Miracle-dz/UniFAR-FTUs huggingface dataset:
Never Enough Time: Mixed Methods Study Identifies Drivers of Temporal Demand That Contribute to Burnout Among Physicians Who Care for Pediatric Hematology-Oncology Patients

PURPOSE: Burnout is a syndrome of emotional exhaustion, depersonalization, and reduced personal accomplishment because of chronic occupational stress. Approximately one third of pediatric hematology-oncology physicians experience burnout. The goal of this mixed methods study was to determine the prevalence and drivers of burnout among physicians caring for pediatric hematology-oncology patients at our institution. MATERIALS AND METHODS: This mixed methods, cross-sectional study was conducted at a large academic cancer center. Validated survey instruments were used to measure burnout, job demands, experience with patient safety events, and workplace culture. Quantitative data informed development of a semistructured interview guide, and physicians were randomly selected to participate in individual interviews. Interviews were transcribed and analyzed via content analysis based on a priori codes. RESULTS: The survey was distributed to 132 physicians, and 53 complete responses were received (response rate 40%). Of the 53 respondents, 15 (28%) met criteria for burnout. Experiencing burnout was associated with increased temporal demand. Twenty-six interviews were conducted. Qualitative themes revealed that frequent meetings, insufficient support staff, and workflow interruptions were key drivers of temporal demand and that temporal demand contributed to burnout through emotional exhaustion and reduced personal accomplishment. CONCLUSION: Nearly one-third of participating physicians met criteria for burnout, and burnout was associated with increased temporal demand. Qualitative interviews identified specific drivers of temporal demand and burnout, which can be targeted for intervention. This methodology can be easily adapted for broad use and may represent an effective strategy for identifying and mitigating institution-specific drivers of burnout.
Two novel loci underlie natural differences in Caenorhabditis elegans abamectin responses

Parasitic nematodes cause a massive worldwide burden on human health along with a loss of livestock and agriculture productivity. Anthelmintics have been widely successful in treating parasitic nematodes. However, resistance is increasing, and little is known about the molecular and genetic causes of resistance for most of these drugs. The free-living roundworm Caenorhabditis elegans provides a tractable model to identify genes that underlie resistance. Unlike parasitic nematodes, C. elegans is easy to maintain in the laboratory, has a complete and well annotated genome, and has many genetic tools. Using a combination of wild isolates and a panel of recombinant inbred lines constructed from crosses of two genetically and phenotypically divergent strains, we identified three genomic regions on chromosome V that underlie natural differences in response to the macrocyclic lactone (ML) abamectin. One locus was identified previously and encodes an alpha subunit of a glutamate-gated chloride channel (glc-1). Here, we validate and narrow two novel loci using near-isogenic lines. Additionally, we generate a list of prioritized candidate genes identified in C. elegans and in the parasite Haemonchus contortus by comparison of ML resistance loci. These genes could represent previously unidentified resistance genes shared across nematode species and should be evaluated in the future. Our work highlights the advantages of using C. elegans as a model to better understand ML resistance in parasitic nematodes.
The receptor-like kinases BAM1 and BAM2 are required for root xylem patterning

