Extreme Deviations Research Articles

Improving the predictive potential of diffusion MRI in schizophrenia using normative models-Towards subject-level classification.

Diffusion MRI studies consistently report group differences in white matter between individuals diagnosed with schizophrenia and healthy controls. Nevertheless, the abnormalities found at the group‐level are often not observed at the individual level. Among the different approaches aiming to study white matter abnormalities at the subject level, normative modeling analysis takes a step towards subject‐level predictions by identifying affected brain locations in individual subjects based on extreme deviations from a normative range. Here, we leveraged a large harmonized diffusion MRI dataset from 512 healthy controls and 601 individuals diagnosed with schizophrenia, to study whether normative modeling can improve subject‐level predictions from a binary classifier. To this aim, individual deviations from a normative model of standard (fractional anisotropy) and advanced (free‐water) dMRI measures, were calculated by means of age and sex‐adjusted z‐scores relative to control data, in 18 white matter regions. Even though larger effect sizes are found when testing for group differences in z‐scores than are found with raw values (p < .001), predictions based on summary z‐score measures achieved low predictive power (AUC < 0.63). Instead, we find that combining information from the different white matter tracts, while using multiple imaging measures simultaneously, improves prediction performance (the best predictor achieved AUC = 0.726). Our findings suggest that extreme deviations from a normative model are not optimal features for prediction. However, including the complete distribution of deviations across multiple imaging measures improves prediction, and could aid in subject‐level classification.

Who should be repairing these hernias? Level of expertise?

: Hiatal hernias are commonly seen in patients presenting with GERD. Surgical management of patients with hiatal hernias remains a challenge given the lack of general consensus on management and operative technique. This has led to gaps in quality and outcomes of care in these patients. Variable levels of knowledge, experience, and expertise among practitioners has resulted in extreme deviations in preoperative evaluation, procedural technique, follow-up, and outcomes, that led to poor confidence in surgical management of GERD and hiatal hernias. We performed a literature review of contemporary and latest studies compiled in review format. The conclusions we made from our review of the literature were that foregut surgeons need to have a comprehensive understanding of foregut physiology and coordinate a thorough preoperative evaluation including independent interpretation of esophageal physiologic testing and the ability to perform endoscopy. Foregut surgeons should have specialized expertise and training in benign foregut procedures, minimally invasive techniques, and have a commitment to long term follow up. Ideally these complex operations would be completed by a minimally invasive trained surgeon at a high-volume center as improved outcomes and decreased costs have been associated with laparoscopic technique and increased surgeon/hospital volume. A multidisciplinary approach should be utilized when feasible.

ГЕОДИНАМІКА

The goal. Identify the relationship between seasonal temperature changes and vertical and horizontal displacements of GNSS control points based on data obtained by the automated monitoring system of the Dnipro HPP dam in the period from 2016 to 2020. Input data. The research used data of uninterrupted GNSS measurements obtained at 16 points of the Dnipro HPP dam from mid-2016 to mid-2020. Method. A specially developed software product analyzes the GNSS time series of measurements pre-processed by the GeoMoS system to determine the parameters of seasonal displacements and their relationship with seasonal changes in air temperature. The GNSS time series analysis. Based on the conducted research, the influence of environmental temperature has a decisive effect on the cyclicity of dam deformations. This applies to both horizontal and vertical displacements but in the absence of significant changes in the water level in the upper reservoir. Values of extreme displacements increase closer to the middle of the dam and decrease at the edges. This tendency is observed every year in the study period. According to the three-year GNSS dam monitoring, the amplitude of semi-annual horizontal oscillations of the control points relative to the dam axis is in the range of 15-18 mm. Almost all vectors of horizontal displacements are perpendicular to the axis of the arcuate dam. In the first half of the year, the vectors of horizontal displacements aim to widen the dam, and in the second half of the year - at compressing the dam. The analysis of the data represents that almost every year, extreme deviations, both horizontal and vertical, occur in February and August. Temperature extremes occur faster than excessive GNSS displacements. For the dam of the Dnipro HPP, the extreme horizontal displacements lag on average by 37 days, and the vertical ones - by 32 days from the extreme temperatures. The deformations of the dam are related to the concrete structure temperature, which changes with a certain delay relative to the air temperature. The magnitudes of extreme displacements and the epoch of their manifestation depend on the dam's design and its technical parameters. For each dam, these extreme displacements and the periods of their representation will be different. Accordingly, monitoring these displacements and their changes over time is one of the criteria for assessing the general condition of the dam. Scientific novelty and practical significance. The regularities of the connection between the change of temperature and the displacements of the GNSS points, revealed during the research, can be used for the further study of data processing and analysis of the hydraulic structures monitoring.

