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A form of dystrophinopathy with mild or subclinical neuromuscular signs has been previously reported in a family of Labrador retrievers. Markedly and persistently elevated creatine kinase activity was first noted at 6 months of age. Skeletal muscle biopsies revealed a dystrophic phenotype, with dystrophin non-detectable on western blotting and immunohistochemical staining, and with increased utrophin expression. In this report we demonstrate with western blotting that α-dystroglycan is present at essentially normal levels. Whole genome sequencing has also now revealed an approximately 400kb tandem genomic DNA duplication including exons 2-7 of the DMD gene that was inserted into intron 7 of the wild type gene. Skeletal muscle cDNA from 2 cases contained DMD transcripts as expected from an in-frame properly-spliced exon 2-7 tandem insertion. A similar 5' duplication involving DMD exons 2-7 has been reported in a human family with dilated cardiomyopathy but without skeletal myopathy. This is the 3rd confirmed mutation in the DMD gene in Labrador retrievers.

We define two maps, one map from the set of conditional probability systems (CPS’s) onto the set of lexicographic probability systems (LPS’s), and another map from the set of LPS’s with full support onto the set of CPS’s. We use these maps to establish a relationship between strong belief (defined on CPS’s) and assumption (defined on LPS’s). This establishes a relationship at the abstract level between these two widely used notions of belief in an extended probability-theoretic setting.

Cocoa extract is a source of flavanols that favorably influence vascular risk factors in small and short-term trials, yet effects on clinical cardiovascular events are untested.We examined whether cocoa extract supplementation decreases total cardiovascular disease (CVD) among older adults.We conducted a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of cocoa extract supplementation and multivitamins for prevention of CVD and cancer among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y), free of major CVD and recently diagnosed cancer. The intervention phase was June 2015 through December 2020. This article reports on the cocoa extract intervention. Participants were randomly assigned to a cocoa extract supplement [500 mg flavanols/d, including 80 mg (-)-epicatechin] or placebo. The primary outcome was a composite of confirmed incident total cardiovascular events, including myocardial infarction (MI), stroke, coronary revascularization, cardiovascular death, carotid artery disease, peripheral artery surgery, and unstable angina.During a median follow-up of 3.6 y, 410 participants taking cocoa extract and 456 taking placebo had confirmed total cardiovascular events (HR: 0.90; 95% CI: 0.78, 1.02; P = 0.11). For secondary endpoints, HRs were 0.73 (95% CI: 0.54, 0.98) for CVD death, 0.87 (95% CI: 0.66, 1.16) for MI, 0.91 (95% CI: 0.70, 1.17) for stroke, 0.95 (95% CI: 0.77, 1.17) for coronary revascularization, neutral for other individual cardiovascular endpoints, and 0.89 (95% CI: 0.77, 1.03) for all-cause mortality. Per-protocol analyses censoring follow-up at nonadherence supported a lower risk of total cardiovascular events (HR: 0.85; 95% CI: 0.72, 0.99). There were no safety concerns.Cocoa extract supplementation did not significantly reduce total cardiovascular events among older adults but reduced CVD death by 27%. Potential reductions in total cardiovascular events were supported in per-protocol analyses. Additional research is warranted to clarify whether cocoa extract may reduce clinical cardiovascular events. This trial is registered at www.clinicaltrials.gov as NCT02422745.

Background Patients with inflammatory bowel diseases (IBD), specifically those treated with anti-tumor-necrosis-factor (TNF)α biologics are at high risk for vaccine preventable infections. Their ability to mount adequate vaccine responses is unclear. Aim To assess serologic responses to mRNA-COVID-19 vaccine, and safety profile, in patients with IBD stratified according to therapy, compared to healthy controls (HC). Methods Prospective, controlled, multi-center Israeli study. Subjects enrolled received two BNT162b2 (Pfizer/BioNTech) doses. Anti-spike antibodies levels and functional activity, anti-TNFα levels and adverse events (AEs) were detected longitudinaly. Results Overall 258 subjects: 185 IBD (67 treated with anti-TNFα, 118 non-anti-TNFα), and 73 HC. After the first vaccine dose all HC were seropositive, while ∼7% of patients with IBD, regardless of treatment, remained seronegative. After the second dose all subjects were seropositive, however anti-spike levels were significantly lower in anti-TNFα treated compared to non-anti-TNFα treated patients, and HC (both P, Graphical abstract

We develop a method for subdividing polyhedral complexes in a way that restricts the possible recession cones and allows one to work with a fixed class of polyhedron. We use these results to construct locally finite completions of rational polyhedral complexes whose recession cones lie in a fixed fan, locally finite polytopal completions of polytopal complexes, and locally finite zonotopal completions of zonotopal complexes., Comment: 20 pages, 5 figures

