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The R package sensobol provides several functions to conduct variance-based uncertainty and sensitivity analysis, from the estimation of sensitivity indices to the visual representation of the results. It implements several state-of-the-art first and total-order estimators and allows the computation of up to fourth-order effects, as well as of the approximation error, in a swift and user-friendly way. Its flexibility makes it also appropriate for models with either a scalar or a multivariate output. We illustrate its functionality by conducting a variance-based sensitivity analysis of three classic models: the Sobol' (1998) G function, the logistic population growth model of Verhulst (1845), and the spruce budworm and forest model of Ludwig, Jones, and Holling (1976).

In this neuropathological study, we investigated neuroinflammation surrounding recent and old cerebral microbleeds (CMBs) and cerebral microinfarcts (CMIs) in 18 cases of cerebral amyloid angiopathy (CAA). We used several serial stainings and immunolabellings to identify microvascular lesions, define their recent or old stage, and characterize neuroinflammatory response (scavenging activity and astrogliosis). We found that both CMBs and CMIs induce a neuroinflammatory response, which was more pronounced in old lesion than recent. Astrogliosis and scavenging activity were differentially prominent according to the ischemic/hemorrhagic nature of the lesion. Our findings provide insights into the pathophysiology of microvascular injuries in CAA. [ABSTRACT FROM AUTHOR]

We reflect on the development of digital twins of the Earth, which we associate with a reductionist view of nature as a machine. The projects of digital twins deviate from contemporary scientific paradigms in the treatment of complexity and uncertainty, and does not engage with critical and interpretative social sciences. We contest the utility of digital twins for addressing climate change issues and discuss societal risks associated with the concept, including the twins' potential to reinforce economicism and governance by numbers, emphasizing concerns about democratic accountability. We propose a more balanced alternative, advocating for independent institutions to develop diverse models, prioritize communication with simple heuristic‐based models, collect comprehensive data from various sources, including traditional knowledge, and shift focus away from physics‐centered variables to inform climate action. We argue that the advancement of digital twins should hinge on stringent controls, favoring a nuanced, interdisciplinary, and democratic approach that prioritizes societal well‐being over blind pursuit of computational sophistication. This article is categorized under:Climate Models and Modeling > Earth System ModelsClimate Models and Modeling > Knowledge Generation with ModelsClimate, History, Society, Culture > Disciplinary Perspectives [ABSTRACT FROM AUTHOR]

Simple Summary: One of the main concerns of veterinarians and researchers involved in animal research work is the improvement of experimental procedures to minimize discomfort to the animal. In the handling of experimental pigs, one of the challenges is immobilization, since due to their size, it is difficult and can cause stress to the animals. Immobilization using a restraint sling is a safe method for the animal and relatively simple for the operators. For this reason, the objective of this study was to evaluate the stress of pigs immobilized with a sling by quantifying salivary cortisol levels. We found that salivary cortisol levels did not increase when pigs were lifted and briefly restrained in the sling, even though some pigs (especially hybrids) showed apparent signs of stress. The lack of correlation between such apparent stress and salivary cortisol levels could be because the vocalizations and movements were not really signs of stress, but simply a way of releasing discomfort, learned in the process of socialization and habituation. In light of this unexpected conclusion, further studies collecting other physiological and behavioral data are needed to clarify what actually happens when pigs are restrained in a sling. The goal of the present study was to evaluate the potential stress developed in farm hybrid pigs and miniature laboratory pigs briefly restrained in a sling, by measuring salivary cortisol levels. The study was performed in 20 healthy pigs grouped into three groups: group HYB-F: hybrid female pigs (n = 12), housed at the CREBA facility (Lleida, Spain); group MIN-F: Specipig® miniature female pigs (n = 4), housed at the CREBA facility; group MIN-M: Specipig® miniature male pigs (n = 4), housed at the Almirall facility (Barcelona, Spain). Upon arrival, the animals were enrolled in a social habituation and training program, which included habituation to a restraint sling. The sling was a stainless steel structure with a canvas hammock which had four openings for placing the animal's feet. The assessment of stress levels in the sling was carried out by measuring cortisol levels in saliva samples. Five saliva samples were collected from each animal over 4 days: Sample 1 (basal sample): taken after animals perceived the presence of the technicians in the pen; Sample 2: taken after animals saw the sling in the pen; Sample 3: taken when animals were in the sling; Sample 4: taken 1 min after the previous one; Sample 5: taken after animals were released back on the floor. In group HYB-F, five animals (5/12) showed strong resistance and could not be restrained in the sling on at least one day. All animals in the groups of miniature pigs could be restrained on all the days. Within each group, the manipulation phase did not affect salivary cortisol levels. Likewise, salivary cortisol levels did not change significantly across days in either group. In conclusion, salivary cortisol levels did not increase when pigs were lifted and briefly restrained in the sling, even though some of them (in particular, the hybrid pigs) showed apparent signs of stress. The lack of correlation between such apparent stress and salivary cortisol levels might be because the vocalizations and movements were not really signs of stress, but simply a way of releasing discomfort, learned in the process of socialization and habituation. In light of this unexpected conclusion, further studies are needed to collect other physiological and behavioral data to clarify what actually happens when pigs are restrained in a sling. [ABSTRACT FROM AUTHOR]

