Miracle-dz/UniFAR-FTUs huggingface dataset:
CD19-directed chimeric antigen receptor T cell therapy in Waldenström macroglobulinemia: a preclinical model and initial clinical experience

Background Waldenström macroglobulinemia (WM) is an incurable disease and, while treatable, can develop resistance to available therapies and be fatal. Chimeric antigen receptor (CAR) T cell therapy directed against the CD19 antigen has demonstrated efficacy in relapsed or refractory B lymphoid malignancies, and is now approved for B cell acute lymphoblastic leukemia and certain B cell lymphomas. However, CAR T therapy has not been evaluated for use in WM. Methods and results We performed preclinical studies demonstrating CAR T cell activity against WM cells in vitro, and developed an in vivo murine model of WM which demonstrated prolonged survival with use of CAR T therapy. We then report the first three patients with multiply relapsed and refractory WM treated for their disease with CD19-directed CAR T cells on clinical trials. Treatment was well tolerated, and observed toxicities were consistent with those seen in CAR T treatment for other diseases, and no grade 3 or higher cytokine release syndrome or neurotoxicity events occurred. All three patients attained at least a clinical response to treatment, including one minimal residual disease-negative complete response, though all three eventually developed recurrent disease between 3 and 26 months after initial treatment. Conclusions This report summarizes preclinical and clinical activity of CD19-directed CAR T therapy in WM, demonstrating early tolerability and efficacy in patients with WM, and representing a possible treatment option in patients with heavily pretreated and relapsed or refractory WM. Larger studies evaluating CAR T therapy in WM are warranted, along with further evaluation into mechanisms of resistance to CAR T therapy.
Trajectory Control–An Effective Strategy for Controlling Multi-DOF Upper Limb Prosthetic Devices

Despite great innovations in upper-extremity prosthetic hardware in recent decades, controlling a multiple joint upper limb prosthesis such as an elbow/wrist/hand system is still an open clinical challenge, in large part due to an insufficient number of control inputs available to users. While simultaneous control is in its early stages, the common control approach is sequential control, in which joints and grasps are driven one at a time. In this paper, we introduce and evaluate a concept we call trajectory control, that builds upon this approach, in which motions of the wrist, elbow, and shoulder DOFs (and subsets of them) are coupled into predefined sets of coordinated trajectories; to be selected by the user and driven with a single input variable. These trajectories were designed based on an earlier motion study of activities of daily life obtained from human demonstrations. We experimentally evaluate the efficacy of our approach through a human subjects study in which tasks are performed in a virtual environment. The results show that as device complexity increased (i.e. greater number of DOFs corresponding to more proximal amputations), participants were able to complete tasks faster with trajectory control while exhibiting similar levels of body compensation when compared to sequential and simultaneous control. Additionally, participants found trajectory control to be more intuitive and displayed more natural movement.
Cultural Evolution of Precise and Agreed-Upon Semantic Conventions in a Multiplayer Gaming App

The amount of information conveyed by linguistic conventions depends on their precision, yet the codes that humans and other animals use to communicate are quite ambiguous: they may map several vague meanings to the same symbol. How does semantic precision evolve, and what are the constraints that limit it? We address this question using a multiplayer gaming app, where individuals communicate with one another in a scaled-up referential game. Here, the goal is for a sender to use black and white symbols to communicate colors. We expected that the players' mappings between symbols and colors would grow more specific over time, through a selection process whereby precise mappings are preferentially copied. We found that players become increasingly more precise in their use of symbols over the course of their interactions. This trend did not, however, result from selective copying of precise mappings. We explore the implications of this result for the study of lexical ambiguity, Zipf's Law of Meaning, and disagreements over semantic conventions.
Implication of novel risk stratification model for acute kidney injury following cardiac surgery

