Background: Methotrexate is widely recommended as a first-line treatment for the intensive systemic and consolidation phases of childhood acute lymphoblastic leukemia. However, methotrexate-induced nephrotoxicity is a severe adverse reaction, of which the mechanism remains unclear. Methods: An untargeted metabolomics analysis of serum from childhood acute lymphoblastic leukemia with delayed methotrexate excretion with or without acute kidney injury was performed to identify altered metabolites and metabolic pathways. An independent external validation cohort and in vitro assays further confirmed the candidate metabolites and the mechanisms underlying the nephrotoxicity of methotrexate. Results: Four metabolites showed significant differences between normal excretion and delayed excretion, seven metabolites reflected the differences between groups with or without acute kidney injury, and six pathways were finally enriched. In particular, oxidized glutathione is confirmed as an candidate metabolite involved in the toxicity of methotrexate. Based on the depletion of glutathione mediated cell death, it was found that methotrexate overload significantly reduced cell viability, triggered reactive oxygen species and intracellular Fe 2+ accumulation, and altered the expression of ferroptosis-related proteins in HK-2 cells. These methotrexate-induced changes were alleviated or reversed by the administration of a ferroptosis inhibitor, further suggesting that ferroptosis promoted methotrexate-induced cytotoxicity in HK-2 cells. Conclusions: Our findings revealed complex metabolomic profiles and provided novel insights into the mechanism by which ferroptosis contributes to the nephrotoxic effects of methotrexate.

Bird diversity has declined as native birds have avoided using the green desert after the Smooth Cordgrass Spartina alterniflora invaded coastal China. After many years of coexistence, a few passerine birds began to enter and use Smooth Cordgrass, but only birds of nonspecialised habitat. In this study, we first found that a native reed-specific bird, the Parrotbill Calamornis heudei, flocked and sang in a Smooth Cordgrass habitat in the whole overwintering period near Sheyang Port in Yancheng, Jiangsu Province. This phenomenon indicates that native obligate birds may be forced to adapt to exotic Smooth Cordgrass habitats after long-term coexistence; obviously, the distribution, feeding and reproduction of birds would be affected. Is this an ecological trap? Which may lead to unknown ecological consequences. We suggest that more research attention should be given to this process occurring along the Chinese coast.

In this paper, we investigate the controllability under positivity constraints from the birth of a size-structured population system with delayed birth process. Firstly, we establish the well-posedness and positivity property of the model. Secondly, and more importantly, we derive a sufficient condition for boundary approximate controllability under state and control positivity constraints. The method relies on the feedback theory of infinite-dimensional positive systems.

Conventional transcranial direct-current stimulation (tDCS) delivered to the primary motor cortex (M1) has been shown to enhance implicit motor sequence learning (IMSL). Conventional tDCS targets M1 but also the motor association cortices (MAC), making the precise contribution of M1 to IMSL presently unclear. We aimed to address the roles of these areas by comparing conventional tDCS of M1 and MAC to High-Definition (HD) tDCS, which more focally targets M1. In this sham-controlled, crossover study in 89 healthy adults, we used mixed-effects models to analyze sequence-specific and general learning effects in the acquisition, short- and long-term consolidation phases of IMSL, as measured by the serial reaction time task. Conventional tDCS did not influence general learning, improved sequence-specific learning during acquisition (anodal: M=42.64 ms, sham: M=32.87 ms, p=.041) and deteriorated it at long-term consolidation (anodal: M=75.37 ms, sham: M=86.63 ms, p=.019). HD tDCS did not influence general learning, slowed performance specifically in sequential blocks across all learning phases (all p’s<.050), and consequently deteriorated sequence-specific learning during acquisition (anodal: M=24.13 ms, sham: M=35.67 ms, p=.014) and long-term consolidation (anodal: M=60.03 ms, sham: M=75.01 ms, p=.002). Our findings indicate that generalized stimulation of M1 and MAC enhanced acquisition, but hindered consolidation of IMSL. In contrast, focal M1 stimulation by HD tDCS worsened overall performance, likely due to cathodal inhibition of MAC as induced by the return electrodes. Consequently, this disruption of performance supports the notion that these areas fundamentally contribute to IMSL as an integral part in the cortico-basal ganglia-thalamo-cortical network.