Performance of the Ionospheric Kappa-Correction of Radio Occultation Profiles Under Diverse Ionization and Solar Activity Conditions.

The kappa‐correction is an easy‐to‐use method to correct for residual ionospheric errors in radio occultation (RO) data. It is a simple empirical model term that only depends on readily available data. While its basic utility was well proven in previous studies, including a recent predecessor study on RO climatologies under solar cycle variations, its performance for individual RO profile correction under diverse and extreme ionization conditions is unclear so far. Here we tackle this gap and focus on investigating (extremely) low and high solar activity and ionization conditions of individual RO events, including inspection of ionospheric symmetry between inbound and outbound raypaths. Using a global multi‐year ensemble of MetOp‐A and GRACE‐A RO events over 2008–2015 as basis, we applied a sampling approach leading to six characteristic condition cases. These cases also relate to day and night time variations and geographic variations from the equatorial to the high latitude region. We inspected the kappa‐correction and its performance relative to the standard bending angle correction for RO‐retrieved stratospheric profiles and found mean deviations in temperature of near −0.3 K in the upper stratosphere (40–45 km) for high ionization conditions, with extreme deviations exceeding −2 K for strong inbound/outbound asymmetry. The kappa‐correction term itself reaches a mean value near 0.05 μrad under these high conditions. Low solar activity and ionization conditions lead to a mean correction smaller than 0.005 μrad and mean temperature deviations smaller than 0.02 K. An intercomparison to other quality datasets, predominantly showed a decrease in mean temperature difference when applying the kappa‐correction.

A prospective validation of the genomic classifier to define high-metastasis risk in a subset of African American men with early localized prostate cancer: VanDAAM study.

5005 Background: Risk stratification of prostate cancer (PC) using routine clinical variables remains suboptimal as they do not account for underlying tumor biology. The genomic classifier provides information on underlying biology and independently predicts an individual patient’s risk of metastasis. Although the performance of the genomic classifier has been tested across different cohorts primarily comprised of White men, its validation as an optimal genomic risk classifier for African American men (AAM) is thus far lacking in a prospective trial. We report the initial results on the prospective validation of the genomic classifier in a matched cohort of AAM and non-AAM (NAAM). Methods: This was a multisite, prospective validation trial of the genomic classifier i.e. Decipher score in AAM. Participants were recruited on a 1:1 enrollment ratio of AAM to NAAM diagnosed with low-intermediate risk PC. Patient on active surveillance were ineligible. NAAM were matched to AAM on PSA, age, biopsy Gleason score, clinical stage, and percent positive biopsy cores. Diagnostic biopsy specimens were processed at a CLIA certified laboratory and Decipher score was assessed using whole transcriptome profiling platform. Total target accrual was 250 men treated for low-intermediate PC over three years. Statistical analyses include categorical comparison of race dependent risk group migration between NCCN risk group and genomic classifier. Relative risk of metastasis was estimated using negative binomial model. Results: Final analytical cohort included 207 evaluable cases (AAM = 102 and NAAM = 107) with comprehensive genomic information. Risk of metastasis was determined based on pretreatment biopsy Decipher score, and patients were classified as low, favorable-, and unfavorable intermediate risk. Despite achieving a robustly matched clinical cohort, we observed significant genomic heterogeneity between AAM and NAAM across NCCN risk groups. In a comparative analysis, 49% of low-favorable intermediate risk AAM harbored high genomic risk tumors as compared to only 10% NAAM, p = 0.02. Similarly, using the modified clinico-genomic risk classifier (cGC), comprised of both Decipher score and clinical variables, AAM experienced an extreme deviation of risk status (difference [δ] between cGC and NCCN ≥ 2) as compared to NAAM (26.8% vs 8.1%, p = 0.03). In a binomial model, low-favorable NCCN risk AAM were 3.9 times more likely to be reclassified as high genomic risk for distant metastasis compared to NAAM (RR = 3.99, 95% CI, 1.15 – 13.86, p = 0.02). Conclusions: Clinical NCCN risk classification is an inadequate surrogate of tumor biology and offers suboptimal risk stratification for AAM with PC. Integration of patient specific genomic classifier into standard of care will improve accuracy in disease risk classification and treatment recommendations for AAM. Clinical trial information: NCT02723734.