Coagulation factor XI (FXI) has increasingly been shown to play an integral role in several physiologic and pathological processes. FXI is among several zymogens within the blood coagulation cascade that are activated by proteolytic cleavage, with FXI converting to the active serine protease form (FXIa). The evolutionary origins of FXI trace back to duplication of the gene that transcribes plasma prekallikrein, a key factor in the plasma kallikrein–kinin system, before further genetic divergence led to FXI playing a unique role in blood coagulation. While FXIa is canonically known for activating the intrinsic pathway of coagulation by catalyzing the conversion of FIX into FIXa, it is promiscuous in nature and has been shown to contribute to thrombin generation independent of FIX. In addition to its role in the intrinsic pathway of coagulation, FXI also interacts with platelets, endothelial cells, and mediates the inflammatory response through activation of FXII and cleavage of high-molecular-weight kininogen to generate bradykinin. In this manuscript, we critically review the current body of knowledge surrounding how FXI navigates the interplay of hemostasis, inflammatory processes, and the immune response and highlight future avenues for research. As FXI continues to be clinically explored as a druggable therapeutic target, understanding how this coagulation factor fits into physiological and disease mechanisms becomes increasingly important. [ABSTRACT FROM AUTHOR]

Hemorrhage remains a major complication of anticoagulants, with bleeding leading to serious and even life-threatening outcomes in rare settings. Currently available anticoagulants target either multiple coagulation factors or specifically coagulation factor (F) Xa or thrombin; however, inhibiting these pathways universally impairs hemostasis. Bleeding complications are especially salient in the medically complex population who benefit from medical devices. Extracorporeal devices—such as extracorporeal membrane oxygenation, hemodialysis, and cardiac bypass—require anticoagulation for optimal use. Nonetheless, bleeding complications are common, and with certain devices, highly morbid. Likewise, pharmacologic prophylaxis to prevent thrombosis is not commonly used with many medical devices like central venous catheters due to high rates of bleeding. The contact pathway members FXI, FXII, and prekallikrein serve as a nexus, connecting biomaterial surface-mediated thrombin generation and inflammation, and may represent safe, druggable targets to improve medical device hemocompatibility and thrombogenicity. Recent in vivo and clinical data suggest that selectively targeting the contact pathway of coagulation through the inhibition of FXI and FXII can reduce the incidence of medical device-associated thrombotic events, and potentially systemic inflammation, without impairing hemostasis. In the following review, we will outline the current in vivo and clinical data encompassing the mechanism of action of drugs targeting the contact pathway. This new class of inhibitors has the potential to herald a new era of effective and low-risk anticoagulation for the management of patients requiring the use of medical devices. [ABSTRACT FROM AUTHOR]