Tamoxifen is the most used hormonal therapy for estrogen receptor positive breast cancer. CYP2D6 is the main enzyme in the metabolic pathway of tamoxifen to endoxifen. Variations in endoxifen plasma concentrations are associated with CYP2D6 polymorphisms. This study aimed to determine the association between the CYP2D6 polymorphisms and endoxifen plasma concentrations in a cohort of Zimbabwean breast cancer patients (n = 40). TaqMan genotyping and copy number assays were done to determine CYP2D6 genotypes. Tamoxifen and metabolites were quantitated using LC-MS/MS. The population had high frequencies of the CYP2D6 reduced function alleles, *17 (15%) and *29 (18%). The median endoxifen concentration was 4.78 ng/ml and 55% of the patients, mostly intermediate metabolizers were below the endoxifen therapeutic threshold 5.97 ng/ml. The CYP2D6 phenotypes and activity scores were significantly associated with endoxifen plasma concentrations (p = 0.0151) and with endoxifen to N-desmethyl tamoxifen ratios (p = 0.0006).

This paper proposes a novel algorithm that accurately predicts market trends and trading entry points for US 30-year-treasury bonds using a hybrid approach of 1-Dimensional Convolutional Neural Network (1DCNN), Long-Short Term Memory (LSTM), and XGBoost algorithms. We compared the performance of various strategies using 1DCNN and LSTM and found that existing state-of-the-art methods based on LSTM have excellent results in market movement prediction tasks, but the effectiveness of 1DCNN and LSTM in terms of trading entry point and market perturbations has not been studied thoroughly. We demonstrate, through experiments that our proposed 1DCNN-BiLSTM-XGBoost algorithm combined with moving averages crossover effectively mitigates noise and market perturbations, leading to high accuracy in spotting trading entry points and trend signals for US 30-year-treasury-bonds. Our experimental study shows that the proposed approach achieves an average of 0.0001% Root Mean Squared Error and 100% R-Square, making it a promising method for predicting the market trends and trading entry points.

The failure mechanisms caused by electrostatic discharge (ESD) effects at ambient temperatures ranging from -75℃ to 125℃ are investigated by Silvaco TCAD simulator. The devices are NMOS transistors fabricated with 28nm fully depleted silicon-on-insulator (FDSOI) technology. Results indicate that with an increase in temperature, the first breakdown voltage of the device decreased by 27.32%, while the holding voltage decreased by approximately 8.49%. The total current density, lattice temperature, and potential etc. were extracted for a detailed insight into the failure process. These findings provide valuable references for the design and development of ESD protection devices applied at different temperature ranges.

This paper studies the practical fixed-time average consensus problem for general continuous linear multi-agent systems under switching topologies. Firstly, a distributed fixed-time consensus control protocol based on dynamic event-triggered mechanism is designed by using the local information exchange between individual agents. The protocol introduces auxiliary dynamic variables, and the triggering condition changes in real time based on the dynamic variable obtained online, which can significantly reduce the number of triggering events, effectively decrease the energy dissipation of the system and the update frequency of the controller. Then, under the designed control protocol, the sufficient conditions for the multi-agent system to solve the practical fixed-time average consensus problem are given, and it is proved that there is no Zeno behavior in the system. Finally, the simulation results verify the effectiveness of the conclusions.

Gorham-Stout disease (GSD) and generalized lymphatic anomaly (GLA) are subtypes of complex lymphatic malformations (CLMs) with osseous involvement that cause significant complications in children, including pain and pathologic fractures. Mutations in cellular growth pathways are common, and the mTOR inhibitor sirolimus alleviates symptoms in some, but not all, patients. We describe two patients, one with GSD and one with GLA, who were found to have EML4::ALK fusions. This report of a targetable, oncogenic fusion in vascular malformations expands our understanding of the genetic basis for CLMs and suggesting additional targeted therapies could be effective.