Comparison of glycoprofiles of rituximab versions licensed for sale in India and an analytical approach for quality assessment

Glycosylation affects clinical efficacy and safety; therefore, is a critical quality attribute of therapeutic monoclonal antibodies. Glycans are often labile and complex in patterns, giving rise to macro- and micro-heterogeneity. Recombinant production, diverse geographical locations, associated transportation and storage conditions further compound the problem. Two-way studies comparing glycoprofile of the originator and its given biosimilar are aplenty. However, the extent of analytical variation and similarity in glycoprofile across all approved versions of a drug is hardly explored. Using UHPLC and mass spectrometry, we compared the glycoprofiles of eight rituximab drug samples licensed for sale in India. While the types of glycans were found identical, the abundance of some glycans varied significantly within the tested population. The quality range of glycosylation parameters of the tested sample population differed significantly from the previously established values for US/EU licensed rituximab. As the mean abundance of the 90% of identified glycans falls within ±3SD, the extent of mutual variations amongst tested lots is less significant compared to the extreme deviation from previously established QR limits. Thus, we propose this approach as an orthogonal method to capture glycan variations in licensed versions of mAbs for quality surveillance and in cases where originator samples' are limiting. SignificanceAs fluctuation in glycosylation may be of clinical significance, we identify that a one-to-one comparison with originator alone is insufficient in sensing the extent of variations in glycosylation parameters in licensed biosimilars of a given therapeutic mAb. Here we propose that future biosimilarity analysis may include an orthogonal approach of generating an additional combined QR range representing variations across the originator and its biosimilars. The glycosylation profiles of eight rituximab drug samples of different make obtained from the point of sale in India were found identical amongst the tested rituximab versions. However, the QR limits corresponding to important glycosylation parameters differed significantly across all tested samples from the previously established QR limits of US- and EU-licensed rituximab in statistical terms. Such an approach may be useful in defining the true range of glycan variations in licensed versions of therapeutic mAbs.

Evaluation of Four-Dimensional Computed Tomography as a Technique for Quantifying Carpal Motion.

Delayed diagnosis of dynamic carpal instability often occurs because early changes in bone alignment and movement are difficult to detect and manifest mainly during a dynamic/functional task. Current diagnostic tools are only able to examine the carpal bones under static or sequential-static conditions. Four-dimensional (three dimensions + time) computed tomography (4DCT) enables quantification of carpal mechanics through 3D volume sequences of the wrist in motion. A comprehensive understanding of carpal mechanics is needed to define normal function and structure and provide targets for treatment of carpal injuries. In this study, measurements of scaphoid translation and joint congruency were taken by creating models from the CT scans of the carpals in extreme frames of motion, registering those models to the neutral position, transforming the models into a local coordinate system, and using software to calculate the joint surface areas (JSA). Results indicated that the centroid of the scaphoid translated 6.4 ± 1.3 mm and extended from extreme radial to extreme ulnar deviation. Results are consistent with the literature. An additional study was performed to measure the responsiveness of the 4DCT technique presented. Bone models from each frame of motion for radio ulnar deviation (RUD) and flexion extension (FE) were created and distinct differences between their JSA were measured qualitatively and quantitatively. The results show that there was statistically significantly different JSA within carpal joints between RUD and FE. These studies provide the first step in developing the methodology when using 4DCT scanning to measure subtle abnormalities in the wrist.

