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Limited research informs the implementation of web-based and mobile learning (mLearning) protocols for the assessment of public building accessibility in occupational therapy graduate students. This study tested the feasibility of a self-paced protocol designed to teach students how to evaluate community environment accessibility. Students across five sites completed an online learning module and community building evaluations. Students were randomized into lecture or lab educational groups and then crossed over to receive the second experience. Outcomes were student satisfaction, self-perceived learning, and knowledge on a researcher-developed measure. Data were analyzed using descriptive statistics. Two hundred and twelve students completed the study. The students were satisfied with their education and their community accessibility knowledge significantly increased from approximately 60% to 85%. Site and order of the learning components did not impact student ability to achieve competence. This multi-site approach is feasible and effective in instructing students in this highly protocolized and specialized area of practice.

ObjectiveTo validate a novel technique to measure limb stiffness in a clinical setting.AnimalsThree horses and three ponies owned by the Royal Veterinary College.ProceduresLimb stiffness indices for both forelimbs were first derived using the gold standard of kinematic analysis. Using the same animals, limb stiffness indices were then calculated using portable floor scales to record weight and an electrogoniometer to record changes in metacarpophalangeal joint angle. The two techniques were then assessed for correlation and repeatability.ResultsThe repeatability of limb stiffness measurement using the novel clinical tool was considered to be good based on a small coefficient of variation (5.70%). The correlation of limb stiffness as derived by both methods was high (r = 0.78, p

The rotating-convection paradigm for tropical cyclone behaviour is shown to provide an attractive and consistent framework for interpreting the dynamics of formation and intensification of at least some medicanes. The ideas are illustrated by a case study of the medicane that formed over the eastern Mediterranean in mid-December 2020. This case study is based on analyses of data from the European Centre for Medium Range Weather Forecasts (ECMWF), imagery from the European geostationary meteorological satellite, Meteosat Second Generation, and output from a convection permitting numerical simulation of the event using the United Kingdom (UK) Met Office regional model with the RAL2 physics configuration. Limitations of the currently widely accepted interpretation of medicanes in terms of the so-called Wind-Induced Surface Heat Exchange (WISHE) intensification mechanism are discussed.

We examine a hierarchy of minimal conceptual models for tropical cyclone intensification. These models are framed mostly in terms of axisymmetric balance dynamics. In the first set of models, the heating rate is prescribed in such a way to mimic a deep overturning circulation with convergence in the lower troposphere and divergence in the upper troposphere, characteristic of a region of deep moist convection. In the second set, the heating rate is related explicitly to the latent heat release of ascending air parcels. The release of latent heat markedly reduces the local static stability of ascending air, raising two possibilities in the balance framework. The first possibility is that the effective static stability and the related discriminant in the Eliassen equation for the overturning circulation in saturated air, although small, remains positive so the Eliassen equation is globally elliptic. The second possibility, the more likely one during vortex intensification, is that the effective static stability in saturated air is negative and the Eliassen equation becomes locally hyperbolic. These models help to understand the differences between the early Ooyama models of 1968 and 1969, the Emanuel, 1989 model, and the later Emanuel models of 1995, 1997 and 2012. They provide insight also into the popular explanation of the WISHE feedback mechanism for tropical cyclone intensification. Some implications for recent work are discussed.

Limited evidence is available relating gait changes to diagnostic anaesthesia. We investigated associations between specific movement patterns and diagnostic anaesthesia of different anatomical structures in a retrospective analysis. Referral-level lameness cases were included with the following criteria: presence of diagnostic anaesthesia of a forelimb and/or hind limb; subjective efficacy classified as “negative”, “partially positive”, or “positive”; quantitative gait data available from inertial measurement units. Gait changes were calculated for three forelimb (palmar digital, abaxial sesamoid, low 4-point nerve block) and five hind limb diagnostic blocks (tarso-metatarsal, metatarsophalangeal joint block, deep branch of lateral plantar, low 6-point, abaxial sesamoid nerve block). Mixed models (random factor “case”, fixed factors “diagnostic anaesthesia type” and “efficacy”, two-way interaction) assessed the head and pelvic movement (p < 0.05, Bonferroni correction). Four parameters were significantly affected by forelimb anaesthesia (N = 265) (all p ≤ 0.031) and six by hind limb anaesthesia (N = 342) efficacy (all p ≤ 0.001). All head movement parameters and pelvic push-off asymmetry were significantly affected by the two-way interaction after forelimb anaesthesia (all p ≤ 0.023) and two pelvic movement symmetry parameters by the two-way interaction after hind limb anaesthesia (all p ≤ 0.020). There are interactions between block efficacy and type resulting in changes in weight-bearing and push-off-associated head and pelvic movement symmetry after diagnostic anaesthesia.

