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International audience; In this work, synchrotron radiation rocking curve imaging (RCI) is used to visualize and characterize dislocations and second-phase defects in a highly perfect and absorbing CdTe(Zn) crystal. This technique requires recording a series of Bragg diffracted images along the rocking curve to produce maps of the ‘local’ integrated intensity, full width at half-maximum and peak position. The diffraction conditions of the reported experiment are such that anomalous transmission (Borrmann effect) is a crucial ingredient for the formation of the image of the defects. The images recorded and maps produced allow the investigation of a series of topics that, to the authors’ knowledge, have not been previously studied. The first of these topics is the variation of the position and width of the Borrmann image of a defect when sitting on the peak and on the flanks of the diffraction curve. The second topic is the way Borrmann imagesshow up on the usual RCI maps. The final topic is the combination of Borrmannand weak-beam images to infer the depth of the defect within the crystal.

Background: It is unclear whether patients with asthma benefit from stepping up to high-dose inhaled corticosteroids (ICSs). Objective: To determine the effectiveness of stepping up to high-dose ICSs. Methods: A historic cohort study of patients with asthma (≥13 years old), identified from 2 large UK electronic medical record databases, was conducted. Patients who remained on medium-dose ICSs were compared with those who stepped up from medium- to high-dose ICSs, whereas patients who stepped up from low- to medium-dose ICSs were compared with those who stepped up from low- to high-dose ICSs. Time to first severe exacerbation (primary outcome) between treatment groups was compared using multivariable Cox proportional hazards models, and the number of exacerbations and antibiotics courses was analyzed using negative binomial regression. Inverse probability of treatment weighting was used to handle confounding. Results: The mean follow-up time to first exacerbation was 2.7 ± 2.7 years for those who remained on stable medium-dose ICSs and 2.0 ± 2.2 years for those who stepped up from medium- to high-dose ICSs. A similar pattern was noted for those who stepped up from low- to medium-dose ICSs (2.6 ± 2.5 years) and from low- to high-dose ICSs (2.3 ± 2.5 years). Patients who stepped up from medium- to high-dose ICSs (n = 6879) had a higher risk of exacerbations during follow-up compared with those who remained on medium-dose ICSs (n = 51,737; hazard ratio, 1.17; 95% CI, 1.12-1.22). This was similar in patients stepping up from low- to high-dose (n = 3232) compared with low- to medium-dose (n = 12,659) ICSs (hazard ratio, 1.10; 95% CI, 1.04-1.17). A step-up to high-dose ICSs was also associated with a higher number of asthma exacerbations and antibiotics courses. No significant difference in associations was found across subgroups of patients with different blood eosinophil counts. Conclusions: We found no evidence that a step-up to high-dose ICSs is effective in preventing future asthma exacerbations.

There is an urgent need, accelerated by the COVID-19 pandemic, for methods that allow clinicians and neuroscientists to remotely evaluate hand movements. This would help detect and monitor degenerative brain disorders that are particularly prevalent in older adults. With the wide accessibility of computer cameras, a vision-based real-time hand gesture detection method would facilitate online assessments in home and clinical settings. However, motion blur is one of the most challenging problems in the fast-moving hands data collection. The objective of this study was to develop a computer vision-based method that accurately detects older adults' hand gestures using video data collected in real-life settings. We invited adults over 50 years old to complete validated hand movement tests (fast finger tapping and hand opening-closing) at home or in clinic. Data were collected without researcher supervision via a website programme using standard laptop and desktop cameras. We processed and labelled images, split the data into training, validation and testing, respectively, and then analysed how well different network structures detected hand gestures. We recruited 1,900 adults (age range 50-90 years) as part of the TAS Test project and developed UTAS7k-a new dataset of 7071 hand gesture images, split 4:1 into clear: motion-blurred images. Our new network, RGRNet, achieved 0.782 mean average precision (mAP) on clear images, outperforming the state-of-the-art network structure (YOLOV5-P6, mAP 0.776), and mAP 0.771 on blurred images. A new robust real-time automated network that detects static gestures from a single camera, RGRNet, and a new database comprising the largest range of individual hands, UTAS7k, both show strong potential for medical and research applications.The online version contains supplementary material available at 10.1007/s00521-022-08090-8.

