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There is a need to develop an anatomy course with contemporary pedagogy that is consistent with the core of the occupational therapy profession. The purpose of this study was to examine students' perception of a blended learning pedagogy applied to an occupation-based anatomy course compared to a traditionally delivered anatomy course using cadaver lab for entry-level doctoral occupational therapy students at a private university in the Pacific Northwest region. A retrospective, nonrandomized, twogroup, post-test only design with data gathered at the completion of each course was used. One student cohort received the occupation-based anatomy course with a traditional in-person learning format and the other received the course guided by the universal design, blended learning format. The primary outcomes were students' course performance and perception of the course. At the completion of the course, both student cohorts had equivalent course performance. Compared to those who received the traditional format, the blended learning format cohort yielded significantly higher scores in 3 out of 5 categories of the course evaluation, including syllabus design, contribution of course content to their needs as a professional, and assessment methods that reflected their learning. The study results suggest that the occupation-based anatomy course guided by a contemporary pedagogical approach is equal to traditional methods in anatomical knowledge acquisition but statistically superior in meeting students' perceived needs as professionals and reflecting their learning.

Abstract Approximately 80% of pediatric tumors occur in low- and middle-income countries (LMIC), where diagnostic tools essential for treatment decisions are often unavailable or incomplete. Development of cost-effective molecular diagnostics will help bridge the cancer diagnostic gap and ultimately improve pediatric cancer outcomes in LMIC settings. We investigated the feasibility of using nanopore whole transcriptome sequencing on formalin-fixed paraffin embedded (FFPE)-derived RNA and a composite machine learning model for pediatric solid tumor diagnosis. Transcriptome cDNA sequencing was performed on a heterogenous set of 221 FFPE and 32 fresh frozen pediatric solid tumor and lymphoma specimens on Oxford Nanopore Technologies’ sequencing platforms. A composite machine learning model was then used to classify transcriptional profiles into clinically actionable tumor types and subtypes. In total, 95.6% and 89.7% of pediatric solid tumors and lymphoma specimens were correctly classified, respectively. 71.5% of pediatric solid tumors had prediction probabilities > 0.8 and were classified with 100% accuracy. Similarly, for lymphomas, 72.4% of samples that had prediction probabilities > 0.6 were classified with 97.6% accuracy. Additionally, FOXO1 fusion status was predicted accurately for 97.4% of rhabdomyosarcomas and MYCN amplification was predicted with 88% accuracy in neuroblastoma. Whole transcriptome sequencing from FFPE-derived pediatric solid tumor and lymphoma samples has the potential to provide clinical classification of both tissue lineage and core genomic classification. Further expansion, refinement, and validation of this approach is necessary to explore whether this technology could be part of the solution of addressing the diagnostic limitations in LMIC.

OBJECTIVES:. Anemia has been associated with an increased risk of both cardiac arrest and stroke, frequent complications of COVID-19. The effect of hemoglobin level at ICU admission on a composite outcome of cardiac arrest or stroke in an international cohort of COVID-19 patients was investigated. DESIGN:. Retrospective analysis of prospectively collected database. SETTING:. A registry of COVID-19 patients admitted to ICUs at over 370 international sites was reviewed for patients diagnosed with cardiac arrest or stroke up to 30 days after ICU admission. Anemia was defined as: normal (hemoglobin ≥ 12.0 g/dL for women, ≥ 13.5 g/dL for men), mild (hemoglobin 10.0–11.9 g/dL for women, 10.0–13.4 g/dL for men), moderate (hemoglobin ≥ 8.0 and < 10.0 g/dL for women and men), and severe (hemoglobin < 8.0 g/dL for women and men). PATIENTS:. Patients older than 18 years with acute COVID-19 infection in the ICU. INTERVENTIONS:. None. MEASUREMENTS AND MAIN RESULTS:. Of 6926 patients (median age = 59 yr, male = 65%), 760 patients (11.0%) experienced stroke (2.0%) and/or cardiac arrest (9.4%). Cardiac arrest or stroke was more common in patients with low hemoglobin, occurring in 12.8% of patients with normal hemoglobin, 13.3% of patients with mild anemia, and 16.7% of patients with moderate/severe anemia. Time to stroke or cardiac arrest by anemia status was analyzed using Cox proportional hazards regression with death as a competing risk. Covariates selected through clinical knowledge were age, sex, comorbidities (diabetes, hypertension, obesity, and cardiac or neurologic conditions), pandemic era, country income, mechanical ventilation, and extracorporeal membrane oxygenation. Moderate/severe anemia was associated with a higher risk of cardiac arrest or stroke (hazard ratio, 1.32; 95% CI, 1.05–1.67). CONCLUSIONS:. In an international registry of ICU patients with COVID-19, moderate/severe anemia was associated with increased hazard of cardiac arrest or stroke.

Background: There has been a trend to transit reprocessing of flexible endoscopes from a high-level disinfectant (HLD) centralized manner to sterilization performed by nursing staff in some Ear, Nose, and Throat (ENT) clinics. In doing so, the clinic nursing staff are responsible for predicting and managing clinical demand for flexible endoscopes. The HLD disinfection process is time-consuming and requires specialized training and competency to be performed safely. Solely depending on human expertise for predicting the flexible endoscope demands is unreliable and produced a concern of an inadequate supply of devices available for diagnostic purposes. Method: The demand for flexible endoscopes for future patient visits has not been well studied but can be modeled based on patients’ historical information, provider, and other visit-related factors. Such factors are available to the clinic before the visit. Binary classifiers can be used to help inform the sterile processing department of reprocessing needs days or weeks earlier for each patient. Results: Among all our trained models, Logistic Regression reports an average AUC ROC score of 89% and accuracy of 80%. Conclusion: The proposed framework not only significantly reduces the reprocessing efforts in terms of time spent on communication, cleaning, scheduling, and transferring scopes, but also helps to improve patient safety by reducing the exposure risk to potential infections.

