Miracle-dz/UniFAR-FTUs huggingface dataset:
A Dysregulated DNA Methylation Landscape Linked to Gene Expression in MLL-Rearranged AML

ABSTRACT Translocations of the KMT2A (MLL) gene define a biologically distinct and clinically aggressive subtype of acute myeloid leukaemia (AML), marked by a characteristic gene expression profile and few cooperating mutations. Although dysregulation of the epigenetic landscape in this leukaemia is particularly interesting given the low mutation frequency, its comprehensive analysis using whole genome bisulphite sequencing (WGBS) has not been previously performed. Here we investigated epigenetic dysregulation in nine MLL-rearranged (MLL-r) AML samples by comparing them to six normal myeloid controls, using a computational method that encapsulates mean DNA methylation measurements along with analyses of methylation stochasticity. We discovered a dramatically altered epigenetic profile in MLL-r AML, associated with genome-wide hypomethylation and a markedly increased DNA methylation entropy reflecting an increasingly disordered epigenome. Methylation discordance mapped to key genes and regulatory elements that included bivalent promoters and active enhancers. Genes associated with significant changes in methylation stochasticity recapitulated known MLL-r AML expression signatures, suggesting a role for the altered epigenetic landscape in the transcriptional programme initiated by MLL translocations. Accordingly, we established statistically significant associations between discordances in methylation stochasticity and gene expression in MLL-r AML, thus providing a link between the altered epigenetic landscape and the phenotype.
Identifying robust correlates of risk preference: A systematic approach using specification curve analysis.

People's risk preferences are thought to be central to many consequential real-life decisions, making it important to identify robust correlates of this construct. Various psychological theories have put forth a series of candidate correlates, yet the strength and robustness of their associations remain unclear because of disparate operationalizations of risk preference and analytic limitations in past research. We addressed these issues with a study involving several operationalizations of risk preference (all collected from each participant in a diverse sample of the German population; N = 916), and by adopting an exhaustive modeling approach-specification curve analysis. Our analyses of 6 candidate correlates (household income, sex, age, fluid intelligence, crystallized intelligence, years of education) suggest that sex and age have robust and consistent associations with risk preference, whereas the other candidate correlates show weaker and more (domain-) specific associations (except for crystallized intelligence, for which there were no robust associations). The results further demonstrate the important role of construct operationalization when assessing people's risk preferences: Self-reported propensity measures picked up various associations with the proposed correlates, but (incentivized) behavioral measures largely failed to do so. In short, the associations between the 6 candidate correlates and risk preference depend mostly on how risk preference is measured, rather than whether and which control variables are included in the model specifications. The present findings inform several theories that have suggested candidate correlates of risk preference, and illustrate how personality research may profit from exhaustive modeling techniques to improve theory and measurement of essential constructs. (PsycINFO Database Record (c) 2020 APA, all rights reserved).
Cricothyroidotomy needle length is associated with posterior tracheal wall injury

Abstract Background: Cricothyroidotomy is the final strategy in the “cannot intubate, cannot oxygenate” scenario, but half of needle cricothyroidotomy attempts result in failure. The most frequent complication in needle cricothyroidotomy is posterior tracheal wall injury. We hypothesized that needle length is related to posterior wall injury and compared needle cricothyroidotomy with a commercial kit to a modified shorter needle to evaluate success and posterior wall injury rates. Methods: The commercial kit has a needle stopper to prevent posterior wall injury, with a penetrating length of 25 mm. We made long stopper to shorten the length by 5 mm (net 20 mm penetrating length). Residents were recruited, received a lecture about cricothyroidotomy and practiced needle cricothyroidotomy using the commercial kit on a simulator. They then performed cricothyroidotomy using the commercial kit or the shorter needle on an ex-vivo porcine larynx covered with artificial skin. An intra-tracheal endoscope recorded the procedure. The video was evaluated for success/failure or posterior wall injury by independent evaluators. Larynxes with a distance from the outer surface to the inner lumen exceeding 13 mm were excluded. The distance in each larynx was measured by dissection after the study. Success and posterior wall injury rates were analyzed using Fisher exact test (P < .05 was statistically significant). Results: Forty-seven residents participated in the study. Data for two residents were excluded. There was no statistically significant difference in success rate between the commercial kit (100%, 45/45) and the shorter needle (91%, 41/45, P = .12). Failure was defined if the needle tip did not reach the lumen in four trials. Cannulated but complicated by posterior wall injury occurred in 33% (15/45) with the commercial kit and 5% (2/43) with the shorter needle (P < .01). Conclusion: During needle cricothyroidotomy, force is needed for the needle to penetrate the cricothyroid ligament. The advancing needle sometimes cannot be stopped after penetrating the cricothyroid ligament. These data suggest that needle length is associated with posterior wall injury.
Manipulated Mesenchymal Stem Cells Applications in Neurodegenerative Diseases