Replicating extensive brain structural heterogeneity in individuals with schizophrenia and bipolar disorder.

Identifying brain processes involved in the risk and development of mental disorders is a major aim. We recently reported substantial interindividual heterogeneity in brain structural aberrations among patients with schizophrenia and bipolar disorder. Estimating the normative range of voxel‐based morphometry (VBM) data among healthy individuals using a Gaussian process regression (GPR) enables us to map individual deviations from the healthy range in unseen datasets. Here, we aim to replicate our previous results in two independent samples of patients with schizophrenia (n1 = 94; n2 = 105), bipolar disorder (n1 = 116; n2 = 61), and healthy individuals (n1 = 400; n2 = 312). In line with previous findings with exception of the cerebellum our results revealed robust group level differences between patients and healthy individuals, yet only a small proportion of patients with schizophrenia or bipolar disorder exhibited extreme negative deviations from normality in the same brain regions. These direct replications support that group level‐differences in brain structure disguise considerable individual differences in brain aberrations, with important implications for the interpretation and generalization of group‐level brain imaging findings to the individual with a mental disorder.

The Extreme Function Theory for Damage Detection: An Application to Civil and Aerospace Structures

Any damaged condition is a rare occurrence for mechanical systems, as it is very unlikely to be observed. Thus, it represents an extreme deviation from the median of its probability distribution. It is, therefore, necessary to apply proper statistical solutions, i.e., Rare Event Modelling (REM). The classic tool for this aim is the Extreme Value Theory (EVT), which deals with uni- or multivariate scalar values. The Extreme Function Theory (EFT), on the other hand, is defined by enlarging the fundamental EVT concepts to whole functions. When combined with Gaussian Process Regression (GPR), the EFT is perfectly suited for mode shape-based outlier detection. In fact, it is possible to investigate the structure’s normal modes as a whole rather than focusing on their constituent data points, with quantifiable advantages. This provides a useful tool for Structural Health Monitoring, especially to reduce false alarms. This recently proposed methodology is here tested and validated both numerically and experimentally for different examples coming from Civil and Aerospace Engineering applications. One-dimensional beamlike elements with several boundary conditions are considered, as well as a two-dimensional plate-like spar and a frame structure.

Anatectic granites in their source region: A comparison between experiments, thermodynamic modelling and nanogranitoids

Anatectic granites represent the products of crustal maturation by partial melting, therefore, studies on their origin are crucial to understanding how continental crust forms and evolves. This contribution compares composition of melts obtained from three tools allowing the investigation of anatectic granites in their source region: experiments, phase equilibria modelling and nanogranitoids. Benchmark experimental runs are selected along with nanogranitoids from the Ivrea–Verbano Zone (IVZ; NW Italy) and compositions of melt are then calculated using the same bulk rock compositions considered in experimental and natural case studies. The possible effects of melt loss, diverse P–T paths and variable equilibration volumes on melt composition are modeled for IVZ rocks. Results are then compared with those of previous comparative studies to verify the presence of systematic compositional divergences and similarities. Collectively, all data reflect pressure and temperature conditions (≈700–950 °C and 0.3–1.5 GPa) typical of the suprasolidus orogenic crust, with source regions ranging from metapelite, metagreywacke to metagranite.Contents of FeO, MgO, K2O and, to a lesser extent, CaO in the melt show the largest divergences. FeO, MgO and CaO tend to be enriched in experimental melts and nanogranitoids, whereas K2O is mostly overestimated in calculated melts.After a consideration of the common pitfalls for each approach we discuss the potential causes for the main geochemical discrepancies. The most extreme deviations of FeO and MgO, often observed in low-T (≤ 750 °C) melts, seem to be related to the selected melt models, which have been mostly calibrated on the basis of high-T (≥800 °C) experiments. Some experimental melts tend to be strongly depleted in K2O due to the metastable persistence of micas at much higher temperatures in laboratory runs, whereas the compositions of nanogranitoids in some investigated rocks may be partially controlled by diffusion in the melt. Disequilibrium melting of plagioclase may explain the CaO enrichment observed in some experimental and natural melts. When local equilibration volumes are considered in the calculations, a better match is observed for some oxides (e.g. FeO and MgO) between nanogranitoids and their calculated counterparts, even though other significant divergences remain unaffected. The combination of diverse petrologic tools, with proper recognition of their shortcomings, represent the best approach to shed light into the complexities of melting processes in nature which control the composition of anatectic granites at the source.

