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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

BackgroundMany studies have examined the Positive Parenting Program (Triple P), yet few have considered its effectiveness during the twin challenges of the opioid crisis and COVID-19 pandemic.ObjectiveThis study examines the implementation of, and parenting outcomes associated with the Positive Parenting Program (Triple P) in 13 counties in central Ohio.Participants and settingThe program was provided to parents who were at heightened risk for substance use. From July 2020 through June 2021, 890 parents received services from Triple P.MethodsParents completed pre- and post-test assessments of protective factors within their families and parenting behaviors. Parents also participated in qualitative interviews regarding their experiences in the program.ConclusionsOverall, the results were promising, with improvements seen in family functioning/resilience, nurturing and attachment, parental laxness, and parental over-reactivity. Parents reported positive experiences participating in the program and felt that their relationship with their child had improved. Despite the profound, recent challenges to parenting and service provision, Triple P continues to show promise as an approach to reducing child maltreatment. Expansion of Triple P to other areas may improve parenting behaviors and reduce child maltreatment among parents at risk for substance use.

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.

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.

Triggering receptor expressed on myeloid cells 2 (TREM2) is a single-pass transmembrane receptor of the immunoglobulin superfamily that is secreted in a soluble (sTREM2) form. Mutations in TREM2 have been linked to increased risk of Alzheimer's disease (AD). A prominent neuropathological component of AD is deposition of the amyloid-β (Aβ) into plaques, particularly Aβ40 and Aβ42. While the membrane-bound form of TREM2 is known to facilitate uptake of Aβ fibrils and the polarization of microglial processes toward amyloid plaques, the role of its soluble ectodomain, particularly in interactions with monomeric or fibrillar Aβ, has been less clear. Our results demonstrate that sTREM2 does not bind to monomeric Aβ40 and Aβ42, even at a high micromolar concentration, while it does bind to fibrillar Aβ42 and Aβ40 with equal affinities (2.6 ± 0.3 µM and 2.3 ± 0.4 µM). Kinetic analysis shows that sTREM2 inhibits the secondary nucleation step in the fibrillization of Aβ, while having little effect on the primary nucleation pathway. Furthermore, binding of sTREM2 to fibrils markedly enhanced uptake of fibrils into human microglial and neuroglioma derived cell lines. The disease-associated sTREM2 mutant, R47H, displayed little to no effect on fibril nucleation and binding, but it decreased uptake and functional responses markedly. We also probed the structure of the WT sTREM2-Aβ fibril complex using integrative molecular modeling based primarily on the cross-linking mass spectrometry data. The model shows that sTREM2 binds fibrils along one face of the structure, leaving a second, mutation-sensitive site free to mediate cellular binding and uptake.

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.

Primary amebic meningoencephalitis (PAM) is a rapidly fatal infection caused by the free-living ameba Naegleria fowleri. PAM occurs principally in healthy children of less than 13 years old with a history of recent exposure to warm fresh water. While as yet not a reportable disease, the Centers for Disease Control and Prevention (CDC) documents a total of 143 cases in the United States. Only four patients have survived. Infection results from water containing N. fowleri entering the nose, followed by migration of the amebae to the brain. Within the brain, N. fowleri infection results in extensive necrosis, leading to death in 3-7 days. Mortality among patients with PAM is greater than 95%. The drugs of choice in treating PAM are the antifungal amphotericin B, and the antileishmanial, miltefosine. However neither drug is FDA-approved for this indication and the use of amphotericin B is associated with severe adverse effects. Moreover, very few patients treated with amphotericin B have survived PAM. Therefore, development of new, safe and effective drugs is a critical unmet need to avert future deaths of children. The molecular mechanisms underlying the pathogenesis of PAM are poorly understood but it is known that cysteine proteases of N. fowleri play a role in the progression of PAM. We therefore assessed the in vitro activity of the synthetic vinyl sulfone cysteine protease inhibitor, K11777, and 33 analogs with valine, phenylalanine or pyridylalanine at P2 position, against cysteine protease activity in the lysate of N. fowleri. Inhibitors with phenylalanine or pyridylalanine at P2 position were particularly effective in inhibiting the cysteine protease activity of N. fowleri cell lysate with IC50 ranging between 3 nM and 6.6 μM. Three of the 34 inhibitors also showed inhibitory activity against N. fowleri in a cell viability assay and were 1.6- to 2.5-fold more potent than the standard of care drug miltefosine. Our study provides the first evidence of the activity of synthetic, small molecule cysteine protease inhibitors against N. fowleri.