Mesenchymal stem cells (MSCs) are multipotent stem cells that have multilinear differentiation and self-renewal abilities. These cells are immune-privileged as they express no or low level of class-II major histocompatibility complex (MHC-II) and other costimulatory molecules. Having neuroprotective and regenerative properties, MSCs can be used to ameliorate several intractable neurodegenerative disorders by affecting both innate and adaptive immune systems. Several manipulations like pretreating MSCs with different conditions or agents, and using molecules derived from MSCs or genetically manipulating them, are the common and practical ways that can be used to strengthen MSCs survival and potency. Improved MSCs can have significantly enhanced impacts on diseases compared to MSCs not manipulated. In this review, we describe some of the most important manipulations that have been exerted on MSCs to improve their therapeutic functions and their applications in ameliorating three prevalent neurodegenerative diseases including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease.
Assessment of Treatment Outcome of Presurgical Nasoalveolar Molding in Patients With Cleft Lip and Palate and Its Postsurgical Stability

Objective: To analyze the effects of presurgical nasoalveolar molding (PNAM) in newborns with cleft lip and palate and evaluate its postsurgical stability at 1-year follow-up using a nasal stent. Design: Prospective clinical trial. Setting: Department of Orthodontics, Maulana Azad Institute of Dental Sciences, Delhi. Patients: Patients with cleft lip and palate of 0 to 6 months. Sample size 25 recruited, 16 satisfactorily completed the procedure. Interventions: Presurgical nasoalveolar molding done as indicated in all the patients. Postsurgical external nasal stents were given for 1 year to maintain the nasal correction. Main Outcome Measures: Changes in cleft defect and maxillary arch were recorded pre- and post-PNAM. Changes in nasal morphological parameters assessed pre- and post-PNAM and 1 year after surgical repair following the use of nasal stent. Results: There was a significant reduction in cleft defect assessed both intraorally ( 4.16 mm) and extra orally ( 4.42 mm) at the end of PNAM therapy (average treatment time 4 months). The nasal morphology improved with an increase in columella height (1.5 mm) and reduction in columella width. Bialar width reduced (2.90 mm) with an increase in nostril height ( 2.10 mm). Better symmetry was achieved in all cases as the nostril height and width difference changed significantly pre- and post-nasoalveolar molding. The percentage increase in columella height was greater for infants less than 6 weeks. Conclusions: Presurgical nasoalveolar molding considerably reduces the cleft gap and improves arch form making surgical union easier along with improved nasal morphology which can be maintained at 1-year postsurgery by use of a postsurgical external nasal stent.
A new natural killer cell-specific gene signature predicting recurrence in colorectal cancer patients

The protective role of Natural Killer (NK) cell tumour immunosurveillance has long been recognised in colorectal cancer (CRC). However, as most patients show limited intra-tumoral NK cell infiltration, improving our ability to identify those with high NK cell activity might aid in dissecting the molecular features which underlie NK cell sensitivity. Here, a novel CRC-specific NK cell gene signature that infers NK cell load in primary tissue samples was derived and validated in multiple patient CRC cohorts. In contrast with other NK cell gene signatures that have several overlapping genes across different immune cell types, our NK cell signature has been extensively refined to be specific for CRC-infiltrating NK cells. The specificity of the signature is substantiated in tumour-infiltrating NK cells from primary CRC tumours at the single cell level, and the signature includes genes representative of NK cells of different maturation states, activation status and anatomical origin. Our signature also accurately discriminates murine NK cells, demonstrating the applicability of this geneset when mining datasets generated from preclinical studies. Differential gene expression analysis revealed tumour-intrinsic features associated with NK cell inclusion versus exclusion in CRC patients, with those tumours with predicted high NK activity showing strong evidence of enhanced chemotactic and cytotoxic transcriptional programs. Furthermore, survival modelling indicated that NK signature expression is associated with improved survival outcomes in CRC patients. Thus, scoring CRC samples with this refined NK cell signature might aid in identifying patients with high NK cell activity who could be prime candidates for NK cell directed immunotherapies.
Transcriptome‐wide study of the response of human trabecular meshwork cells to the substrate stiffness increase

