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Question Je vois frequemment des nourrissons qui ont des symptomes laissant presager une allergie apres l’introduction a une preparation standard a base de lait de vache. Les parents s’inquietent et demandent des recommandations concernant les options de rechange a ce lait maternise. Quelles sont les meilleures preparations pour les enfants allergiques au lait de vache? Reponse L’allergie au lait de vache est courante, et les criteres habituels pour le diagnostic sont l’elimination, la provocation (au moyen d’un protocole de provocation alimentaire a double insu contre placebo) et la re-elimination. L’allergie est traitee en eliminant de l’alimentation les proteines de lait de vache. Parmi les options de rechange a ce lait maternise figurent les preparations au lait de vache hydrolysees, et les preparations a base de riz, de soja ou d’acides

BackgroundThe oral, selective Janus kinase (JAK)1/JAK2 inhibitor baricitinib demonstrated efficacy in hospitalised adults with COVID-19. This study evaluates the efficacy and safety of baricitinib in critically ill adults with COVID-19 requiring invasive mechanical ventilation (IMV) or extracorporeal membrane oxygenation (ECMO).MethodsCOV-BARRIER was a global, phase 3, randomised, double-blind, placebo-controlled trial in patients with confirmed SARS-CoV-2 infection (ClinicalTrials.govNCT04421027). This addendum trial added a critically ill cohort not included in the main COV-BARRIER trial. Participants on baseline IMV/ECMO were randomly assigned 1:1 to baricitinib 4-mg (n=51) or placebo (n=50) for up to 14 days in combination with standard of care (SOC). Prespecified endpoints included all-cause mortality through days 28 and 60, and number of ventilator-free days, duration of hospitalisation, and time to recovery through day 28. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively.FindingsSOC included baseline systemic corticosteroid use in 86% of participants. Treatment with baricitinib significantly reduced 28-day all-cause mortality compared to placebo (39·2% vs 58·0%; hazard ratio [HR]=0·54 [95%CI 0·31–0·96]; p=0·030). One additional death was prevented for every six baricitinib-treated participants. Significant reduction in 60-day mortality was also observed (45·1% vs 62·0%; HR=0·56 [95%CI 0·33–0·97]; p=0·027).Baricitinib-treated participants showed numerically more ventilator-free days (8.1 vs 5.5 days, p=0.21) and spent over 2 days less in the hospital than placebo-treated participants (23·7 vs 26·1 days, p=0·050). The rates of infections, blood clots, and adverse cardiovascular events were similar between treatment arms.InterpretationIn critically ill patients with COVID-19 already receiving IMV/ECMO, treatment with baricitinib as compared to placebo (in combination with SOC, including corticosteroids) showed mortality HR of 0·56, corresponding to a 44% relative reduction at 60 days. This is consistent with the mortality reduction observed in less severely ill hospitalised primary COV-BARRIER study population.FundingEli Lilly and Company.Research in contextEvidence before this studyWe evaluated current and prior studies assessing the efficacy and safety of interventions in patients requiring invasive mechanical ventilation (IMV) and searched current PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “critical illness”, “invasive mechanical ventilation”, “baricitinib”, and “JAK inhibitor” for articles in English, published until December 1, 2020, regardless of article type. We also reviewed the NIH and IDSA COVID-19 guidelines and reviewed similar terms on clinicaltrials.gov. When the critical illness addendum study to COV-BARRIER study was designed, there was only one open-label study of dexamethasone showing mortality benefit in hospitalised patients with COVID-19 requiring IMV. Small studies of interleukin-6 inhibitors had shown no effect and larger trials were underway. Guidelines recommended use of dexamethasone with or without remdesivir and recommended against the use of interleukin-6 inhibitors, except in a clinical trial. Overall, there were no reported double-blind, placebo-controlled phase 3 trials which included corticosteroids as part of SOC investigating the efficacy and safety of novel