Significance Plant miRNAs can move from cell to cell through cytoplasmic channels called plasmodesmata, transmitting positional information that is decoded to make developmental decisions; one well-studied example of this is xylem patterning in the root of the model plant Arabidopsis thaliana, which depends on the formation of opposing gradients of two miRNAs and their target transcripts. Here, we show that two plasma membrane- and plasmodesmata-localized proteins, BAM1 and BAM2, are required for maintaining appropriate levels and distribution of the miRNA target transcripts, and hence for proper root xylem patterning, uncovering additional players in the regulation of this developmental process and adding one more function, direct or indirect, to the ever-growing portfolio of BAM1 and BAM2. Xylem patterning in the root is established through the creation of opposing gradients of miRNAs and their targets, transcripts of the HD-ZIP III family of transcriptions factors, enabled by the cell-to-cell spread of the former. The miRNAs regulating xylem patterning, miR165/6, move through plasmodesmata, but how their trafficking is regulated remains elusive. Here, we describe that simultaneous mutation of the plasma membrane- and plasmodesmata-localized receptor-like kinases (RLKs) BARELY ANY MERISTEM (BAM) 1 and 2 or expression of the geminivirus-encoded BAM1/2-interactor C4 results in higher accumulation and broader distribution of the HD-ZIP III transcripts despite normal total accumulation of miR165/6, and ultimately causes defects in xylem patterning, which depend on the function of the aforementioned miRNA targets. Taken together, our results show that BAM1 and BAM2 are redundantly required for proper xylem patterning in the Arabidopsis root, by ensuring the proper distribution and accumulation of miR165/6-targeted transcripts.
The flavodoxin FldA activates the class Ia ribonucleotide reductase of Campylobacter jejuni

Campylobacter jejuni is a microaerophilic zoonotic pathogen with an atypical respiratory Complex I that oxidizes a flavodoxin (FldA) instead of NADH. FldA is essential for viability and is reduced via pyruvate and 2‐oxoglutarate oxidoreductases (POR/OOR). Here, we show that FldA can also be reduced by FqrB (Cj0559), an NADPH:FldA reductase. An fqrB deletion mutant was viable but displayed a significant growth defect. FqrB is related to flavoprotein reductases from Gram‐positive bacteria that can reduce NrdI, a specialized flavodoxin that is needed for tyrosyl radical formation in NrdF, the beta subunit of class 1b‐type (Mn) ribonucleotide reductase (RNR). However, C. jejuni possesses a single class Ia‐type (Fe) RNR (NrdAB) that would be expected to be ferredoxin dependent. We show that CjFldA is an unusually high potential flavodoxin unrelated to NrdI, yet growth of the fqrB mutant, but not the wild‐type or a complemented strain, was stimulated by low deoxyribonucleoside (dRNS) concentrations, suggesting FldA links FqrB and RNR activity. Using purified proteins, we confirmed the NrdB tyrosyl radical could be regenerated in an NADPH, FqrB, and FldA dependent manner, as evidenced by both optical and electron paramagnetic resonance (EPR) spectroscopy. Thus, FldA activates RNR in C. jejuni, partly explaining its essentiality.
The course of physical functioning in the first two years after stroke depends on peoples’ individual movement behavior patterns

Background and purpose Deterioration of physical functioning after stroke in the long term is regarded as a major problem. Currently, the relationship between “peoples'” movement behavior patterns (the composition of sedentary behavior and physical activity during waking hours) directly after stroke and the development of physical functioning over time is unknown. Therefore, the objectives of this study were to investigate (1) the course of physical functioning within the first two years after returning home after stroke, and (2) the association between physical functioning and baseline movement behavior patterns. Method In the longitudinal RISE cohort study, 200 persons with a first-ever stroke discharged to the home-setting were included. Participants’ physical functioning was assessed within three weeks, at six months, and one and two years after discharge using the Stroke Impact Scale (SIS) 3.0 subscale physical and the five-meter walk test (5MWT). Three distinct movement behavior patterns were identified in a previous study at baseline and were used in the current study: (1) sedentary exercisers (sufficiently active and 64% of waking hours sedentary), (2) sedentary movers’ (inactive and 63% of waking hours sedentary), and (3) sedentary prolongers (inactive and >78% of waking hours sedentary accumulated in long prolonged bouts). The association between movement behavior patterns and the course of physical functioning was determined using longitudinal generalized estimating equations analyses. Results Overall participants’ physical functioning increased between discharge and six months and declined from six months up to two years. Physical functioning remained stable during the first two years after stroke in sedentary exercisers. Physical functioning improved during the first six months after discharge in sedentary movers and sedentary prolongers and deteriorated in the following six months. Only physical functioning (SIS) of sedentary prolongers further declined from one up to two years. A similar pattern was observed in the 5MWT. Conclusion Movement behavior patterns identified directly after returning home in people with stroke are associated with and are predictive of the course of physical functioning. Highly sedentary and inactive people with stroke have unfavorable outcomes over time than individuals with higher amounts of physical activity.
Adsorption studies on the removal of Eriochrome black-T from aqueous solution using Nteje clay