Abstract Background Utilization of electronic patient-reported outcome (ePRO) tools to monitor symptoms in patients undergoing cancer treatment has shown clinical benefits. Tennessee Oncology (TO) implemented an ePRO platform in 2019, allowing patients to report their health status online. We conducted a real-world, multicenter, observational, non-interventional cohort study to evaluate utilization of this platform in adults with solid tumors who initiated immuno-oncology (IO) therapy as monotherapy or in combination at TO clinics. Methods Patients initiating IO therapy prior to platform implementation were included in a historical control (HC) cohort; those initiating treatment after implementation were included in the ePRO cohort, which was further divided into ePRO users (platform enrollment ≤ 45 days from IO initiation) and non-users. Data were extracted from electronic medical records; patients were followed for up to 6 months (no minimum follow up). Outcomes included patient characteristics, treatment patterns, duration of therapy (DoT), and overall survival (OS). Results Data were collected for 538 patients in the HC and 1014 in the ePRO cohort; 319 in the ePRO cohort were ePRO users (uptake rate 31%). Baseline age was higher, more patients had stage IV disease at diagnosis, and more received monotherapy (82 vs 52%, respectively) in the HC vs the ePRO cohort. Median follow-up was 181.0 days (range 0.0–182.6) in the HC and 175.0 (0.0–184.0) in the ePRO cohort. Median DoT of index IO regimen was 5.1 months (95% confidence interval [CI], 4.4–NE) in the HC cohort vs not estimable (NE) in the ePRO cohort. Multivariable regression adjusting for baseline differences confirmed lower risk of treatment discontinuation in the ePRO vs HC cohort: hazard ratio (HR) 0.83 (95% CI, 0.71–0.97); p

Abstract Neurogenins are proneural transcription factors required to specify neuronal identity. Their overexpression in human pluripotent stem cells rapidly produces cortical-like neurons with spiking activity and, because of this, they have been widely adopted for human neuron disease models. However, we do not fully understand the key downstream regulatory effectors responsible for driving neural differentiation. Here, using inducible expression of NEUROG1 and NEUROG2, we identify transcription factors (TFs) required for directed neuronal differentiation by combining expression and chromatin accessibility analyses with a pooled in vitro CRISPR-Cas9 screen targeting all ~1900 TFs in the human genome. The loss of one of these essential TFs (ZBTB18) yields few MAP2-positive neurons. Differentiated ZBTB18-null cells have radically altered gene expression, leading to cytoskeletal defects and stunted neurites and spines. In addition to identifying key downstream TFs for neuronal differentiation, our work develops an integrative multi-omics and TFome-wide perturbation platform to rapidly characterize essential TFs for the differentiation of any human cell type.

Summary: Background: ABVD (doxorubicin, bleomycin, vinblastine, and dexamethasone) is a proven, curative regimen for Hodgkin lymphoma (HL). Prospective data describing HL treatment in sub-Saharan Africa are limited. We aimed to fill this knowledge gap, using data from Malawi. Methods: We report a prospective observational cohort of HL (aged ≥ 15) from a single, tertiary referral centre in Malawi. We enrolled patients with pathologicially confirmed Hodgkin lymphoma between June 1, 2013, and Dec 31, 2021 with follow-up censored on May 31, 2022. Patients were treated with ABVD and concurrent antiretroviral therapy if HIV-positive and were followed up for 5 years. The primary outcome was overall survival; secondary outcomes included progression-free survival, response assessment, and adverse events. Microcosting of HL diagnosis, treatment, and follow-up was embedded. Findings: We enrolled 38 patients with a median age of 27 years (interquartile range 19–46); eleven (28%) were HIV-positive. Of 35 patients treated with ABVD, 24 (71%) had stage III/IV, nine (26%) unfavourable limited stage, and two (6%) favourable limited stage. Among HIV-infected individuals, mean CD4 count at HL diagnosis was 179 cells/uL and ten (91%) had HIV RNA < 400 copies/mL. Grade 3/4 neutropenia occurred in 24 (68%) patients and caused treatment delay in 16 (46%). Of ten deaths, seven were due to HL, two possible treatment-related toxicity, and one uncertain. 2-year overall survival was 82% (95% CI 70–96%) and 2-year progression-free survival was 64% (95% CI 50–83%). PFS appeared better for HIV-positive patients (HR 0.23 (95% CI 0.05–1.02)) after controlling for stage and performance status (p = 0.05). We estimated $2708 (2022 USD) for HL diagnosis, treatment, and follow-up in our cohort. Interpretation: Our findings suggest that treatment with ABVD is safe, efficacious, and affordable for HL in Malawi. Outcomes are worse than in high-income countries due to HL progression. Future studies are needed to understand outcome inequities and to assess efficacy of therapies for patients with relapsed or refractory HL in Malawi. Funding: National Institutes of Health, Lineberger Comprehensive Cancer Center.

