Miracle-dz/UniFAR-FTUs huggingface dataset:
A Rapid Method to Estimate Hepatocyte Loss Due to Drug‐Induced Liver Injury

It is not currently possible to rapidly estimate the extent of hepatocyte loss during drug‐induced liver injury (DILI). We used a proprietary mechanistic model (DILIsym) to estimate percentage hepatocyte loss due to DILI that resulted from four different patterns of serum alanine aminotransferase (ALT) over time: rapid onset and rapid decrease in ALT levels, moderate onset and moderate decrease in ALT levels, moderate onset and extended duration (over 1 month) of ALT elevations, and an ALT profile with multiple peaks. Using these data, we derived a novel parameter, PALT = ALT_AUC*Peak ALT0.18/105 ((IU/L)2*h), where AUC is area under the curve, that correlated well with hepatocyte loss estimates derived by DILIsym in patients with DILI due to six different hepatotoxic drugs. Although further validation will be required, the fact that PALT can be derived rapidly using publicly available pharmacokinetic software may make it a useful parameter to improve the safety of drugs.
Phase I and phase II metabolism simulation of antitumor-active 2-hydroxyacridinone with electrochemistry coupled on-line with mass spectrometry

Abstract Here, we report the metabolic profile and the results of associated metabolic studies of 2-hydroxy-acridinone (2-OH-AC), the reference compound for antitumor-active imidazo- and triazoloacridinones. Electrochemistry coupled with mass spectrometry was applied to simulate the general oxidative metabolism of 2-OH-AC for the first time. The reactivity of 2-OH-AC products to biomolecules was also examined. The usefulness of the electrochemistry for studying the reactive drug metabolite trapping (conjugation reactions) was evaluated by the comparison with conventional electrochemical (controlled-potential electrolysis) and enzymatic (microsomal incubation) approaches. 2-OH-AC oxidation products were generated in an electrochemical thin-layer cell. Their tentative structures were assigned based on tandem mass spectrometry in combination with accurate mass measurements. Moreover, the electrochemical conversion of 2-OH-AC in the presence of reduced glutathione and/or N-acetylcysteine unveiled the formation of reactive metabolite-nucleophilic trapping agent conjugates (m/z 517 and m/z 373, respectively) through the thiol group. This glutathione S-conjugate was also identified after electrolysis experiment as well as was detected in liver microsomes. Summing up, the present work illustrates that the electrochemical simulation of metabolic reactions successfully supports the results of classical electrochemical and enzymatic studies. Therefore, it can be a useful tool for synthesis of drug metabolites, including reactive metabolites.
Reply to: Beyond Tube‐Feeding: Relationship‐Centered, Comfort Care for Individuals with Eating Challenges in Dementia

cial or other unsatisfactory means. Comfort feeding has appeared in recommendations of an international clinical nutrition working group (European Society of Clinical nutrition and Metabolism), but there remains a paucity of research examining its application and effectiveness since it was first proposed almost a decade ago. As described in Rousseau’s anecdote, family members turn to the medical profession to provide their loved ones with what they perceive to be the best care, often ending with tragic results. This scenario will continue to occur until we determine how to translate comfort feeding as a best practice in long-term and acute care settings. Research to better understand the tensions that occur in this stage of the dementia journey and how comfort feeding can be incorporated into care management will help direct this knowledge translation and advancement in practice.
From cellular morphology to molecular and epigenetic anomalies of myelodysplastic syndromes

Myelodysplastic syndromes (MDSs) are a myeloid neoplasm with a propensity for natural evolution or transformation to acute leukemias (AL) over time. Mechanisms for MDS transformation to AL remain poorly understood but are related to genomic instability, which affects the production of the different cell lineages. Genomic instability is also generated by dysfunctional telomeres. Indeed telomeres, the protective ends of chromosomes are the backbone of genome stability. Nuclear telomere remodeling is an early indicator of nuclear remodeling preceding the onset of genomic instability and MDS. This review aims to revisit the pathogenesis and pathophysiology of MDS from morphology and cytogenetics to molecular and epigenetic mechanisms. Furthermore, this review will highlight and discuss recent breakthroughs in dysfunctional telomeres and nuclear telomere architecture roles in the pathogenesis and physiopathology of MDS in the global context of genomic instability.
Obstructive Sleep Apnea in Neuro-Ophthalmology.

