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Introduction: Kalmegh (Andrographis paniculata) is commonly used for treating uncomplicated Upper Respiratory Tract Infection (URTI) in complementary and alternative system of medicine. AP-Bio®(KalmCold®) is a standardized extract derived from the leaves of A. paniculata. This study was proposed to evaluate its efficacy using validated scales and objective measures. Methods: Participants were randomized in a ratio of 1:1:1 to receive either AP-Bio® 200 mg/day, AP-Bio® 400 mg/day or placebo for 7 days. The primary outcome measure was Wisconsin Upper Respiratory Symptom Survey (WURSS-21) score. The secondary outcome measures were nasal mucous weight, nasal muco-ciliary clearance function and Interleukin-8 in nasal wash, as well as safety and tolerability. Results: A total of n = 331 participants were screened and N = 300 participants were enrolled. The absolute WURSS-21 global score [mean (Standard Deviation - SD)] in the AP-Bio® 400 mg group [5.70 (5.31)] was less than the AP-Bio® 200 mg group [5.81 (4.83)] on Day-3. However, it was much higher in the placebo group [9.55 (14.27)]. AP-Bio® 400 mg group (Mean Difference - MD [Standard Error - SE] = −3.85 [1.52]; 95% CI = −6.85, - 0.85; adjusted p = 0.034) and 200 mg group (MD [SE] = −3.74 [1.51]; 95% CI = −6.73, - 0.76; adjusted p = 0.038) had significantly lower score than placebo. Similarly, on Day-3, the change in global score from baseline was significantly better in the AP-Bio® 400 mg group (MD [SE] = −3.91; [1.82] 95% CI = −7.50, - 0.32; adjusted p = 0.038) and AP-Bio® 200 mg group (MD [SE] = −3.84 [1.97]; 95% CI = −7.72, - 0.04; adjusted p = 0.044) in comparison to the placebo group. Nasal mucous weight, tissue paper counts used, and interleukin-8 showed a trend towards AP-Bio® groups having a favourable outcome when compared with placebo but did not reach statistical significance due to a small sample size. None of the study participants complained of any adverse physical symptoms. However, incident eosinophilia was noted in n = 20 participants on day 3. (n = 6 in AP-Bio® 200 mg group, n = 7 in Ap-Bio® 400 mg group and n = 13 in placebo group; p = 0.181). Conclusions: Participants in both the AP-Bio® dose groups showed positive tendency towards resolution of URTI symptoms when compared with placebo on Day-3 but not on Day-5 and Day-7.

Purpose: Spinal cord delineation is critical to the delivery of stereotactic body radiation therapy (SBRT). Although underestimating the spinal cord can lead to irreversible myelopathy, overestimating the spinal cord may compromise the planning target volume coverage. We compare spinal cord contours based on computed tomography (CT) simulation with a myelogram to spinal cord contours based on fused axial T2 magnetic resonance imaging (MRI). Methods and Materials: Eight patients with 9 spinal metastases treated with spinal SBRT were contoured by 8 radiation oncologists, neurosurgeons, and physicists, with spinal cord definition based on (1) fused axial T2 MRI and (2) CT-myelogram simulation images, yielding 72 sets of spinal cord contours. The spinal cord volume was contoured at the target vertebral body volume based on both images. The mixed-effect model assessed comparisons of T2 MRI- to myelogram-defined spinal cord in centroid deviations (deviations in the center point of the cord) through the vertebral body target volume, spinal cord volumes, and maximum doses (0.035 cc point) to the spinal cord applying the patient's SBRT treatment plan, in addition to in-between and within-subject variabilities. Results: The estimate for the fixed effect from the mixed model showed that the mean difference between 72 CT volumes and 72 MRI volumes was 0.06 cc and was not statistically significant (95% confidence interval, –0.034, 0.153; P = .1832). The mixed model showed that the mean dose at 0.035 cc for CT-defined spinal cord contours was 1.24 Gy lower than that of MRI-defined spinal cord contours and was statistically significant (95% confidence interval, –2.292, –0.180; P = .0271). Also, the mixed model indicated no statistical significance for deviations in any of the axes between MRI-defined spinal cord contours and CT-defined spinal cord contours. Conclusions: CT myelogram may not be required when MRI imaging is feasible, although uncertainty at the cord-to-treatment volume interface may result in overcontouring and hence higher estimated cord dose-maximums with axial T2 MRI-based cord definition.

Glioblastomas are among the deadliest human cancers and are highly vascularized. Angiogenesis is dynamic during brain development, almost quiescent in the adult brain but reactivated in vascular-dependent CNS pathologies, including brain tumors. The oncofetal axis describes the reactivation of fetal programs in tumors, but its relevance in endothelial and perivascular cells of the human brain vasculature in glial brain tumors is unexplored. Nucleolin is a regulator of cell proliferation and angiogenesis, but its roles in the brain vasculature remain unknown. Here, we studied the expression of Nucleolin in the neurovascular unit in human fetal brains, adult brains, and human gliomas in vivo as well as its effects on sprouting angiogenesis and endothelial metabolism in vitro. Nucleolin is highly expressed in endothelial and perivascular cells during brain development, downregulated in the adult brain, and upregulated in glioma. Moreover, Nucleolin expression correlated with glioma malignancy in vivo. In culture, siRNA-mediated Nucleolin knockdown reduced human brain endothelial cell (HCMEC) and HUVEC sprouting angiogenesis, proliferation, filopodia extension, and glucose metabolism. Furthermore, inhibition of Nucleolin with the aptamer AS1411 decreased brain endothelial cell proliferation in vitro. Mechanistically, Nucleolin knockdown in HCMECs and HUVECs uncovered regulation of angiogenesis involving VEGFR2 and of endothelial glycolysis. These findings identify Nucleolin as a neurodevelopmental factor reactivated in glioma that promotes sprouting angiogenesis and endothelial metabolism, characterizing Nucleolin as an oncofetal protein. Our findings have potential implications in the therapeutic targeting of glioma.

Background: People living with chronic kidney disease (CKD) have been disproportionately affected by the coronavirus disease 2019 (COVID-19) pandemic, including higher rates of infection, hospitalization, and death. Data on responsiveness to COVID-19 vaccination strategies and immunogenicity are limited, yet required to inform vaccination strategies in this at-risk population. Objective: The objective of this study is to characterize the longitudinal serologic response to COVID-19 vaccination. Design: This is a prospective observational cohort study. Setting: Participating outpatient kidney programs within Ontario and British Columbia. Patients: Up to 2500 participants with CKD G3b-5D receiving COVID-19 vaccination, including participants receiving dialysis and kidney transplant recipients (CKD G1T-5T). Measurements: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) IgG antibodies (anti-spike, anti-receptor binding domain, anti-nucleocapsid) will be detected by ELISA (enzyme-linked immunosorbent assay) from serum or dried blood spot testing. In a subset of participants, neutralizing antibodies against novel variants of concern will be evaluated. Peripheral blood mononuclear cells will be collected for exploratory immune profiling of SARS-CoV-2 specific cellular immunity. Methods: Participants will be recruited prior to or following any COVID-19 vaccine dose and have blood sampled for serological testing at multiple timepoints: 1, 3, 6, 9, and 12 months post vaccination. When possible, samples will be collected prior to a dose or booster. Participants will remain in the study for at least 1 year following their last COVID-19 vaccine dose. Strengths and limitations: The adaptive design of this study allows for planned modification based on emerging evidence or rapid changes in public health policy surrounding vaccination. Limitations include incomplete earlier timepoints for blood collection due to rapid vaccination of the population. Conclusions: This large multicenter serologic study of participants living with kidney disease will generate data on the kinetics of SARS-CoV-2 immune response to vaccination across the spectrum of CKD, providing insights into the amplitude and duration of immunity conferred by COVID-19 vaccination and allowing for characterization of factors associated with immune response. The results of this study may be used to inform immunization guidelines and public health recommendations for the 4 million Canadians living with CKD.