To the Editor, Risk stratification and early intervention to acute kidney injury (AKI) following cardiac surgery are of great importance. Irqsusi et al. validated the predictive ability of a formula: [urinary concentration of tissue inhibitor of metalloproteinases‐2 (TIMP‐2)] × [urinary concentration of insulin‐like growth factor‐binding protein (IGFBP7)], for the development of postoperative AKI. Several concerns have been raised. Several clinical variables including baseline serum creatinine level, Cleveland score, and Leicester score were significantly different between those with and without AKI. These variables might be potential confounders that affected the predictive ability of the formula. Also, it is of great interest whether the formula was statistically superior to these conventional risks in predicting the development of AKI. Another concern is the predictive powers of each item: TIMP‐2 and IGFBP7. Weighting on each item might further improve the predictability of the formula. The second concern is an intervention to AKI. A patient who had the highest Cleveland score of 7 points could avoid the development of AKI. A detailed description of this patient, including clinical presentation and treatments, might let us know optimal therapeutic/ preventive intervention for those with high risk. CONFLICT OF INTEREST The authors declare no conflict of interest.
Comparison of next generation diagnostic systems (NGDS) for the detection of SARS‐CoV‐2

The World Health Organization (WHO) declared coronavirus disease 2019 (COVID‐19) a pandemic in March 2020. Initially, supply chain disruptions and increased demand for testing led to shortages of critical laboratory reagents and inadequate testing capacity. Thus, alternative means of biosample collection and testing were essential to overcome these obstacles and reduce viral transmission. This study aimed to 1) compare the sensitivity and specificity of Cepheid GeneXpert® IV and BioFire® FilmArray® 2.0 next generation detection systems to detect SARS‐CoV‐2, 2) evaluate the performance of both platforms using different biospecimen types, and 3) assess saline as an alternative to viral transport media (VTM) for sample collection.
Vector analysis of moderate to high myopic astigmatism after small-incision lenticule extraction (SMILE): 12-month follow-up

Purpose To evaluate the refractive outcomes of small-incision lenticule extraction (SMILE) surgery in moderate to high myopic astigmatism Study Design Prospective interventional case series Methods This study evaluated 111 eyes of 68 patients treated with femtosecond SMILE surgery for the correction of myopia and astigmatism. Inclusion criteria were myopia of − 0.5 D or more and astigmatism between − 1.0 D and −5.0 D. Refractive and visual measurements were obtained preoperatively, 1 and 12 month(s) postoperatively. Vector analysis was used to study the astigmatic outcomes at 12-month follow-up. Comparison of results in two groups of patients with astigmatism below and over 3.00 D was performed. Results The preoperative mean spherical equivalent was −5.48 ± 2.17 D (range − 1.75 to − 10.00 D) and the mean cylinder was −2.02 ± 1.09 D (range − 1.00 to − 5.00 D). The mean postoperative cylinder value was −0.60 ± 0.52 D at 12-month visit. The 12-month safety and efficacy indices were 0.98 ± 0.07 and 0.97 ± 0.12, respectively. The high astigmatism group showed significantly lower safety and efficacy indices. The postoperative residual astigmatism was 0.5 D or less in 73% of the eyes. Higher amount of residual astigmatism was observed in the high astigmatism group. The angle of error was ± 5 degrees in 49% and ± 15 degrees in 87% of the eyes. Conclusion SMILE surgery is effective and safe method for correcting myopic astigmatism. Vector analysis indicated a tendency for the under correction of astigmatism in subjects with high astigmatism.
Release of CHK-2 from PPM-1.D anchorage schedules meiotic entry

Transition from the stem/progenitor cell fate to meiosis is mediated by several redundant posttranscriptional regulatory pathways in Caenorhabditis elegans. Interfering with all three branches causes tumorous germ lines. SCFPROM-1 comprises one branch and mediates a scheduled degradation step at entry into meiosis. prom-1 mutants show defects in the timely initiation of meiotic prophase I events, resulting in high rates of embryonic lethality. Here, we identify the phosphatase PPM-1.D/Wip1 as crucial substrate for PROM-1. We report that PPM-1.D antagonizes CHK-2 kinase, a key regulator for meiotic prophase initiation, including DNA double-strand breaks, chromosome pairing, and synaptonemal complex formation. We propose that PPM-1.D controls the amount of active CHK-2 via both catalytic and noncatalytic activities; notably, noncatalytic regulation seems to be crucial at meiotic entry. PPM-1.D sequesters CHK-2 at the nuclear periphery, and programmed SCFPROM-1–mediated degradation of PPM-1.D liberates the kinase and promotes meiotic entry.
Using artificial intelligence methods for systematic review in health sciences: A systematic review