BACKGROUND Obstructive sleep apnea (OSA) is a common pulmonary disorder with many systemic sequelae. Its association with diseases seen in neuro-ophthalmology is being increasingly recognized. Treatment of OSA with continuous positive airway pressure (CPAP) may reverse the pathology in some eye diseases. EVIDENCE ACQUISITION We conducted a search of the literature using the Ovid Medline database and Google Scholar, focusing on articles that explored the association between OSA and ophthalmic conditions. These included hypertensive retinopathy, diabetic retinopathy, central serous retinopathy (CSR), retinal vein occlusion (RVO), nonarteritic anterior ischemic optic neuropathy (NAION), glaucoma, idiopathic intracranial hypertension (IIH), papilledema, and stroke. RESULTS There is evidence of an independent association between OSA, and both hypertension and Type 2 diabetes mellitus, as well as the retinopathy associated with each disease. Evidence also suggests a link between OSA and CSR, NAION, and stroke. The evidence remains controversial or insufficient for convincing causative association with RVO, glaucoma, and IIH. However, in patients presenting with CSR, and IIH, underlying OSA is a common finding. CPAP reverses some pathological changes, but the evidence is limited. CONCLUSIONS OSA is associated with many diseases seen in neuro-ophthalmology clinics. More studies are required to assess the real ability of CPAP to reverse pathological changes. Ophthalmologists can screen for undiagnosed OSA in patients presenting with certain eye diseases.
Innovation in Pharmacovigilance: Use of Artificial Intelligence in Adverse Event Case Processing

Automation of pharmaceutical safety case processing represents a significant opportunity to affect the strongest cost driver for a company's overall pharmacovigilance budget. A pilot was undertaken to test the feasibility of using artificial intelligence and robotic process automation to automate processing of adverse event reports. The pilot paradigm was used to simultaneously test proposed solutions of three commercial vendors. The result confirmed the feasibility of using artificial intelligence–based technology to support extraction from adverse event source documents and evaluation of case validity. In addition, the pilot demonstrated viability of the use of safety database data fields as a surrogate for otherwise time‐consuming and costly direct annotation of source documents. Finally, the evaluation and scoring method used in the pilot was able to differentiate vendor capabilities and identify the best candidate to move into the discovery phase.
A simple care bundle to reduce unplanned admission rate for day case pediatric circumcision

An electronic review of unplanned day case admission rates in our hospital demonstrated an average annual rate for pediatric circumcision of 2%‐3% in recent years with high levels of perioperative strong opiate use. This lay above target unplanned admission rates (<2%) set out by the Royal College of Anaesthetists for day case surgery. A targeted quality improvement initiative was undertaken to improve patient flow through the pediatric day case surgery unit for elective circumcision. Among the reasons for unplanned admission, factors modifiable by the anesthetist (pain, postoperative nausea and vomiting, somnolence) are significant contributors.
Decoupled Classification Refinement: Hard False Positive Suppression for Object Detection

In this paper, we analyze failure cases of state-of-the-art detectors and observe that most hard false positives result from classification instead of localization and they have a large negative impact on the performance of object detectors. We conjecture there are three factors: (1) Shared feature representation is not optimal due to the mismatched goals of feature learning for classification and localization; (2) multi-task learning helps, yet optimization of the multi-task loss may result in sub-optimal for individual tasks; (3) large receptive field for different scales leads to redundant context information for small objects. We demonstrate the potential of detector classification power by a simple, effective, and widely-applicable Decoupled Classification Refinement (DCR) network. In particular, DCR places a separate classification network in parallel with the localization network (base detector). With ROI Pooling placed on the early stage of the classification network, we enforce an adaptive receptive field in DCR. During training, DCR samples hard false positives from the base detector and trains a strong classifier to refine classification results. During testing, DCR refines all boxes from the base detector. Experiments show competitive results on PASCAL VOC and COCO without any bells and whistles. Our codes are available at: this https URL
Modular, general purpose ODE integration package to solve large number of independent ODE systems on GPUs