Introduction A 43‐year‐old male with no known past medical history presented to a primary stroke center for sudden onset headache, nausea, vomiting, and dizziness while driving. A computed tomography angiogram of the head and neck revealed a left vertebral artery occlusion, and the patient was transferred to our comprehensive stroke center for further evaluation and treatment. Upon arrival at our facility, the patient was noted to have a national institute of health stroke scale score of 7 with left facial droop, dysarthria, and right upper extremity dysmetria. A cerebral angiogram revealed a tortuous left vertebral artery with dissection in the V4 segment. Subsequent brain diffusion weighted imaging revealed an acute infarct in the right lateral medulla measuring 1.4cm and several acute cerebellar infarcts. (fig. 1) In the postangiography period, the patient had dysphagia, sialorrhea, multiple aspiration episodes, and oral secretions requiring early tracheostomy and percutaneous endoscopic gastrostomy on hospital day (HD) #6. The subsequent hospital course was complicated by prolonged singultus lasting until HD #23 and repetitive vomiting requiring a transition from a gastric to a gastro‐jejunal feeding tube. Methods A central hypoventilation syndrome (CHS) prolonged ventilator weaning. Despite preserved ability to take large‐volume voluntary breaths, the patient experienced multiple episodes of sleep‐associated apnea and rapid shallow breathing pattern during daily spontaneous breathing trials (SBT). The apnea episodes were registered with ventilator apnea alarms set at 20 seconds. This pattern continued when attempting an SBT utilizing a T‐piece adaptor. The ability to maintain adequate minute ventilation in an asleep state subsequently improved, and the patient was able to tolerate 48 hours of spontaneous breathing with no apnea on HD #35. Results Few cases of CHS secondary to lateral medullary infarction (LMI) have been documented in the literature.(1‐3) As the respiratory drive originates from neurons in the latero‐rostro‐ventral medulla, infarcts in this brainstem region may lead to respiratory failure. More specifically to our patient, ataxic breathing may result from lesions in the rostro‐ventral medulla with yawning and hiccups being seen in lesions to the posterolateral medulla.(4) As our patient presented with a sizable 1.4cm lesion, likely impairing these brainstem centers, it is expected that his symptoms would account for multiple respiratory symptoms. The unique feature of the acquired CHS in the setting of LMI is its unilateral location implying lateralization of the respiratory control. In addition to the aforementioned symptoms, his lesion likely led to prolonged weaning from the ventilator as has been described previously.(5) Conclusions This case raises awareness regarding potentially disastrous complications of the lateral medullary syndrome like central hypoventilation syndrome. We urge caution and careful evaluation of patients with lateral medullary infarctions for disorders of the respiratory control system.

IntroductionOptimal anticoagulation therapy is essential for the prevention of thrombotic and hemorrhagic complications in pediatric patients supported with extracorporeal membrane oxygenation (ECMO). Recent data have demonstrated bivalirudin has the potential to surpass and replace heparin as the anticoagulant of choice.MethodsWe conducted a systematic review comparing the outcomes of heparin-based versus bivalirudin-based anticoagulation in pediatric patients supported on ECMO to identify the preferred anticoagulant to minimize bleeding events, thrombotic complications, and associated mortality. We referenced the PubMed, Cochrane Library, and Embase databases. These databases were searched from inception through October 2022. Our initial search identified 422 studies. All records were screened by two independent reviewers using the Covidence software for adherence to our inclusion criteria, and seven retrospective cohort studies were identified as appropriate for inclusion.ResultsIn total, 196 pediatric patients were anticoagulated with heparin and 117 were anticoagulated with bivalirudin while on ECMO. Across the included studies, it was found that for patients treated with bivalirudin, trends were noted toward lower rates of bleeding, transfusion requirements, and thrombosis with no difference in mortality. Overall costs associated with bivalirudin therapy were lower. Time to therapeutic anticoagulation varied between studies though institutions had different anticoagulation targets.ConclusionBivalirudin may be a safe, cost-effective alternative to heparin in achieving anticoagulation in pediatric ECMO patients. Prospective multicenter studies and randomized control trials with standard anticoagulation targets are needed to accurately compare outcomes associated with heparin versus bivalirudin in pediatric ECMO patients.

Introduction: Abdominal Aortic Aneurysm (AAA) is a highly morbid condition and is the 11th leading cause of death in the United States. Treatment options are limited to operative interventions, with minimal non-operative options. Prior literature has demonstrated a benefit to the use of mesenchymal stem cells (MSCs) in attenuating AAA formation. We demonstrate the utility of MSCs in treating AAA in swine, focusing on the mechanical and structural characteristics of aortic tissue after treatment. Methods: 16 Yorkshire pigs underwent retroperitoneal exposure of the infrarenal aorta, with subsequent induction of AAA with peri-adventitial elastase and collagenase. A 1 × 4 cm piece of Gelfoam, an absorbable gelatin-based hemostatic agent, was soaked in media or human MSCs and placed directly on the vessel for control and experimental animals. At postoperative day 21, animals were sacrificed and the infrarenal aorta at this location was harvested for analysis. Tensile strength was measured using a tensiometer, from which Young's modulus and maximum strain were calculated. Results: All animals survived the surgery and post-operative course. Young's elastic modulus for the aneurysm control group was 15.83 ± 1.61 compared to 22.13 ± 2.34 for the stem cell treated segment, p = 0.0316. There was no significant difference in the peak stress between groups. Conclusions: This is the first study to demonstrate the mechanical effects of stem cell therapy on a model of AAA in swine. Young's modulus, which characterizes the intrinsic capacity of a tissue to withstand stress, was greater in the animals treated with MSCs compared to control animals with aneurysms. This methodology can be utilized in future large animal models to develop cell and drug-based therapies for AAA.