treatments in the NIAID-OS 7 population. Baricitinib’s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential antiviral mechanism for targeting host proteins mediating viral endocytosis Data from the NIAID sponsored ACTT-2 trial showed that baricitinib when added to remdesivir improved time to recovery and other outcomes including mortality compared to placebo plus remdesivir. A numerically larger proportion of participants who received baricitinib plus remdesivir showed an improvement in ordinal scale compared to those who received placebo plus remdesivir at day 15 in participants requiring IMV (NIAID-OS score of 7) at baseline. We designed COV-BARRIER, a phase 3, global, double-blind, randomised, placebo-controlled trial, to evaluate the efficacy and safety of baricitinib in combination with SOC (including corticosteroids) for the treatment of hospitalised adults with COVID-19 who did not require mechanical ventilation (i.e., NIAID-OS 4-6). A significant reduction in mortality was found after 28 days between baricitinib and placebo (HR 0·57, corresponding to a 43% relative reduction, p=0·0018); one additional death was prevented per 20 baricitinib-treated participants. In the more severely ill NIAID-OS 6 subgroup, one additional death was prevented per nine baricitinib-treated participants (HR 0·52, corresponding to a 48% relative reduction, p=0·0065). We therefore implemented an addendum to the COV-BARRIER trial to evaluate the benefit/risk of baricitinib in the critically ill NIAID-OS 7 population and considered the sample size of 100 participants sufficient for this trial.Added value of this studyThis was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC), including antivirals, anticoagulants, and corticosteroids, in patients who were receiving IMV or extracorporeal membrane oxygenation at enrolment. This was a multinational, randomised, double-blind, placebo-controlled trial in regions with high COVID-19 hospitalisation rates. Treatment with baricitinib reduced 28-day all-cause mortality compared to placebo (HR 0·54, 95% CI 0·31–0·96; nominal p=0·030), corresponding to a 46% relative reduction, and significantly reduced 60-day all-cause mortality (HR 0·56, 95% CI 0·33–0·97; p=0·027); overall, one additional death was prevented per six baricitinib-treated participants. Numerical improvements in endpoints such as number of ventilator-free days, duration of hospitalisation, and time to recovery were demonstrated. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively.The COV-BARRIER study overall trial results plus these COV-BARRIER addendum study data in mechanically ventilated and ECMO patients provide important information in context of other large, phase 3 randomised trials in participants with invasive mechanical ventilation at baseline. The RECOVERY study reported mortality of 29·3% following treatment with dexamethasone compared to 41·4% for usual care (rate ratio of 0·64, corresponding to a 36% relative reduction) and 49% mortality in participants who received tocilizumab compared to 51% for usual care (rate ratio of 0.93, corresponding to a 7% relative reduction). The ACTT-2 study reported 28-day mortality of 23·1% and 22·6% in the baricitinib plus remdesivir and placebo plus remdesivir groups, respectively, in this critically ill patient population; however, the primary outcome of this trial was time to recovery, so was not powered to detect a change in mortality.Implications of all the available evidenceIn this phase 3 addendum trial, baricitinib given in addition to SOC (which predominantly included corticosteroids) had a significant effect on mortality reduction by 28 days in critically ill patients, an effect which was maintained by 60 days. These data were comparable with those seen in the COV-BARRIER primary study population of hospitalised patients, but which excluded patients who required IMV or extracorporeal membrane oxygenation at enrolment. These findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on the available evidence, baricitinib is a novel treatment option to decrease mortality in hospitalised, critically ill patients with COVID-19 even when started late in the disease process after steroids, mechanical ventilation, and ECMO have already been implemented.