Children with congenital heart disease (CHD) often experience feeding intolerance due to aspiration, inability to tolerate feed volume, or reflux within the first few months of life, requiring a surgically placed gastrostomy tube (GT) for durable enteral access. However, complications such as GT dislodgement, cellulitis, and leakage related to GT use are common. GT-related complications can lead to unscheduled pediatric surgery clinic or emergency room (ER) visits, which can be time consuming for the family and increase overall healthcare costs. We sought to identify factors associated with GT complications within 2 wk after GT surgery and 1-y after discharge home following GT placement in infants with CHD.We performed a retrospective cohort study using the Society of Thoracic Surgeons database and electronic medical records from a tertiary children's hospital. We identified infants1 y old underwent CHD surgery followed by GT surgery between September 2013-August 2018. Demographics, pre-operative feeding regimen, comorbidities, and GT-related utilization were measured. Postoperative GT complications (e.g., GT cellulitis, leakage, dislodgement, obstruction, and granulation tissue) within 2 wk after the GT surgery and an unplanned pediatric surgery clinic or ER visit within 1-y after discharge home were captured. Bivariate comparisons and multivariable logistic regression evaluated factors associated with GT complications and unplanned clinic or ER visits. A Kaplan-Meier failure curve examined the timing of ER/clinic visits.Of 152 infants who underwent CHD then GT surgeries, 66% (N = 101) had postoperative GT complications. Overall, 83 unscheduled clinic visits were identified after discharge, with 37% (N = 31) due to concerns about granulation tissue. Of 137 ER visits, 48% (N = 66) were due to accidental GT dislodgement. Infants who were hospitalized for ≥2 wk after GT surgery had more complications than those discharged home within 2 wk of the GT surgery (40.6% versus 15.7%, P = 0.002). Infants receiving oral nutrition before CHD surgery (38.6% versus 60%, P=0.001) or with single ventricle defects (19.8% versus 37.3%, P = 0.02) had fewer GT complications. After adjusting for type of cardiac anomaly, infants receiving oral nutrition prior to CHD surgery had a decreased likelihood of GT complications (odds ratio OR 0.46; 95% confidence intervals CI:0.23-0.93). A Kaplan-Meier failure curve demonstrated that 50% of the cohort experienced a complication leading to an unscheduled ER/clinic visit within 6 mo after discharge.Unplanned visits to the ER or pediatric surgery clinic occur frequently for infants with CHD requiring a surgically placed GT. Oral feedings before cardiac surgery associated with fewer GT complications. Prolonged hospitalization associated with more GT complications. Optimizing outpatient care and family education regarding GT maintenance may reduce unscheduled visits for this high-risk, device-dependent infant population.

Catalytic transformations involving Pd(0)/Pd(II) catalytic cycles are very well known, and processes involving high-valent Pd(III) and Pd(IV) and low-valent Pd(I) intermediates have also gained interest in recent years. Although low-valent Pd(I) intermediates are proposed in these catalytic cycles, isolated and characterized mononuclear Pd(I) species are very rare. Herein, we report the isolation of two heteroleptic mononuclear Pd(I) complexes stabilized by dithiapyridinophane ligands that were fully characterized by single-crystal X-ray diffraction; EPR, IR, UV-vis spectroscopies; and computational studies. Excitingly, one of these Pd(I) complexes shows Kumada Csp

Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions. Significance: We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations. This article is highlighted in the In This Issue feature, p. 2483

A palladium-catalyzed Heck reaction between 2-oxyacrylates and aryl bromides was developed, where DavePhos was a unique ligand that efficiently promoted the reaction. The products, 2-oxycinnamates, served as excellent precursors, providing synthetically useful monoaryl pyruvates or ortho ester-protected monoaryl pyruvates depending on the nature of the 2-oxy group. The formation of such ortho esters via alkoxide addition is novel, and computational studies identified a plausible mechanism with an oxyallyl zwitterion as the key intermediate.