Purpose:: Pregnancy has been associated with long-term lower urinary tract symptoms such as nocturia. The purpose of this study was to explore potential associations between delivery modality and fetal size during pregnancy and the presence of nocturia. Materials and Methods:: Using the National Health and Nutrition Examination Survey (NHANES) database from 2005/06-2017/18, we categorized females by status of prior delivery modalities: nulligravida, vaginal deliveries, and cesarean deliveries. Groups were weighed and case-control matched for age, race, BMI, and number of deliveries. The association of delivery modality and fetal size (≥9 pounds or

This article extends the application of an existing change-detection-based, time-series soil moisture retrieval algorithm to nonconcurrent active and passive measurements from WindSat/AMSR2 and the Soil Moisture Active Passive radar, which was active from late April until mid-July of 2015. A time series of L-band radar backscatter observations was used to populate an underdetermined matrix equation whose optimal solution was derived via a bounded linear least squares estimator, and whose bounds were derived from a time series of radiometer-derived soil moisture estimates (taken by either WindSat or AMSR2). Surface soil moisture estimates are compared with in-situ measurement probes, which were treated as ground truth. Error statistics and time-series results for the validation sites are presented here and conclusions derived therefrom. The overall RMSE and unbiased RMSE for the retrieval algorithm, taken across all reference pixels considered in the study, were 0.070 $\mathbf{m}^{3}/\mathbf{m}^{3}$ and 0.067 $\mathbf{m}^{3}/\mathbf{m}^{3}$, respectively, when using WindSat to constrain the algorithm. When using AMSR2 to constrain the algorithm, the RMSE and unbiased RMSE were 0.093 $\mathbf{m}^{3}/\mathbf{m}^{3}$ and 0.090 $\mathbf{m}^{3}/\mathbf{m}^{3}$, respectively.

IntroductionNot all patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection develop symptomatic coronavirus disease 2019 (COVID-19), making it challenging to assess the burden of COVID-19-related hospitalizations and mortality. We aimed to determine the proportion, resource utilization, and outcomes of SARS-CoV-2 positive patients admitted for COVID-19, and assess the impact of using the Center for Disease Control's (CDC) discharge diagnosis-based algorithm and the Massachusetts state department's drug administration-based classification system on identifying admissions for COVID-19.MethodsIn this retrospective cohort study, we enrolled consecutive SARS-CoV-2 positive patients admitted to one of five hospitals in British Columbia between December 19, 2021 and May 31,2022. We completed medical record reviews, and classified hospitalizations as being primarily for COVID-19 or with incidental SARS-CoV-2 infection. We applied the CDC algorithm and the Massachusetts classification to estimate the difference in hospital days, intensive care unit (ICU) days and in-hospital mortality and calculated sensitivity and specificity.ResultsOf 42,505 Emergency Department patients, 1,651 were admitted and tested positive for SARS-CoV-2, with 858 (52.0%, 95% CI 49.6-54.4) admitted for COVID-19. Patients hospitalized for COVID-19 required ICU admission (14.0% versus 8.2%, pConclusionHalf of SARS-CoV-2 hospitalizations were for COVID-19 during the Omicron wave. The CDC algorithm was more specific and sensitive than the Massachusetts classification, but underestimated the burden of COVID-19 admissions.Trial registrationClinicaltrials.gov, NCT04702945.

Harding et al. present a biophysical and structural characterization of the complex between huntingtin (HTT) and HAP40 proteins. They show that the abundance of HAP40 is coupled with that of HTT and that there is greater conformational variety in the exon 1 of the mutant HTT than WT, important for the future drug discovery studies targeting Huntington’s disease.

Abstract We reviewed the literature (January 2010–June 2021) on the effectiveness of debulking strategies before venetoclax initiation in patients with chronic lymphocytic leukemia to reduce tumor burden, downgrade tumor lysis syndrome (TLS) risk, and avoid hospitalization. Low TLS incidence and reduced TLS risk based on tumor burden were reported following debulking in clinical trials. Real‐world observational studies reporting debulking regimens recorded no TLS events, and those without debulking strategies had greater TLS incidence. Debulking prior to venetoclax considerably reduces TLS incidence. Further clinical trials and real‐world studies may provide additional evidence on effectiveness of debulking in reducing TLS incidence and hospitalization need.

Abstract Background Early Neonatal mortality (ENM) (

Abstract Developing an intervention that results in virologic control following discontinuation of antiretroviral therapy (ART) is a major objective of HIV-1 cure research. In this study, we investigated the therapeutic efficacy of a vaccine consisting of adenovirus serotype 26 (Ad26) and modified vaccinia Ankara (MVA) with or without an SIV Envelope (Env) gp140 protein with alum adjuvant in combination with the TLR7 agonist vesatolimod (GS-9620) in 36 ART-suppressed, SIVmac251-infected rhesus macaques. Ad26/MVA therapeutic vaccination led to robust humoral and cellular immune responses, and the Env protein boost increased antibody responses. Following discontinuation of ART, virologic control was observed in 5/12 animals in each vaccine group, compared with 0/12 animals in the sham control group. These data demonstrate therapeutic efficacy of Ad26/MVA vaccination with vesatolimod but no clear additional benefit of adding an Env protein boost. SIV-specific cellular immune responses correlated with virologic control. Our findings show partial efficacy of therapeutic vaccination following ART discontinuation in SIV-infected rhesus macaques.

Abstract Background Undergraduate medical students in India participate in various research activities However, plagiarism is rampant, and we hypothesize that it is the lack of knowledge on how to avoid plagiarism. This study’s objective was to measure the extent of knowledge and attitudes towards plagiarism among undergraduate medical students in India. Methods It was a multicentre, cross-sectional study conducted over a two-year period (January 2018 – December 2019). Undergraduate medical students were given a pre-tested semi-structured questionnaire which contained: (a) Demographic details; (b) A quiz developed by Indiana University, USA to assess knowledge; and (c) Attitudes towards Plagiarism (ATP) questionnaire. Results Eleven medical colleges (n = 4 government medical colleges [GMCs] and n = 7 private medical colleges [PMCs]) participated. A total of N = 4183 students consented. The mean (SD) knowledge score was 4.54 (1.78) out of 10. The factors (adjusted odds ratio [aOR]; 95% Confidence interval [CI]; p value) that emerged as significant predictors of poor knowledge score were early years of medical education (0.110; 0.063, 0.156;

Abstract Currently, most CNS tumors require tissue sampling to discern their molecular/genomic landscape. However, growing research has shown the powerful role imaging can play in non-invasively and accurately detecting the molecular signature of these tumors. The overarching theme of this review article is to provide neuroradiologists and neurooncologists with a framework of several important molecular markers, their associated imaging features and the accuracy of those features. A particular emphasis is placed on those tumors and mutations that have specific or promising imaging correlates as well as their respective therapeutic potentials.