Life emerged in a geochemical context, possibly in the midst of mineral substrates. However, it is not known to what extent minerals and dissolved inorganic ions could have facilitated the evolution of biochemical reactions. Herein, we have experimentally shown that iron sulfide minerals can act as electron transfer agents for the reduction of the ubiquitous biological protein cofactor nicotinamide adenine dinucleotide (NAD

Question Un fumeur adolescent m’a souvent consulte a la clinique pour me demander de l’aider pour arreter de fumer. Je sais que le bupropion est un medicament de premiere intention pour la cessation tabagique, mais est-il efficace et securitaire chez les adolescents? Reponse La plupart des fumeurs adolescents au Canada aimeraient cesser de fumer, mais plus de 90 % des tentatives echouent. Le bupropion semble etre plus efficace que les autres options pharmacologiques pour ameliorer l’abstinence a court terme chez les adolescents; toutefois, Sante Canada ne l’a pas homologue pour les personnes de moins de 18 ans. Le bupropion n’est pas associe a un plus grand nombre d’evenements indesirables dans les essais sur la cessation du tabagisme. Plus de recherches sont necessaires sur l’efficacite et l’innocuite du bupropion a long terme dans cette population.

IMPORTANCE: The past 4 decades have seen substantial changes in allogeneic blood or marrow transplantation (BMT) practice, with the overarching goal of expanding the eligible patient pool while optimizing disease-free survival. OBJECTIVE: To determine trends in life expectancy and cause-specific late mortality after allogeneic BMT performed over a 40-year period. DESIGN, SETTING, AND PARTICIPANTS: A retrospective cohort study of 4741 individuals who lived 2 or more years after allogeneic BMT performed between January 1, 1974, and December 31, 2014, was conducted at City of Hope, University of Minnesota, or University of Alabama at Birmingham. The end of follow-up was March 23, 2020. EXPOSURES: Allogeneic BMT performed in 3 eras: 1974-1989, 1990-2004, and 2005-2014. MAIN OUTCOMES AND MEASURES: All-cause, recurrence-related, and nonrecurrence-related mortality and projected reduction in life expectancy. Information regarding vital status and cause of death was obtained from the National Death Index Plus and Accurint databases. RESULTS: Of the 4741 individuals included in the study, 2735 (57.7%) were male; median age at BMT was 33 years (range, 0-75 years). The cumulative incidence of recurrence-related mortality plateaued at 10 years, reaching 12.2% (95% CI, 11.0%-13.4%) at 30 years from BMT. In contrast, the incidence of nonrecurrence-related mortality continued to increase and was 22.3% (95% CI, 20.4%-24.3%) at 30 years. Leading causes of nonrecurrence-related mortality included infection (30-year cumulative incidence, 10.7%; standardized mortality ratio [SMR], 52.0), subsequent malignant neoplasms (30-year cumulative incidence, 7.0%; SMR, 4.8), cardiovascular disease (30-year cumulative incidence, 4.6%; SMR, 4.1), and pulmonary disease (30-year cumulative incidence, 2.7%; SMR, 13.9). Compared with the general population, the relative mortality remained higher at 30 or more years after BMT (SMR, 5.4; 95% CI, 4.0-7.1). The cohort experienced a 20.8% reduction in life expectancy (8.7 years of life lost). Compared with 1974-1989 (reference), the adjusted 10-year hazard ratio (HR) of all-cause mortality declined over the 3 eras (1990-2004: HR, 0.67; 95% CI, 0.53-0.85; 2005-2014: HR, 0.52; 95% CI, 0.39-0.69; P

A better understanding of the metabolic alterations in immune cells during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may elucidate the wide diversity of clinical symptoms experienced by individuals with coronavirus disease 2019 (COVID-19). Here, we report the metabolic changes associated with the peripheral immune response of 198 individuals with COVID-19 through an integrated analysis of plasma metabolite and protein levels as well as single-cell multiomics analyses from serial blood draws collected during the first week after clinical diagnosis. We document the emergence of rare but metabolically dominant T cell subpopulations and find that increasing disease severity correlates with a bifurcation of monocytes into two metabolically distinct subsets. This integrated analysis reveals a robust interplay between plasma metabolites and cell-type-specific metabolic reprogramming networks that is associated with disease severity and could predict survival.