A general purpose, modular program package for the integration of large number of independent ordinary differential equation systems capable of using professional graphics cards is presented. The available numerical schemes are the explicit and adaptive Runge–Kutta–Cash–Karp algorithm and the explicit fourth order Runge–Kutta method with fixed time step. In order to harness the huge processing power of graphics cards, the intermediate points of the computed trajectories are not stored. As a compensate, with pre-declared device functions, the required special features or properties of a solution can be easily extracted and stored each into a dedicated variable. For instance, the maximum and minimum values and/or their time instances. Event handling is also incorporated into the package in order to detect special points which can be stored as well. Moreover, again with pre-declared device function calls at such special points, the efficient handling of nonsmooth dynamics—e.g. impact dynamics—is possible. Several test cases are presented to demonstrate the flexibility of the pre-declared device functions and the strength of the program package. The applied models are the simple Duffing oscillator, the more complex Keller–Miksis equation known in bubble dynamics, and a system describing the behaviour of a pressure relief valve that can exhibit impact dynamics.
Improving resource elasticity in cloud computing thanks to model-free control

In cloud computing management, the dynamic adaptation of computing resource allocations under timevarying workload is an active domain of investigation. Several control strategies were already proposed. Here the modelfree control setting and the corresponding “intelligent” controllers, which are most successful in many concrete engineering situations, are employed for the “horizontal elasticity. ” When compared to the commercial “Auto-Scaling” algorithms, our easily implementable approach, behaves better even with sharp workload fluctuations. This is confirmed by experiments on Amazon Web Services (AWS).
Viral replication modes in single-peak fitness landscapes: a dynamical systems analysis

Positive-sense, single-stranded RNA viruses are important pathogens infecting almost all types of organisms. Experimental evidences from mutant distributions and amplification kinetics of viral RNA suggest that these pathogens may follow different RNA replication modes, ranging from the stamping machine replication (SMR) to the geometric replication (GR) modes. Despite previous theoretical works have focused on the evolutionary dynamics of RNA viruses amplifying their genomes with different strategies, few is known in terms of the bifurcations and transitions involving error thresholds (mutation-induced dominance of mutants) and lethal mutagenesis (mutation-induced extinction of all sequences). Here we analyze a dynamical system describing the intracellular amplification of viral RNA genomes evolving on a single-peak fitness landscape focusing on three cases considering neutral, deleterious, and lethal mutants spectra. In our model, the different replication modes are introduced with parameter α: with α ≳ 0 for the SMR and α = 1 for the GR. We analytically derive the critical mutation rates causing lethal mutagenesis and error catastrophe, governed by transcritical bifurcations that depend on parameters α, k1 (replicative fitness of mutants), and on the spontaneous degradation rates of the sequences, ϵ. For the lethal case the critical mutation rate involving lethal mutagenesis is . Here, the SMR involves lower critical mutation rates, being the system more robust to lethal mutagenesis replicating closer to the GR mode. This result is also found for the neutral and deleterious cases, but for these later cases lethal mutagenesis can shift to the error catastrophe once the replication mode surpasses a threshold given by .
Vergence Profile and Prevalance of Non-Strabismic Vergence Anomalies Among School Children in Abia State, Nigeria