Local adaptation to annually changing environments has evolved in numerous species. Seasonal coat colour change is an adaptation that has evolved in multiple mammal and bird species occupying areas that experience seasonal snow cover. It has a critical impact on fitness as predation risk may increase when an individual is mismatched against its habitat’s background colour. In this paper we investigate the impact of landscape covariates on moult timing in a native winter-adapted herbivore, the mountain hare (Lepus timidus), throughout Norway. Data was collected between 2011 and 2019 at 678 camera trap locations deployed across an environmental gradient. Based on this data, we created a Bayesian multinomial logistic regression model that quantified the correlations between landscape covariates and coat colour phenology and analysed among season and year moult timing variation. Our results demonstrate that mountain hare moult timing is strongly correlated with altitude and latitude with hares that live at higher latitudes and altitudes keeping their winter white coats for longer than their conspecifics that inhabit lower latitudes and altitudes. Moult timing was also weakly correlated with climate zone with hares that live in coastal climates keeping their winter white coats for longer than hares that live in continental climates. We found evidence of some among year moult timing variation in spring, but not in autumn. We conclude that mountain hare moult timing has adapted to local environmental conditions throughout Norway.

What is atrial fibrillation? A RETRO-spective analysis Thomas Rostock, MD1, Alexander P. Benz, MD, MSc1,2 and Raphael Spittler, MD, MSc11 University Hospital Mainz, Center for Cardiology, Department of Cardiology II / Electrophysiology, Mainz, Germany2 Population Health Research Institute, McMaster University, Hamilton, Ontario, CanadaRunning title: RETRO mapping of AFWord count: 1435Corresponding author:Thomas Rostock, MDUniversity Hospital MainzCenter for CardiologyCardiology II / ElectrophysiologyLangenbeckstr. 155131 Mainz, GermanyEmail: [email protected]: None declared.Funding: None.Keywords: Atrial fibrillation, mapping, mechanisms, wavefrontIdeally, before implementing any treatment as standard of care, pathophysiological mechanisms need to be identified in order to elaborate and define potential therapeutic targets. Philosophy of science described the fundamental role of categories for components of biological mechanisms: entities and activities. In this regard, activities between different entities are considered to establish a specifically organized biological phenomenon (1).More than six decades ago, pioneer research on mechanisms of atrial fibrillation (AF) by Moe and co-workers introduced the “multiple wavelet hypothesis” (2). It was not until the mid 1980s that a group of researchers led by Allessie performed high-density atrial mapping in the canine heart and demonstrated multiple wandering wavelets with a continuous beat-to-beat change in activation pattern (3). Based on this concept, the surgical MAZE procedure developed by Cox et al. aimed at creating anatomical barriers for multiple reentrant wavefronts by means of surgical incisions transecting the atria into separated areas was introduced (4). The identification of focal repetitive electrical discharges arising from the pulmonary veins by Haissaguerre and colleagues in the late 1990s ushered in a new era in the interventional treatment of AF (5). This new pathophysiological concept not only provided a fundamentally new target for the interventional treatment of AF, it also shifted the focus of research from the perpetuating substrate to initiating triggers. However, while patients with “short-lived” episodes of AF typically respond well to pulmonary vein isolation, efficacy of catheter ablation is limited in many patients with persistent AF. This led researchers to re-appraise mechanisms of the atrial arrhythmogenic substrate. Using computational mapping of AF models, several mathematical methods for signal processing (e.g., dominant frequency, Hilbert transformation, etc.), optical mapping, non-invasive panoramic mapping and rotational activity mapping were investigated in the pre-clinical and clinical setting for characterization of electrophysiological mechanisms during electrically established AF (6). Interestingly, there is one specific key feature collectively described: activation patterns of consecutive phases during AF demonstrate spatiotemporal organization with varying stability. Thus, accumulating data derived from contemporary AF mapping studies challenge the concept of a global randomly meandering atrial activation causing different phenotypes of AF.In this issue of the Journal , Smith and colleagues (9) report from a prospective, observational study on a novel, computationally acquired and algorithm-based AF mapping technology developed in conjunction with a proprietary software (MATLAB). This mapping tool has been previously introduced by the same group and is called RETRO-Mapping (7). RETRO-Mapping is a technological expansion of RIPPLE-Mapping, an algorithm that is independent of time-window settings, also developed by the group of Linton et al (8). The basic principle of RETRO-Mapping is an analysis of cross-referenced electrode activation derived from a multi-polar catheter in the surface-covered area during AF. The current study was designed as a proof-of-concept investigation aimed at the evaluation of patterns of AF activation. A 20-pole spiral double loop catheter (AF Focus II, St. Jude Medical) was placed at the posterior left atrium. After stabilization, local electrograms during AF >30 seconds were obtained. Anatomical positions of the catheters electrodes were visualized with the NavX Ensite X system and exported into the RETRO-Mapping software along with their corresponding electrophysiological data. The algorithm calculated three parameter of wavefront propagation: cycle length, conduction velocity, and wavefront direction. The midpoint between two adjacent electrodes of the loop catheter corresponds to the