BackgroundSickle cell disease (SCD) and beta thalassemia (β-thalassemia) are among the most common and severe genetically inherited disorders in the world. Although the maternal carrier status of these beta hemoglobinopathies is screened as a part of routine prenatal care in the US, the paternal carrier status is usually unavailable. Under this current screening paradigm, identification of the majority of SCD and beta thalassemia cases could therefore be delayed until newborn screening results are available. An effective reflex, non-invasive prenatal test (NIPT) that uses only maternal blood would permit prenatal detection of sickle cell disease and beta thalassemia by screening for these disorders without the need for paternal DNA. This screening would enable patients and healthcare providers to make informed decisions about diagnostic testing, and it could expand gene therapy treatment options by requesting cord blood banking at delivery. We have previously developed a single-gene NIPT platform (UNITY™) for SCD and beta thalassemia with extensive analytic validation and initial clinical validation in our prior studies.ObjectivesThe objective of this study is to further assess the clinical validity of single-gene NIPT for SCD and beta thalassemia in a larger pregnancy population.Study DesignPregnant women who screened positive for at least one allele of a beta hemoglobinopathy were enrolled at two academic medical centers for this retrospective cohort study. Single-gene NIPT for SCD and beta thalassemia was performed in blinded fashion on maternal blood samples to determine the fetal genotype and disease status. Single-gene NIPT findings were compared with either newborn screen results or genotyping of umbilical cord blood.ResultsSingle-gene NIPT detection of fetuses that are affected versus unaffected with SCD and beta thalassemia was 100% concordant with newborn screening follow-up data, even in challenging samples that contained a low fetal fraction (ConclusionsSingle-gene NIPT is a highly accurate screen for prenatal detection of SCD and beta thalassemia. The results further suggest that the maternal carrier screen with reflex single-gene NIPT workflow can significantly improve the detection rates of at-risk pregnancies from 98%.AJOG at a GlanceA.Why was this study conducted?Effective non-invasive prenatal testing (NIPT) is needed to permit safe in utero diagnosis of sickle cell disease (SCD) and beta thalassemia (β-thalassemia), and permit collection and banking of cord blood for future cell therapy. We have previously developed a single-gene NIPT method for SCD and β-thalassemia, with extensive analytic validation and initial clinical validation in our prior studies.B.What are the key findings?Our single-gene NIPT detection of SCD and β-thalassemia disease was 100% concordant with newborn screening follow-up data in 79 pregnancies at risk for beta hemoglobinopathies. Furthermore, a more stringent requirement, the detection of exact fetal genotype, was concordant in 67 out of 68 (98.5%) of pregnancies.C.What does this study add to what is already known?Our results validated that single-gene NIPT is an accurate and significantly improved screen for prenatal detection of SCD and β-thalassemia compared to current carrier screen workflow.

We investigate the rheological properties of interpenetrating networks reconstituted from the main cytoskeletal components: filamentous actin, microtubules, and vimentin intermediate filaments. The elastic modulus is determined largely by actin, with little contribution from either microtubules or vimentin. However, vimentin dramatically impacts the relaxation, with even small amounts significantly increasing the relaxation time of the interpenetrating network. This highly unusual decoupling between dissipation and elasticity may reflect weak attractive interactions between vimentin and actin networks.

Occasional sleeplessness in children is common, with as many as 25% of all healthy children experiencing a problem sleeping at some point over the course of their childhood. Occasional sleeplessness is poorly understood, has a significant impact on quality of life in children and their families, and is often challenging to manage. There is substantial evidence supporting the safe and effective use of the widely available dietary supplement melatonin for children with chronic conditions. This article summarizes the views expressed in a recent Consensus Panel meeting convened to evaluate the use of melatonin in children, as well as the published scientific literature related to the effectiveness and safety of melatonin, with a focus on occasional sleeplessness in healthy children. We provide an evidence-based framework for the implementation of a standard process to effectively manage occasional sleeplessness in children and adolescents. Unsubstantiated concerns in the past may have limited melatonin's use in children with conditions for which the supplement may support a better sleep pattern and, by doing so, may help to improve quality of life. Melatonin dietary supplements using high quality standards may be provided to children together with cognitive-behavioral therapy after proper sleep evaluation and after improved sleep hygiene, family education, and sleep diary activities have failed to resolve sleep difficulties. [ Pediatr Ann . 2021;50(9):e391–e395.]

Background: ADS-5102, a delayed-release, extended-release (DR/ER) amantadine, improved walking speed in MS in a Phase 2 trial. Objective: The aim of this study was to present primary results of a Phase 3, double-blind, ADS-5102 trial (INROADS) for walking speed. Methods: Adult participants with MS and walking impairment, not currently using amantadine or dalfampridine, underwent 4-week placebo run-in before randomization 1:1:1 to placebo, 137 or 274 mg/day ADS-5102 for 12 weeks. Primary outcome was the proportion of responders (20% increase in Timed 25-Foot Walk (T25FW) speed) for 274 mg ADS-5102 versus placebo at end of double-blind (Study Week 16). Additional measures included Timed Up and Go (TUG), 2-Minute Walk Test (2MWT), and 12-item Multiple Sclerosis Walking Scale (MSWS-12). Results: In total, 558 participants were randomized and received double-blind treatment. Significantly more participants responded with 274 mg ADS-5102 (21.1%) versus placebo (11.3%). Mean T25FW speed also significantly improved (0.19 ft/s) versus placebo (0.07 ft/s). Other measures were not significant using prespecified hierarchical testing procedure. Adverse events led to discontinuation for 3.8% (placebo), 6.4% (137 mg ADS-5102), and 20.5% (274 mg ADS-5102). Conclusion: INROADS met its primary endpoint, showing a significantly greater proportion of participants with meaningful improvement in walking speed for 274 mg ADS-5102 versus placebo. Numeric dose response was seen for some secondary efficacy outcomes and adverse events.