: Adsorption studies including the kinetics and thermodynamics in the removal of Eriochrome black-T (EBT) dye was studied using local clay. Acid activation using hydrochloric acid (HCl) and tetraoxosulphate VI acid (H 2 SO 4 ) were used to prepare the clay for adsorption. Batch studies were used to investigate the effects of contact time, dosage, pH and initial ion concentration. Under the same conditions, the clay activated with HCl was seen to be a better adsorbent than the clay activated with H 2 SO 4 . In the equilibrium studies, Freundlich isotherm best conformed to the adsorption data. The maximum amounts of EBT adsorbed per unit mass (qe) were 16.26 and 15.88 mg/g for NHC and NHS clays respectively. The kinetic models studied include Lagregen second order, Pseudo second-order, Intra-particle and Battachayra-Venkobachor models. The kinetic study showed that the Pseudo second-order and Battachayra-Venkobachormodels best described the kinetics of the adsorption process. The thermodynamic study involved the determination of Gibbs free energy change ( D G), the entropy change ( D S) and the enthalpy change ( D H). The positive D S and negative D G values indicated that the adsorption process is feasible and spontaneous.
Targeting angiotensin type 2 receptors located on pressor neurons in the nucleus of the solitary tract to relieve hypertension in mice.

AIMS These studies evaluate whether angiotensin type-2 receptors (AT2Rs) that are expressed on γ-aminobutyric acid (GABA) neurons in the nucleus of the solitary tract (NTS) represent a novel endogenous blood pressure lowering mechanism. METHODS AND RESULTS Experiments combined advanced genetic and neuroanatomical techniques, pharmacology, electrophysiology and optogenetics in mice to define the structure and cardiovascular-related function of NTS neurons that contain AT2R. Using mice with Cre-recombinase directed to the AT2R gene, we discovered that optogenetic stimulation of AT2R-expressing neurons in the NTS increases GABA release and blood pressure. To evaluate the role of the receptor, per se, in cardiovascular regulation, we chronically delivered C21, a selective AT2R agonist, into the brains of normotensive mice and found that central AT2R activation reduces GABA-related gene expression and blunts the pressor responses induced by optogenetic excitation of NTS AT2R neurons. Next, using in situ hybridization, we found that the levels of Agtr2 mRNAs in GABAergic NTS neurons rise during experimentally-induced hypertension, and we hypothesized that this increased expression may be exploited to ameliorate the disease. Consistent with this, final experiments revealed that central administration of C21 attenuates hypertension, an effect that is abolished in mice lacking AT2R in GABAergic NTS neurons. CONCLUSIONS These studies unveil novel hindbrain circuits that maintain arterial blood pressure, and reveal a specific population of AT2R that can be engaged to alleviate hypertension. The implication is that these discrete receptors may serve as an access point for activating an endogenous depressor circuit. TRANSLATIONAL PERSPECTIVE Hypertension is a widespread health problem and risk factor for cardiovascular disease and stroke. Although treatment options exist, many patients suffer from resistant hypertension, which is associated with enhanced sympathetic drive. Thus, many available therapeutics focus on dampening pressor mechanisms. The present studies take the alternative approach of treating hypertension by exploiting an endogenous depressor mechanism.
Type III secretion system effector proteins are mechanically labile