Previously, we showed that extracellular matrices (ECMs), produced ex vivo by various types of stromal cells, direct bone marrow mesenchymal stem cells (BM-MSCs) in a tissue-specific manner and recapitulate physiologic changes characteristic of the aging microenvironment. In particular, BM-MSCs obtained from elderly donors and cultured on ECM produced by young BM stromal cells showed improved quantity, quality and osteogenic differentiation. In the present study, we searched for matrix components that are required for a functional BM-MSC niche by comparing ECMs produced by BM stromal cells from "young" (≤25 y/o) versus "elderly" (≥60 y/o) donors. With increasing donor age, ECM fibrillar organization and mechanical integrity deteriorated, along with the ability to promote BM-MSC proliferation and responsiveness to growth factors. Proteomic analyses revealed that the matricellular protein, Cyr61/CCN1, was present in young, but undetectable in elderly, BM-ECM. To assess the role of Cyr61 in the BM-MSC niche, we used genetic methods to down-regulate the incorporation of Cyr61 during production of young ECM and up-regulate its incorporation in elderly ECM. The results showed that Cyr61-depleted young ECM lost the ability to promote BM-MSC proliferation and growth factor responsiveness. However, up-regulating the incorporation of Cyr61 during synthesis of elderly ECM restored its ability to support BM-MSC responsiveness to osteogenic factors such as BMP-2 and IGF-1. We next examined aging bone and compared bone mineral density and Cyr61 content of L4-L5 vertebral bodies in "young" (9-11 m/o) and "elderly" (21-33 m/o) mice. Our analyses showed that low bone mineral density was associated with decreased amounts of Cyr61 in osseous tissue of elderly versus young mice. Our results strongly demonstrate a novel role for ECM-bound Cyr61 in the BM-MSC niche, where it is responsible for retention of BM-MSC proliferation and growth factor responsiveness, while depletion of Cyr61 from the BM niche contributes to an aging-related dysregulation of BM-MSCs. Our results also suggest new potential therapeutic targets for treating age-related bone loss by restoring specific ECM components to the stem cell niche.

Inferring past demographic history of natural populations from genomic data is of central concern in many studies across research fields. Previously, our group had developed dadi, a widely used demographic history inference method based on the allele frequency spectrum (AFS) and maximum likelihood optimization. However, dadi’s maximum likelihood optimization procedure is computationally expensive. Here, we developed donni (demography optimization via neural network inference), a new inference method based on dadi that is more efficient while maintaining comparable inference accuracy. For each dadi-supported demographic model, donni simulates the expected AFS and trains a multilayer perceptron algorithm to infer the model parameters from input AFS. We demonstrated that for many demographic models, donni can infer some parameters, such as population size changes and inbreeding coefficients, very well (ρ ≈0.9) and other parameters, such as migration rates and times of demographic events, fairly well (ρ ≈0.6−0.7). Importantly, donni provides parameter inference instantaneously from input AFS, with accuracy comparable to parameters inferred by dadi’s likelihood optimization while bypassing its long and computationally intensive evaluation process. Donni’s performance demonstrates that supervised machine learning algorithms may be a promising avenue for developing more sustainable and computationally efficient demographic history inference methods.