Valuated term orders are studied for the purposes of Gr\"{o}bner theory over fields with valuation. The points of a usual tropical variety correspond to certain valuated terms preorders. Generalizing both of these, the set of all ``well-behaved'' valuated term preorders is canonically in bijection with the points of a space introduced in our previous work on tropical adic geometry. In this paper we interpret these points geometrically by explicitly characterizing them in terms of classical polyhedral geometry. This characterization gives a bijection with equivalence classes of flags of polyhedra as well as a bijection with a class of prime filters on a lattice of polyhedral sets. The first of these also classifies valuated term orders. The second bijection is of the same flavor as the bijections from [van der Put and Schneider, 1995] in non-archimedean analytic geometry and indicates that the results of that paper may have analogues in tropical adic geometry., Comment: This was originally the second half of arXiv:2209.15116v2

For over 25 years, common belief has been widely viewed as necessary for joint behavior. But this is not quite correct. We show by example that what can naturally be thought of as joint behavior can occur without common belief. We then present two variants of common belief that can lead to joint behavior, even without standard common belief ever being achieved, and show that one of them, action-stamped common belief, is in a sense necessary and sufficient for joint behavior. These observations are significant because, as is well known, common belief is quite difficult to achieve in practice, whereas these variants are more easily achievable., Comment: In Proceedings TARK 2023, arXiv:2307.04005

We examine the aesthetic characteristics of row tile patterns defined by repeating strips of polygons. In experiment 1 participants rated the perceived beauty of equilateral triangle, square and rectangular tilings presented at vertical and horizontal orientations. The tiles were shifted by one-fourth increments of a complete row cycle. Shifts that preserved global symmetry were liked the most. Local symmetry by itself did not predict ratings but tilings with a greater number of emergent features did. In a second experiment we presented row tiles using all types of three- and four-sided geometric figures: acute, obtuse, isosceles and right triangles, kites, parallelograms, a rhombus, trapezoid, and trapezium. Once again, local polygon symmetry did not predict responding but measures of correspondence between local and global levels did. In particular, number of aligned polygon symmetry axes and number of aligned polygon sides were significantly and positively correlated with beauty ratings. Preference was greater for more integrated tilings, possibly because they encourage the formation of gestalts and exploration within and across levels of spatial scale.

Infectious diarrhea is caused by a variety of pathogens, including viruses, bacteria, and parasitic organisms. Though the causative agent of diarrhea has historically been evaluated via stool cultures, recently, culture-independent diagnostic tests (CIDT) have been developed and utilized with increasing frequency. Current practice guidelines recommend their use as adjuncts to stool cultures for diagnosing acute and chronic diarrhea. The three principal CIDT are microscopy, enzyme-based immunoassays (EIAs), and molecular based polymerase chain reaction (PCR). This review explores the common causes of infectious diarrhea, the basics of stool culture, the diagnostic utility of these three culture-independent modalities, and the strengths and weaknesses of all currently available clinical techniques. It also outlines considerations for specific populations including returning travelers and those with inflammatory bowel disease.

GoalsTo define fragmentation in neurologic care delivery, explain the positive and negative drivers in neurologic practice that contribute to fragmentation, illustrate situations that increase fragmentation risk, emphasize the costs and impact on both patients and providers, and propose solutions that allow for more cohesive care.Work GroupThe Transforming Leaders Program (TLP) class of 2020 was tasked by American Academy of Neurology (AAN) leadership to identify the leading trends in inpatient and outpatient neurology and to predict their effects on future neurologic practice.MethodsResearch material included AAN databases, PubMed searches, discussion with topic experts, and AAN leadership.ResultsTrends in care delivery are driven by changes in the work force, shifts in health care delivery, care costs, changes in evidence-based care, and patient factors. These trends can contribute to care fragmentation. Potential solutions to these problems are proposed based on care models developed in oncology and medicine.LimitationsThis article shares our opinions as there is a lack of evidence-based guidelines for optimal neurologic care delivery.