Naked mole-rats (Heterocephalus glaber) are small rodents native to east Africa, living in subterranean colonies of up to 300 individuals. Within each colony, reproduction is restricted to a single breeding female and 1-3 breeding males; all other colony members are reproductively suppressed and socially subordinate unless removed from the suppressive cues of the colony. Due to their striking reproductive skew, naked mole-rats are often considered eusocial mammals. Consistent with this idea, there are behavioral specializations and at least some evidence for morphological distinctions within and between the breeding and non-breeding members of the colony. Importantly, naked mole-rats show plasticity in their behavioral phenotype whereby changes in the social environment influence expression of both type and amount of social behavior. Thus, naked mole-rats provide the opportunity to examine the proximate mechanisms controlling individual differences in social behavior, shedding light on how mammals live in complex social groups.

Folates (also known as vitamin B9) have a critical role in cellular metabolism as the starting point in the synthesis of nucleic acids, amino acids and the universal methylating agent S-adenylsmethionine(1,2). Folate deficiency is associated with a number of developmental, immune and neurological disorders(3–5). Mammals cannot synthesize folates de novo; several systems have therefore evolved to take up folates from the diet and distribute them within the body(3,6). The proton-coupled folate transporter (PCFT) (also known as SLC46A1) mediates folate uptake across the intestinal brush border membrane and the choroid plexus(4,7), and is an important route for the delivery of antifolate drugs in cancer chemotherapy(8–10). How PCFT recognizes folates or antifolate agents is currently unclear. Here we present cryo-electron microscopy structures of PCFT in a substrate-free state and in complex with a new-generation antifolate drug (pemetrexed). Our results provide a structural basis for understanding antifolate recognition and provide insights into the pH-regulated mechanism of folate transport mediated by PCFT.

Lung transplant recipients (LTR) with Covid-19 may have higher mortality than non-lung solid organ transplant recipients (SOTR), but direct comparisons are limited. Risk factors for mortality specifically in LTR have not been explored. We performed a multicenter cohort study of adult SOTR with Covid-19 to compare mortality by 28-days between hospitalized LTR and non-lung SOTR. Multivariable logistic regression models were used to assess comorbidity-adjusted mortality among LTR vs. non-lung SOTR and to determine risk factors for death in LTR. Of 1,616 SOTR with Covid-19, 1,051 (65%) were hospitalized including 117/159 (74%) LTR and 934/1457 (64%) non-lung SOTR (p=0.02). Mortality was higher among LTR compared to non-lung SOTR (24% vs. 16%, respectively, p=0.035) and lung transplant was independently associated with death after adjusting for age and comorbidities (aOR 1.7, 95% CI 1.0-2.6, p=0.05). Among LTR, independent risk factors for mortality included single lung transplant (aOR 2.8, 95% CI 1.0-7.7, p=0.04) and chronic lung allograft dysfunction (aOR 3.6, 95% CI 1.0-12.4, p=0.05), but not age >65 years, heart failure, or obesity. Among SOTR hospitalized for Covid-19, LTR had higher mortality than non-lung SOTR. In LTR, single lung transplant and chronic allograft dysfunction were independently associated with mortality.