Effective business owners and managers must understand and apply skills from a variety of disciplines, including legal studies, marketing, and economics. The ability of professionals from diverse backgrounds to communicate, debate, and problem-solve can be the difference between a project's success and failure. The authors are faculty members from different academic and professional backgrounds who teach different subjects at the same business school. Two teach legal studies, one teaches economics, and one teaches marketing. The authors chose a topical issue that would interest students and developed a mock trial exercise to help students understand and practice how subject matter specialists collaborate in the business world. Each exercise involved classes from two different business disciplines--one legal studies class and one other class. Following an introduction, Part II of this article provides an overview of the academic literature regarding the value of cross-disciplinary collaboration in business and business education as well as the value of experiential learning and specifically the value of conducting a mock trial. Part III describes each instance of the exercise in detail and provides a roadmap and supplemental materials for teachers who would like to implement a similar exercise in their classrooms. Part IV presents detailed assessment results. Part V discusses which aspects of the exercises the authors found particularly valuable and which aspects could be improved. This section also includes conclusions and suggestions for teachers implementing the exercise in future classes.

Purpose: Many children with severe intellectual and developmental disabilities are at a higher risk for hearing loss than their peers who are typically developing. Unfortunately, they do not consistently participate in routine school-based hearing screenings. The current study investigated the feasibility of increasing their participation using an otoacoustic emissions protocol and documented results relative to student educational profiles. Method: A total of 43 students with significant cognitive disabilities enrolled at a public school exclusively serving this population participated in the study. All but 9, who were excluded because of known hearing loss, were screened by a licensed audiologist assisted by audiology doctoral students. The protocol included otoscopy, tympanometry, distortion product otoacoustic emissions (DPOAEs), and teacher surveys. Results: DPOAE screening was attempted on 33 students without previously diagnosed hearing loss and successfully completed for 26 (78.8%). Two students (4.6%) with absent otoacoustic emissions and normal tympanograms were referred for further assessment due to concerns about possible sensorineural hearing loss in one or both ears, and 10 (23.3%) had abnormal tympanograms in one or both ears. Conclusions: Considering the high risk of sensorineural hearing loss for children with significant disabilities, it is important for them to be included in school hearing screenings. The results of this study demonstrate the feasibility of using DPOAEs for school-based hearing screenings with this population with an interprofessional team of licensed audiologists, educators, and speech-language pathologists. The results further suggest that students with significant disabilities and hearing loss may be unidentified and underserved. Given the complex needs of this population, an interprofessional practice model for hearing screenings and intervention services is recommended.

Measurement(s) Phylogenetic Analysis • computational phylogenetic analysis • Data Quality Technology Type(s) Maximum Likelihood Estimation • digital curation Sample Characteristic - Organism Cyanobacteria/Melainabacteria group Machine-accessible metadata file describing the reported data: https://doi.org/10.6084/m9.figshare.15032181

Purpose: Children who are hard of hearing (CHH) have restricted access to acoustic and linguistic information. Increased audibility provided by hearing aids influences language outcomes, but the benefits of hearing aids are often limited by acoustic factors and distance. Remote microphone (RM) systems further increase auditory access by reducing the negative consequences of these factors. The purpose of this article was to identify factors that influence likelihood of RM system receipt and to investigate the effects of RM systems in home settings on later language outcomes. We used propensity score matching to compare language outcomes between children with and without access to personal RM systems in home settings. This article provides a description of how and why to perform propensity score-matching analyses with clinical populations. Method: Participants were 132 CHH. Through parent report, we identified children who received RM systems for home use by 4 years of age. Logistic regression was used to determine factors that predict likelihood of RM system receipt in home settings. Propensity score matching was conducted on a subgroup of 104 participants. Performance on language measures at age 5 years was compared across propensity-matched children who did and did not receive RMs for personal use. Results: Likelihood of RM receipt was associated with degree of hearing loss, maternal education, and location (recruitment site). Comparisons between matched pairs of children with and without RM systems in early childhood indicated significantly better discourse skills for children whose families owned RM systems, but no significant differences for vocabulary or morphosyntax. Conclusion: Results provide preliminary evidence that the provision of personal RM systems for preschool-age CHH enhances higher-level language skills. The propensity score-matching technique enabled us to use an observational, longitudinal data set to examine a question of clinical interest.

Social work educators are increasingly exploring how to effectively use technology in their classrooms. The purpose of this study was to explore how a technology-enhanced active learning classroom influenced social work students' engagement and overall learning experiences. An online survey was conducted with 125 social work students from micro and macro courses. When compared to macro courses, students from micro social work courses more positively reported active participation, effective teaching, and technical skills as benefits of the classroom. Furthermore, the dynamic learning environment and instructors' effective teaching significantly affected students' positive learning experience. Social work programs should develop various teaching methods for active learning classrooms to develop students' practice skills that can be transferred to the real world.

Alpha/beta hydrolase domain-containing 5 (ABHD5), also termed CGI-58, is the key upstream activator of adipose triglyceride lipase (ATGL), which plays an essential role in lipid metabolism and energy storage. Mutations in ABHD5 disrupt lipolysis and are known to cause the Chanarin-Dorfman syndrome. Despite its importance, the structure of ABHD5 remains unknown. In this work, we combine computational and experimental methods to build a 3D structure of ABHD5. Multiple comparative and machine learning-based homology modeling methods are used to obtain possible models of ABHD5. The results from Gaussian accelerated molecular dynamics and experimental data of the apo models and their mutants are used to select the most likely model. Moreover, ensemble docking is performed on representative conformations of ABHD5 to reveal the binding mechanism of ABHD5 and a series of synthetic ligands. Our study suggests that the ABHD5 models created by deep learning-based methods are the best candidate structures for the ABHD5 protein. The mutations of E41, R116, and G328 disturb the hydrogen bonding network with nearby residues and suppress membrane targeting or ATGL activation. The simulations also reveal that the hydrophobic interactions are responsible for binding sulfonyl piperazine ligands to ABHD5. Our work provides fundamental insight into the structure of ABHD5 and its ligand-binding mode, which can be further applied to develop ABHD5 as a therapeutic target for metabolic disease and cancer.