position of bipolar electrograms. Through a process called triangulation, midpoints were used to define corners for the segmentation of the left atrial posterior wall into triangles. The idea of triangulation of the covered area is to obtain the most appropriate position of two adjacent midpoints for further comparison of two local electrograms connected by the edge of a triangle. The geometric and activation properties of connected electrograms allowed for further analysis used for calculation of cycle length. A dichotomization of tissue excitability (depolarized myocardial tissue was coded as 1, and repolarized tissue was coded as 0) was used to create binary images. The Euclidean distance transform algorithm calculated the distance of pixels with a value of 0 to the nearest pixel with a value of 1. Incorporating distance information and the sampling frequency of the mapping algorithm as a marker of time, conduction velocity is calculated. Smith and colleagues used the Sobel operator for image processing to analyze wavefront direction. This mathematical filter calculates the gradient of image intensity at each point. These data are then used to detect areas where the intensity changes rapidly, which helps to identify edges of an image. The activation edge direction was derived from these edges and was used to calculate the overall wavefront direction. The researchers were interested in (1) whether an advancing wavefront maintained its direction and (2) whether the plane wavefront would be predictive of the subsequent wavefront direction.In eight patients with three types of AF (paroxysmal, persistent without amiodarone and persistent under amiodarone treatment), more than 34.000 activation edges of plane wavefronts (i.e., linear wavefront activations of the mapping field) were detected. With increasing intervals between new wavefront activations, the difference of wavefront directions also increased in a linear relationship. Smaller direction changes were observed in patients with persistent AF with amiodarone as compared to those with persistent AF without amiodarone. However, the greatest variability in activation changes was observed in paroxysmal AF. Activation direction consistency, indicated by small variations between wavefront directions, was highest in persistent AF with amiodarone and lowest in paroxysmal AF. More than half of all wavefront activation patterns predicted the pattern of the subsequent wavefront. In this context, the highest predictive value of activation patterns for subsequent wavefronts was found in persistent AF without amiodarone (the AF type with the shortest cycle length).With the presented study, Smith and colleagues shed some light on the complexities surrounding AF activation patterns. Gleaned from human high-density contact mapping of electrophysiological features during AF, data were processed with a dedicated software in order to transform AF activation patterns into a color-coded two-dimensional model. This novel software package may provide real-time calculation of conduction velocity and cycle length during a mapping/ablation procedure and could potentially be incorporated into existing 3-dimensional mapping systems. The authors are to be commended for providing a potential solution for processing electrophysiological activation data of AF with the potential to include this information into the ablation procedure. Furthermore, the data of this study reinforce the paradigm that AF perpetuation follows an organized and repetitive activation pattern (10).While the study has a clear scientific basis, there are some practical issues to be considered. First, the current technology is limited by the apparent inapplicability to fibrotic atrial tissue which may represent an anatomical substrate in patients with more advanced types of persistent AF. Second, the algorithm characterized paroxysmal AF by features indicating more “disorganized” patterns as compared to the persistent AF types. The reasons for this observation currently remain unclear since paroxysmal AF with focal triggering (and maintaining) sources predominantly located within the pulmonary veins (and not the atria) and longer AF cycle lengths appears to represent a more organized type of AF. Third, with the current type of visualization of activation patterns, focally activated wavefronts cannot be distinguished from rotor activity or even passively activated areas. Fourth, only a small area covered by the double-looped mapping catheter can be mapped at a given time. However, even with larger high-density contact mapping catheters (e.g., the basket catheter), it still remains impossible to simultaneously cover the entire surface of the left atrium. In this context, the data of the presented study also may help to overcome this limitation since they revealed that a preceding wavefront predicted the subsequent activation pattern, potentially indicating similar wavefront configurations in neighboring areas. Sixth, calculation models used in this study are evaluated with a limited number of electrodes. Thus, it needs to be determined if larger areas represented by considerably more electrodes (and data) can undergo computational analysis in the same way (and in real-time). Finally, further and much larger studies are needed to determine how best to incorporate information on AF mechanism and visualization of atrial activation during AF in the clinical setting. Thus, next steps of research may include characterization of appropriate targets for the interventional treatment.At the end of the day, the clinical electrophysiological community should welcome efforts aimed at improving our understanding of the underlying mechanisms of particularly non-pulmonary vein dependent AF. This seems critical in order to define a tailored approach to the individual patient. The alternative is a continued focus on “empirical” ablation without fully appreciating the underlying pathophysiology. For now, durable pulmonary vein isolation is the only pathophysiologically established treatment in AF ablation, but hopefully will not remain the only in the future.