Introduction: To assess the impact of the COVID-19 pandemic impact on hemodialysis (HD) centers, The Dialysis Outcomes and Practice Patterns Study and ISN collaborated on a web-survey of centers. Methods: A combined approach of random sampling and open invitation was used between March 2020 and March 2021. Responses were obtained from 412 centers in 78 countries and all 10 ISN regions. Results: In 8 regions, rates of SARS-CoV-2 infection were

Abstract Junctional ectopic tachycardia (JET) is a potentially life‐threatening postoperative arrhythmia in children with specific congenital heart defects and can contribute significantly to postoperative morbidity for at‐risk populations. In adults, β1‐adrenergic receptor (ADRB1) and β2‐adrenergic receptor (ADRB2) genotypes have been associated with increased risk for arrhythmias. However, their association with arrhythmia risk in children is unknown. We aimed to test associations between ADRB1 and ADRB2 genotypes and postoperative JET in patients with congenital heart defects. Children who underwent cardiac surgery were genotyped for the ADRB1 p.Ser49Gly (rs1801252; c.145A>G), p.Arg389Gly (rs1801253; c.1165C>G), ADRB2 p.Arg16Gly (rs1042713; c.46A>G), and p.Glu27Gln (rs1042714; c.79G>C) polymorphisms. The occurrence of postoperative JET was assessed via cardiologist‐interpreted electrocardiograms. Genotype associations with JET were analyzed via logistic regression, adjusted for clinical variables associated with JET, with separate analysis in patients not on a β‐blocker. Of the 343 children included (median age 8 months, 53% boys, 69% European ancestry), 45 (13%) developed JET. The Arg389Arg genotype was not significantly associated with JET in the overall population (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 0.96–4.03, p = 0.064), but was nominally associated in patients not taking a β‐blocker (n = 324, OR = 2.25, 95% CI = 1.05–4.80. p = 0.034). None of the other variants were associated with JET. These data suggest that the ADRB1 Arg389Arg genotype may predict risk for JET following cardiac surgery in pediatric patients in the absence of β‐blockade. Whether treatment with a β‐blocker ameliorates this association requires further research.

Abstract The Environmental Determinants of Diabetes in the Young (TEDDY) study enrolled 8676 children, 3–4 months of age, born with HLA-susceptibility genotypes for islet autoimmunity (IA) and type 1 diabetes (T1D). Whole-genome sequencing (WGS) was performed in 1119 children in a nested case–control study design. Telomere length was estimated from WGS data using five tools: Computel, Telseq, Telomerecat, qMotif and Motif_counter. The estimated median telomere length was 5.10 kb (IQR 4.52–5.68 kb) using Computel. The age when the blood sample was drawn had a significant negative correlation with telomere length (P = 0.003). European children, particularly those from Finland (P = 0.041) and from Sweden (P = 0.001), had shorter telomeres than children from the U.S.A. Paternal age (P = 0.019) was positively associated with telomere length. First-degree relative status, presence of gestational diabetes in the mother, and maternal age did not have a significant impact on estimated telomere length. HLA-DR4/4 or HLA-DR4/X children had significantly longer telomeres compared to children with HLA-DR3/3 or HLA-DR3/9 haplogenotypes (P = 0.008). Estimated telomere length was not significantly different with respect to any IA (P = 0.377), IAA-first (P = 0.248), GADA-first (P = 0.248) or T1D (P = 0.861). These results suggest that telomere length has no major impact on the risk for IA, the first step to develop T1D. Nevertheless, telomere length was shorter in the T1D high prevalence populations, Finland and Sweden.

We describe an acute, postoperative dysarthria-facial paresis. While the rare stroke syndrome has been described previously, we present an under-described clinical nuance to its presentation with a particularly clear imaging correlation. A 78-year-old, right-handed man with a past medical history of aortic stenosis presented after a transcatheter aortic valve replacement. Immediately postoperatively, no neurological deficits were noted. That evening, he described his speech as “drunken.” He was later noted to have a right lower facial droop in addition to the speech change. His speech exhibited labial, lingual, and (to a lesser degree) guttural dysarthria. At the patient’s request due to claustrophobia, he received 2 mg of oral lorazepam prior to cranial imaging. Afterwards, he was sleepy but arousable, yet was unable to put pen to paper when asked to write. Right lower facial paresis persisted, but he now demonstrated a right pronator drift, which resolved after 14 h without other evolution to his clinical examination. Brainstem lesions above the level of the pontine facial nucleus may present with central facial paresis contralateral to the lesion. An associated dysarthria may have both labial and lingual features in the absence of tongue or pharyngeal weakness. Our review of reported cases of dysarthria in isolation, dysarthria in combination with facial paresis, and facial paresis finds that all presentations may result from cortical, subcortical, or brainstem involvement. Stroke mechanisms are most commonly thromboembolic or small-vessel-ischemic in either the anterior or posterior circulations.

Purpose To conduct a systematic review of preclinical and clinical peer-reviewed evidence linking alterations in oxidative stress biomarkers or outcome measures that were also prevalent in specific age-related lower urinary tract (LUT) disorders. Methods PubMed, Scopus, CINAHL, and Embase were searched for peer-reviewed studies published between January 2000 and March 2021. Animal and human studies that reported on the impact of oxidative stress in age-related LUT disorders through structural or functional changes in the LUT and changes in biomarkers were included. The PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) protocol was followed. Results Of 882 articles identified, 21 studies (13 animal; 8 human) met inclusion criteria. Across LUT disorders, common structural changes were increased bladder and prostate weights, ischemic damage, nerve damage and detrusor muscle hypertrophy; common functional changes included decreased bladder contraction, increased bladder sensation and excitability, decreased perfusion, and increased inflammation. The disorders were associated with increased levels of biomarkers of oxidative stress that provided evidence of either molecular damage, protective mechanisms against oxidative stress, neural changes, or inflammation. In all cases, the effect on biomarkers and enzymes was greater in aged groups compared to younger groups. Conclusions Increased oxidative stress, often associated with mitochondrial dysfunction, plays a significant role in the pathogenesis of age-related LUT disorders and may explain their increasing prevalence. This systematic review identifies potential markers of disease progression and treatment opportunities; further research is warranted to evaluate these markers and the mechanisms by which these changes may lead to age-related LUT disorders.

In this article, we explore demands and tensions involved when schools implement ambitious mathematics teaching (AMT). Following a description of a framework that distinguishes between internal and external demands, we characterize the tension between these in terms of alignment, balance, and buffering, which collectively speak to coherence. We then describe AMT and how it represents a departure from traditional mathematics instruction found in most countries. We applied the framework to an illustrative case and found that while the school devoted considerable resources to reforming mathematics teaching and learning, challenges persisted. These challenges include ongoing language and participatory demands for students and, for teachers, balancing the demands of implementing AMT with a range of other initiatives. The framework provides a means of exploring the full range of demands associated with ambitious instructional reforms, how these demands are mitigated or exacerbated, and the kinds of resources necessary to sustain AMT.