ABSTRACT Increasing data volumes on high-throughput sequencing instruments such as the NovaSeq 6000 leads to long computational bottlenecks for common metagenomics data preprocessing tasks such as adaptor and primer trimming and host removal. Here, we test whether faster recently developed computational tools (Fastp and Minimap2) can replace widely used choices (Atropos and Bowtie2), obtaining dramatic accelerations with additional sensitivity and minimal loss of specificity for these tasks. Furthermore, the taxonomic tables resulting from downstream processing provide biologically comparable results. However, we demonstrate that for taxonomic assignment, Bowtie2’s specificity is still required. We suggest that periodic reevaluation of pipeline components, together with improvements to standardized APIs to chain them together, will greatly enhance the efficiency of common bioinformatics tasks while also facilitating incorporation of further optimized steps running on GPUs, FPGAs, or other architectures. We also note that a detailed exploration of available algorithms and pipeline components is an important step that should be taken before optimization of less efficient algorithms on advanced or nonstandard hardware. IMPORTANCE In shotgun metagenomics studies that seek to relate changes in microbial DNA across samples, processing the data on a computer often takes longer than obtaining the data from the sequencing instrument. Recently developed software packages that perform individual steps in the pipeline of data processing in principle offer speed advantages, but in practice they may contain pitfalls that prevent their use, for example, they may make approximations that introduce unacceptable errors in the data. Here, we show that differences in choices of these components can speed up overall data processing by 5-fold or more on the same hardware while maintaining a high degree of correctness, greatly reducing the time taken to interpret results. This is an important step for using the data in clinical settings, where the time taken to obtain the results may be critical for guiding treatment.

White matter hyperintensities (WMHs) are associated with cognitive decline. Assessing the effect of WMH on WM microstructural changes and its relationships with structural and functional connectivity to multiple cognitive domains are helpful to better understand the pathophysiological processes of cognitive impairment. 65 participants (49 normal and 16 MCI subjects, age: 67.4 ± 8.3 years, 44 females) were studied at 3T. The WMHs and fifty fiber tracts were automatically segmented from the T1/T2-weighted images and diffusion-weighted images, respectively. Tract-profiles of WMH were compared with those of apparent fiber density (AFD). The relationship between AFD and tract connectivity (TC) was assessed. Functional connectivity (FC) between tract ends obtained from resting-state functional MRI was examined in relation to TC. Tract-specific relationships of WMH, TC and FC with a multi-domain neuropsychological test battery and Montreal Cognitive Assessment (MoCA) were also separately assessed by lasso linear regression. Indirect pathways of TC and FC between WMH and multiple cognitive measures were tested using the mediation analysis. Higher WMH loads in WM tracts were locally matched with the reduced AFD, which was related to decrease in TC. However, no direct relationship was found between TC and FC. Tract-specific changes on WMH, TC and FC for each cognitive performance may explain that macro- and microstructural and functional changes are associated differently with each cognitive domain in a fiber specific manner. In these identified tracts, the differences between normal and MCI for WMH and TC were increased, and the relationships of WMH, TC and FC with cognitive outcomes were more significant, compared to the results from all tracts. Indirect pathways of two-step (TC-FC) between WMH and all cognitive domains were significant (p < 0.0083 with Bonferroni correction), while the separated indirect pathways through TC and through FC were different depending on cognitive domain. Deterioration in specific cognitive domains may be affected by alterations in a set of different tracts that are differently associated with macrostructural, microstructural, and function changes. Thus, assessments of WMH and its associated changes on specific tracts help for better understanding of the interrelationships of multiple changes in cognitive impairment.

We report observations of the Didymos–Dimorphos binary asteroid system using the Atacama Large Millimeter/submillimeter Array (ALMA) and the Atacama Compact Array (ACA) in support of the Double Asteroid Redirection Test mission. Our observations on UT 2022 September 15 provided a preimpact baseline and the first measure of Didymos–Dimorphos’s spectral emissivity at λ = 0.87 mm, which was consistent with the handful of siliceous and carbonaceous asteroids measured at millimeter wavelengths. Our postimpact observations were conducted using four consecutive executions each of ALMA and the ACA spanning from T+3.52 to T+8.60 hr, sampling thermal emission from the asteroids and the impact ejecta. We scaled our preimpact baseline measurement and subtracted it from the postimpact observations to isolate the flux density of millimeter-sized grains in the ejecta. Ejecta dust masses were calculated for a range of materials that may be representative of Dimorphos’s S-type asteroid material. The average ejecta mass over our observations is consistent with 1.3–6.4 × 10 ^7 kg, with the lower and higher values calculated for amorphous and crystalline silicates, respectively. Owing to the likely crystalline nature of S-type asteroid material, the higher value is favored. These ejecta masses represent 0.3%–1.5% of Dimorphos’s total mass and are in agreement with lower limits on the ejecta mass based on measurements at optical wavelengths. Our results provide the most sensitive measure of millimeter-sized material in the ejecta and demonstrate the power of ALMA for providing supporting observations to spaceflight missions.