With the advent of new terminologies to categorize and characterize the simple and complex monogenetic volcanoes, also came the semantic issues, which caused a predicament for the usage of terms like simple, complex, polycyclic, polymagmatic, complex monogenetic volcanoes with polygenetic inheritance. To analyse and validate this nomenclature, we studied an overlapping volcanic structure located south of the present‐day town of Irapuato, Central Mexico, that appears to be a monogenetic complex at first sight. Field observations, tephra stratigraphy, petrography and geochemistry of the tephra deposits confirms that the structure is in fact a cluster of three simple (San Joaquin tuff ring and two scoria mounds) and one complex, polycyclic, polymagmatic (La Sanabria‐San Roque tuff ring) monogenetic volcanoes formed by independent events, governed by distinct conduits and magma bodies of different origin (subduction‐related, OIB and E‐MORB origin) and separated by different tephra sequences of dissimilar components and depositional characteristics. We estimate the magma volumes (using the juvenile content and their vesicularity percentage) to be at 0.40–1.31 × 108, 0.25 × 108 and 0.42–0.90 × 108 m3 for San Joaquin, La Sanabria and San Roque, reckoning an eruption duration of 77 and 48 and 81 days, respectively (considering an average eruption rate of 6 m3/s from the well‐documented shallow crater (<30 m), Ukinrek maars in Alaska) occurring within the age range of 40–70 k years (crater diameter and depth ratio). This study not only aided to validate the above‐mentioned terms for monogenetic volcanoes, but also reconsider a few of them and avoid confusion with the polygenetic counterparts. [ABSTRACT FROM AUTHOR]

The study examined psychology students' understanding of interaction graphs. The sample was divided into two groups based on the students' level of instruction. In an interview, each student solved an interaction problem with graphic representations taken from their textbooks. There were two different types of task: a selection task and an interpretation task. The understanding and assessment of the adequacy of the graphic format were analysed categorically, and the differences between groups were studied. The data generally showed a low level of understanding of interaction graphs, although there were differences that revealed better results in the group with more instruction. Likewise, students generally preferred bar graphs over line graphs to represent interaction. However, students who clearly perceived the interaction chose line graphs to represent it. These data point to the need for statistical instruction based not only on the construction of graphs but also on their interpretation aimed at detecting conceptual relationships. [ABSTRACT FROM AUTHOR]

Heme is a primordial macrocycle upon which most aerobic life on Earth depends. It is essential to the survival and health of nearly all cells, functioning as a prosthetic group for oxygen‐carrying proteins and enzymes involved in oxidation/reduction and electron transport reactions. Heme is essential for the function of numerous hemoproteins and has numerous other roles in the biochemistry of life. In mammals, heme is synthesised from glycine, succinyl‐CoA, and ferrous iron in a series of eight steps. The first and normally rate‐controlling step is catalysed by 5‐aminolevulinate synthase (ALAS), which has two forms: ALAS1 is the housekeeping form with highly variable expression, depending upon the supply of the end‐product heme, which acts to repress its activity; ALAS2 is the erythroid form, which is regulated chiefly by the adequacy of iron for erythroid haemoglobin synthesis. Abnormalities in the several enzymes of the heme synthetic pathway, most of which are inherited partial enzyme deficiencies, give rise to rare diseases called porphyrias. The existence and role of heme importers and exporters in mammals have been debated. Recent evidence established the presence of heme transporters. Such transporters are important for the transfer of heme from mitochondria, where the penultimate and ultimate steps of heme synthesis occur, and for the transfer of heme from cytoplasm to other cellular organelles. Several chaperones of heme and iron are known and important for cell health. Heme and iron, although promoters of oxidative stress and potentially toxic, are essential cofactors for cellular energy production and oxygenation. [ABSTRACT FROM AUTHOR]

