining production in Norway needs to be increased 500-1000 times to achieve the target. Suitable pH soil for terrestrial ESW is 5-7, and 75 µm and 30 µm were chosen based on the shrinking core model. At soil pH of 7-8, weathering can still proceed, although it requires 10 µm grain size for a considerable weathering amount, e.g. 70-80% weathered in 25 years. This was proven to be highly inefficient, resulting to more CO2 being emitted than sequestered. Of all the mechanical processes involved to spread grounded olivine on arable land, transport contributed to the highest reduction of CO2 potential. However, fast weathering rates are found in countries with higher mean annual tem

Background: Stigma in lung cancer has been associated with diagnostic and treatment delay and with poor outcomes. Personality has impact on the perception of someone's life situation and interacts with psychosocial variables and coping strategies. The vulnerability to stigma is still under-researched. The aim of this study was to investigate this vulnerability by examining the associations between stigma and personality dimensions (i.e., temperament and character traits). Subjects and methods: Seventy six (76) inpatients of the two teaching hospitals with the diagnosis of non-small-cell lung cancer were consecutively included in the study. Patients were assessed with self-reporting scales: Cataldo Lung Cancer Stigma Scale (CLCSS) and Temperament and Character Inventory (TCI). Sociodemographic and clinical data were also collected. Results: Personality dimensions Self-directedness and Persistence showed to be significant predictors of stigma in the linear regression (R=0.519; F=3.104; P=0.007). Stigma and personality dimensions were not associated with age, gender, tumor stage and smoking status. Conclusion: Stigma is associated with particular character (i.e., Self-directedness) and temperament (i.e., Persistence) dimensions. Given the negative clinical outcomes of stigma in lung cancer patients, personality should be taken into account during screening and treatment planning phases.

Chamomile (Matricaria chamomilla L.) dried flowers contain a group of interesting biologically active compounds such as sesquiterpenes, flavonoids, coumarins, vitamins, phenolic acids and glucosides. Therefore, the aim of the present study was to characterize the composition in bioactive compounds (specialized metabolites) present in water and ethanol extracts of chamomile flowers, together with monitoring the impact of different extraction techniques (conventional vs. ultrasound-assisted extraction (UAE)) on the parameters under investigation. UAE treatment significantly decreased the extraction time of bioactive compounds from herbal material. Polyphenolic compounds content and antioxidant capacity were significantly higher in UAE extracts. Moreover, solvent type had a significant impact on the specialized metabolites content, while the highest vitamin C and polyphenols content were recorded in 50% ethanol (v/v) extracts. Optimization of basic extraction factors: solvent type, temperature and technique is crucial for obtaining the extracts with the highest content of specialized metabolites and antioxidant capacity.

Slaven Lupi-Ferandin,1 Sandro Glumac,2 Nancy Poljak,3 Tea Galic,4,5 Natalija Ivkovic,6 Ognjen Brborovic,7 Renata Pecotic,5,6 Zoran Dogas5,6 1Department of Maxillofacial and Oral Surgery, University Hospital of Split, Split, Croatia; 2Department of Anesthesiology and Intensive Care, University Hospital of Split, Split, Croatia; 3Study of Dental Medicine, School of Medicine, University of Zagreb, Zagreb, Croatia; 4Study of Dental Medicine, School of Medicine, University of Split, Split, Croatia; 5Department of Neuroscience, School of Medicine, University of Split, Split, Croatia; 6Sleep Medicine Center, School of Medicine, University of Split, Split, Croatia; 7Department of Social Medicine and Organization of Health Care, Andrija Stampar School of Public Health, School of Medicine, University of Zagreb, Zagreb, CroatiaCorrespondence: Zoran DogasDepartment of Neuroscience, School of Medicine, University of Split, Soltanska 2, Split 21000, CroatiaTel +385 21557903Fax +385 21557895Email zdogas@gmail.comAim: To evaluate the health-related life quality of patients after surgically treated midface fractures.Patients and Methods: This retrospective cohort study compared the 36-Item Short Form Health Survey (SF-36) scores of 42 male patients following surgically treated maxillary or zygomatic fractures with the reported normative data of the SF-36 for the Croatian population.Results: The current study showed that the health-related life quality of surgically treated patients was comparable to similar age, gender, and regional demographics in the Croatian population norm. However, we revealed a significant deterioration of the “Emotional wellbeing” domain in younger patients (P = 0.03) and a severely affected domain of “Physical functioning” in older patients (P = 0.049).Conclusion: There was a significant negative psychological impact from facial trauma on younger patients. In contrast, older patients were more prone to physica

Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been hindered by their low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells for a patient's lifetime. Using a human HSC engrafted mouse model and a human iNKT TCR gene engineering approach, we demonstrated the efficient and long-term generation of HSC-iNKT cells in vivo. These HSC-iNKT cells closely resembled endogenous human iNKT cells, could deploy multiple mechanisms to attack tumor cells, and effectively suppressed tumor growth in vivo in multiple human tumor xenograft mouse models. Preclinical safety studies showed no toxicity or tumorigenicity of the HSC-iNKT cell therapy. Collectively, these results demonstrated the feasibility, safety, and cancer therapy potential of the proposed HSC-iNKT cell therapy and laid a foundation for future clinical development.