In this study, an electrochemical immunosensor for the detection of the 19 kDa Mycobacterium tuberculosis lipoprotein LpqH was developed using a monoclonal antibody immobilized on a chitosan-coated iron oxide bio-composite. The bio-composite is composed of magnetic iron oxide at its core and a non-magnetic thin film on the surface formed by chitosan, providing the chemistry for monoclonal antibody immobilization. Cyclic voltammetry was used to characterize and test the immunosensor assembly. Electrochemical measurements showed a strong relationship between the LpqH concentration in phosphate-buffered saline solution and the measured anodic peak current. The electrochemical immunosensor showed a limit of detection equal to 40 μg/mL (2 μM) LpqH.

Suctioning of newborns immediately after birth, as part of delivery room resuscitation, is only recommended if the airway is obstructed. The aim of this study was to describe the use of suctioning during newborn resuscitation among survivors versus those who died within 3 days and potential suction-related heart rate responses and associations to newborn characteristics. This was a retrospective observational study from July 2013 to July 2016 in a referral hospital in rural Tanzania. Research assistants observed and documented all deliveries, newborn resuscitations were video-recorded, and newborn heart rates were captured with a dry-electrode electrocardiogram. Liveborn infants ≥34 weeks gestation who received ventilation and with complete datasets were eligible. All 30 newborns who died were included, and a total of 46 survivors were selected as controls. Videos were annotated and heart rate patterns were observed before and after the suction events. Suctioning was performed more frequently than recommended. No differences were found in suctioning characteristics between newborns who died versus those who survived. In 13% of suction events, a significant heart rate change (i.e., arrhythmia or brief/sustained >15% fall in heart rate) was observed in relation to suctioning. This represents a potential additional harm to already depressed newborns undergoing resuscitation.

Keywords Total Knee Arthroplasty, robotic-assisted, opioid use Background With the rise of robotic arm-assisted total knee arthroplasty (TKA) cases, there is a need to determine if there are clinical benefits associated with this technology. The purpose of this study was to further evaluate if robotic-assisted TKAs result in improved inpatient post-operative outcomes compared to conventional TKAs. Materials and Methods After IRB approval, a retrospective chart review of 100 robotic-assisted primary TKAs and 100 matched controls undergoing conventional TKA was performed. Patients underwent primary TKA from 2016 to 2018 with minimum 6-month postoperative follow-up by a single fellowship-trained arthroplasty surgeon at a high-volume joint center. Exclusion criteria included 40. Demographics and post-operative outcomes, including length of stay (LOS), opioid consumption, duration of opioid use, and discharge status, were recorded. Results There were no significant differences in pre-operative demographics between the two groups. A decrease in LOS (1.58 vs. 2.18 days, p < 0.001) and morphine equivalents (73.52 vs. 102.50, p = 0.017) was reported for the robotic TKA group compared to the control group. The robotic group also reported fewer patients at six weeks postoperatively requiring opioids compared to the control group (37 vs. 61, p = 0.001). Average KOOS Jr at 6-months postoperatively was 81.73 for the control group and 78.22 in the robotic group (p = 0.039). Conclusion Robotic-assisted TKA patients experienced significantly decreased LOS, morphine equivalents, and opioid usage at 6-week postoperatively, indicating that there are early clinical benefits of robotic-assisted TKA. No significant differences between the robotic and control groups were reported in pre-operative KOOS Jr. Although average 6-month postoperative KOOS Jr was slightly higher for the control group, the difference was clinically insignificant. Our average KOOS Jr for both cohorts was higher than the national 1-year postoperative average, 76.8.

Background and Study Aim. Inter-repetition rest pertains to a short period of rest between repetitions during strength training. Manipulating inter-repetition rest may influence fatigue accumulation, manifesting alteration in lifting mechanics. This study aimed to examine the effects of different inter-repetition rest protocols on joint velocity and ground reaction force during snatch exercise. Material and Methods. Fifteen male (n=15) athletes participated in this study (age = 23.0 ±2.31 years; body weight = 65.32 ± 1.37 kg; height = 168.80 ± 5.64 cm; snatch one repetition maximum (1RM)/bodyweight = 0.78 ± 0.12), performing three sets of 5 repetitions at 85% 1 Repetition Maximum snatch with 10, 30, or 50 seconds of inter-repetition rest implemented randomly across three sessions. Ankle, knee, and hip kinematics and ground reaction force in the three protocols were used for comparison. The participants visited the exercise science laboratory for four sessions between 0800-1700 hrs. These sessions were separated by 72 hours. Results. One-way repeated measure analysis of variances (ANOVA) showed a significant effect of inter-repetition rest on the maintenance of kinematic and kinetic variables. The ground reaction force for 10 seconds inter-repetition rest protocol showed a significant drop in force output across repetition (p = .037, p < 0.05). Conclusions. The utilization of inter-repetition rest in snatch exercise may reduce neuromuscular fatigue across repetitions, maintaining consistent performance output. Specifically, the 50 second inter-repetition rest protocol reduced the negative effect of neuromuscular fatigue in the kinematic and kinetic variables during snatch exercise.

The small size (≤15-nt) of micorexons poses difficulties for genome annotation and identification using standard RNA sequence mapping approaches. Here, the authors develop computational pipelines to discover and predict microexons in plants and reveal diverse evolutionary trajectories via genomewide microexon modeling.

In August 2020, soil moisture active passive (SMAP) released a new version of its soil moisture and vegetation optical depth (VOD) retrieval products. In this article, we review the methodology followed by the SMAP regularized dual-channel retrieval algorithm. We show that the new implementation generates SM retrievals that not only satisfy the SMAP accuracy requirements, but also show a performance comparable to the single-channel algorithm that uses the V polarized brightness temperature. Due to a lack of in situ measurements we cannot evaluate the accuracy of the VOD. In this article, we show analyses with the intention of providing an understanding of the VOD product. We compare the VOD results with those from SMOS. We also study the relation of the SMAP VOD with two vegetation parameters: tree height and biomass.

The National Aeronautics and Space Administration Soil Moisture Active Passive (SMAP) mission has been validating its soil moisture (SM) products since the start of data production on March 31, 2015. Prior to launch, the mission defined a set of criteria for core validation sites (CVS) that enable the testing of the key mission SM accuracy requirement (unbiased root-mean-square error 3/m3). The validation approach also includes other (“sparse network”) in situ SM measurements, satellite SM products, model-based SM products, and field experiments. Over the past six years, the SMAP SM products have been analyzed with respect to these reference data, and the analysis approaches themselves have been scrutinized in an effort to best understand the products’ performance. Validation of the most recent SMAP Level 2 and 3 SM retrieval products (R17000) shows that the L-band (1.4 GHz) radiometer-based SM record continues to meet mission requirements. The products are generally consistent with SM retrievals from the European Space Agency Soil Moisture Ocean Salinity mission, although there are differences in some regions. The high-resolution (3-km) SM retrieval product, generated by combining Copernicus Sentinel-1 data with SMAP observations, performs within expectations. Currently, however, there is limited availability of 3-km CVS data to support extensive validation at this spatial scale. The most recent (version 5) SMAP Level 4 SM data assimilation product providing surface and root-zone SM with complete spatio–temporal coverage at 9-km resolution also meets performance requirements. The SMAP SM validation program will continue throughout the mission life; future plans include expanding it to forested and high-latitude regions.