Abstract Background Polyamine catabolism plays a key role in maintaining intracellular polyamine pools, yet its physiological significance is largely unexplored. Here, we report that the disruption of polyamine catabolism leads to severe cerebellar damage and ataxia, demonstrating the fundamental role of polyamine catabolism in the maintenance of cerebellar function and integrity. Methods Mice with simultaneous deletion of the two principal polyamine catabolic enzymes, spermine oxidase and spermidine/spermine N1-acetyltransferase (Smox/Sat1-dKO), were generated by the crossbreeding of Smox-KO (Smox −/− ) and Sat1-KO (Sat1 −/− ) animals. Development and progression of tissue injury was monitored using imaging, behavioral, and molecular analyses. Results Smox/Sat1-dKO mice are normal at birth, but develop progressive cerebellar damage and ataxia. The cerebellar injury in Smox/Sat1-dKO mice is associated with Purkinje cell loss and gliosis, leading to neuroinflammation and white matter demyelination during the latter stages of the injury. The onset of tissue damage in Smox/Sat1-dKO mice is not solely dependent on changes in polyamine levels as cerebellar injury was highly selective. RNA-seq analysis and confirmatory studies revealed clear decreases in the expression of Purkinje cell-associated proteins and significant increases in the expression of transglutaminases and markers of neurodegenerative microgliosis and astrocytosis. Further, the α-Synuclein expression, aggregation, and polyamination levels were significantly increased in the cerebellum of Smox/Sat1-dKO mice. Finally, there were clear roles of transglutaminase-2 (TGM2) in the cerebellar pathologies manifest in Smox/Sat1-dKO mice, as pharmacological inhibition of transglutaminases reduced the severity of ataxia and cerebellar injury in Smox/Sat1-dKO mice. Conclusions These results indicate that the disruption of polyamine catabolism, via coordinated alterations in tissue polyamine levels, elevated transglutaminase activity and increased expression, polyamination, and aggregation of α-Synuclein, leads to severe cerebellar damage and ataxia. These studies indicate that polyamine catabolism is necessary to Purkinje cell survival, and for sustaining the functional integrity of the cerebellum.

Abstract Background The mechanisms involved in the pathogenesis of autoimmune disorders, including systemic lupus erythematosus (SLE), have not been fully elucidated. Some of these mechanisms involve epigenetic regulation of gene expression. The histone methyltransferase Ezh2 contributes to epigenetic regulation of gene expression, is highly expressed in germinal center (GC) B cells and follicular T helper (TFH) cells, and may be involved in lupus pathogenesis. Methods The murine bm12 model of lupus-like chronic graft versus host disease (cGVHD) was induced by intra-peritoneal injection of negatively isolated allogeneic CD4+ T cells. Lupus-like disease development was monitored by ELISA determination of serum anti-dsDNA and anti-chromatin antibody titers. Immune cell activation and Ezh2 expression were evaluated by flow cytometry and Western blotting. Results Decreased autoantibody production and GC formation are observed when Ezh2-deficient CD4+ T cells are used instead of wild-type (WT) to induce cGVHD and when mice that receive allogeneic WT donor T cells to induce cGVHD are treated with GSK503, an Ezh2-specific inhibitor. In the bm12 cGVHD model, WT donor T cells are normally fully activated 1 week after infusion into an allogeneic host, exhibit a TFH cell (PD-1hi/CXCR5hi) phenotype with upregulated Ezh2, and activate B cells to form germinal centers (GCs). In contrast, Ezh2-deficient donor T cells generate fewer TFH cells that fail to activate B cells or promote GC formation. Despite similar T-independent, LPS-induced B cell responses, OVA-immunized CD4.Ezh2-KO mice had a skewed low-affinity IgM phenotype in comparison to similarly treated WT mice. In addition, early after OVA immunization, more CD4+ T cells from B6.CD4.Ezh2-KO mice had a CD44lo/CD62Llo phenotype, which suggests arrested or delayed activation, than CD4+ T cells from ovalbumin-immunized B6.WT mice. Conclusion Ezh2 gene deletion or pharmacological Ezh2 inhibition suppresses autoantibody production and GC formation in bm12 lupus-like cGVHD and decreases affinity maturation and isotype switching in response to immunization with a T cell-dependent antigen. Ezh2 inhibition may be useful for the treatment of lupus and other autoimmune disorders.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper.

We revisit the theoretical possibility of long-term, sustained tropical cyclone solutions using a state-of-the-art numerical model that incorporates the most recent observational guidance for subgrid scale parameters and airsea exchange coefficients of heat and momentum. Emphasis is placed on the realism of such solutions and the sources of cyclonic relative angular momentum (RAM) that are necessary to replenish that lost by friction at the surface. For simplicity, we confine our attention to strictly axisymmetric numerical experiments.We are able to replicate Hakim’s long-term simulation of a quasi-steady state cyclone in a 1500 km radial domain. The structure of the wind field is found to be somewhat realistic compared to observations, but sustained by unrealistic processes. Artificial sources of cyclonic RAM are quantified and the lateral damping of the anticyclonic wind near the outer boundary is found to make the largest contribution to the source of cyclonic RAM. When the domain size is extended to 9,000 km radius and lateral damping is removed altogether, a quasi-steady vortex emerges, but the structure of this vortex has many unrealistic features. In this solution, the remaining upper-level Rayleigh damping contributes a major portion of the needed source of cyclonic RAM. In a simulation in which the upper-level damping is removed also, the solution is found to be neither quasi-steady nor realistic.These findings call into question the realism of long-term, sustained tropical cyclone simulations, which require a sufficiently large source of cyclonic RAM to facilitate the existence of a quasi-steady state. Keywords: tropical cyclones, steady-state, angular momentum