Resume Question Les repercussions de la maladie au coronavirus 2019 (COVID-19) sur la morbidite et la mortalite chez les enfants se sont revelees relativement faibles. Si un enfant se presente a ma clinique avec une fievre persistante et une hyperinflammation systemique sans aucune exposition connue a la COVID-19, quelle est la probabilite qu’il soit atteint du syndrome inflammatoire multisystemique de l’enfant (MIS-C)? Que sait-on actuellement du MIS-C et quel est le pronostic pour les enfants qui en souffrent? Reponse En plein cœur de la pandemie de la COVID-19, l’emergence d’un nouveau probleme presente encore une fois un defi additionnel aux cliniciens, aux professionnels de la sante publique et a la population pediatrique. Le syndrome inflammatoire multisystemique chez les enfants est rare, mais potentiellement grave, et il a ete observe chez des enfants dont la maladie a la COVID-19 a ete confirmee environ 2 a 6 semaines avant l’apparition des symptomes. Au nombre des signes et des symptomes courants figurent une fievre persistante, une hyperinflammation systemique, des malaises gastro-intestinaux (p. ex. douleurs abdominales, vomissements, diarrhee), des changements mucocutanes (p. ex. eruptions cutanees, conjonctivite), une cephalee ou une dysfonction cardiaque. Etant donne que de nombreux enfants sont asymptomatiques ou ne presentent que des symptomes legers de la COVID-19, le developpement du MIS-C peut sembler soudain et surprenant aux familles et aux medecins. Meme si les enfants atteints du MIS-C necessitent habituellement une hospitalisation, les issues sont largement favorables grâce a une reconnaissance rapide du syndrome et a une therapie intense.

Question A 12-year-old child underwent adenotonsillectomy for treatment of obstructive sleep apnea (OSA) but continues to snore at night and struggles with attentiveness at school. The child’s parent uses a continuous positive airway pressure (CPAP) machine at night and wonders whether the same therapy could be used in children. Answer Unlike in adults, pediatric OSA is commonly related to adenotonsillar hypertrophy and is often amenable to treatment with adenotonsillectomy. As an alternative to surgery or in cases of postsurgical persistence of OSA, CPAP has shown effectiveness in improving both polysomnographic parameters and daytime neurobehavioural symptoms in children with OSA. Adherence to CPAP therapy is a challenge in children and requires parental education and special considerations such as a mask acclimatization period.

IntroductionBrief Resolved Unexplained Events (BRUEs) are a common presentation among infants. While most of these events are benign and self-limited, guidelines published by the American Academy of Pediatrics inaccurately identify many patients as higher-risk of a serious underlying aetiology (positive predictive value 5%). Recently, new clinical prediction rules have been derived to more accurately stratify patients. This data were however geographically limited to the USA, with no large studies to date assessing the BRUE population in a different healthcare setting. The study’s aim is to describe the clinical management and outcomes of infants presenting to Canadian hospitals with BRUEs and to externally validate the BRUE clinical prediction rules in identified cases.Methods and analysisThis is a multicentre retrospective study, conducted within the Canadian Paediatric Inpatient Research Network (PIRN). Infants (The primary outcome will be the presence of a serious underlying illness. Secondary outcomes will include BRUE recurrence and length of hospital stay. We will describe the rates of hospital admissions and whether hospitalisation was associated with an earlier diagnosis or treatment. Variation across Canadian hospitals will be assessed using intraclass correlation coefficient. To validate the newly developed clinical prediction rule, measures of goodness of fit will be evaluated. For this validation, a sample size of 1182 is required to provide a power of 80% to detect patients with a serious underlying illness with a significance level of 5%.Ethics and disseminationEthics approval has been granted by the UBC Children’s and Women’s Research Board (H21-02357). The results of this study will be disseminated as peer-reviewed manuscripts and presentations at national and international conferences.

A person's daily nutrient intake and overall nutritional status are determined by a complex interplay of the types and amounts of foods ingested in combination with the timing and frequency of eating.The aim was to summarize frequency of eating occasion data examined by the 2020 Dietary Guidelines Advisory Committee, the macronutrient contributions they provide, and meal frequency relative to dietary quality among the US population (≥2 y), with a focus on sex, age, race/Hispanic origin, and income.Demographic and 24-h recall data from the 2013-2016 NHANES were examined. An eating occasion was defined as "any ingestive event (e.g., solid food, beverage, water) that is either energy yielding or non-energy yielding"; all eating occasions were further divided into discrete meals and snacks. Frequency of meals and snacks was defined as "the number of daily EOs [eating occasions]," respectively. Diet quality was assessed via the Healthy Eating Index (HEI)-2015.Most Americans consume 2 (28%) to 3 (64%) meals on a given day and90% consume 2 to 3 snacks on that day. Adult, Hispanic, and non-Hispanic Black and lower-income (131% family poverty-to-income ratio) Americans had a lower frequency of eating than children or adolescents, non-Hispanic White, and non-Hispanic Asian Americans and higher-income Americans, respectively. Americans who reported 3 meals on a given day consumed a diet higher in dietary quality than Americans who consumed 2 meals on a given day (HEI-2015: 61.0 vs. 55.0), regardless of population subgroup.The frequency of the types of eating occasions differs according to age, race and Hispanic origin, and income. Dietary quality is associated with the number of meals consumed. Healthy dietary patterns can be constructed in a variety of ways to suit different life stages, cultural practices, and income levels; improved diet quality and careful consideration of nutrient density when planning meals are warranted.