Theoretical estimations of solvation free energy by continuum solvation models are generally not accurate. Here the authors report a polarizable force field fitted entirely to first-principles calculations for the estimation of free energy of solvation of arbitrary molecules.

To meet the requirements of California's Sustainable Groundwater Management Act, there is a critical need for crop production strategies with less reliance on irrigation from surface and groundwater sources. One strategy for improving agricultural water use efficiency is reducing tillage and maintaining residues on the soil surface. We evaluated high residue no-till versus standard tillage in the San Joaquin Valley with and without cover crops on the yields of two crops, garbanzo and sorghum, for 4 years. The no-till treatment had no primary or secondary tillage. Sorghum yields were similar in no-till and standard tillage systems while no-till garbanzo yields matched or exceeded those of standard tillage, depending on the year. Cover crops had no effect on crop yields. Soil cover was highest under the no-till with cover crop system, averaging 97% versus 5% for the standard tillage without cover crop system. Our results suggest that garbanzos and sorghum can be grown under no-till practices in the San Joaquin Valley without loss of yield.

Abstract Background Chronic tinnitus affects millions of people globally and constitutes the most commonly compensated disability among military service members in the United States. Existing treatment options largely surround helping patients cope with their disease as opposed to directly suppressing tinnitus perception. The current study investigated the efficacy of electrical stimulation of the cochlea on chronic disabling tinnitus. Methods In this single-arm, open-label clinical trial, 22 adult subjects with severe-range asymmetric or unilateral non-pulsatile tinnitus underwent electrical stimulation of the cochlea through use of an extra-cochlear electrode positioned on the cochlear promontory. Each subject underwent 3 stimulation treatments over 3 weeks at 7-day intervals. Tinnitus severity was determined by Tinnitus Handicap Inventory (THI), Tinnitus Functional Index (TFI), and Tinnitus Visual Analog Scale (VAS). Inclusion criteria required subjects have no worse than moderate sensorineural hearing loss determined by pre-enrollment audiometric testing. The primary outcome was nadir post-treatment THI scores, obtained at seven timepoints following electrical stimulation, with clinically significant improvement defined as a decrease of ≥ 7. Results All 22 (100%) subjects experienced clinically significant improvement in the THI during the study period with a mean decrease in scores of − 31 (95% CI − 38 to − 25) from a baseline of 48. Twenty (91%) experienced clinically significant improvement detectable on at least two of the three tinnitus survey instruments and 17 (77%) experienced clinically significant improvement detectable on all three survey instruments (i.e., THI, TFI, and VAS). Eight (36%) subjects reported either complete (THI of 0; n = 3) or near-complete (THI 1–4; n = 5) suppression of their tinnitus following a stimulation session. Thirteen (59%) subjects reported a nadir following stimulation at or below the threshold for “no or slight handicap” on the THI (≤ 16). No adverse events were observed. Conclusions These findings establish the foundation for the development of an extra-cochlear implantable device that delivers electrical stimulation to the cochlea for the treatment of disabling tinnitus. For patients considering device implantation, trans-tympanic cochlear promontory stimulation can facilitate patient selection. Trial Registration ClinicalTrials.gov Identifier: NCT03759834. URL: https://clinicaltrials.gov/ct2/show/NCT03759834

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

Precision agriculture is experiencing substantial development through the improved availability of cost-effective instruments for data collection. This includes ground-based proximal sensing technologies that are able to compete with satellite and aircraft observation systems, due to low operational costs, high operational flexibility, and high spatial resolution. This article was therefore designed to compare the performance of multiple sensing systems mounted on a smart buggy platform. A number of proximal sensing technologies were then evaluated and intercompared for their accuracy in retrieving high resolution near-surface soil moisture. The sensors tested included an L-band microwave radiometer (ELBARA III), a global navigation satellite system reflectometer sensor (LARGO), and an electromagnetic induction sensor (EM38). Data were collected during the fifth Soil Moisture Active Passive Experiment (SMAPEx-5) in Yanco, NSW, Australia, in September 2015. Observations from each sensor were converted to surface soil moisture values which were in turn evaluated against reference measurements obtained by in situ soil moisture measurements. The sensing technologies tested here have been individually assessed by many other studies, but within different regions and environments including surface condition, local weather, observing height, size of footprint, etc. Consequently, this article has used a single platform to intercompare the different sensors to be evaluated concurrently. Results from this article indicated that the L-band microwave radiometer achieved the best performance in retrieving surface soil moisture. The average RMSE and R were found to be 0.055 cm3/cm3 and 0.68 for ELBARA III, 0.084 cm3/cm3 and 0.51 for LARGO, and 0.090 cm3/cm3 and 0.32 for the EM38.

ABSTRACT For fungal plant pathogens, the germinating spore provides the first interaction with the host. Spore germlings move across the plant surface and use diverse penetration strategies for ingress into plant surfaces. Penetration strategies include pressurized melanized appressoria, which facilitate physically punching through the plant cuticle, and nonmelanized appressoria, which penetrate with the help of enzymes or cuticular damage to breach the plant surface. Two well-studied plant pathogens, Fusarium graminearum and Magnaporthe oryzae, are typical of these two modes of penetration. We applied comparative transcriptomics to Fusarium graminearum and Magnaporthe oryzae to characterize the genetic programming of the early host-pathogen interface. Four sequential stages of development following spore localization on the plant surface, from spore swelling to appressorium formation, were sampled for each species on culture medium and on barley sheaths, and transcriptomic analyses were performed. Gene expression in the prepenetration stages in both species and under both conditions was similar. In contrast, gene expression in the final stage was strongly influenced by the environment. Appressorium formation involved the greatest number of differentially expressed genes. Laser-dissection microscopy was used to perform detailed transcriptomics of initial infection points by F. graminearum. These analyses revealed new and important aspects of early fungal ingress in this species. Expression of the trichothecene genes involved in biosynthesis of deoxynivalenol by F. graminearum implies that toxisomes are not fully functional until after penetration and indicates that deoxynivalenol is not essential for penetration under our conditions. The use of comparative gene expression of divergent fungi promises to advance highly effective targets for antifungal strategies. IMPORTANCE Fusarium graminearum and Magnaporthe oryzae are two of the most important pathogens of cereal grains worldwide. Despite years of research, strong host resistance has not been identified for F. graminearum, so other methods of control are essential. The pathogen takes advantage of multiple entry points to infect the host, including breaches in the florets due to senescence of flower parts and penetration of the weakened trichome bases to breach the epidermis. In contrast, M. oryzae directly punctures leaves that it infects, and resistant cultivars have been characterized. The threat of either pathogen causing a major disease outbreak is ever present. Comparative transcriptomics demonstrated its potential to reveal novel and effective disease prevention strategies that affect the initial stages of disease. Shedding light on the basis of this diversity of infection strategies will result in development of increasingly specific control strategies.