The exponential increase in published articles makes a thorough and expedient review of literature increasingly challenging. This review delineated automated tools and platforms that employ artificial intelligence (AI) approaches and evaluated the reported benefits and challenges in using such methods. A search was conducted in 4 databases (Medline, Embase, CDSR, and Epistemonikos) up to April 2021 for systematic reviews and other related reviews implementing AI methods. To be included, the review must use any form of AI method, including machine learning, deep learning, neural network, or any other applications used to enable the full or semi‐autonomous performance of one or more stages in the development of evidence synthesis. Twelve reviews were included, using nine different tools to implement 15 different AI methods. Eleven methods were used in the screening stages of the review (73%). The rest were divided: two in data extraction (13%) and two in risk of bias assessment (13%). The ambiguous benefits of the data extractions, combined with the reported advantages from 10 reviews, indicating that AI platforms have taken hold with varying success in evidence synthesis. However, the results are qualified by the reliance on the self‐reporting of the review authors. Extensive human validation still appears required at this stage in implementing AI methods, though further evaluation is required to define the overall contribution of such platforms in enhancing efficiency and quality in evidence synthesis.
CircPAG1 interacts with miR-211-5p to promote the E2F3 expression and inhibit the high glucose-induced cell apoptosis and oxidative stress in diabetic cataract

ABSTRACT Circular RNAs (circRNAs) are regulatory endogenous RNAs in human diseases by sponging microRNAs (miRNAs) to affect the gene expression. However, little research focused on the circRNA/miRNA/mRNA axis in diabetic cataract. This study was performed for the exploration of circRNA phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (circPAG1) in diabetic cataract. Human lens epithelial cells were treated with high glucose. The quantitative real-time polymerase chain reaction was used for the expression detection of circPAG1, microRNA-211-5p (miR-211-5p), and E2F transcription factor 3 (E2F3). Cell viability and proliferation were detected using Cell Counting Kit-8 assay and EdU assay. Cell apoptosis was analyzed by flow cytometry. The protein levels were measured by Western blot. Oxidative stress was assessed by malondialdehyde, reactive oxygen species, and superoxide dismutase via the corresponding detection kits. The target interaction was validated using the dual-luciferase reporter assay and RNA immunoprecipitation assay. The expression of circPAG1 was downregulated in diabetic cataract patients. The upregulation of circPAG1 could attenuate the high glucose-induced inhibition of cell viability and proliferation but promotion of cell apoptosis and oxidative stress. CircPAG1 served as a miR-211-5p sponge, and the protective role of circPAG1 was partly achieved by sponging miR-211-5p. MiR-211-5p targeted E2F3 and circPAG1 upregulated the E2F3 level by absorbing miR-211-5p. Inhibition of miR-211-5p repressed the high glucose-mediated cell dysfunction by increasing the expression of E2F3. This study clarified that circPAG1 protected human lens epithelial cells from the high glucose-induced cell damages by the mediation of miR-211-5p/E2F3 axis.
Laryngeal High-Speed Videoendoscopy with Laser Illumination: A Preliminary Report.