Background: The prevalence of obesity is already a worldwide health concern. The development of straightforward guidelines regarding the whole available armamentarium (i.e., medical, endoscopic, and surgical interventions in conjunction with a guidance program) is paramount to offering the best multimodal approach to patients with obesity. Methods: The International Federation for Surgery of Obesity and Metabolic Disorders-European Chapter (IFSO-EC) identified a panel of experts to develop the present guidelines. The panel formulated a series of clinical questions (based on the patient, intervention, comparison, and outcome conceptual framework), which have been voted on and approved. A GRADE methodology will be applied to assess the quality of evidence and formulate recommendations employed to minimize selection and information biases. This approach aims to enhance the reliability and validity of recommendations, promoting greater adherence to the best available evidence. Results: These guidelines are intended for adult patients with a body mass index (BMI) ≥ 30 kg/m2 who are candidates for metabolic bariatric surgery (MBS). The expert panel responsible for developing these guidelines comprised 25 panelists (92% were bariatric surgeons) and 3 evidence reviewers, with an average age of 50.1 ± 10.2 years. The panel focused on 3 key questions regarding the combined use of structured lifestyle interventions, approved obesity management medications, and endoscopic weight loss procedures with MBS. Conclusions: The complexity of obesity as a chronic disease requires a comprehensive knowledge of all the available and feasible therapeutic options. The IFSO-EC society felt the urgent need to develop methodologically valid guidelines to give a full picture and awareness of the possible surgical and non-surgical therapeutic strategies employed with a multimodal approach. [ABSTRACT FROM AUTHOR]

BackgroundDonor availability and transplantation-related risks limit the broad use of allogeneic hematopoietic-cell transplantation in patients with transfusion-dependent β-thalassemia. After previously establishing that lentiviral transfer of a marked β-globin (βA-T87Q) gene could substitute for long-term red-cell transfusions in a patient with β-thalassemia, we wanted to evaluate the safety and efficacy of such gene therapy in patients with transfusion-dependent β-thalassemia.MethodsIn two phase 1-2 studies, we obtained mobilized autologous CD34+ cells from 22 patients (12 to 35 years of age) with transfusion-dependent β-thalassemia and transduced the cells ex vivo with LentiGlobin BB305 vector, which encodes adult hemoglobin (HbA) with a T87Q amino acid substitution (HbAT87Q). The cells were then reinfused after the patients had undergone myeloablative busulfan conditioning. We subsequently monitored adverse events, vector integration, and levels of replication-competent lentivirus. Efficacy assessments included levels of total hemoglobin and HbAT87Q, transfusion requirements, and average vector copy number.ResultsAt a median of 26 months (range, 15 to 42) after infusion of the gene-modified cells, all but 1 of the 13 patients who had a non-β0/β0 genotype had stopped receiving red-cell transfusions; the levels of HbAT87Q ranged from 3.4 to 10.0 g per deciliter, and the levels of total hemoglobin ranged from 8.2 to 13.7 g per deciliter. Correction of biologic markers of dyserythropoiesis was achieved in evaluated patients with hemoglobin levels near normal ranges. In 9 patients with a β0/β0 genotype or two copies of the IVS1-110 mutation, the median annualized transfusion volume was decreased by 73%, and red-cell transfusions were discontinued in 3 patients. Treatment-related adverse events were typical of those associated with autologous stem-cell transplantation. No clonal dominance related to vector integration was observed.ConclusionsGene therapy with autologous CD34+ cells transduced with the BB305 vector reduced or eliminated the need for long-term red-cell transfusions in 22 patients with severe β-thalassemia without serious adverse events related to the drug product. (Funded by Bluebird Bio and others; HGB-204 and HGB-205 ClinicalTrials.gov numbers, NCT01745120 and NCT02151526 .).

BackgroundSubclinical hypothyroidism (SCH) is a common condition in elderly people, defined as elevated serum thyroid-stimulating hormone (TSH) with normal circulating free thyroxine (fT4). Evidence is lacking about the effect of thyroid hormone treatment. We describe the protocol of a large randomised controlled trial (RCT) of Levothyroxine treatment for SCH.MethodsParticipants are community-dwelling subjects aged ≥65 years with SCH, diagnosed by elevated TSH levels (≥4.6 and ≤19.9 mU/L) on a minimum of two measures ≥ three months apart, with fT4 levels within laboratory reference range. The study is a randomised double-blind placebo-controlled parallel group trial, starting with levothyroxine 50 micrograms daily (25 micrograms in subjects