Elevated intraocular pressure, a major risk factor of glaucoma, is caused by the abnormal function of trabecular outflow pathways. Human trabecular meshwork (HTM) tissue plays an important role in the outflow pathways. However, the molecular mechanisms that how TM cells respond to the elevated IOP are largely unknown. We cultured primary HTM cells on polyacrylamide gels with tunable stiffness corresponding to Young's moduli ranging from 1.1 to 50 kPa. Then next‐generation RNA sequencing (RNA‐seq) was performed to obtain the transcriptomic profiles of HTM cells. Bioinformatics analysis revealed that genes related to glaucoma including DCN, SPARC, and CTGF, were significantly increased with elevated substrate stiffness, as well as the global alteration of HTM transcriptome. Extracellular matrix (ECM)‐related genes were selectively activated in response to the elevated substrate stiffness, consistent with the known molecular alteration in glaucoma. Human normal and glaucomatous TM tissues were also obtained to perform RNA‐seq experiments and supported the substrate stiffness‐altered transcriptome profiles from the in vitro cell model. The current study profiled the transcriptomic changes in human TM cells upon increasing substrate stiffness. Global change of ECM‐related genes indicates that the in vitro substrate stiffness could greatly affect the biological processes of HTM cells. The in vitro HTM cell model could efficiently capture the main pathogenetic process in glaucoma patients, and provide a powerful method to investigate the underlying molecular mechanisms.
Treatment of verbal short-term memory abilities to improve language function in aphasia: A case series treatment study

ABSTRACT Recent approaches to interventions for aphasia have incorporated verbal short-term memory (STM) and working memory (WM) components. We investigated whether a treatment involving repetition of word sequences after a response delay would improve tolerance of increased verbal STM load in repetition and, consequently, improve performance on repetition and other language tasks. Eight individuals with aphasia participated. We used a single subject design with outcome measures on near-transfer tasks closely related to the treatment task and far-transfer tasks more distantly related to the treatment task. We minimized repeated presentation of stimuli in all phases of treatment to control for confounding effects of repeated exposure of treated items. Four participants demonstrated modest acquisition effects. On outcome measures, we observed improvements by some participants on near-transfer tasks, (repetition of concrete and abstract word strings and verbal spans) and far-transfer tasks (naming and discourse). Some participants demonstrated a significant decline in word repetition accuracy after a response delay before treatment, indicating difficulty in maintaining activation of linguistic representations. It was these participants who showed the most improvement on outcome measures. More studies are needed to determine who will respond to this treatment and what factors might influence the effectiveness of this treatment approach.
Weighted log-rank tests for clustered censored data: Saddlepoint p-values and confidence intervals

Clustered data with censored failure times frequently arise in clinical trials and tumorigenicity studies. For such data, the common and extensively used class of two-sample tests is the weighted log-rank tests. In this article, a double saddlepoint approximation is used to calculate the p-values of the null permutation distribution of these tests. This technique is demonstrated using three real clustered data sets. Comprehensive simulation studies are conducted to appraise the efficiency of the saddlepoint approximation. This approximation is far superior to the asymptotic normal approximation. This precision allows us to determine almost exact confidence intervals for the treatment impact.
Neurophysiological Biomarkers of Parkinson’s Disease

Background: There is a need for reliable and robust Parkinson’s disease biomarkers that reflect severity and are sensitive to disease modifying investigational therapeutics. Objective: To demonstrate the utility of EEG as a reliable, quantitative biomarker with potential as a pharmacodynamic endpoint for use in clinical assessments of neuroprotective therapeutics for Parkison’s disease. Methods: A multi modal study was performed including aquisition of resting state EEG data and dopamine transporter PET imaging from Parkinson’s disease patients off medication and compared against age-matched controls. Results: Qualitative and test/retest analysis of the EEG data demonstrated the reliability of the methods. Source localization using low resolution brain electromagnetic tomography identified significant differences in Parkinson’s patients versus control subjects in the anterior cingulate and temporal lobe, areas with established association to Parkinson’s disease pathology. Changes in cortico-cortical and cortico-thalamic coupling were observed as excessive EEG beta coherence in Parkinson’s disease patients, and correlated with UPDRS scores and dopamine transporter activity, supporting the potential for cortical EEG coherence to serve as a reliable measure of disease severity. Using machine learning approaches, an EEG discriminant function analysis classifier was identified that parallels the loss of dopamine synapses as measured by dopamine transporter PET. Conclusion: Our results support the utility of EEG in characterizing alterations in neurophysiological oscillatory activity associated with Parkinson’s disease and highlight potential as a reliable method for monitoring disease progression and as a pharmacodynamic endpoint for Parkinson’s disease modification therapy.
Developing and Testing Automatic Models of Patient Communicative Health Literacy Using Linguistic Features: Findings from the ECLIPPSE study