Alpha-dystroglycan (αDG) is a highly glycosylated cell surface protein with a significant role in cell-to-extracellular matrix interactions in muscle. αDG interaction with extracellular ligands relies on the activity of the LARGE1 glycosyltransferase that synthesizes and extends the heteropolysaccharide matriglycan. Abnormalities in αDG glycosylation and formation of matriglycan are the pathogenic mechanisms for the dystroglycanopathies, a group of congenital muscular dystrophies. Muscle biopsies were evaluated from related 6-week-old Labrador retriever puppies with poor suckling, small stature compared to normal litter mates, bow-legged stance and markedly elevated creatine kinase activities. A dystrophic phenotype with marked degeneration and regeneration, multifocal mononuclear cell infiltration and endomysial fibrosis was identified on muscle cryosections. Single nucleotide polymorphism (SNP) array genotyping data on the family members identified three regions of homozygosity in 4 cases relative to 8 controls. Analysis of whole genome sequence data from one of the cases identified a stop codon mutation in the LARGE1 gene that truncates 40% of the protein. Immunofluorescent staining and western blotting demonstrated the absence of matriglycan in skeletal muscle and heart from affected dogs. Compared to control, LARGE enzyme activity was not detected. This is the first report of a dystroglycanopathy in dogs.

Cancer cell metabolism is often deregulated as a result of adaption to meeting energy and biosynthesis demands of rapid growth or direct mutation of key metabolic enzymes. Better understanding of such deregulation can provide new insights on targetable vulnerabilities, but is complicated by the difficulty in probing cell metabolism at different levels of resolution and under different experimental conditions. We construct computational models of glucose and glutamine metabolism with focus on the effect of IDH1/2-mutations in cancer using a combination of experimental metabolic flux data and patient-derived gene expression data. Our models demonstrate the potential of computational exploration to reveal biologic behavior: they show that an exogenously-mutated IDH1 experimental model utilizes glutamine as an alternative carbon source for lactate production under hypoxia, but does not fully-recapitulate the patient phenotype under normoxia. We also demonstrate the utility of using gene expression data as a proxy for relative differences in metabolic activity. We use the approach of probabilistic model checking and the freely-available Probabilistic Symbolic Model Checker to construct and reason about model behavior.

Pigment production and distribution is controlled through multiple genes, resulting in a wide range of coat color phenotypes in dogs. Dogs that produce only the pheomelanin pigment vary in intensity from white to deep red. The Poodle breed has a wide range of officially recognized coat colors, including the pheomelanin-based white, cream, apricot, and red coat colors, which are not fully explained by the previously identified genetic variants involved in pigment intensity. Here, a genome-wide association study for pheomelanin intensity was performed in Poodles which identified an association on canine chromosome 18. Whole-genome sequencing data revealed an SNN retrocopy insertion (SNNL1) in apricot and red Poodles within the associated region on chromosome 18. While equal numbers of melanocytes were observed in all Poodle skin hair bulbs, higher melanin content was observed in the darker Poodles. Several genes involved in melanogenesis were also identified as highly overexpressed in red Poodle skin. The most differentially expressed gene however was GPR22, which was highly expressed in red Poodle skin while unexpressed in white Poodle skin (log2 fold change in expression 6.1, P

Summary Background Etrolizumab is a gut-targeted, anti-β7 integrin, monoclonal antibody. In an earlier phase 2 induction study, etrolizumab significantly improved clinical remission compared with placebo in patients with moderately to severely active ulcerative colitis. We aimed to evaluate the efficacy and safety of etrolizumab in patients with moderately to severely active ulcerative colitis who had been previously treated with anti-tumour necrosis factor (TNF) agents. Methods HICKORY was a multicentre, phase 3, double-blind, placebo-controlled study in adult (18–80 years) patients with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6–12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) previously treated with TNF inhibitors. Patients were recruited from 184 treatment centres across 24 countries in North America, South America, Europe, Asia, Oceania, and the Middle East. Patients needed to have an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. In cohort 1, patients received open-label etrolizumab 105 mg every 4 weeks for a 14-week induction period. In cohort 2, patients were randomly assigned (4:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks for the 14-week induction phase. Patients in either cohort achieving clinical response to etrolizumab induction were eligible for the maintenance phase, in which they were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg or placebo every 4 weeks through to week 66. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants (induction randomisation only), baseline disease activity, week 14 MCS remission status (maintenance randomisation only), and induction cohort (maintenance randomisation only). All patients and study site personnel were masked to treatment assignment. Primary endpoints were remission (Mayo Clinic total score [MCS] ≤2, with individual subscores of ≤1 and a rectal bleeding subscore of 0) at week 14, and remission at week 66 among patients with a clinical response (MCS with ≥3-point decrease and ≥30% reduction from baseline, plus ≥1 point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) at week 14. Efficacy was analysed using a modified intent-to-treat population. Safety analyses included all patients who received at least one dose of study drug during the induction phase. This study is registered at ClinicalTrials.gov , NCT02100696 . Findings HICKORY was conducted from May 21, 2014, to April 16, 2020, during which time 1081 patients were screened, and 609 deemed eligible for inclusion. 130 patients were included in cohort 1. In cohort 2,479 patients were randomly assigned to the induction phase (etrolizumab n=384, placebo n=95). 232 patients were randomly assigned to the maintenance phase (etrolizumab to etrolizumab n=117, etrolizumab to placebo n=115). At week 14, 71 (18·5%) of 384 patients in the etrolizumab group and six (6·3%) of 95 patients in the placebo group achieved the primary induction endpoint of remission (p=0·0033). No significant difference between etrolizumab and placebo was observed for the primary maintenance endpoint of remission at week 66 among patients with a clinical response at week 14 (27 [24·1%] of 112 vs 23 [20·2%] of 114; p=0·50). Four patients in the etrolizumab group reported treatment-related adverse events leading to treatment discontinuation. The proportion of patients reporting at least adverse event was similar between treatment groups for induction (etrolizumab 253 [66%] of 384; placebo 63 [66%] of 95) and maintenance (etrolizumab to etrolizumab 98 [88%] of 112; etrolizumab to placebo 97 [85%] of 114). The most common adverse event in both groups was ulcerative colitis flare. Most adverse events were mild or moderate. During induction, the most common serious adverse event was ulcerative colitis flare (etrolizumab ten [3%] of 384; placebo: two [2%] of 95). During maintenance, the most common serious adverse event in the etrolizumab to etrolizumab group was appendicitis (two [2%] of 112) and the most common serious adverse events in the etrolizumab to placebo group were ulcerative colitis flare (two [2%] of 114) and anaemia (two [2%] of 114). Interpretation HICKORY demonstrated that a significantly higher proportion of patients with moderately to severely active ulcerative colitis who had been previously treated with anti-TNF agent were able to achieve remission at week 14 when treated with etrolizumab compared with placebo; however, there was no significant difference between groups in remission at week 66 among patients with a clinical response at week 14. Funding F Hoffmann-La Roche.