ABSTRACT Purpose: To determine the prevalence of non-strabismic vergence anomalies and their relationship with age, gender, and school level in children aged 10–16 years Method: A cross-sectional study was conducted among 537 children (255 male, 282 females; mean age 13.0 ± 2.0, years) selected from nine schools using stratified, cluster, and random sampling. The participants completed a Convergence Insufficiency Symptom Survey (CISS) and eye examinations, including the measurement of visual acuity, non-cycloplegic refraction, cover test, near point of convergence, fusional vergences, accommodative functions, and ocular health evaluation. All binocular tests were performed following the subjective refraction with the corrective lenses in place, if prescribed. Results: The prevalence of low suspect, high suspect, and definite convergence insufficiency was 9.6%, 5.8%, and 4.1%, respectively. Other prevalence estimates included convergence excess (2.9%), fusional vergence dysfunction (2.6%), basic exophoria (1.7%), basic esophoria (2.8%), divergence insufficiency (0.8%), and divergence excess (0.6%). The prevalence of high suspect (p < 0.01) and definite (p < 0.01) convergence insufficiency was significantly higher in older than younger children, and as expected, in secondary more so than primary school children (p = 0.01). There was no statically significant association between gender and various vergence anomalies. Conclusion: The study showed that vergence anomalies are common vision conditions among Abia State school children. Given the importance of visual skills in learning and academic achievements, there is a need to develop screening and management strategies that will target those visual conditions to prevent educational and social progress being affected.
OpenNahele: the open Hawaiian forest plot database

Abstract Background This data paper provides a description of OpenNahele, the open Hawaiian forest plot database. OpenNahele includes 530 forest plots across the Hawaiian archipelago containing 43,590 individuals of 185 native and alien tree, shrub and tree fern species across six islands. We include estimates of maximum plant size (D950.1 and Dmax3) for 58 woody plant species, a key functional trait associated with dispersal distance and competition for light. OpenNahele can serve as a platform to test key ecological, evolutionary and conservation questions in a hotspot archipelago. New information OpenNahele is the first database that compiles data from a large number of forest plots across the Hawaiian archipelago to allow broad and high resolution studies of biodiversity patterns. Keywords: Hawaii, forests, islands, biodiversity, community ecology, evolutionary ecology
Shear bond strength of metal brackets to ceramic surfaces using a universal bonding resin

Background Assure Plus is a recently introduced universal adhesive with the ability to bond to various restorations. This study compared the shear bond strength of brackets bonded to two types of ceramics using conventional bonding agent and Assure Plus. Surface damage caused by debonding was also evaluated. Material and Methods In this in vitro study, 40 feldspathic and lithium disilicate ceramic discs were sandblasted, etched with 9.6% hydrofluoric acid and divided into two groups. In group 1, silane was applied and air-dried followed by application of Transbond XT primer, which was light-cured. In group 2, Assure Plus was applied and air-dried. In both groups, maxillary central incisor brackets were bonded. After incubation in distilled water at 37°C for 24 hours and 2000 thermal cycles, bond strength was measured using a universal testing machine, and the adhesive remnant index (ARI) and failure modes were determined. ANOVA and LSD tests were used to compare bond strength values; chi-squared test was used to compare ARI scores. Results Bracket bond to lithium disilicate by Assure Plus was significantly stronger than that to Feldspathic porcelain (P=0.041). Only in the Assure Plus/lithium disilicate group did some adhesive remain on the surface following debonding (40% of samples, P<0.05). Cohesive porcelain fracture had the lowest frequency in the lithium disilicate/Assure Plus group. Conclusions Assure Plus provided high bond strength between ceramic and brackets and minimized damage to lithium disilicate ceramic during debonding. Assure Plus is recommended for use in orthodontic treatment of adults with ceramic restorations. Key words:Adhesives, ceramics, dental bonding, shear bond strength.
How to Optimize Cancer Treatment in Older Patients: An Overview of Available Geriatric Tools

Cancer is a disease of older people, but this age group has often been excluded from clinical trials of cancer, which leads to poor transportability of standardized treatments in older cancer patients. One of the main reasons for the exclusion is the heterogeneity of older people in several domains: social environment, comorbidities, dependency, functional status, nutritional status, cognition status, and mood status. Comprehensive geriatric assessment aims to assess this heterogeneity and has identified frequent health problems often unknown before therapeutic decisions, which allows for targeted geriatric interventions with or without follow-up and appropriate cancer treatment selection. Several tools and scores have been developed for a complementary approach. These tools have the following characteristics: they screen for vulnerability to select patients who may benefit from a comprehensive geriatric assessment; are predictive tools for survival, postoperative complications, or chemotherapy-related toxicity; are decisional algorithms for cancer treatment; or define a core set of geriatric data to be collected in clinical cancer trials. Here, we present an overview of the geriatric tools that were published in PubMed from 2000 to 2017, that could help in the therapeutic decision-making for older cancer patients.
A Randomized, Open‐Label, Crossover Phase 1 Study to Evaluate the Effects of Food on the Pharmacokinetics of a Single Oral Dose of a 15‐mg Tylerdipine Tablet in Healthy Chinese Male Volunteers