Multi-kinase RET inhibitors, such as cabozantinib and RXDX-105, are active in lung cancer patients with RET fusions; however, the overall response rates to these two drugs are unsatisfactory compared to other targeted therapy paradigms. Moreover, these inhibitors may have different efficacies against RET rearrangements depending on the upstream fusion partner. A comprehensive preclinical analysis of the efficacy of RET inhibitors is lacking due to a paucity of disease models harboring RET rearrangements. Here, we generated two new patient-derived xenograft (PDX) models, one new patient-derived cell line, one PDX-derived cell line, and several isogenic cell lines with RET fusions. Using these models, we re-examined the efficacy and mechanism of action of cabozantinib and found that this RET inhibitor was effective at blocking growth of cell lines, activating caspase 3/7 and inhibiting activation of ERK and AKT. Cabozantinib treatment of mice bearing RET fusion-positive cell line xenografts and two PDXs significantly reduced tumor proliferation without adverse toxicity. Moreover, cabozantinib was effective at reducing growth of a lung cancer PDX that was not responsive to RXDX-105. Transcriptomic analysis of lung tumors and cell lines with RET alterations showed activation of a MYC signature and this was suppressed by treatment of cell lines with cabozantinib. MYC protein levels were rapidly depleted following cabozantinib treatment. Taken together, our results demonstrate that cabozantinib is an effective agent in preclinical models harboring RET rearrangements with three different 5′ fusion partners (CCDC6, KIF5B and TRIM33). Notably, we identify MYC as a protein that is upregulated by RET expression and downregulated by treatment with cabozantinib, opening up potentially new therapeutic avenues for the combinatorial targetin of RET fusion- driven lung cancers. The novel RET fusion-dependent preclinical models described here represent valuable tools for further refinement of current therapies and the evaluation of novel therapeutic strategies.

The Pedra de Fogo Formation in the Parnaíba Basin of northeastern Brazil hosts a recently discovered lacustrine fauna and provides the only known record of the Captorhinidae in South America. Here, new captorhinid remains from this unit are described. Two partial mandibles, including one formerly ascribed to the genus Captorhinus, are here referred to Captorhinikos sp. a genus previously described from North America. The natural mould of a large mandible probably represents a new taxon within the captorhinid subclade Moradisaurinae, and a small skull roof is regarded as Captorhinidae indet. Captorhinids are generally considered to have been herbivores or omnivores. The Pedra de Fogo captorhinids likely played an important ecological role as primary consumers in the palaeoenvironment of this geological unit, which is also known for its extensive record of petrified forests. The new finds reinforce the close relationships between the continental faunas of palaeotropical western Gondwana and palaeoequatorial North America during the Cisuralian.

Abstract Background Maternal early warning systems reduce maternal morbidity. We developed an electronic maternal surveillance system capable of visually summarizing the labor and delivery census and identifying changes in clinical status. Automatic page alerts to clinical providers, using an algorithm developed at our institution, were incorporated in an effort to improve early detection of maternal morbidity. We report the frequency of pages generated by the system. To our knowledge, this is the first time such a system has been used in peripartum care. Methods Alert criteria were developed after review of maternal early warning systems, including the Maternal Early Warning Criteria (MEWC). Careful consideration was given to the frequency of pages generated by the surveillance system. MEWC notification criteria were liberalized and a paging algorithm was created that triggered paging alerts to first responders (nurses) and then managing services due to the assumption that paging all clinicians for each vital sign triggering MEWC would generate an inordinate number of pages. For preliminary analysis, to determine the effect of our automated paging algorithm on alerting frequency, the paging frequency of this system was compared to the frequency of vital signs meeting the Maternal Early Warning Criteria (MEWC). This retrospective analysis was limited to a sample of 34 patient rooms uniquely capable of storing every vital sign reported by the bedside monitor. Results Over a 91-day period, from April 1 to July 1, 2017, surveillance was conducted from 64 monitored beds, and the obstetrics service received one automated page every 2.3 h. The most common triggers for alerts were for hypertension and tachycardia. For the subset of 34 patient rooms uniquely capable of real-time recording, one vital sign met the MEWC every 9.6 to 10.3 min. Anecdotally, the system was well-received. Conclusions This novel electronic maternal surveillance system is designed to reduce cognitive bias and improve timely clinical recognition of maternal deterioration. The automated paging algorithm developed for this software dramatically reduces paging frequency compared to paging for isolated vital sign abnormalities alone. Long-term, prospective studies will be required to determine its impact on patient outcomes.