OBJECTIVE: To determine whether red blood cell distribution width (RDW) is associated with an increased odds of mortality in hospitalized dogs and cats. DESIGN: Retrospective, single-center study; data collected from 2007 to 2017. SETTING: University teaching hospital. ANIMALS: Six thousand six hundred and sixty-one animals (5,183 dogs and 1,478 cats). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Medical records were identified from animals presented to the emergency service and admitted to the ICU with a CBC and serum biochemistry performed on admission. Patients were stratified into quintiles based upon presenting RDW, and logistic regression modeling was performed to evaluate the relationship between RDW and in-hospital mortality. Canine patients with a presenting RDW in the upper fourth and fifth quintiles had an increased odds of all-cause in-hospital mortality (P < 0.0001). Specifically, dogs in the upper fifth quintile had a 2.1-fold greater odds of death compared to dogs in the first quintile, and dogs in the upper fourth quintile had a 1.9-fold greater odds of death compared to dogs in the first quintile. This relationship remained significant after adjusting for age, sex, key laboratory values excluding HCT, medical vs surgical disease, and diagnosis category. This relationship was no longer significant with the inclusion of HCT. No significant association was identified between presenting RDW and in-hospital mortality in cats. CONCLUSIONS: Hospitalized dogs with higher RDW on presentation to the emergency service have greater odds of all-cause in-hospital mortality compared to dogs with a lower RDW. A similar association between RDW and mortality was not found in cats. Further studies are warranted to assess the usefulness of this biomarker for specific diseases in dogs and to better understand the mechanisms driving the association between increased RDW and mortality in canine patients.

Profiling the adaptive immune repertoire using next generation sequencing (NGS) has become common in human medicine, showing promise in characterizing clonal expansion of B cell clones through analysis of B cell receptors (BCRs) in patients with lymphoid malignancies. In contrast, most work evaluating BCR repertoires in dogs has employed traditional PCR-based approaches analyzing the IGH locus only. The objectives of this study were to: (1) describe a novel NGS protocol to evaluate canine BCRs; (2) develop a bioinformatics pipeline for processing canine BCR sequencing data; and (3) apply these methods to derive insights into BCR repertoires of healthy dogs and dogs undergoing treatment for B-cell lymphoma. RNA from peripheral blood mononuclear cells of healthy dogs (n = 25) and dogs newly diagnosed with intermediate-to-large B-cell lymphoma (n = 18) with intent to pursue chemotherapy was isolated, converted into cDNA and sequenced by NGS. The BCR repertoires were identified and quantified using a novel analysis pipeline. The IGK repertoires of the healthy dogs were far less diverse compared to IGL which, as with IGH, was highly diverse. Strong biases at key positions within the CDR3 sequence were identified within the healthy dog BCR repertoire. For a subset of the dogs with B-cell lymphoma, clonal expansion of specific IGH sequences pre-treatment and reduction post-treatment was observed. The degree of expansion and reduction correlated with the clinical outcome in this subset. Future studies employing these techniques may improve disease monitoring, provide earlier recognition of disease progression, and ultimately lead to more targeted therapeutics.