Tylerdipine hydrochloride is a novel L‐type and T‐type dual calcium channel antagonist that has the potential effects of expanding blood vessels and lowering blood pressure. It is expected to reduce the side effect of ankle edema observed with other drugs in the same class. A randomized, open‐label, crossover phase 1 study was performed to evaluate the effect of food on the bioavailability of tylerdipine. Fourteen healthy male volunteers were enrolled. The administration of tylerdipine after a high‐fat meal increased the bioavailability of tylerdipine. In the fed state there was a 130% increase in the mean total systemic exposure (AUCinf) and a 73% increase in the mean peak plasma concentration (Cmax) compared with that in the fasting state. The geometric mean ratios (90% confidence interval) of Cmax and AUCinf were 2.54 (1.94, 3.33) and 1.75 (1.50, 2.04) for tylerdipine. The exposures of the 2 main metabolites M2 and M4 were increased by approximately 10% after a high‐fat meal. The median time to peak plasma concentration of tylerdipine showed no difference between fasting and fed states.
A Novel Insight Into the Challenges of Diagnosing Degenerative Cervical Myelopathy Using Web-Based Symptom Checkers

Background Degenerative cervical myelopathy (DCM) is a common debilitating condition resulting from degeneration of the cervical spine. While decompressive surgery can halt disease progression, existing spinal cord damage is often permanent, leaving patients with lifelong disability. Early surgery improves the likelihood of recovery, yet the average time from the onset of symptoms to correct diagnosis is over 2 years. The majority of delays occur initially, before and within primary care, mainly due to a lack of recognition. Symptom checkers are widely used by patients before medical consultation and can be useful for preliminary triage and diagnosis. Lack of recognition of DCM by symptom checkers may contribute to the delay in diagnosis. Objective The aims of this study were to investigate whether Web-based symptom checkers were able to recognize relevant symptoms of DCM, to characterize the DCM differential they returned , and to evaluate the diagnostic performance of recognized DCM symptoms. Methods We pooled classical DCM symptoms from leading review articles. These symptoms were entered into the algorithms used by the top 20 symptom checker websites (N=4; Google Search). The most widely cited symptom checker, WebMD, was used to characterize the differential diagnosis for DCM symptoms. Results A total of 31 classical DCM symptoms were identified, of which 45% (14/31) listed DCM as a differential and 10% (3/31) placed DCM in the top third of the differential. The mean differential rank for motor symptoms was significantly better than that for arthritic symptoms (P=.01) and the average differential rank for all symptoms (P=.048). The symptom checker WebMD performed best at recognizing DCM, placing the condition nearer to the top of the differential list (mean rank of 5.6) than either Healthline (rank of 12.9, P=.02) or Healthtools.AARP (rank of 15.5, P=.001). On WebMD, only one combination of symptoms resulted in DCM as the primary differential: neck, shoulder, and arm pain with hand weakness. Moreover, 151 differential diagnoses for DCM symptoms were recorded on WebMD. Multiple sclerosis and peripheral neuropathy were the most common differentials, shortlisted for 52% (16/31) and 32% (10/31) of the DCM symptoms, respectively. Conclusions DCM symptoms are poorly identified by Web-based symptom checkers, which leads to a large differential of many other common conditions. While a diagnosis becomes more likely as the number of symptoms increases, this represents more advanced disease and will not support much-needed earlier diagnosis. Symptom checkers remain an attractive concept with potential. Further research is required to support their optimization.