A novel transformerless three-phase unidirectional bridgeless flying capacitor (UBFC) rectifier for medium-voltage and high-voltage applications is presented by this paper. The rectifier consists of three single-phase rectifiers in wye connection, the DC outputs of the three single-phase rectifiers are connected in parallel to provide a high common DC-link bus which makes it convenient to connect with NPC or FC multilevel inverters. To avoid phase to phase current circulation, an additional inductor and diode are added to each single-phase rectifier. Compared with conventional bidirectional multilevel converters, only half IGBTs are employed with lower voltage stress, line-frequency transformers are no longer be required, which makes the proposed rectifier has a series of advantages such as reduced cost, simplified control complexity, increased reliability and improved overall efficiency. The basic operating principle of the proposed rectifier in continuous conduction mode is discussed, an improved carrier-based level-shifted PWM modulation method integrated with voltage balancing and the double closed-loop control strategy are proposed to achieve more voltage levels and keep the flying capacitors in balance. The feasibility of proposed rectifier is verified by the simulation as well as experimental results.

Objective: to explore the impact of attending a clinical placement on selecting a career in obstetrics and gynaecology Design: Mixed methods study Setting: Imperial College London Population: Fifth year medical students attending a clinical placement in obstetrics and gynaecology Methods: Between January 2021- January 2022, questionnaires were used and semi-structured focus groups conducted, which were audio recorded. Descriptive statistics were conducted and a framework analysis on transcribed focus groups. Main outcome measure: the impact of the clinical placement on career choices Results: Six main themes were identified from the analysis; three contributing to considering a career in obstetrics and gynaecology; pregnancy is not an illness, extraordinary experience of observing childbirth and variable specialty and three themes emerged contributing to not considering a career; lack of work-life balance, high stakes specialty and the emotional toll. Even at an undergraduate level, medical students exhibited concerns about the long term feasibility of achieving work life balance and avoiding professional burnout, which was partly attributed to the responsibility of looking after both the woman and baby. Conclusions: Obstetrics and gynaecology is a challenging high stakes specialty but is also highly rewarding. Students experiences of childbirth during a clinical placement appear to contribute to the consideration of a career in obstetrics and gynaecology. It is crucial to provide a supported and realistic introduction to the specialty, to recruit enthusiastic junior doctors who will be resilient to the pressures of obstetrics.