Significance The type III secretion system (T3SS) is an important virulence factor that enables some bacteria to directly inject effector proteins into host cells, facilitating colonization. To be secreted, effector proteins must be unfolded, and tightly packed proteins like GFP cannot be secreted through the T3SS, leading to the model that effector proteins have low thermodynamic stability. We show that two model effector proteins have thermodynamic stabilities similar to tightly packed proteins (GFP and ubiquitin) but are much more mechanically labile. These results strongly suggest that mechanical stability predicts whether a protein is compatible with secretion through the T3SS and may shed light on the distinct evolutionary pressures that resulted in the sequence divergence of effector proteins from their nonsecreted homologues. Multiple gram-negative bacteria encode type III secretion systems (T3SS) that allow them to inject effector proteins directly into host cells to facilitate colonization. To be secreted, effector proteins must be at least partially unfolded to pass through the narrow needle-like channel (diameter <2 nm) of the T3SS. Fusion of effector proteins to tightly packed proteins—such as GFP, ubiquitin, or dihydrofolate reductase (DHFR)—impairs secretion and results in obstruction of the T3SS. Prior observation that unfolding can become rate-limiting for secretion has led to the model that T3SS effector proteins have low thermodynamic stability, facilitating their secretion. Here, we first show that the unfolding free energy (ΔGunfold0) of two Salmonella effector proteins, SptP and SopE2, are 6.9 and 6.0 kcal/mol, respectively, typical for globular proteins and similar to published ΔGunfold0 for GFP, ubiquitin, and DHFR. Next, we mechanically unfolded individual SptP and SopE2 molecules by atomic force microscopy (AFM)-based force spectroscopy. SptP and SopE2 unfolded at low force (Funfold ≤ 17 pN at 100 nm/s), making them among the most mechanically labile proteins studied to date by AFM. Moreover, their mechanical compliance is large, as measured by the distance to the transition state (Δx‡ = 1.6 and 1.5 nm for SptP and SopE2, respectively). In contrast, prior measurements of GFP, ubiquitin, and DHFR show them to be mechanically robust (Funfold > 80 pN) and brittle (Δx‡ < 0.4 nm). These results suggest that effector protein unfolding by T3SS is a mechanical process and that mechanical lability facilitates efficient effector protein secretion.
Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma.

Hemorrhagic transformation is a complication of recombinant tissue-plasminogen activator (rtPA) treatment. The most severe form, parenchymal hematoma, can result in neurological deterioration, disability, and death. Our objective is to identify single nucleotide variations associated with a risk of parenchymal hematoma following thrombolytic therapy in acute ischemic stroke patients. A fixed-effect genome-wide metanalysis was performed combining two-stage Genome Wide Association studies (GWAs) (n = 1,904). The Discovery Stage (3 cohorts) comprised 1,324 ischemic stroke individuals, of whom 5.4% had a parenchymal hematoma. Genetic variants yielding a p-value <1x10-5 were analyzed in the Validation Stage (6 cohorts), formed by 580 ischemic stroke patients with 12.1% hemorrhagic events. All the participants received rtPA; cases were parenchymal hematoma type 1 or 2 as defined by the ECASS criteria. Genome-wide significant findings (p < 5x10-8) were characterized by in-silico functional annotation, gene expression, and DNA regulatory elements. We analyzed 7,989,272 single nucleotide polymorphisms (SNPs) and identified a Genome-wide association locus on chromosome 20 in the Discovery Cohort; functional annotation indicated that the ZBTB46 gene was driving the association for Chrosome 20. The top SNP was rs76484331 in the ZBTB46 gene (p = 2.49x10-8; odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55). In the Replication Cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal hematoma (p = 0.01), and the overall association after meta-analysis increased (p = 1.61x10-8; OR: 5.84; 95%CI: 3.16-10.76). ZBTB46 codes the Zinc Finger and BTB domain-containing protein 46 that acts as a transcription factor. In-silico studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conculsion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal hematoma following rtPA treatment.
Long-term neurobehavioral correlates of brain cortical microinfarcts in a memory clinic cohort in Singapore