Quality of oxytocin and misoprostol in health facilities of Rwanda.

Sustainable Development Goal 3.1 calls for a reduction of the maternal mortality ratio to less than 70 per 100,000 live births by 2030. The most important cause of maternal mortality is post-partum haemorrhage (PPH). Oxytocin injections and misoprostol tablets are medicines of first choice for the management of PPH in low- and middle-income countries (LMICs). Unfortunately, both substances are chemically unstable, and previous studies have revealed serious quality problems of these medicines in LMICs. The present study is the first report on their quality in Rwanda. From 40 randomly selected health facilities (hospitals, health centers, retail pharmacies and private clinics) in different parts of Rwanda, as well as from six wholesalers and government stores, oxytocin injections and misoprostol tablets were collected. Oxytocin storage temperatures in the health facilities were monitored for six months using temperature data loggers, and found to correctly follow the storage requirements stated by the manufacturers (2–8°C, or room temperature) with few minor deviations. Oxytocin injections (57 samples, representing seven batches of four brands) were tested for their oxytocin content and pH value according to the United States Pharmacopeia. Twenty-four samples from three European manufacturers passed all tests. However, all nine samples of one batch of a Chinese manufacturer showed an excessive content of oxytocin (range 117.2–121.5% of the declared amount). Another batch of the same manufacturer showed extreme variations of the concentration of the preservative benzyl alcohol. Misoprostol tablets (25 samples, representing ten batches of six brands) were tested for content and dissolution according to the International Pharmacopoeia. Fifteen samples passed, but all 10 samples of two brands from India failed with extreme deviations, containing only 42.5–48.7% of the stated amount of misoprostol. In conclusion, oxytocin quality in Rwanda was better than reported from other African countries. However, two extremely substandard brands of misoprostol tablets were found. The Rwandan authorities reacted quickly and efficiently, and recalled these substandard medicines from the market. For oxytocin and misoprostol, with their well-known problems of quality and stability, procurement should possibly be restricted to medicines which are WHO-prequalified or which have been manufactured in countries with stringent regulatory authorities.

Criminalizing Migration

Abstract Beginning in the 1980s, the United States embarked on a decades-long restructuring of federal laws criminalizing migration and increasing the consequences for migrants engaging in criminal activity. Today, the results are clear: a law enforcement apparatus and immigration prison system propelled by a vast infrastructure of laws and policies. The presidency of Donald Trump augmented this trend and brought it to public attention. But lost in President Trump's unique flair is an ideological commitment shared by multiple presidential administrations and legislators from both major political parties to use the criminal justice system and imprisonment to sift migrants. Examining these ideological attachments reveals Trump-era policies to be the outer edge of decades-long trends rather than extreme and momentary deviations from the norm.