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.

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

BackgroundChagas disease, caused by the protozoan Trypanosoma cruzi, is the leading cause of heart failure in Latin America. The clinical treatment of Chagas disease is limited to two 60 year-old drugs, nifurtimox and benznidazole, that have variable efficacy against different strains of the parasite and may lead to severe side effects. CYP51 is an enzyme in the sterol biosynthesis pathway that has been exploited for the development of therapeutics for fungal and parasitic infections. In a target-based drug discovery program guided by x-ray crystallography, we identified the 4-aminopyridyl-based series of CYP51 inhibitors as being efficacious versus T.cruzi in vitro; two of the most potent leads, 9 and 12, have now been evaluated for toxicity and efficacy in mice.Methodology/principal findingsBoth acute and chronic animal models infected with wild type or transgenic T. cruzi strains were evaluated. There was no evidence of toxicity in the 28-day dosing study of uninfected animals, as judged by the monitoring of multiple serum and histological parameters. In two acute models of Chagas disease, 9 and 12 drastically reduced parasitemia, increased survival of mice, and prevented liver and heart injury. None of the compounds produced long term sterile cure. In the less severe acute model using the transgenic CL-Brenner strain of T.cruzi, parasitemia relapsed upon drug withdrawal. In the chronic model, parasitemia fell to a background level and, as evidenced by the bioluminescence detection of T. cruzi expressing the red-shifted luciferase marker, mice remained negative for 4 weeks after drug withdrawal. Two immunosuppression cycles with cyclophosphamide were required to re-activate the parasites. Although no sterile cure was achieved, the suppression of parasitemia in acutely infected mice resulted in drastically reduced inflammation in the heart.Conclusions/significanceThe positive outcomes achieved in the absence of sterile cure suggest that the target product profile in anti-Chagasic drug discovery should be revised in favor of safe re-administration of the medication during the lifespan of a Chagas disease patient. A medication that reduces parasite burden may halt or slow progression of cardiomyopathy and therefore improve both life expectancy and quality of life.

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.

Leishmania protozoan parasites (Trypanosomatidae family) are the causative agents of cutaneous, mucocutaneous and visceral leishmaniasis worldwide. While these diseases are associated with significant morbidity and mortality, there are few adequate treatments available. Sterol 14alpha-demethylase (CYP51) in the parasite sterol biosynthesis pathway has been the focus of considerable interest as a novel drug target in Leishmania. However, its essentiality in Leishmania donovani has yet to be determined. Here, we use a dual biological and pharmacological approach to demonstrate that CYP51 is indispensable in L. donovani. We show via a facilitated knockout approach that chromosomal CYP51 genes can only be knocked out in the presence of episomal complementation and that this episome cannot be lost from the parasite even under negative selection. In addition, we treated wild-type L. donovani and CYP51-deficient strains with 4-aminopyridyl-based inhibitors designed specifically for Trypanosoma cruzi CYP51. While potency was lower than in T. cruzi, these inhibitors had increased efficacy in parasites lacking a CYP51 allele compared to complemented parasites, indicating inhibition of parasite growth via a CYP51-specific mechanism and confirming essentiality of CYP51 in L. donovani. Overall, these results provide support for further development of CYP51 inhibitors for the treatment of visceral leishmaniasis.

Leishmania protozoan parasites (Trypanosomatidae family) are the causative agents of cutaneous, mucocutaneous and visceral leishmaniasis worldwide. While these diseases are associated with significant morbidity and mortality, there are few adequate treatments available. Sterol 14alpha-demethylase (CYP51) in the parasite sterol biosynthesis pathway has been the focus of considerable interest as a novel drug target in Leishmania. However, its essentiality in Leishmania donovani has yet to be determined. Here, we use a dual biological and pharmacological approach to demonstrate that CYP51 is indispensable in L. donovani. We show via a facilitated knockout approach that chromosomal CYP51 genes can only be knocked out in the presence of episomal complementation and that this episome cannot be lost from the parasite even under negative selection. In addition, we treated wild-type L. donovani and CYP51-deficient strains with 4-aminopyridyl-based inhibitors designed specifically for Trypanosoma cruzi CYP51. While potency was lower than in T. cruzi, these inhibitors had increased efficacy in parasites lacking a CYP51 allele compared to complemented parasites, indicating inhibition of parasite growth via a CYP51-specific mechanism and confirming essentiality of CYP51 in L. donovani. Overall, these results provide support for further development of CYP51 inhibitors for the treatment of visceral leishmaniasis.

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.