Background: The six-minute walk (6MW) test is a validated assessment method in Multiple Sclerosis (MS) research. While the total distance covered during six minutes (6MWTD) is often used as the standard measurement of gait capacity (i.e., the maximum distance one can achieve), we hypothesize that endurance (i.e., ability to maintain speed over a prolonged time) can be inferred by the gait speed trajectory (GST) during the 6MW test (6MWGST).Objective: To characterize group differences in 6MWGST between MS patients and healthy controls (HCs), and to assess information added by 6MWGST for discerning between MS patients and HCs.Methods: We performed a secondary data analysis on a cross-sectional cohort of 40 MS and 20 HC subjects with three repeated 6MW tests. We modeled 6MWGST using a linear mixed-effects model with time in minutes and replicated walks nested within individuals. We compared the discernibility of 6MWGST with that of conventional metrics using likelihood ratio tests and receiver operating characteristic (ROC) analysis on logistic regression models.Results: MS subjects showed a concave, quadratic GST during 6MW tests, slowing down more than the HC subjects, especially at the beginning of 6MW tests. Despite accelerating at the end of the 6MW, MS subjects were unable to attain or surpass their initial 6MW gait speeds. 6MWGST added useful information (p = 0.002) to the conventional metrics (e.g., 6MWTD) for discerning between MS and HC subjects, and increased the area under the ROC curve from 0.83 to 0.93 (p = 0.037).Conclusions: The distinctive 6MWGST pattern of MS patients provided increased discernibility compared with currently used gait metrics. Both gait capacity measured by the 6MWTD, and gait endurance measured by parameters of 6MWGST, are significant functional indicators for the MS population.

Intermediate filaments are integral components of the cytoskeleton in metazoan cells. Due to their specific viscoelastic properties they are principal contributors to flexibility and tear strength of cells and tissues. Vimentin, an intermediate filament protein expressed in fibroblasts and endothelial cells, assembles into ~11 nm thick biopolymers, that are involved in a wide variety of cellular functions in health and disease. Here, we reveal the structure of in-situ polymerized vimentin filaments to a subnanometer resolution by applying cryo-electron tomography to mouse embryonic fibroblasts grown on electron microscopy grids. We show that vimentin filaments are tube-like assemblies with a well-defined helical symmetry. Their structure is comprised of five octameric, spring-like protofibrils harboring 40 vimentin polypeptide chains in cross-section. The protofibrils are connected by the intrinsically disordered head and helix 1A domains of vimentin. Individual filaments display two polymerization states characterized by either the presence or absence of a luminal density along the helical axis. The structure of vimentin filaments unveils the generic building plan of the intermediate filament superfamily in molecular details.

BACKGROUNDCoronavirus disease 2019 (COVID-19) is associated with endothelial activation and coagulopathy, which may be related to pre-existing or infection-induced pro-thrombotic autoantibodies such as those targeting angiotensin II type I receptor (AT1R-Ab).METHODSWe compared prevalence and levels of AT1R-Ab in COVID-19 cases with mild or severe disease to age and sex matched negative controls.RESULTSThere were no significant differences between cases and controls. However, there were trends toward a higher proportion with AT1R-Ab positivity among severe cases versus controls (32% vs. 11%, p=0.1) and higher levels in those with mild COVID-19 compared to controls (median 9.5U/mL vs. 5.9U/mL, p=0.06).CONCLUSIONSThese findings suggest that AT1R-Ab are not consistently associated with COVID-19 but do not exclude a contribution to endothelial pathology in a subset of people.