POST-IMPACT VIBRATIONS OF A SQUARE NONLINEAR DISPATIVE OSCILLATOR

An oscillator damped by viscous linear resistance, due to the instantaneous increase in its mass after impact, can become a dissipative oscillatory system under the action of dry or positional friction. In the article describes the oscillations of a dissipative oscillator with an asymmetric quadratically nonlinear elastic characteristic and dry Coulomb friction, arising as a result of an inelastic vertical impact of a rigid body on it. In the article, the Cox model is used, which does not take into account local deformations of solid bodies subjected to impact. The paper establishes the dependences on the impact velocity and the values of other parameters at which the effect of asymmetry of the elastic characteristic of the system may appear or may not appear. The conditions are derived when the dynamic effect of asymmetry of the power characteristic is manifested in the system. It consists in the fact that the maximum displacement of the oscillator (oscillation range) in the direction of the shock pulse is less than the opposite extreme displacement (range) after the shock oscillations. The existence of such a critical value of the shock impulse is established, the excess of which leads to the loss of motion stability. The second integral of the oscillation equation describes the movement of the oscillator in time, expressed in terms of Jacobi elliptic functions. An approximate formula for their calculation is proposed. Formulas are also derived to determine the time to reach extreme deviations of the system from the equilibrium position. This time is expressed in terms of elliptic integrals of the first kind, which refer to the tabulated functions. Examples of calculations are considered, where, in addition to using the derived formulas, numerical computer integration of the original nonlinear differential equation of motion is carried out. A comparison of the results obtained for the displacement values of a quadratically nonlinear oscillator with dry friction expressed in terms of Jacobi elliptic functions and obtained by numerical integration is carried out. Good consistency of the calculation results in two ways confirmed the adequacy of the obtained analytical solutions of the nonlinear Cauchy problem.

Quantifying performance of sheltered link-way facility in Singapore using human-centric indicators

ABSTRACT Pedestrian link-ways are important street facility for first-/last-mile mobility. This study compared pedestrians’ walking experiences on sheltered/unsheltered link-ways by collecting their perceived walking time/distance. It is found that, first, pedestrians (51 along sheltered and 49 along unsheltered link-ways) generally walk at a faster pace along unsheltered link-ways as compared to sheltered link-way. Second, participants are found to more likely over-perceive walking times and distances (with odds of three to one) along unsheltered link-way than sheltered link-way, and with more extreme deviations on unsheltered link-ways. Third, sheltered link-ways accrued better Level of Service (LOS) ratings on factors such as weather protection, distance, accessibility/user-friendliness, comfort, safety and level of crowdedness. The study demonstrates value-add application of cognitive bias approach for examining the walking experience, and provides human-centric indicators to justify the provision of shelters to the link-way for the benefits of pedestrian users.

Epigenome-wide associations between observed maternal sensitivity and offspring DNA methylation: a population-based prospective study in children.

Experimental work in animals has shown that DNA methylation (DNAm), an epigenetic mechanism regulating gene expression, is influenced by typical variation in maternal care. While emerging research in humans supports a similar association, studies to date have been limited to candidate gene and cross-sectional approaches, with a focus on extreme deviations in the caregiving environment. Here, we explored the prospective association between typical variation in maternal sensitivity and offspring epigenome-wide DNAm, in a population-based cohort of children (N = 235). Maternal sensitivity was observed when children were 3- and 4-years-old. DNAm, quantified with the Infinium 450 K array, was extracted at age 6 (whole blood). The influence of methylation quantitative trait loci (mQTLs), DNAm at birth (cord blood), and confounders (socioeconomic status, maternal psychopathology) was considered in follow-up analyses. Genome-wide significant associations between maternal sensitivity and offspring DNAm were observed at 13 regions (p < 1.06 × 10-07), but not at single sites. Follow-up analyses indicated that associations at these regions were in part related to genetic factors, confounders, and baseline DNAm levels at birth, as evidenced by the presence of mQTLs at five regions and estimate attenuations. Robust associations with maternal sensitivity were found at four regions, annotated to ZBTB22, TAPBP, ZBTB12, and DOCK4. These findings provide novel leads into the relationship between typical variation in maternal caregiving and offspring DNAm in humans, highlighting robust regions of associations, previously implicated in psychological and developmental problems, immune functioning, and stress responses.