The most common reason for dissatisfaction and reoperation in lower blepharoplasty patients is persistent bulging of the lateral fat pad. This compartment contributes the most to fat herniation and yet is the most commonly overlooked. The addition of a septal window, a small opening of the septum on the most prominent part of the lateral fat compartment, helps with precise removal of lateral fat and allows for additional fat excision after septal reset without disrupting the arcuate expansion.Our lower blepharoplasty approach includes 1) a subcilliary incision; 2) aggressive lateral fat excision through a septal window; 3) central and medial fat excision, transposition, and septal reset; 4) canthopexy; 5) orbicularis oculi muscle suspension; and 6) no dissection of orbicularis oculi medially and no skin resected medially to avoid lid retraction. We performed a retrospective review of all lower blepharoplasty cases by a single surgeon over 10 years. Demographics and operative outcomes were queried.There were 224 cases, 90% were women with a mean age of 58.2 years. The most common postoperative occurrences were eyelid edema, malar edema, and chemosis, all of which were self-limiting. Two patients needed additional removal of lateral fat of their lower eyelids.Two patients had lid retraction, one of which had a previous facial nerve palsy and the other did not have a canthopexy and developed transient unilateral lid retraction that resolved with conservative treatment. Resumption of full activities and exercises at 6 weeks was typical.The septal window facilitates aggressive resection of the lateral fat pad and additional fat excision after septal reset to create a smooth lid-cheek junction. In our practice, it is a critical component of a successful lower blepharoplasty.

Congenital heart disease (CHD) is a common birth defect in the United States. CHD infants are more likely to have smaller head circumference and neurodevelopmental delays; however, the cause is unknown. Altered cerebrovascular hemodynamics may contribute to neurologic abnormalities, such as smaller head circumference, thus we created a novel Cerebrovascular Stability Index (CSI), as a surrogate for cerebral autoregulation. We hypothesized that CHD infants would have an association between CSI and head circumference. We performed a prospective, longitudinal study in CHD infants and healthy controls. We measured CSI and head circumference at 4 time points (newborn, 3, 6, 9 months). We calculated CSI by subtracting the average 2-min sitting from supine cerebral oxygenation (rcSO(2)) over three consecutive tilts (0–90°), then averaged the change score for each age. Linear regressions quantified the relationship between CSI and head circumference. We performed 177 assessments in total (80 healthy controls, 97 CHD infants). The average head circumference was smaller in CHD infants (39.2 cm) compared to healthy controls (41.6 cm) (p < 0.001) and head circumference increased by 0.27 cm as CSI improved in the sample (p = 0.04) overall when combining all time points. Similarly, head circumference increased by 0.32 cm as CSI improved among CHD infants (p = 0.04). We found CSI significantly associated with head circumference in our sample overall and CHD infants alone, which suggests that impaired CSI may affect brain size in CHD infants. Future studies are needed to better understand the mechanism of interaction between CSI and brain growth.

In this paper, one of the very first 800V Fuel Cell DC-DC Converter (FDC) is developed for the next generation FCEV. The higher boost gain ratio and switching loss associated with increasing dc-link voltage, along with gradually increasing power density and efficiency demanded in the next generation EV power converters, make the conventional boost converter not suitable for 800V FDC. This paper proposes a new design approach in which a ZVT high step-up Dual Floating Output Boost Converter (DFOBC) is introduced. Due to higher voltage gain, the operating duty cycle of DFOBC is reduced and lies in the vicinity of D = 0.5, which reduces filter size. The ZVT cells greatly reduce switching losses at 300kHz, which enables using only a single discrete SiC mosfet for the main switch of 25kW module, contributing to volume and cost reduction. Moreover, the proposed converter successfully demonstrates the possibility of using planar core and PCB windings at 100kW power level, which is rarely seen in the previous works. Finally, a 25kW prototype of the proposed ZVT DFOBC is built and test. The power density of 63kW/L excluding heatsink is achieved. The peak and full-load efficiency are measured to be 99.0% and 97.7%, respectively.