Adenosine monophosphate-activated protein kinase (AMPK) regulates multiple signaling pathways involved in glucose and lipid metabolism in response to changes in hormonal and nutrient status. Cell culture studies have shown that AMPK phosphorylation and inhibition of the rate-limiting enzyme in the mevalonate pathway 3-hydroxy-3-methylglutaryl (HMG) coenzyme A (CoA) reductase (HMGCR) at serine-871 (Ser871; human HMGCR Ser872) suppresses cholesterol synthesis. In order to evaluate the role of AMPK-HMGCR signaling in vivo, we generated mice with a Ser871-alanine (Ala) knock-in mutation (HMGCR KI). Cholesterol synthesis was significantly suppressed in wild-type (WT) but not in HMGCR KI hepatocytes in response to AMPK activators. Liver cholesterol synthesis and cholesterol levels were significantly up-regulated in HMGCR KI mice. When fed a high-carbohydrate diet, HMGCR KI mice had enhanced triglyceride synthesis and liver steatosis, resulting in impaired glucose homeostasis. Conclusion: AMPK-HMGCR signaling alone is sufficient to regulate both cholesterol and triglyceride synthesis under conditions of a high-carbohydrate diet. Our findings highlight the tight coupling between the mevalonate and fatty acid synthesis pathways as well as revealing a role of AMPK in suppressing the deleterious effects of a high-carbohydrate diet.

Invariant natural killer T (iNKT) cells are potent immune cells for targeting cancer; however, their clinical application has been hindered by their low numbers in cancer patients. Here, we developed a proof-of-concept for hematopoietic stem cell-engineered iNKT (HSC-iNKT) cell therapy with the potential to provide therapeutic levels of iNKT cells for a patient's lifetime. Using a human HSC engrafted mouse model and a human iNKT TCR gene engineering approach, we demonstrated the efficient and long-term generation of HSC-iNKT cells in vivo. These HSC-iNKT cells closely resembled endogenous human iNKT cells, could deploy multiple mechanisms to attack tumor cells, and effectively suppressed tumor growth in vivo in multiple human tumor xenograft mouse models. Preclinical safety studies showed no toxicity or tumorigenicity of the HSC-iNKT cell therapy. Collectively, these results demonstrated the feasibility, safety, and cancer therapy potential of the proposed HSC-iNKT cell therapy and laid a foundation for future clinical development.

Background: Antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor have shown efficacy in the prevention of migraine attacks. We investigated the efficacy and tolerability of fremanezumab, a fully humanised CGRP antibody, in patients with migraine who had previously not responded to two to four classes of migraine preventive medications. Methods: The randomised, double-blind, placebo-controlled, parallel-group, phase 3b FOCUS trial was done at 104 sites (including hospitals, medical centres, research institutes, and group practice clinics) across Belgium, the Czech Republic, Denmark, Finland, France, Germany, Italy, the Netherlands, Poland, Spain, Sweden, Switzerland, the UK, and the USA. We enrolled participants aged 18–70 years with episodic or chronic migraine who had documented failure to two to four classes of migraine preventive medications in the past 10 years. Failure was defined as no clinically meaningful improvement after at least 3 months of therapy at a stable dose, as per the treating physician's judgment; discontinuation because of adverse events that made treatment intolerable; or treatment contraindicated or unsuitable for the preventive treatment of migraine for the patient. Participants were randomly assigned (1:1:1) by electronic interactive response technology to subcutaneously administered quarterly fremanezumab (month 1, 675 mg; months 2 and 3: placebo), monthly fremanezumab (month 1: 225 mg in episodic migraine and 675 mg in chronic migraine; months 2 and 3: 225 mg in both migraine subgroups), or matched monthly placebo for 12 weeks. The primary outcome was mean change from baseline in the monthly average number of migraine days during the 12-week treatment period. This trial is registered with ClinicalTrials.gov, number NCT03308968, and is now completed. Findings: Between Nov 10, 2017, and July 6, 2018, 838 participants with episodic (329 [39%]) or chronic (509 [61%]) migraine were randomly assigned to placebo (n=279)

AMP-activated protein kinase (AMPK) is a known regulator of whole-body energy homeostasis, but the downstream AMPK substrates mediating these effects are not entirely clear. AMPK inhibits fatty acid synthesis and promotes fatty acid oxidation by phosphorylation of acetyl-CoA carboxylase (ACC) 1 at Ser79 and ACC2 at Ser212. Using mice with Ser79Ala/Ser212Ala knock-in mutations (ACC DKI) we find that inhibition of ACC phosphorylation leads to reduced appetite in response to fasting or cold exposure. At sub-thermoneutral temperatures, ACC DKI mice maintain normal energy expenditure and thermogenesis, but fail to increase appetite and lose weight. We demonstrate that the ACC DKI phenotype can be mimicked in wild type mice using a ghrelin receptor antagonist and that ACC DKI mice have impaired orexigenic responses to ghrelin, indicating ACC DKI mice have a ghrelin signaling defect. These data suggest that therapeutic strategies aimed at inhibiting ACC phosphorylation may suppress appetite following metabolic stress.