We have measured the complex refractive indices, from 0.4 to 1.6 μ m, of five laboratory-generated organic refractory materials (tholins) produced at low temperature (150 K) using plasma chemistry in the stream of a supersonic expansion in NASA Ames’ COsmic SImulation Chamber (COSmIC) facility. Three samples were produced from N _2 :CH _4 gas precursors (with different voltages inducing different degrees of ionization in the plasma), one sample was produced from N _2 :CH _4 :C _2 H _2 , and one sample was produced from Ar:CH _4 in order to produce a purely carbonaceous sample. The optical constants, n and k , of the samples were determined using spectral reflectance measurements. We observe that both n and k appear to be correlated with the nitrogen content in the solid sample, with samples containing more nitrogen having higher n and k . Comparisons to previous laboratory studies and Titan aerosol optical constants derived from observations show that the COSmIC tholins with a higher nitrogen content (higher n and k ) are closer analogs of Titan aerosols. We also present a new analysis of Cassini Visible Infrared Mapping Spectrometer observations of Titan’s atmosphere in the visible to near infrared using the COSmIC tholin optical constants in a radiative transfer model. The COSmIC tholin sample produced from N _2 :CH _4 with the lowest energy level has a spectral behavior that appears well suited to reproduce the observed Titan aerosol properties. This study has therefore demonstrated that this COSmIC tholin sample has valuable and promising optical properties for the analysis of Cassini’s Titan atmospheric observations.

This conceptual paper draws on varied academic disciplines to set forth a model of educational leadership grounded in social justice and responsive to the unique challenges and strengths of rural Appalachian schools and communities. Model development grew out of discussions between faculty and graduate students in an educational leadership doctoral program, spurring a dialogue that merged theory and practice through (1) critical readings of traditional leadership models and of alternative models that purport to better meet the needs of economically disadvantaged students and families, and (2) a close examination of practice in the professional lives of the authors, each of whom serves or has served as a school administrator in a rural Appalachian setting. Following a discussion of the leadership model, consideration is given to the implications for leadership preparation programs and practices. [The citation information shown on the attached PDF (v5 n2 Oct-Dec 2010) is incorrect, according to the information displayed on the provider site.]

IMPORTANCE:. Factors associated with mortality in coronavirus disease 2019 patients on invasive mechanical ventilation are still not fully elucidated. OBJECTIVES:. To identify patient-level parameters, readily available at the bedside, associated with the risk of in-hospital mortality within 28 days from commencement of invasive mechanical ventilation or coronavirus disease 2019. DESIGN, SETTING, AND PARTICIPANTS:. Prospective observational cohort study by the global Coronavirus Disease 2019 Critical Care Consortium. Patients with laboratory-confirmed coronavirus disease 2019 requiring invasive mechanical ventilation from February 2, 2020, to May 15, 2021. MAIN OUTCOMES AND MEASURES:. Patient characteristics and clinical data were assessed upon ICU admission, the commencement of invasive mechanical ventilation and for 28 days thereafter. We primarily aimed to identify time-independent and time-dependent risk factors for 28-day invasive mechanical ventilation mortality. RESULTS:. One-thousand five-hundred eighty-seven patients were included in the survival analysis; 588 patients died in hospital within 28 days of commencing invasive mechanical ventilation (37%). Cox-regression analysis identified associations between the hazard of 28-day invasive mechanical ventilation mortality with age (hazard ratio, 1.26 per 10-yr increase in age; 95% CI, 1.16–1.37; p < 0.001), positive end-expiratory pressure upon commencement of invasive mechanical ventilation (hazard ratio, 0.81 per 5 cm H2O increase; 95% CI, 0.67–0.97; p = 0.02). Time-dependent parameters associated with 28-day invasive mechanical ventilation mortality were serum creatinine (hazard ratio, 1.28 per doubling; 95% CI, 1.15–1.41; p < 0.001), lactate (hazard ratio, 1.22 per doubling; 95% CI, 1.11–1.34; p < 0.001), Paco2 (hazard ratio, 1.63 per doubling; 95% CI, 1.19–2.25; p < 0.001), pH (hazard ratio, 0.89 per 0.1 increase; 95% CI, 0.8–14; p = 0.041), Pao2/Fio2 (hazard ratio, 0.58 per doubling; 95% CI, 0.52–0.66; p < 0.001), and mean arterial pressure (hazard ratio, 0.92 per 10 mm Hg increase; 95% CI, 0.88–0.97; p = 0.003). CONCLUSIONS AND RELEVANCE:. This international study suggests that in patients with coronavirus disease 2019 on invasive mechanical ventilation, older age and clinically relevant variables monitored at baseline or sequentially during the course of invasive mechanical ventilation are associated with 28-day invasive mechanical ventilation mortality hazard. Further investigation is warranted to validate any causative roles these parameters might play in influencing clinical outcomes.

The natural history of Alzheimer’s Disease (AD) includes significant alterations in the human connectome, and this disconnection results in the dementia of AD. The organizing principle of our research project is the idea that the expression of cognitive dysfunction in the elderly is the result of two independent processes — the neuropathology associated with AD, and second the neuropathological changes of cerebrovascular disease. Synaptic loss, senile plaques, and neurofibrillary tangles are the functional and diagnostic hallmarks of AD, but it is the structural changes as a consequence of vascular disease that reduce brain reserve and compensation, resulting in an earlier expression of the clinical dementia syndrome. This work is being completed under the auspices of the Human Connectome Project (HCP). We have achieved an equal representation of Black individuals (vs. White individuals) and enrolled 60% Women. Each of the participants contributes demographic, behavioral and laboratory data. We acquire data relative to vascular risk, and the participants also undergo in vivo amyloid imaging, and magnetoencephalography (MEG). All of the data are publicly available under the HCP guidelines using the Connectome Coordinating Facility and the NIMH Data Archive. Locally, we use these data to address specific questions related to structure, function, AD, aging and vascular disease in multi-modality studies leveraging the differential advantages of magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), MEG, and in vivo beta amyloid imaging.