Recent studies have shown that preference judgments can vary considerably from one person to another and when these data are averaged the results can be misleading. In the current study we examine individual differences in aesthetic preference for randomized visual patterns. In experiment 1 we start with a structured checkerboard and progressively randomize its alternating black and white squares by 10% increments. In experiment 2 we begin with a structured square array of vertical line segments and progressively randomize line orientation. In both experiments there were strong differences in responding with most participants favoring either ordered or randomized versions. We found differences in Big Five trait scores across these groupings. Individuals who scored high on extroversion, agreeableness, and conscientiousness all preferred random patterns. Preference results for openness and neuroticism varied across the experiments. Explanations for predicted and obtained trait outcomes are provided.

Preference for angular vs. curved forms has a long history in psychology but few of the many studies conducted have examined actual degree of angularity. In two experiments we present observers with randomly positioned and randomly oriented texture displays of angles viewed within a circular frame. The angle conditions varied from 0°-180° in 20° increments, covering the entire spectrum of possibilities including acute, obtuse, right, and straight line angles. In Experiment 1, 25 undergraduates rated the perceived beauty of these displays. In Experiment 2, the same stimulus set and procedure were used with 27 participants instead judging perceived threat. Based on the findings in the literature, we predicted that sharper angles would be judged less beautiful and more threatening. The results were mostly confirmed. Acute angles are preferred less but there are also distinct preferences for right angles and straight lines, perhaps due to their greater familiarity in constructed environments. There was a consistent and anticipated finding for threat in the second study: the sharper an angle the greater its perceived threat. Fear of sharp objects as assessed in a personality questionnaire was found to positively correlate with threat judgements. Future work should look more closely at degree of angularity in embedded object contours and at individual response differences.

Pigment production and distribution is controlled through multiple genes, resulting in a wide range of coat color phenotypes in dogs. Dogs that produce only the pheomelanin pigment vary in intensity from white to deep red. The Poodle breed has a wide range of officially recognized coat colors, including the pheomelanin-based white, cream, apricot, and red coat colors, which are not fully explained by the previously identified genetic variants involved in pigment intensity. Here, a genome-wide association study for pheomelanin intensity was performed in Poodles which identified an association on canine chromosome 18. Whole-genome sequencing data revealed an SNN retrocopy insertion (SNNL1) in apricot and red Poodles within the associated region on chromosome 18. While equal numbers of melanocytes were observed in all Poodle skin hair bulbs, higher melanin content was observed in the darker Poodles. Several genes involved in melanogenesis were also identified as highly overexpressed in red Poodle skin. The most differentially expressed gene however was GPR22, which was highly expressed in red Poodle skin while unexpressed in white Poodle skin (log2 fold change in expression 6.1, P

In this report, we describe a novel genetic basis for congenital dyserythropoietic anemia and polymyopathy in Labrador Retriever littermates characterized by incidental detection of marked microcytosis, inappropriate metarubricytosis, pelvic limb weakness and muscle atrophy. A similar syndrome has been described in English Springer Spaniel littermates with an early onset of anemia, megaesophagus, generalized muscle atrophy and cardiomyopathy. Muscle histopathology in both breeds showed distinctive pathological changes consistent with congenital polymyopathy. Using whole genome sequencing and mapping to the CanFam4 (

Familial mitral valve prolapse in human beings has been associated with several genetic variants; however, in most cases, a known variant has not been identified. Dogs also have a naturally occurring form of familial mitral valve disease (MMVD) with similarities to the human disease. A shared genetic background and clinical phenotype of this disease in some dog breeds has indicated that the disease may share a common genetic cause. We evaluated DNA from 50 affected dogs from five different dog breeds in a whole genome sequencing approach to identify shared variants across and within breeds that could be associated with MMVD. No single causative genetic mutation was found from the 50 dogs with MMVD. Ten variants were identified in 37/50 dogs around and within the MED13L gene. These variants were no longer associated with MMVD when evaluated with a larger cohort including both affected and unaffected dogs. No high/moderate impact variants were identified in 10/10 miniature poodles, one was identified in 10/10 Yorkshire Terriers and 10/10 dachshunds, respectively, 14 were identified in 10/10 Miniature schnauzers, and 19 in 10/10 CKCS. Only one of these could be associated with the cardiac valve (Chr12:36801705, COL12A1; CKCS) but when evaluated in an additional 100 affected CKCS the variant was only identified in 84/100 affected dogs, perhaps indicating genetic heterogeneity in this disease. Our findings indicate that development of MMVD in the dog may be related to a combination of genetic and environmental factors that impact specific molecular pathways rather than a single shared genetic variant across or within breeds.