ABSTRACT Patients with diabetes and limited health literacy (HL) may have suboptimal communication exchange with their health care providers and be at elevated risk of adverse health outcomes. These difficulties are generally attributed to patients’ reduced ability to both communicate and understand health-related ideas as well as physicians’ lack of skill in identifying those with limited HL. Understanding and identifying patients with barriers posed by lower HL to improve healthcare delivery and outcomes is an important research avenue. However, doing so using traditional methods has proven difficult and infeasible to scale. This study using corpus analyses, expert human ratings of HL, and natural language processing (NLP) approaches to estimate HL at the individual patient level. The goal of the study is to better understand HL from a linguistic perspective and to open new research areas to enhance population management and individualized care. Specifically, this study examines HL as a function of patients’ demonstrated ability to communicate health-related information to their providers via secure messages. The study develops an NLP-based HL model and validates the model by predicting patient-related events such as medical outcomes and hospitalizations. Results indicate that the developed model predicts human ratings of HL with ~80% accuracy. Validation indicates that lower HL patients are more likely to be nonwhite and have lower educational attainment. In addition, patients with lower HL suffered more negative health outcomes and had higher healthcare service utilization.
Chemical Composition and Insecticidal Activity of Crithmum Maritimum L. Essential Oil against Stored‐Product Beetle Tribolium Castaneum

Several plant essential oils have been used against diverse insect pests since, unlike conventional pesticides, they pose almost no risk to humans and the environment. For this reason, the essential oil (EO) isolated from the fresh leaves of Crithmum maritimum L. and its fractions (F1–F5) obtained by chromatographic simplification were investigated for their chemical profile, as well as for their toxicity and repellency effects against Tribolium castaneum (Herbst) adults. The analysis by GC/MS allowed the identification of 92.8–99.1 % of the compositions of the total oil (EO) and of its fractions (F1–F5). The EO and its fractions F3–F5 were characterized by the presence of a high amount of phenylpropanoids (94.4, 94.8, 93.6, and 88.7 %, respectively): in all the samples, dill apiole was the most abundant component (EO: 94.1 %, F3: 94.6 %, F4: 93.4 %, and F5: 83.3 %). In addition, the repellency assay results showed that the volatile fraction F5 and the complete EO exhibited a higher repellency towards T. castaneum (97 % and 93 %, respectively) after 2 h of exposure at the dose of 0.04 μL/cm2. The median lethal dose of the topical application of the EO was 9 %. Furthermore, the fraction F1 possessed interesting contact toxicity against T. castaneum (80 % of mortality) at the concentration of 10 %. These results suggested that the essential oil of C. maritimum leaves might be used as an alternative to synthetic insecticides in order to prevent insects from damaging the stored products.
Systematic evaluation and meta-analysis of quality and safety of life in patients with chronic rhinosinusitis treated by acupuncture

Abstract Background: This study aims to assess the quality and safety of life in patients with chronic rhinosinusitis (CRS) treated by acupuncture. Methods: An extensive database search was executed to find the randomized controlled trials on acupuncture vs. sham acupuncture, and any other treatments for patients with CRS. Review Manager 5 (RevMan) was used for the data analysis. A strict methodology was used when the meta-analysis was performed. Results: This study systematically assesses the effectiveness and safety of acupuncture in patients with CRS. The primary outcomes include health-related quality of life, disease severity, treatment-related adverse events. The secondary outcomes are comprised of recurrence rate, endoscopic score, computerized tomography (CT) scan score and objective physiological measures. Conclusion: This article summarizes the current evidence base for the quality of life and safety of acupuncture in patients with CRS. Systematic review registration: International Prospective Register of Systematic Reviews PROSPERO (registration number CRD42018114432).
Exploring hair steroid concentrations in asylum seekers, internally displaced refugees, and immigrants

Abstract The study of physiology in response to war and forced displacement can yield insight into the origin of stress-related mental health disorders. Previous studies found alterations in hair cortisol concentrations (HCC) in refugees. However, the direction of this alteration in HCC, as well as the association between HCC and psychological stress, remain unclear. Mixed findings can potentially be explained by the lack of contextual factors that have been taken into account. In this explorative study, we investigated HCCs in three female refugee samples (N = 89) in different contexts. Samples were i) asylum seekers from Syria, who sought protection in Germany two years ago (n = 37), ii) internally displaced persons (IDPs), who fled a genocide and lived in conditions of onging insecurity in Iraq (n = 14), and iii) Kurdish immigrants and former asylum seekers, who resettled to Germany 18 years ago and were used as reference group (n = 38). HCC was assessed in the scalp-nearest 6 cm of hair (2*3 cm segments). Data on mental and physical health, exposure to traumatic events, and time between immigration and HCC assessments were collected. Syrian asylum seekers had lower HCC than immigrant controls (η2 = .06). PTSD symptoms and perceived stress were associated with elevated cortisol levels in IDPs (r = .66 and r = .56), while time since immigration was associated with cortisol levels only in immigrant controls (r = .38). We discuss our findings with regard to the importance of contextual factors, particularly time since displacement and on-going insecurity, when studying physiological reactions in refugees. Lay summary Female Syrian asylum seekers had lower levels of hair cortisol concentration than Kurdish immigrants in Germany. Hair cortisol concentration was associated with post-traumatic stress symptoms only in internally displaced women who were exposed to ongoing stress and insecurity in Iraq.