The authors of this article describe an adaptation of the rent-seeking game by Goeree and Holt (1999) to the recruiting of athletes by NCAA Division I football and basketball teams. Students engage in an effort-based lottery, i.e., recruiting to sign a blue-chip prospect. The winner gets the prize--the player's marginal revenue product in excess of his grant in aid. Students recruit in three scenarios: by recruiting legally, by recruiting legally or with illegal bribes, and by offering wages to athletes in an auction. The authors demonstrate the game's use in a principles course, but it is easily adaptable to other courses. To aid instructors unfamiliar with sports and NCAA recruiting, they include a comprehensive lesson plan with suggested readings and multimedia.

Background and Aims: Activation of the inflammasome NLRP3 (NOD-, LRR- and pyrin domain containing 3) contributes to the development of non-alcoholic fatty liver disease (NAFLD) and progression to non-alcoholic steatohepatitis (NASH). Therefore, this study explored the therapeutic effects of a novel and selective NLRP3 antagonist in a murine dietary model of NASH.Methods: Groups of 12-week-old ApoE-/- mice were fed ad lib for 7 weeks with a methionine/choline deficient (MCD) and western diet (WD). After 3 weeks of diet-induced injury, mice were injected i. p. with the NLRP3 antagonist IFM-514 (100 mg/kg body weight) or vehicle (0.5% carmellose) every day, 5 days/week for a further 4 weeks. Several markers of inflammation, fibrosis and steatosis were evaluated. Whole transcriptome sequencing and panel RNA expression analysis (NanoString) were performed.Results: IFM-514 inhibited IL-1β production in mice challenged with 20 mg/kg lipopolysaccharide, and in mouse and human inflammatory cells in vitro. IFM-514 inhibited hepatic inflammation in the in vivo non-alcoholic steatohepatitis model assessed by H&E staining and in the hepatic gene expression of inflammasome-related proinflammatory cytokines. This effect was associated with significant reduction in caspase-1 activation. Similarly, IFM-514 was efficacious in vivo in MDC-fed ApoE-/- mice, markedly reducing portal pressure, Sirius red staining and 4-hydroxyproline content compared to vehicle-treated mice. Moreover, IFM-514 significantly reduced hepatic steatosis in MCD-fed ApoE-/- mice, as evidenced by NAFLD scores, oil red O staining, hepatic triglycerides and gene expression. In WD treated animals, similar trends in inflammation and fibrosis were observed, although not sufficient IFM-514 levels were reached.Conclusion: Overall, IFM-514 reduced liver inflammation and fibrosis, with mild effects on liver steatosis in experimental murine NASH. Blocking of NLRP3 may be an attractive therapeutic approach for NASH patients.

The goal of the Changing the Culture project at the University of Rhode Island is to develop a multi-institutional, statewide network of disability resource mentors, whereby faculty and administrators encourage their department colleagues to develop policies and teaching practices that are inclusive of students with disabilities. The CTC program is systematically increasing the number of disability resource mentors in private and public postsecondary institutions in Rhode Island. One of several outcomes of the project's seminar, and the resulting day-to-day presence of disability resource mentors, has been increased system-wide inclusiveness for students with disabilities. (Contains 3 tables.)

Abstract Background Peak reverse torque (PRT) is a valid method to evaluate implants’ secondary stability in the healing bone. The secondary stability is achieved by the implant over time and it has been positively correlated with the implants’ osseointegration level. In other words, peak reverse torque is the force required to break the bone-implant interface. The purpose of this study was to compare the peak reverse torque for the self-tapping and non-self-tapping screws used in a dynamic compression plate–screw–bone construct after 60 days of loading when used to stabilize 2.5-cm defects in the tibia of goats. The second objective was to compare the peak removal torque of the screws placed in the different positions to evaluate the impact of construct biomechanics on implants osseointegration. Results In total, 176 non-self-tapping screws and 66 self-tapping screws were used to fix the 8-holes dynamic compression plates to the bones. The screws were placed in the tibiae from proximal (position sites 1,2, 3) to distal (position sites 4,5,6) and were removed 60 days post-implantation. The animals remained weight-bearing throughout the study period. The screws placed in the proximal diaphysis had significantly less peak reverse torque than screws placed in the distal diaphysis in both groups (p