In Germany, rock salt formations are possible host rock candidates for a repository for heat-emitting radioactive waste. The safety concept of a repository in salt bases on a multibarrier system consisting mainly of the geological barrier salt and geotechnical seals ensuring safe containment. Crushed salt will be used for backfilling of cavities and sealing measures in drifts and shafts due to its favourable properties and its easy availability (mined-off material). The creep of the rock salt leads to crushed salt compaction with time. Thereby, the crushed salts' porosity is reduced from the initial porosity of 30 %–40 % to a value comparable to the porosity of undisturbed rock salt ( ≤1 %). In such low porosity ranges, technical impermeability is assumed. The compaction behaviour of crushed salt is rather complex and involves several coupled THM processes (Krohn et al., 2017; Hansen et al., 2014). It is influenced by internal properties like humidity and grain size distribution, as well as boundary conditions such as temperature, compaction rate or stress state. However, the current process understanding has some important gaps referring to the material behaviour, experimental database and numerical modelling. It needs to be extended and validated, especially in the low porosity range. The objective of the KOMPASS project was development of methods and strategies for the reduction of deficits in the prediction of crushed salt compaction leading to an improvement of the prognosis quality. Key results are as follows (KOMPASS Phase 1, 2020): selection of an easily available and permanently producible synthetic crushed salt mixture, acting as a reference material for generic investigations; development and proof of different techniques for producing pre-compacted samples for further investigations; establishment of a tool of microstructure investigation methods to demonstrate the comparability of grain structures of pre-compacted samples with in-situ compacted material for future investigations; execution of various laboratory experiments using pre-compacted samples, e.g. long-term creep tests which deliver reliable information about time- and stress-dependent compaction behaviour; development of a complex experimental investigation strategy to derive necessary model parameters considering individual functional dependencies. Its technical feasibility was successfully verified; benchmarking with various existing numerical models using datasets from three different triaxial long-term tests. The result was not entirely satisfactory; however, the number of influencing factors is small and further validation work has to be done. Overall, the KOMPASS project has made significant progress in the approaches to solving the outstanding question, building the basis for further investigations.

A potential repository site for high-level radioactive waste should ensure the highest possible safety level over a period of one million years. In addition to design issues, demonstrating the integrity of the barrier is essential as it ensures the long-term containment of radioactive waste. Therefore, a multi-disciplinary approach is necessary for the characterization of the surrounding rock and for the understanding of the occurring physical processes. For site selection, however, the understanding of the respective system is essential as well: Do fault zones exist in the relevant area? Are these active and relevant for interpreting system behavior? What is the role of the existing heterogeneities of the claystone and how do these site-dependent conditions influence the physical effects? To answer these questions, the site-selection procedure requires underground exploration, which includes geophysical and geological investigations on milli- to decameter scales. Their results serve as the basis for numerical modelling. This combined, multi-disciplinary interpretation requires extensive knowledge of the various methods, their capabilities, limitations, and areas of application. In the cyclic deformation (CD-A) experiment in the Mont Terri rock laboratory, the hydraulic–mechanical effects due to excavation and the climatic conditions within the rock laboratory are investigated in two niches in the Opalinus Clay. The twin niches differ mainly with regard to the relative humidity inside them, but are also characterized by different boundary conditions such as existing fault zones, the technical construction of the neighboring gallery, etc. In order to gain insights into the relevance of the individual influences, comparative studies are being carried out on both niches. The presented results provide a first insight into the initial experimental years of the CD-A long-term experiment and illustrate the benefits of multi-disciplinary investigations in terms of system understanding and the scale dependency of physical effects. Amongst other effects, the assessment of the impact of heterogeneities on the deformation behavior and the evolution of pore water pressure is very complex and benefits from geological interpretation and measurements of for example deformation, water content, and pore pressure. The numerical modeling allows statements about the interaction of different processes and thus enables an interpretation of the overall system, taking into account the knowledge gained by the multi-disciplinary investigation.