Introduction: Advances in computer image analysis have enabled the use of new functional imaging methods in the diagnosis of laryngeal diseases. Particularly interesting techniques of dynamic laryngeal imaging involve High Speed Videoendoscopy (HSV). This still-developed technique allows to overcome the limitations of laryngovideostroboscopy (LVS) and a more detailed analysis of the glottal function based on the image of the actual vibrations of the vocal folds. It also enables the determination of objective coefficients parameterizing phonatory vibrations of the vocal folds. Aim: The aim of this pilot study was to evaluate the use of a high-speed videoendoscopy set with laser illumination for the diagnosis of glottic pathology in ENT practice. Material and methods: The study included 40 patients who underwent LVS followed by HSV. The modern HSV examination kit - Advanced Larynx Imager System (ALIS), used for the first time in a clinical setting in Poland, is characterized by significantly improved, compared to the previously used high-speed cameras, operational parameters - a light head, the possibility of continuous lighting operation without excessive heating of the head tip, registration of the image in full color scale. Thanks to such modernization, the safety and course of the examination do not differ from laryngoscopy conducted with commonly used recorders. The device owes some of these improvements to a laser illuminator which was used for the first time as the main light source in a high-speed camera. In the study, two cases were selected to present the results of HSV and the analysis of the generated kymograms - a woman with no glottic pathology and a man with a polyp of the right vocal fold. In the first case, the HSV examination compared with the LVS revealed a discrete glottis functional disorder in the form of a tendency to hyperphonation. The patient with an organic lesion had a clearly visible irregularity of vocal fold vibrations, which also allowed to trace mucosal wave disturbances related to its reflection from the pathological structure of the glottis and the formation of a return wave, both on the fold affected by the lesion and, to a lesser extent, contralaterally. The glottic dysfunctions observed in the studied patients were confirmed in the generated kymograms and the graphs of the glottal width waveform (GWW), as well as in the parameters calculated on their basis, assessing the frequency and amplitude of phonatory vibrations. Conclusions: The use of high-speed videoendoscopy allows for a much more accurate assessment of the phonatory function of the glottis than in laryngovideostroboscopy. The presented HSV system allows for obtaining high quality kinematic images of the larynx, color fidelity, and contrast. The use of this technology in laryngological practice enables precise structural and functional assessment of the glottis and detection of discrete phonation disorders that elude the techniques used so far.
High-throughput glycolytic inhibitor discovery targeting glioblastoma by graphite dots–assisted LDI mass spectrometry

Malignant tumors will become vulnerable if their uncontrolled biosynthesis and energy consumption engaged in metabolic reprogramming can be cut off. Here, we report finding a glycolytic inhibitor targeting glioblastoma with graphite dots–assisted laser desorption/ionization mass spectrometry as an integrated drug screening and pharmacokinetic platform (GLMSD). We have performed high-throughput virtual screening to narrow an initial library of 240,000 compounds down to the docking of 40 compounds and identified five previously unknown chemical scaffolds as promising hexokinase-2 inhibitors. The best inhibitor (Compd 27) can regulate the reprogrammed metabolic pathway in U87 glioma cells (median inhibitory concentration ~ 11.3 μM) for tumor suppression. Highly effective therapy against glioblastoma has been demonstrated in both subcutaneous and orthotopic brain tumors by synergizing Compd 27 and temozolomide. Our glycolytic inhibitor discovery can inspire personalized medicine targeting reprogrammed metabolisms of malignant tumors. GLMSD enables large, high-quality data for next-generation artificial intelligence–aided drug development.
Machine learning algorithm can provide assistance for the diagnosis of non-ST-segment elevation myocardial infarction

Introduction Our aim was to use the constructed machine learning (ML) models as auxiliary diagnostic tools to improve the diagnostic accuracy of non-ST-elevation myocardial infarction (NSTEMI). Materials and methods A total of 2878 patients were included in this retrospective study, including 1409 patients with NSTEMI and 1469 patients with unstable angina pectoris. The clinical and biochemical characteristics of the patients were used to construct the initial attribute set. SelectKBest algorithm was used to determine the most important features. A feature engineering method was applied to create new features correlated strongly to train ML models and obtain promising results. Based on the experimental dataset, the ML models of extreme gradient boosting, support vector machine, random forest, naïve Bayesian, gradient boosting machines and logistic regression were constructed. Each model was verified by test set data, and the diagnostic performance of each model was comprehensively evaluated. Results The six ML models based on the training set all play an auxiliary role in the diagnosis of NSTEMI. Although all models taken for comparison performed differences, the extreme gradient boosting ML model performed the best in terms of accuracy rate (0.95±0.014), precision rate (0.94±0.011), recall rate (0.98±0.003) and F-1 score (0.96±0.007) in NSTEMI. Conclusions The ML model constructed based on clinical data can be used as an auxiliary tool to improve the accuracy of NSTEMI diagnosis. According to our comprehensive evaluation, the performance of the extreme gradient boosting model was the best.
Low-density lipoprotein cholesterol levels exceed the recommended European threshold for PCSK9i initiation: lessons from the HEYMANS study