Changes of cardiac-induced regional pulsatility can be associated with specific regions of brain volumetric changes, and these are related with cognitive alterations. Thus, mapping of cardiac pulsatility over the entire brain can be helpful to assess these relationships. A total of 108 subjects (age: 66.5 ± 8.4 years, 68 females, 52 healthy controls, 11 subjective cognitive decline, 17 impaired without complaints, 19 MCI and 9 AD) participated. The pulsatility map was obtained directly from resting-state functional MRI time-series data at 3T. Regional brain volumes were segmented from anatomical MRI. Multidomain neuropsychological battery was performed to test memory, language, attention and visuospatial construction. The Montreal Cognitive Assessment (MoCA) was also administered. The sparse partial least square (SPLS) method, which is desirable for better interpreting high-dimensional variables, was applied for the relationship between the entire brain voxels of pulsatility and 45 segmented brain volumes. A multiple holdout SPLS framework was used to optimize sparsity for assessing the pulsatility-volume relationship model and to test the reliability by fitting the models to 9 different splits of the data. We found statistically significant associations between subsets of pulsatility voxels and subsets of segmented brain volumes by rejecting the omnibus null hypothesis (any of 9 splits has p < 0.0056 (=0.05/9) with the Bonferroni correction). The pulsatility was positively associated with the lateral ventricle, choroid plexus, inferior lateral ventricle, and 3rd ventricle and negatively associated with hippocampus, ventral DC, and thalamus volumes for the first pulsatility-volume relationship. The pulsatility had an additional negative relationship with the amygdala and brain stem volumes for the second pulsatility-volume relationship. The spatial distribution of correlated pulsatility was observed in major feeding arteries to the brain regions, ventricles, and sagittal sinus. The indirect mediating pathways through the volumetric changes were statistically significant between the pulsatility and multiple cognitive measures (p < 0.01). Thus, the cerebral pulsatility, along with volumetric measurements, could be a potential marker for better understanding of pathophysiology and monitoring disease progression in age-related neurodegenerative disorders.

The purpose of this retrospective study was to evaluate the risk factors for short-term postoperative complications in the 8 weeks after unilateral tibial plateau leveling osteotomy (TPLO) for cranial cruciate ligament rupture in small dogs weighing less than 15 kg. Medical records were retrospectively reviewed for 90 dogs weighing 15kg. In this study, patients in which 2.4-mm TPLO plates were used were more likely to develop postoperative complications. Dogs weighing

Abstract: Microtubules are polymers composed of αβ-tubulin subunits that provide structure to cells and play a crucial role in in the development and function of neuronal processes and cilia, microtubule-driven extensions of the plasma membrane that have sensory (primary cilia) or motor (motile cilia) functions. To stabilize microtubules in neuronal processes and cilia, α tubulin is modified by the posttranslational addition of an acetyl group, or acetylation. We discovered that acetylated tubulin in microtubules interacts with the membrane sphingolipid, ceramide. However, the molecular mechanism and function of this interaction are not understood. Here, we show that in human induced pluripotent stem cell–derived neurons, ceramide stabilizes microtubules, which indicates a similar function in cilia. Using proximity ligation assays, we detected complex formation of ceramide with acetylated tubulin in Chlamydomonas reinhardtii flagella and cilia of human embryonic kidney (HEK293T) cells, primary cultured mouse astrocytes, and ependymal cells. Using incorporation of palmitic azide and click chemistry–mediated addition of fluorophores, we show that a portion of acetylated tubulin is S-palmitoylated. S-palmitoylated acetylated tubulin is colocalized with ceramide-rich platforms in the ciliary membrane, and it is coimmunoprecipitated with Arl13b, a GTPase that mediates transport of proteins into cilia. Inhibition of S-palmitoylation with 2-bromo palmitic acid or inhibition of ceramide biosynthesis with fumonisin B1 reduces formation of the Arl13b-acetylated tubulin complex and its transport into cilia, concurrent with impairment of ciliogenesis. Together, these data show, for the first time, that ceramide-rich platforms mediate membrane anchoring and interaction of S-palmitoylated proteins that are critical for cilium formation, stabilization, and function.

OBJECTIVE:To determine if a commercial myostatin reducer (Fortetropin®) would inhibit disuse muscle atrophy in dogs after a tibial plateau leveling osteotomy. DESIGN:A prospective randomized, double-blinded, placebo-controlled clinical trial. ANIMALS:One hundred client-owned dogs presenting for surgical correction of cranial cruciate ligament rupture by tibial plateau leveling osteotomy. PROCEDURES:Patients were randomly assigned into the Fortetropin® or placebo group and clients were instructed to add the assigned supplement to the dog's normal diet once daily for twelve weeks. Enrolled patients had ultrasound measurements of muscle thickness, tape measure measurements of thigh circumference, serum myostatin level assays, and static stance analysis evaluated at weeks 0, 8, and 12. RESULTS:From week 0 to week 8, there was no change for thigh circumference in the Fortetropin® group for the affected limb (-0.54cm, P = 0.31), but a significant decrease in thigh circumference for the placebo group (-1.21cm, P = 0.03). There was no significant change in serum myostatin levels of dogs in the Fortetropin® group at any time point (P>0.05), while there was a significant rise of serum myostatin levels of dogs in placebo group during the period of forced exercise restriction (week 0 to week 8; +2,892 pg/ml, P = 0.02). The percent of body weight supported by the affected limb increased in dogs treated with Fortetropin® (+7.0%, P

The Central Dogma of molecular biology describes the transfer of genetic information within organisms and is a core concept in the biological sciences. However foundational, the Central Dogma is often misrepresented when taught in introductory college biology courses. In particular, the Central Dogma is often taught with a requisite DNA step, an incorrect conception that omits the possibility of RNA-based molecular systems, such as SARS-CoV-2, the causative agent of COVID-19. In this new contribution, we offer a practical way to clarify correct conceptions and make them immediately relevant through COVID-19. In this new digital ‘sorting cards’ activity, students collaboratively synthesize and map their knowledge of core molecular biology. Building off of the typically-presented concepts of the Central Dogma, we also introduce two sorting card “expansion packs” for double-stranded DNA viruses and single-stranded RNA viruses. We provide activity templates for all sets of cards using a free web-based collaborative platform suitable for sudden shifts to online learning (as in our implementation), pre-planned online learning, and in-person classes. While truly hands-on activities can be difficult to replicate in the context of online learning, the use of collaborative websites and creative freedom in this activity encourages student engagement in and ownership of their learning.