Objective Advance consent is a recognised method of obtaining informed consent for participation in research, whereby a potential participant provides consent for future involvement in a study contingent on qualifying for the study’s inclusion criteria on a later date. The goal of this study is to map the existing literature on the use of advance consent for enrolment in randomised controlled trials (RCTs) for emergency conditions.Design Scoping review designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses–Extension for Scoping Reviews guidelines.Data sources We searched electronic databases including MEDLINE, Embase, Web of Science and the Cochrane Register of Clinical Trials from inception to 10 February 2020.Eligibility criteria Eligible studies included articles that discussed or employed the use of advance consent for enrolment in RCTs related to emergency conditions. There were no restrictions on the type of eligible study. Data were extracted directly from included papers using a standardised data charting form. We produced a narrative review including article type and authors’ dispositions towards advance consent.Results Our search yielded 1039 titles with duplicates removed. Six articles met inclusion criteria. Three articles discussed the theoretical use of research advance directives in emergency conditions; one article evaluated stakeholders’ perceptions of advance consent; and one article described a method for patients to document their preferences for participation in future research. Only one study employed advance consent to enrol participants into a clinical trial for an emergency condition.Conclusion Our review demonstrates that there has been minimal exploration of advance consent for enrolment in RCTs for emergency conditions. Future studies could aim to assess the acceptability of advance consent to participants, along with the feasibility of enrolling research participants using this method of consent.Protocol The protocol for this scoping review was published a priori.

Rationale & Objective: Anemia management in patients treated with maintenance dialysis remains a challenge. We sought to update information in this area by evaluating the association between hemoglobin and various outcome and utilization measures using data-rich Medicare sources. Study Design: Observational cohort study using data from the Consolidated Renal Operations in a Web-enabled Network and Medicare claims. Setting & Participants: We studied 371,250 prevalent patients treated with hemodialysis, covering 3,326,072 patient-months in 2019. Exposure: Monthly patient hemoglobin concentrations. Outcomes: We examined several outcomes, including mortality, all-cause hospitalization, cause-specific hospitalization, and emergency department utilization in the month following the exposure measurement. Analytical Approach: For each monthly observation period, we calculated unadjusted and adjusted (for demographics and comorbid condition) hazard ratios using Cox regression. Results: The hemoglobin concentration was 11.5 g/dL. All-cause hospitalization, cause-specific hospitalization (including cardiovascular, infection, and several subcategories including coronavirus disease 2019 hospitalization), and emergency department utilization were inversely associated with hemoglobin concentration, with risk reduction stabilizing at hemoglobin levels of approximately 11.5-12 g/dL and higher. Limitations: As with prior observational studies, the observed associations are not necessarily causal. Conclusions: In a large US hemodialysis population, there were better clinical outcomes at higher hemoglobin concentrations over short exposure and follow-up periods, consistent with other observational studies that generally used longer exposure and follow-up times. Mortality risk increased at hemoglobin concentrations >11.5 g/dL, consistent with findings from erythropoiesis-stimulating agent clinical trials. The apparently beneficial short-term effects associated with higher hemoglobin concentrations suggest that hemoglobin measurements capture unmeasured elements of patient risk.

Urinary catheterization facilitates urinary tract colonization by E. coli and increases infection risk. Here, we aimed to identify strain-specific characteristics associated with the transition from colonization to infection in catheterized patients. In a single-site study population, we compared E. coli isolates from patients with catheter-associated asymptomatic bacteriuria (CAASB) to those with catheter-associated urinary tract infection (CAUTI). CAUTI isolates were dominated by a phylotype B2 subclade containing the multidrug-resistant ST131 lineage relative to CAASB isolates, which were phylogenetically more diverse. A distinctive combination of virulence-associated genes was present in the CAUTI-associated B2 subclade. Catheter-associated biofilm formation was widespread among isolates and did not distinguish CAUTI from CAASB strains. Preincubation with CAASB strains could inhibit catheter colonization by multiple ST131 CAUTI isolates. Comparative genomic analysis identified a group of variable genes associated with high catheter biofilm formation present in both CAUTI and CAASB strains. Among these, ferric citrate transport (Fec) system genes were experimentally associated with enhanced catheter biofilm formation using reporter and fecA deletion strains. These results are consistent with a variable role for catheter biofilm formation in promoting CAUTI by ST131-like strains or resisting CAUTI by lower-risk strains that engage in niche exclusion.

ObjectiveTo identify demographic and clinical factors predictive of having a missed opportunity (MO) for HIV screening.DesignRetrospective cohort study.MethodsElectronic medical records were queried for individuals newly diagnosed with HIV in different sites within a large urban academic medical center in New York City between 2018 and 2022. The primary outcome was having one or more MO for HIV screening within the institution, defined as any encounter at which screening was not performed in the 365 days preceding the HIV diagnosis.ResultsOver one third of new diagnoses had at least one MO in the preceding year. Older individuals, cisgender women and those assigned female sex at birth, and heterosexual individuals were more likely to have at least one MO. An initial CD4 < 200 cells/ul was more likely among men who have sex with women specifically. Most MOs occurred in the emergency department and outpatient settings, with minimal HIV prevention discussions documented during each MO.ConclusionsThese findings suggest that populations perceived to be at lower risk for HIV are more likely to have MOs and possibly late diagnoses, and that universal HIV screening must be implemented into the workflows of emergency department and outpatient settings to facilitate early diagnosis and reduce the incidence of HIV.

Sex hormones can affect cellular physiology and modulate synaptic plasticity, but it is not always clear whether or how sex-dependent differences identified in vitro express themselves as functional dimorphisms in the brain. Historically, most experimental neuroscience has been conducted using only male animals and the literature is largely mute about whether including female mice in will introduce variability due to inherent sex differences or endogenous estrous cycles. Though this is beginning to change following an NIH directive that sex should be included as a factor in vertebrate research, the lack of information raises practical issues around how to design experimental controls and apply existing knowledge to more heterogeneous populations. Various lines of research suggest that visual processing can be affected by sex and estrous cycle stage. For these reasons, we performed a series of in vivo electrophysiological experiments to characterize baseline visual function and experience-dependent plasticity in the primary visual cortex (V1) of male and female mice. We find that sex and estrous stage have no statistically significant effect on baseline acuity measurements, but that both sex and estrous stage have can modulate two mechanistically distinct forms of experience dependent cortical plasticity. We also demonstrate that resulting variability can be largely controlled with appropriate normalizations. These findings suggest that V1 plasticity can be used for mechanistic studies focusing on how sex hormones effect experience dependent plasticity in the mammalian cortex.