The aim of this article was to review the current knowledge relating to work-related musculoskeletal disorders (WRMDs) and non-fatal injuries in emergency medical technicians and paramedics (EMTs-Ps). A literature search was conducted in PubMed, Google Scholar, and Clinical Key. The annual prevalence of back pain ranged from 30% to 66%, and back injuries and contusions from 4% to 43%. Falls, slips, trips, and overexertion while lifting or carrying patients or instruments ranged from 10% to 56%, with overexertion being the most common injury. Risk factors were predominantly lifting, working in awkward postures, loading patients into the ambulance, and cardiopulmonary resuscitation procedures. Lack of job satisfaction and social support was associated with WRMDs and injuries. EMTs-Ps had the highest rate of worker compensation claim rates compared to other healthcare professionals. Positive ergonomic intervention results included electrically powered stretchers, backboard wheeler, descent control system, and the transfer sling.

Reicht es aus, wenn Lehrende Zeit und Energie darauf verwenden, qualitativ hochwertige Lehr- und Lernmaterialien zu erstellen, oder sollten sie auch (mehr) Zeit darauf verwenden, den Studierenden das effektive und effiziente Lesen bzw. Betrachten dieses Materials zu vermitteln? Darf davon ausgegangen werden, dass die Studierenden diese Fähigkeiten ohnehin bereits mitbringen? Im Rahmen einer qualitativen Eye-Tracking-Studie mit Novizen und Experten wurde diese Fragestellung am Beispiel einer Rechnernetze-Grafik untersucht. Mit Hilfe eines eigenentwickelten Werkzeugs zur Generierung von Areas-of-Interest-Sequenzdiagrammen wurden die gewonnenen Messergebnisse ausgewertet. Im Resultat zeigten sich deutliche Unterschiede hinsichtlich der Betrachtungsweisen. Nicht nur das Vorgehen, sondern auch die Informationsaufnahme unterschieden sich prägnant. Im Folgenden werden die Studie, der theoretische Hintergrund, die gewonnenen Ergebnisse sowie das eigenentwickelte Analysewerkzeug für Messungen aus Eye-Tracking-Studien vorgestellt.

Background: Marijuana blunts, which are tobacco cigar wrappers filled with marijuana, are commonly smoked in the US as a means of cannabis use. The use of marijuana blunts presents toxicity concerns because the smoke contains both marijuana-related and tobacco-related chemicals. Thus, it is important to understand the chemical composition of mainstream smoke (MSS) from marijuana blunts. This study demonstrates the ability to detect and identify chemical constituents exclusively associated with blunt MSS in contrast to tobacco cigar MSS (designated as ‘new exposures’) through non-targeted chemical analysis. Methods: Samples collected separately from blunt MSS and tobacco cigar MSS were analyzed using two-dimensional gas chromatography–time-of-flight mass spectrometry (GC × GC-TOFMS). Results and Discussion: Two new exposures, which likely represent only a subset of all new exposures, were identified by evaluating the data from thousands of detected signals and then confirming selected compound identities in analyses using authentic chemical standards. The two confirmed new exposures, mellein and 2-phenyl-2-oxazoline, are not cannabinoids and, to the best of our knowledge, have not been previously reported in association with cannabis, tobacco, or smoke of any kind. In addition, we detected and quantified three phenols (2-, 3-, and 4-ethylphenol) in blunt MSS. Given the toxicity of phenols, quantifying the levels of other phenols could be pursued in future research on blunt MSS. Conclusion: This study shows the power and utility of GC × GC-TOFMS as a methodology for non-targeted chemical analysis to identify new chemical exposures in blunt MSS and to provide data to guide further investigations of blunt MSS.

Understanding the potential inhalation toxicity of poorly characterized aerosols is challenging both because aerosols may contain numerous chemicals and because it is difficult to predict which chemicals may present significant inhalation toxicity concerns at the observed levels. We have developed a novel systematic procedure to address these challenges through non-targeted chemical analysis by two-dimensional gas chromatography–time-of-flight mass spectrometry (GC × GC-TOFMS) and assessment of the results using publicly available toxicity data to prioritize the tentatively identified detected chemicals according to potential inhalation toxicity. The procedure involves non-targeted chemical analysis of aerosol samples utilizing GC × GC-TOFMS, which is selected because it is an effective technique for detecting chemicals in complex samples and assigning tentative identities according to the mass spectra. For data evaluation, existing toxicity data (e.g. from the U.S. Environmental Protection Agency CompTox Chemicals Dashboard) are used to calculate multiple toxicity metrics that can be compared among the tentatively identified chemicals. These metrics include hazard quotient, incremental lifetime cancer risk, and metrics analogous to hazard quotient that we designated as exposure–(toxicology endpoint) ratios. We demonstrated the utility of our procedure by detecting, identifying, and prioritizing specific chemicals of potential inhalation toxicity concern in the mainstream smoke generated from the machine-smoking of marijuana blunts. By designing a systematic approach for detecting and identifying numerous chemicals in complex aerosol samples and prioritizing the chemicals in relation to different inhalation toxicology endpoints, we have developed an effective approach to elucidate the potential inhalation toxicity of aerosols.