BackgroundPrescription of three or more short-acting β2-agonist (SABA) canisters per year in adult and adolescent asthma populations is associated with a risk of severe exacerbations; however, evidence in children aged MethodsThis study analysed data on children and adolescents with asthma in three age cohorts: 1‒5 years, 6‒11 years and 12‒17 years from the Clinical Practice Research Datalink Aurum database for the period 1 January 2007 to 31 December 2019. Associations between SABA prescriptions (three or moreversusfewer than three canisters per year) at baseline, defined as 6 months after an asthma diagnosis as a binary exposure variable, and the rate of future asthma exacerbations, defined as oral corticosteroid burst therapy, an emergency department visit or hospital admission, were assessed by multilevel negative binomial regression, adjusted for relevant demographic and clinical confounders.ResultsOverall 48 560, 110 091 and 111 891 paediatric patients with asthma were aged 1‒5, 6‒11 and 12‒17 years, respectively. During the baseline period, 22 423 (46.2%), 42 137 (38.3%) and 40 288 (36.0%) in these three age cohorts, respectively, were prescribed three or more SABA canisters per year. Across all age ranges, the rate of future asthma exacerbations in those prescribed three or moreversusfewer than three SABA canisters per year was at least two-fold higher. >30% of patients across all age cohorts were not prescribed inhaled corticosteroids (ICS), and the median proportion of days covered was only 33%, suggesting inadequate prescribing of ICSConclusionIn children, higher SABA prescriptions at baseline were associated with increased future exacerbation rates. These findings highlight the need for monitoring prescription of three or more SABA canisters per year to identify children with asthma at risk of exacerbations.

Background The prognosis for patients with pediatric high-grade glioma (pHGG) is poor despite aggressive multimodal therapy. Objective responses to targeted therapy with BRAF inhibitors have been reported in some patients with recurrent BRAF-mutant pHGG but are rarely sustained. Methods We performed a retrospective, multi-institutional review of patients with BRAF-mutant pHGG treated with off-label BRAF +/– MEK inhibitors as part of their initial therapy. Results Nineteen patients were identified, with a median age of 11.7 years (range, 2.3–21.4). Histologic diagnoses included HGG (n = 6), glioblastoma (n = 3), anaplastic ganglioglioma (n = 4), diffuse midline glioma (n = 3), high-grade neuroepithelial tumor (n = 1), anaplastic astrocytoma (n = 1), and anaplastic astroblastoma (n = 1). Recurrent concomitant oncogenic alterations included CDKN2A/B loss, H3 K27M, as well as mutations in ATRX, EGFR, and TERT. Eight patients received BRAF inhibitor monotherapy. Eleven patients received combination therapy with BRAF and MEK inhibitors. Most patients tolerated long-term treatment well with no grade 4–5 toxicities. Objective and durable imaging responses were seen in the majority of patients with measurable disease. At a median follow-up of 2.3 years (range, 0.3–6.5), three-year progression-free and overall survival for the cohort were 65% and 82%, respectively, and superior to a historical control cohort of BRAF-mutant pHGG patients treated with conventional therapies. Conclusions Upfront targeted therapy for patients with BRAF-mutant pHGG is feasible and effective, with superior clinical outcomes compared to historical data. This promising treatment paradigm is currently being evaluated prospectively in the Children’s Oncology Group ACNS1723 clinical trial.

Supplementary Figure from Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort

Accurate ancestry inference is critical for identifying genetic contributors of cancer disparities among populations. Although methods to infer genetic ancestry have historically relied upon genome-wide markers, the adaptation to targeted clinical sequencing panels presents an opportunity to incorporate ancestry inference into routine diagnostic workflows. We show that global ancestral contributions and admixture of continental populations can be quantitatively inferred using markers captured by the MSK-IMPACT clinical panel. In a pan-cancer cohort of 45,157 patients, we observed differences by ancestry in the frequency of somatic alterations, recapitulating known associations and revealing novel associations. Despite the comparable overall prevalence of driver alterations by ancestry group, the proportion of patients with clinically actionable alterations was lower for African (30%) compared with European (33%) ancestry. Although this result is largely explained by population-specific cancer subtype differences, it reveals an inequity in the degree to which different populations are served by existing precision oncology interventions.Significance:We performed a comprehensive analysis of ancestral associations with somatic mutations in a real-world pan-cancer cohort, including >5,000 non-European individuals. Using an FDA-authorized tumor sequencing panel and an FDA-recognized oncology knowledge base, we detected differences in the prevalence of clinically actionable alterations, potentially contributing to health care disparities affecting underrepresented populations.This article is highlighted in the In This Issue feature, p. 2483

Supplementary Data from Genetic Ancestry Correlates with Somatic Differences in a Real-World Clinical Cancer Sequencing Cohort