National strategies for addressing chronic kidney disease (CKD) are crucial to improving kidney health. We sought to describe country-level variations in non-communicable disease (NCD) strategies and CKD-specific policies across different regions and income levels worldwide. The International Society of Nephrology Global Kidney Health Atlas (GKHA) was a multinational cross-sectional survey conducted between July and October 2018. Responses from key opinion leaders in each country regarding national NCD strategies, the presence and scope of CKD-specific policies, and government recognition of CKD as a health priority were described overall and according to region and income level. 160 countries participated in the GKHA survey, comprising 97.8% of the world's population. Seventy-four (47%) countries had an established national NCD strategy, and 53 (34%) countries reported the existence of CKD-specific policies, with substantial variation across regions and income levels. Where CKD-specific policies existed, non-dialysis CKD care was variably addressed. 79 (51%) countries identified government recognition of CKD as a health priority. Low- and low-middle income countries were less likely to have strategies and policies for addressing CKD and have governments which recognise it as a health priority. The existence of CKD-specific policies, and a national NCD strategy more broadly, varied substantially across different regions around the world but was overall suboptimal, with major discrepancies between the burden of CKD in many countries and governmental recognition of CKD as a health priority. Greater recognition of CKD within national health policy is critical to improving kidney healthcare globally.

BackgroundCeliac disease has an increasing incidence worldwide and is treated with lifelong adherence to a gluten-free diet. We aimed to describe gluten-free diet adherence rates in children with screening-identified celiac disease, determine adherence-related factors, and compare adherence to food records in a multinational prospective birth cohort study.MethodsChildren in The Environmental Determinants of Diabetes in the Young study with celiac disease were included. Subjects had at least annual measurement of adherence (parent-report) and completed 3-day food records. Descriptive statistics, t-tests, Kruskal-Wallis tests and multivariable logistic and linear regression were employed.ResultsTwo hundred ninety (73%) and 199 (67%) of subjects were always adherent to a gluten-free diet at 2 and 5 years post celiac disease diagnosis respectively. The percentage of children with variable adherence increased from 1% at 2 years to 15% at 5 years. Children with a first-degree relative with celiac disease were more likely to be adherent to the gluten-free diet. Gluten intake on food records could not differentiate adherent from nonadherent subjects. Adherent children from the United States had more gluten intake based on food records than European children (P < .001 and P = .007 at 2 and 5 years respectively).ConclusionApproximately three-quarters of children with screening-identified celiac disease remain strictly adherent to a gluten-free diet over time. There are no identifiable features associated with adherence aside from having a first-degree relative with celiac disease. Despite good parent-reported adherence, children from the United States have more gluten intake when assessed by food records. Studies on markers of gluten-free diet adherence, sources of gluten exposure (particularly in the United States), and effects of adherence on mucosal healing are needed.

Touch system function requires precise interactions between specialized skin cells and somatosensory axons, as exemplified by the vertebrate mechanosensory Merkel cell-neurite complex. Development and patterning of Merkel cells and associated neurites during skin organogenesis remain poorly understood, partly due to the in utero development of mammalian embryos. Here, we discover Merkel cells in the zebrafish epidermis and identify Atonal homolog 1a (Atoh1a) as a marker of zebrafish Merkel cells. We show that zebrafish Merkel cells derive from basal keratinocytes, express neurosecretory and mechanosensory machinery, extend actin-rich microvilli, and complex with somatosensory axons, all hallmarks of mammalian Merkel cells. Merkel cells populate all major adult skin compartments, with region-specific densities and distribution patterns. In vivo photoconversion reveals that Merkel cells undergo steady loss and replenishment during skin homeostasis. Merkel cells develop concomitant with dermal appendages along the trunk and loss of Ectodysplasin signaling, which prevents dermal appendage formation, reduces Merkel cell density by affecting cell differentiation. By contrast, altering dermal appendage morphology changes the distribution, but not density, of Merkel cells. Overall, our studies provide insights into touch system maturation during skin organogenesis and establish zebrafish as an experimentally accessible in vivo model for the study of Merkel cell biology.

Tuberous Sclerosis Complex (TSC) is caused by loss of function variants in either TSC1 or TSC2 and is characterized by broad phenotypic heterogeneity. Currently, there is limited knowledge regarding the role of the mitochondrial genome (mtDNA) in TSC pathogenesis. In this study, we aimed to determine the prevalence and spectrum of germline and somatic mtDNA variants in TSC and identify potential disease modifiers. Analysis of mtDNA amplicon massively parallel sequencing (aMPS) data, off-target mtDNA from whole-exome sequencing (WES), and/or qPCR, revealed mtDNA alterations in 270 diverse tissues (139 TSC-associated tumors and 131 normal tissue samples) from 199 patients and six healthy individuals. Correlation of clinical features to mtDNA variants and haplogroup analysis was done in 102 buccal swabs (age: 20–71 years). No correlation was found between clinical features and either mtDNA variants or haplogroups. No pathogenic variants were identified in the buccal swab samples. Using in silico analysis, we identified three predicted pathogenic variants in tumor samples: MT-ND4 (m.11742G>A, p. Cys328Tyr, VAF: 43%, kidney angiomyolipoma), MT-CYB (m.14775T>C, p. Leu10Pro, VAF: 43%, LAM abdominal tumor) and MT-CYB (m.15555C>T, p. Pro270Leu, VAF: 7%, renal cell carcinoma). Large deletions of the mitochondrial genome were not detected. Analysis of tumors from 23 patients with corresponding normal tissue did not reveal any recurrent tumor-associated somatic variants. The mtDNA/gDNA ratio between tumors and corresponding normal tissue was also unchanged. Overall, our findings demonstrate that the mitochondrial genome is highly stable across tissues and within TSC-associated tumors.

C-C motif chemokine receptor-like 2 (CCRL2) is a non-signaling 7 transmembrane receptor that binds chemotactic ligands to shape leukocyte recruitment to sites of inflammation. However, there is a lack of consensus on the ligands that directly bind CCRL2 or their functional impact. Studies with CCRL2 knockout mice have demonstrated that neutrophils have impaired degranulation and migration in response to CXCL8, where the underlying molecular mechanism is proposed to be due to the formation of CCRL2 heterodimers with the chemokine receptor CXCR2. Herein, we characterized the ligands that bind directly to CCRL2 and interrogated the impact of CCRL2 neutralization on CXCL8 signaling in neutrophils using pharmacological antibody tools. Using flow cytometry and Surface Plasmon Resonance microscopy (SPRm) cell binding experiments, we confirmed that chemerin, but not previously reported C-C chemokines, binds CCRL2. Furthermore, we identified human and mouse CCRL2 antibodies that neutralized chemerin binding to CCRL2. Unexpectedly, we found that neutralization of CCRL2 with these antibodies did not attenuate CXCL8-induced human neutrophil degranulation nor CXCL8-induced murine neutrophil recruitment to the peritoneum. Based on the observed differences in modulating CCRL2 function with neutralizing antibodies compared to the reported CCRL2 deficient murine models, we hypothesize that the ligand binding function of CCRL2 is dispensable for CXCL8 signaling in neutrophils. Finally, extensive profiling of CCRL2 expression on peripheral blood leukocytes revealed monocytes, dendritic cells (DC), and subpopulations of natural killer T (NKT) cells as additional targets, highlighting potential roles for CCRL2 in human cell types beyond neutrophils that warrants future investigation.

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.