Assessing the forcing level of air cooled diesel engine considering parameter spread of boosting system

Spread of parameter values of piston internal combustion engine boosting parts is normally due to extreme deviations (spread, error margin) of original parts and quality of assembly. Spread of relation of boosting pressure to counter pressure at outlet of turbo compressors Pk/Pt of the same type affects not only the engine parameters, but also thermal expansion of cylinder-piston group parts and cylinder head. At stable relation value of Pk/Pt, boosting pressure and maximal air flow, turbo compressor allows us to reduce the thermal factor of combustion chamber and cylinder head due to higher values of air excess ratios. This is very important, first of all for air cooled engine as in case of dramatic surge of its thermal factor we face a risk of cracks occurring in inter valve and inter valve- nozzle connectors of cylinder head fire bottom, cracking of setting bevels at valves of gas distribution mechanism. We analyzed the impact of technological spread of boosting details parameter on the value of achieved forcing limit. Impact analysis of technological spread of turbo compressor parameters on diesel engine performance was done on the basis of test results of ten B-400 engines, fitted with randomly selected pairs of TKP8,5-C7 turbo compressors out of a lot of 20 pieces. For each turbo compressor we determined preliminarily characteristics and efficiency factors nK, of turbine nT and of a unit as a whole n™.

Natural history of the electrical axis during the first four weeks of life

Abstract Background The QRS axis represents the sum of the amplitudes and orientation of the ventricular depolarization. In newborns, the QRS axis is generally directed downward and to the right and left axis deviation (LAD) may be associated with heart disease. Accurate interpretation of abnormalities in the QRS axis may facilitate early diagnosis of heart diseases in newborns. Purpose To describe the evolution of the QRS axis during the first four weeks of life and provide updated, digitalized, normal values from healthy newborns. Methods Electrocardiograms from 12,317 newborns (age 0–28 days) included in a regional, prospective, general population study from 2016–2018 were analyzed. Electrocardiograms were obtained and analyzed with a computerized algorithm with manual validation. The algorithm calculated the QRS mean axis using the net amplitudes of three leads I, II, and III. The four main QRS axis classifications were: “adult normal” axis (+1° to +90°), left axis deviation (LAD, 0° to −90°), right axis deviation (RAD, +91° to +180°), and extreme axis deviation (EAD, +181° to +270°). Echocardiograms were performed according to standard guidelines. Only newborns with an echocardiography excluding structural heart disease were included. Results Electrocardiograms from 12,317 newborns with a median age at examination of 12 days (52% boys) were included. The median QRS axis was 119° at the ages 0–7 days and shifted leftwards to 102° at the ages 22–28 days (p&amp;lt;0.001). We found that girls had significant less pronounced right axis deviation than boys (111° vs 117°, p&amp;lt;0.001) and that increasing gestational age was associated with more pronounced right axis deviation (104° vs 116°, p&amp;lt;0.05). Infant size did not affect the axis (p&amp;gt;0.05). Only 0.5% had LAD (0° to −90°) and 1.1% had an axis within the interval +240° to +30° indicating that a QRS axis in this expanded interval is unusual in healthy newborns. Conclusion The QRS axis showed a gradual leftward-shift during the first four weeks of life and was affected by sex and gestation age but unaffected by infant size. LAD occurred in only 0.5% of the newborns. Our data serve as updated reference values, which may facilitate clinical handling of newborns. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): This work was supported by the Danish Children Heart Foundation, Snedkermester Sophus Jacobsen and wife Astrid Jacobsen's foundation (Grant 19-R112-A5248-26048), the Research Council at Herlev-Gentofte Hospital and Toyota-Fonden, Denmark.

The Speed of Development of Adolescent Brain Age Depends on Sex and Is Genetically Determined.

Children and adolescents show high variability in brain development. Brain age—the estimated biological age of an individual brain—can be used to index developmental stage. In a longitudinal sample of adolescents (age 9–23 years), including monozygotic and dizygotic twins and their siblings, structural magnetic resonance imaging scans (N = 673) at 3 time points were acquired. Using brain morphology data of different types and at different spatial scales, brain age predictors were trained and validated. Differences in brain age between males and females were assessed and the heritability of individual variation in brain age gaps was calculated. On average, females were ahead of males by at most 1 year, but similar aging patterns were found for both sexes. The difference between brain age and chronological age was heritable, as was the change in brain age gap over time. In conclusion, females and males show similar developmental (“aging”) patterns but, on average, females pass through this development earlier. Reliable brain age predictors may be used to detect (extreme) deviations in developmental state of the brain early, possibly indicating aberrant development as a sign of risk of neurodevelopmental disorders.