Autoantibody biomarkers are valuable tools used to diagnose and manage autoimmune diseases in dogs. However, prior publications have raised concerns over a lack of standardization and sufficient validation for the use of biomarkers in veterinary medicine.Systematically compile primary research on autoantibody biomarkers for autoimmune disease in dogs, summarize their methodological features, and evaluate their quality; synthesize data supporting their use into a resource for veterinarians and researchers.Not used.Five indices were searched to identify studies for evaluation: PubMed, CAB Abstracts, Web of Science, Agricola, and SCOPUS. Two independent reviewers (AET and ELC) screened titles and abstracts for exclusion criteria followed by full-text review of remaining articles. Relevant studies were classified based on study objectives (biomarker, epitope, technique). Data on study characteristics and outcomes were synthesized in independent data tables for each classification.Ninety-two studies qualified for final analysis (n = 49 biomarker, n = 9 epitope, and n = 34 technique studies). A high degree of heterogeneity in study characteristics and outcomes reporting was observed. Opportunities to strengthen future studies could include: (1) routine use of negative controls, (2) power analyses to inform sample sizes, (3) statistical analyses when appropriate, and (4) multiple detection techniques to confirm results.These findings provide a resource that will allow veterinary clinicians to efficiently evaluate the evidence supporting the use of autoantibody biomarkers, along with the varied methodological approaches used in their development.

Although older adults commonly take multivitamin-multimineral (MVM) supplements to promote health, evidence on the use of daily MVMs on invasive cancer is limited.The study objective was to determine if a daily MVM decreases total invasive cancer among older adults.We performed a randomized, double-blind, placebo-controlled, 2-by-2 factorial trial of a daily MVM and cocoa extract for prevention of cancer and cardiovascular disease (CVD) among 21,442 US adults (12,666 women aged ≥65 y and 8776 men aged ≥60 y) free of major CVD and recently diagnosed cancer. The intervention phase was from June 2015 through December 2020. This article reports on the MVM intervention. Participants were randomly assigned to daily MVM or placebo. The primary outcome was total invasive cancer, excluding nonmelanoma skin cancer. Secondary outcomes included major site-specific cancers, total CVD, all-cause mortality, and total cancer risk among those with a baseline history of cancer.During a median follow-up of 3.6 y, invasive cancer occurred in 518 participants in the MVM group and 535 participants in the placebo group (HR: 0.97; 95% CI: 0.86, 1.09; P = 0.57). We observed no significant effect of a daily MVM on breast cancer (HR: 1.06; 95% CI: 0.79, 1.42) or colorectal cancer (HR: 1.30; 95% CI: 0.80, 2.12). We observed a protective effect of a daily MVM on lung cancer (HR: 0.62; 95% CI: 0.42, 0.92). The composite CVD outcome occurred in 429 participants in the MVM group and 437 participants in the placebo group (HR: 0.98; 95% CI: 0.86, 1.12). MVM use did not significantly affect all-cause mortality (HR: 0.93; 95% CI: 0.81, 1.08). There were no safety concerns.A daily MVM supplement, compared with placebo, did not significantly reduce the incidence of total cancer among older men and women. Future studies are needed to determine the effects of MVMs on other aging-related outcomes among older adults. This trial is registered at www.clinicaltrials.gov as NCT02422745.

For brain–computer interfaces (BCIs) to be viable for long-term daily usage, they must be able to quickly identify and adapt to signal disruptions. Furthermore, the detection and mitigation steps need to occur automatically and without the need for user intervention while also being computationally tractable for the low-power hardware that will be used in a deployed BCI system. Here, we focus on disruptions that are likely to occur during chronic use that cause some recording channels to fail but leave the remaining channels unaffected. In these cases, the algorithm that translates recorded neural activity into actions, the neural decoder, should seamlessly identify and adjust to the altered neural signals with minimal inconvenience to the user. First, we introduce an adapted statistical process control (SPC) method that automatically identifies disrupted channels so that both decoding algorithms can be adjusted, and technicians can be alerted. Next, after identifying corrupted channels, we demonstrate the automated and rapid removal of channels from a neural network decoder using a masking approach that does not change the decoding architecture, making it amenable for transfer learning. Finally, using transfer and unsupervised learning techniques, we update the model weights to adjust for the corrupted channels without requiring the user to collect additional calibration data. We demonstrate with both real and simulated neural data that our approach can maintain high-performance while simultaneously minimizing computation time and data storage requirements. This framework is invisible to the user but can dramatically increase BCI robustness and usability.