Recurrent facial Microcystic adnexal carcinoma and hair transplantation on scar site

Abstract Objective The objective of this study was to characterize the clinical features, developmental milestones, and the natural history of Pelizaeus Merzbacher disease (PMD) associated with PLP1 gene duplications. Methods The study examined 16 PMD Patients ranging in age from 7 to 48, who had a documented PLP1 gene duplication. The

Phytoplankton have short generation times, flexible reproduction strategies, large population sizes, and high standing genetic diversity, traits that should facilitate rapid evolution under directional selection. We quantified local adaptation of copper tolerance in a population of the diatom Skeletonema marinoi from a mining exposed inlet in the Baltic Sea and in a non-exposed population 100 km away. We hypothesized that mining pollution has driven evolution of elevated copper tolerance in the impacted population of S. marinoi. Assays of 58 strains originating from sediment resting stages revealed no difference in the average tolerance to copper between the two populations. However, variation within populations was greater at the mining site, with three strains displaying hyper-tolerant phenotypes. In an artificial evolution experiment, we used a novel intraspecific metabarcoding locus to track selection and quantify fitness of all 58 strains during co-cultivation in one control and one toxic copper treatment. As expected, the hyper-tolerant strains enabled rapid evolution of copper tolerance in the mining exposed population through selection on available strain diversity. Within 42 days, in each experimental replicate a single strain dominated (30-99% abundance) but different strains dominated the different treatments. The reference population developed tolerance beyond expectations primarily due to slowly developing plastic response in one strain, suggesting that different modes of copper tolerance are present in the two populations. Our findings provide novel empirical evidence that standing genetic diversity of phytoplankton resting stage allows populations to evolve rapidly (20-50 generations) and flexibly on timescales relevant for seasonal bloom progressions.

In optic pathway glioma (OPG), bevacizumab-based therapy (BBT) has promising effects on radiographic tumor burden, but impact on vision is less clear. This single-institution study characterized visual acuity (VA) and visual field (VF) outcomes in 17 pediatric OPG patients treated with BBT. VA was stable or improved in 14 patients. Nine patients had evaluable VF data, 6 of whom experienced stability or improvement. Among 6 patients with vision deterioration as a treatment indication, stable or improved was observed for both VA and VF in 5 patients. In summary, BBT was associated with favorable visual outcomes in most patients with OPG.

Centuries of human development have altered the connectivity of rivers, adversely impacting ecosystems and the services provided. Significant investments in natural resource projects are made annually with the goal to restore function to degraded rivers and floodplains and protect freshwater resources. Yet restoration projects often fall short of their objectives, in part, due to the lack of systems-based, strategic planning. To evaluate channel-floodplain (dis)connectivity and erosion/incision hazard at the regional scale, we calculate Specific Stream Power (SSP), an estimate of the energy of a river, using a topographically-based, low-complexity hydraulic model. Other basin-wide SSP modeling approaches neglect reach-specific geometric information embedded in Digital Elevation Models. Our approach leverages this information to generate reach-specific SSP-flow curves. We extract measures from these curves that describe (dis)connected floodwater storage capacity and erosion hazard at individual design storm flood stages and demonstrate how these measures may be used to identify watershed-scale patterns in connectivity. We show proof-of-concept using 25 reaches in the Mad River watershed in central Vermont and demonstrate that the SSP results have acceptable agreement with a well-calibrated process-based model (2D Hydraulic Engineering Center’s River Analysis System) across a broad range of design events. While systems-based planning of regional restoration and conservation activities has been limited largely due to computational and human resource requirements, measures derived from low complexity models can provide an overview of reach-scale conditions at the regional level and aid planners in identifying areas for further restoration and/or conservation assessments.