Background Cortical cerebral microinfarcts are a small vessel disease biomarker underlying cognitive impairment and dementia. However, it is unknown whether cortical cerebral microinfarcts are associated with neuropsychiatric disturbances, and whether its effects are independent of conventional small vessel disease markers. Aims We investigated the associations of cortical cerebral microinfarcts burden with incidence and progression of neuropsychiatric subsyndromes in a memory clinic cohort of elderly in Singapore. Methods In this prospective cohort, 496 subjects underwent detailed neuropsychological and clinical assessments, 3T brain MRI, and Neuropsychiatric Inventory assessment at baseline and two years later. Cortical cerebral microinfarcts and other small vessel disease markers, including white matter hyperintensities, lacunes, and microbleeds, were graded according to established criteria. Neuropsychiatric symptoms (NPS) were clustered into subsyndromes of hyperactivity, psychosis, affective, and apathy following prior findings. Functional decline was determined using the clinical dementia rating (CDR) scale. Results The presence of multiple cortical cerebral microinfarcts (≥2) was associated with higher total NPS scores (β = 4.19, 95% CI = 2.81–5.58, p < 0.001), particularly hyperactivity (β = 2.01, 95% CI = 1.30–2.71, p < 0.01) and apathy (β = 1.42, 95% CI = 0.65–2.18, p < 0.01) at baseline. Between baseline and year-2, multiple cortical cerebral microinfarcts were associated with accelerated progression in total NPS scores (β = 0.29, 95% CI = 0.06–0.53, p = 0.015), driven by hyperactivity (β = 0.45, 95% CI = 0.17–0.72, p < 0.01). Subjects with multiple cortical cerebral microinfarcts also had a faster functional decline, as measured with the CDR-sum-of-boxes scores, when accompanied with progression (β = 0.31, 95% CI = 0.11–0.51, p < 0.01) or hyperactivity in total NPS (β = 0.34, 95% CI = 0.13–0.56, p < 0.01). Conclusion Cortical cerebral microinfarcts are associated with incidence and progression of geriatric neurobehavioral disturbances, independent of conventional small vessel disease markers. The impact of incident cortical cerebral microinfarcts on neurocognitive and neuropsychiatric trajectories warrants further investigations.
A Natural Language Processing–Based Virtual Patient Simulator and Intelligent Tutoring System for the Clinical Diagnostic Process: Simulator Development and Case Study

Background Shortage of human resources, increasing educational costs, and the need to keep social distances in response to the COVID-19 worldwide outbreak have prompted the necessity of clinical training methods designed for distance learning. Virtual patient simulators (VPSs) may partially meet these needs. Natural language processing (NLP) and intelligent tutoring systems (ITSs) may further enhance the educational impact of these simulators. Objective The goal of this study was to develop a VPS for clinical diagnostic reasoning that integrates interaction in natural language and an ITS. We also aimed to provide preliminary results of a short-term learning test administered on undergraduate students after use of the simulator. Methods We trained a Siamese long short-term memory network for anamnesis and NLP algorithms combined with Systematized Nomenclature of Medicine (SNOMED) ontology for diagnostic hypothesis generation. The ITS was structured on the concepts of knowledge, assessment, and learner models. To assess short-term learning changes, 15 undergraduate medical students underwent two identical tests, composed of multiple-choice questions, before and after performing a simulation by the virtual simulator. The test was made up of 22 questions; 11 of these were core questions that were specifically designed to evaluate clinical knowledge related to the simulated case. Results We developed a VPS called Hepius that allows students to gather clinical information from the patient’s medical history, physical exam, and investigations and allows them to formulate a differential diagnosis by using natural language. Hepius is also an ITS that provides real-time step-by-step feedback to the student and suggests specific topics the student has to review to fill in potential knowledge gaps. Results from the short-term learning test showed an increase in both mean test score (P<.001) and mean score for core questions (P<.001) when comparing presimulation and postsimulation performance. Conclusions By combining ITS and NLP technologies, Hepius may provide medical undergraduate students with a learning tool for training them in diagnostic reasoning. This may be particularly useful in a setting where students have restricted access to clinical wards, as is happening during the COVID-19 pandemic in many countries worldwide.