Cosmic rates of black hole mergers and pair-instability supernovae from chemically homogeneous binary evolution

ABSTRACT During the first three observing runs of the Advanced gravitational-wave detector network, the LIGO/Virgo collaboration detected several black hole binary (BHBH) mergers. As the population of detected BHBH mergers grows, it will become possible to constrain different channels for their formation. Here we consider the chemically homogeneous evolution (CHE) channel in close binaries, by performing population synthesis simulations that combine realistic binary models with detailed cosmological calculations of the chemical and star-formation history of the Universe. This allows us to constrain population properties, as well as cosmological and aLIGO/aVirgo detection rates of BHBH mergers formed through this pathway. We predict a BHBH merger rate at redshift zero of $5.8 \textrm {Gpc}^{-3} \textrm {yr}^{-1}$ through the CHE channel, to be compared with aLIGO/aVirgo’s measured rate of ${53.2}_{-28.2}^{+55.8} \text{Gpc}^{-3}\text{yr}^{-1}$, and find that eventual merger systems have BH masses in the range $17{-}43 \,\textrm {M}_{\odot }$ below the pair-instability supernova (PISN) gap, and ${\gt}124 \textrm {M}_{\odot }$ above the PISN gap. We investigate effects of momentum kicks during black hole formation, and calculate cosmological and magnitude limited PISN rates. We also study the effects of high-redshift deviations in the star formation rate. We find that momentum kicks tend to increase delay times of BHBH systems, and our magnitude limited PISN rate estimates indicate that current deep surveys should be able to detect such events. Lastly, we find that our cosmological merger rate estimates change by at most ${\sim}8{{\ \rm per\ cent}}$ for mild deviations of the star formation rate in the early Universe, and by up to ${\sim}40\,\text{per cent}$ for extreme deviations.

Protocol concordance and impact of protocol deviations on selected outcomes in delivery of high-dose methotrexate in acute lymphoblastic leukemia in Sri Lanka.

17 Background: In Sri Lanka, children with acute lymphoblastic leukemia are treated on the UKALL 2011 protocol, which includes high-dose methotrexate (HDMTX) in high risk patients. Safe delivery of HDMTX is challenging in low resource settings, where deviation from accepted guidelines can occur frequently and result in toxicity, subsequent treatment delays, and in extreme cases, death. The goal of this study was to compare current practices to the treatment and supportive care details described in the protocol to identify the incidence and impact of guideline-discordant care to deliver HDMTX more safely children with cancer in Sri Lanka. Methods: We reviewed medical records to assess guideline concordance in 4 critical aspects of HDMTX delivery: 2 consecutive alkaline urine pH readings in the 2-hour period before starting HDMTX, 24-hour duration of MTX infusion (as opposed to early stop), the first dose of folinic acid administered later than 36 hours from start of HDMTX infusion (no inappropriately early rescue), and the administration of at least 3 folinic acid doses per course (appropriate duration of rescue). We analyzed how each deviation influenced AKI (creatinine increase of 0.3 mg/dL or more), infection, and treatment delays (defined as recovery delayed 7 days or longer from the 14 days expected between courses of HDMTX). Results: We analyzed 309 HDMTX courses in 91 patients younger than 20 years, including 105 girls (34%). In 83 courses (27%) alkaline urine was not documented prior to the start of MTX. Infusion time was less than 24 hours in 239 courses (77%), most of which finished 20-21 hours. In 37 courses (12%), the first folinic acid dose was given inappropriately early, and in 25 courses (8%) less than 3 doses of folinic acid were given. There were 2 episodes of AKI, 43 infections, 11 treatment delays and one death. None of the 4 guideline deviations were significantly associated with AKI or treatment delays. Patient sex was also not associated with any difference in guideline discordance or outcome (p&gt;0.1 in all cases). Conclusions: Significant deviations from HDMTX administration guidelines were common, especially early completion of infusion. However, outcomes were not impacted so quality standards may require adjustment to focus only on extreme deviations likely to impact patient outcomes.