Tumors often exhibit a pH gradient, with an acidic extracellular space and alkaline cytoplasm. Here the authors develop a computational model to show how alkaline pHi supports changes inherent to cancer cell metabolism and acidification disables these adaptations, and demonstrate the effect of acidic pHi on breast cancer cell survival.

Abstract Background The annual killifish Austrofundulus limnaeus inhabits ephemeral ponds in northern Venezuela, South America, and is an emerging extremophile model for vertebrate diapause, stress tolerance, and evolution. Embryos of A. limnaeus regularly experience extended periods of desiccation and anoxia as a part of their natural history and have unique metabolic and developmental adaptations. Currently, there are limited genomic resources available for gene expression and evolutionary studies that can take advantage of A. limnaeus as a unique model system. Results We describe the first draft genome sequence of A. limnaeus. The genome was assembled de novo using a merged assembly strategy and was annotated using the NCBI Eukaryotic Annotation Pipeline. We show that the assembled genome has a high degree of completeness in genic regions that is on par with several other teleost genomes. Using RNA-seq and phylogenetic-based approaches, we identify several candidate genes that may be important for embryonic stress tolerance and post-diapause development in A. limnaeus. Several of these genes include heat shock proteins that have unique expression patterns in A. limnaeus embryos and at least one of these may be under positive selection. Conclusion The A. limnaeus genome is the first South American annual killifish genome made publicly available. This genome will be a valuable resource for comparative genomics to determine the genetic and evolutionary mechanisms that support the unique biology of annual killifishes. In a broader context, this genome will be a valuable tool for exploring genome-environment interactions and their impacts on vertebrate physiology and evolution.

INTRODUCTION: White matter hyperintensities (WMH) may promote clinical Alzheimer's disease (AD) disparities between Black American (BA) and non‐Hispanic White (nHW) populations. Using a novel measurement, unhealthy white matter connectivity (UWMC), we interrogated racialized group differences in associations between WMH in AD pathology‐affected regions and cognition. METHODS: UWMC is the proportion of white matter fibers that pass through WMH for every pair of brain regions. Individual regression models tested associations of UWMC in beta‐amyloid (Aβ) or tau pathology‐affected regions with cognition overall, stratified by racialized group, and with a racialized group interaction. RESULTS: In 201 older adults ranging from cognitively unimpaired to AD, BA participants exhibited greater UWMC and worse cognition than nHW participants. UWMC was negatively associated with cognition in 17 and 5 Aβ‐ and tau‐affected regions, respectively. Racialization did not modify these relationships. DISCUSSION: Differential UWMC burden, not differential UWMC‐and‐cognition associations, may drive clinical AD disparities between racialized groups. Highlights: Unhealthy white matter connectivity (UWMC) in Alzheimer's disease (AD) pathology–affected brain regions is associated with cognition.Relationships between UWMC and cognition are similar between Black American (BA) and non‐Hispanic White (nHW) individuals.More UWMC may partially drive higher clinical AD burden in BA versus nHW populations.UWMC risk factors, particularly social and environmental, should be identified. [ABSTRACT FROM AUTHOR]

Conceptual metaphor theory (CMT) proposes that there is a large system of conceptual metaphors in our cognition known as event-structure metaphors (ESMs). Through ESMs, we understand the conceptual domains of actions, causes, changes, states, purposes, and so forth in terms of the aspects of the domain of motion in space. ESMs are largely organized under two systems, or branches--the location and object branches. Earlier studies present linguistic evidence that these ESM conceptual systems are expressed in unrelated spoken languages (English, Hungarian, Chinese, and Arabic) thus supporting the claim that ESMs are universal. In this article, I explore the question of whether the location branch of event-structure metaphors (location ESM) is exhibited in American Sign Language (ASL). The article begins with a brief review of the conceptual metaphor theory and its application to signed languages. This is followed by a summary of the location ESM and references to studies that support its cross-linguistic universality. A description of data and methods used in this investigation is given. I then define each of the eleven submappings of the location ESM system. For each respective submapping, I reference English examples from the CMT literature. I then analyze evidence selected from ASL corpora suggesting that each of the submappings in the location ESM system is exhibited in ASL. This study is the first systematic investigation in a signed language that supports the claim of universality of each main submapping in the location ESM system.

Current strategies for producing antibody-drug conjugates often rely on inefficient conjugation chemistry or on generating mutations in the antibody sequence. Here the authors demonstrate a mutation-free, single-step conjugation platform utilizing a buried lysine residue.

Percutaneous image-guided biopsies of pancreatic malignancies may prove challenging and nondiagnostic due to a variety of anatomic considerations. For patients with complex post-surgical anatomy, such as a Roux-en-Y gastric bypass, diagnosis via endoscopic ultrasound with fine-needle aspiration may not be possible because of an inability to reach the proximal duodenum. This report describes the first diagnostic case of transbiliary intravascular ultrasound-guided biopsy of a pancreatic head mass in a patient with prior Roux-en-Y gastric bypass for which a diagnosis could not be achieved via percutaneous and endoscopic approaches. Transbiliary intravascular ultrasound-guided biopsy resulted in a diagnosis of pancreatic adenocarcinoma, allowing the initiation of chemotherapy.