Abstract Aims To describe the characteristics of patients receiving evolocumab in clinical practice across 12 European countries and simulate the association between low-density lipoprotein cholesterol (LDL-C) reduction and cardiovascular (CV) risk reduction. Methods and results The characteristics of hyperlipidaemic patients at initiation of evolocumab and treatment patterns study—HEYMANS (n = 1952) is a prospective registry of patients ≥18 years old who initiated evolocumab from 1 August 2015 onwards. Mean (standard deviation) age was 60 (10.8), 85% had a prior CV event, 45% were diagnosed with familial hypercholesterolaemia (FH), and 60% had statin intolerance. At evolocumab initiation, 43% were receiving any statin, 16% were receiving ezetimibe without statin, and 41% received no background lipid-lowering therapy (LLT), with LDL-C levels reflecting local proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) reimbursement criteria. Median LDL-C decreased from 3.98 to 1.63 mmol/L within 3 months of evolocumab initiation and was maintained over 24 months. Overall, 58% achieved risk-based 2019 European Society of Cardiology/European Atherosclerosis Society LDL-C goals but that proportion was higher (68%) in patients receiving background LLT compared with those not receiving background LLT (44%). In patients with atherosclerotic cardiovascular disease without FH, the simulated relative CV risk reduction associated with evolocumab treatment was 34% (25–44%). Conclusion Across Europe, LDL-C levels at evolocumab initiation were three times higher than recommended thresholds for PCSK9i initiation, reflecting disparities between implementation and guidelines. More patients attained risk-based LDL-C goals when receiving evolocumab in combination with LLT vs. those not receiving combination therapy. Population health could be improved and LDL-C goals better attained if LDL-C thresholds for PCSK9i reimbursement were lowered, enabling more patients to receive combination therapy when needed.
Neutral Loss Mass Spectral Data Enhances Molecular Similarity Analysis in METLIN.

Neutral loss (NL) spectral data presents a mirror of MS2 data and is a valuable yet largely untapped resource for molecular discovery and similarity analysis. Tandem mass spectrometry (MS2) data is effective for the identification of known molecules and the putative identification of novel, previously uncharacterized molecules (unknowns). Yet, MS2 data alone is limited in characterizing structurally related molecules. To facilitate unknown identification and complement the METLIN-MS2 fragment ion database for characterizing structurally related molecules, we have created a MS2 to NL converter as a part of the METLIN platform. The converter has been used to transform METLIN's MS2 data into a neutral loss database (METLIN-NL) on over 860 000 individual molecular standards. The platform includes both the MS2 to NL converter and a graphical user interface enabling comparative analyses between MS2 and NL data. Examples of NL spectral data are shown with oxylipin analogues and two structurally related statin molecules to demonstrate NL spectra and their ability to help characterize structural similarity. Mirroring MS2 data to generate NL spectral data offers a unique dimension for chemical and metabolite structure characterization.
In vivo macromolecular crowding is differentially modulated by aquaporin 0 in zebrafish lens: Insights from a nanoenvironment sensor and spectral imaging

Macromolecular crowding is crucial for cellular homeostasis. In vivo studies of macromolecular crowding and water dynamics are needed to understand their roles in cellular physiology and fate determination. Macromolecular crowding in the lens is essential for normal optics, and an understanding of its regulation will help prevent cataract and presbyopia. Here, we combine the use of the nanoenvironmental sensor [6-acetyl-2-dimethylaminonaphthalene (ACDAN)] to visualize lens macromolecular crowding with in vivo studies of aquaporin 0 zebrafish mutants that disrupt its regulation. Spectral phasor analysis of ACDAN fluorescence reveals water dipolar relaxation and demonstrates that mutations in two zebrafish aquaporin 0s, Aqp0a and Aqp0b, alter water state and macromolecular crowding in living lenses. Our results provide in vivo evidence that Aqp0a promotes fluid influx in the deeper lens cortex, whereas Aqp0b facilitates fluid efflux. This evidence reveals previously unidentified spatial regulation of macromolecular crowding and spatially distinct roles for Aqp0 in the lens.