Keratin intermediate filaments are an essential and major component of the cytoskeleton in epithelial cells. They form a stable yet dynamic filamentous network extending from the nucleus to the cell periphery. Keratin filaments provide cellular resistance to mechanical stresses, ensure cell and tissue integrity in addition to regulatory functions. Mutations in keratin genes are related to a variety of epithelial tissue diseases that mostly affect skin and hair. Despite their importance, the molecular structure of keratin filaments remains largely unknown. In this study, we analyzed the structure of keratin 5/keratin 14 filaments within ghost keratinocytes by cryo-electron microscopy and cryo-electron tomography. By averaging a large number of keratin segments, we have gained insights into the helical architecture of the filaments. Interestingly, two-dimensional classification revealed profound variations in the diameter of keratin filaments and their subunit organization. Reconstitution of filaments of substantial length from keratin segments uncovered a high degree of internal heterogeneity along single filaments, which can contain regions of helical symmetry, regions with less symmetry and regions with significant diameter fluctuations. Cross section views of filaments revealed that keratins form hollow cylinders consisting of multiple protofilaments, with an electron dense core located in the center of the filament. These findings shed light on the complex architecture of keratin filaments, which demonstrate a remarkable degree of heterogeneity, suggesting that they are highly flexible, dynamic cytoskeletal structures.

The objective of this study was to estimate the impact of the coronavirus disease 2019 pandemic on pediatric emergency department (PED) visits after declaration of stay-at-home orders within British Columbia, Canada, and the change in cases by acuity and age for 6 months during the pandemic.Retrospective data on PED visits at British Columbia Children's Hospital were collected between December 1, 2019, and August 31, 2020, and for 2 previous years. An interrupted time-series analysis was performed to estimate the difference in daily visits after stay-at-home orders on March 17, 2020, as well as before and after. Further analysis was performed to estimate the drop and recovery of admission and visits by age and acuity.After adjustment for year and seasonality, we documented a drop in the expected number of daily visits of 83 (95% confidence interval [CI], 78-89) after stay-at-home orders. Thereafter, daily visits increased by 12.9 (95% CI, 11.3-14.4) every month. Probability of admission adjusted for seasonality and acuity increased 6.9% (95% CI, 4.9%-9.0%) after stay-at-home orders and decreased in the odds of -0.7% (95% CI, -1% to -0.4%) monthly thereafter.The coronavirus disease 2019 pandemic has had a dramatic and lasting impact on the number of PED visits, with contracted rates 6 months into the pandemic. Further increase in acuity-adjusted rate of admissions after stay at home orders suggests that individuals may be delaying arrival to the emergency department. Further assessment is needed to determine if patients are seeking care through other venues or not seeking care altogether.

Neonates with hypoxic-ischemic encephalopathy (HIE) on therapeutic hypothermia (TH) therapy may show persistent pulmonary hypertension of the newborn (PPHN). In Japan, the reported mortality rate is lower than in the US, possibly due to treatment differences of newborns with moderate to severe HIE and PPHN. This study aimed to determine the feasibility and long-term outcomes of inhaled nitric oxide (iNO) and TH therapy in newborns with moderate to severe HIE and PPHN.This was a retrospective review of neonates with moderate to severe HIE that were treated with TH from 2008 to 2017 at a large medical center in Japan. We documented their long-term neurological prognosis, measuring their developmental and Gross Motor Function Classification System level at 18 months old.A total of 37 neonates with moderate to severe HIE underwent TH therapy and six of them were started with iNO therapy for PPHN. iNO with TH was safely administered to all six newborns with moderate to severe HIE with PPHN. In two neonates TH was discontinued because of intraventricular hemorrhage (IVH) and severe hypotension. Neurological outcomes were similar in newborns who were treated with iNO and TH and those who were treated with TH alone.These initial findings suggest that monitoring hematological and cardiovascular status is important with iNO for severe asphyxia in infants with PPHN. Safer and more feasible protocols are needed for when iNO and TH therapy are administered together.

The ability of a cell to regulate its mechanical properties is central to its function. Emerging evidence suggests that interactions between the cell nucleus and cytoskeleton influence cell mechanics through poorly understood mechanisms. Here we show that A- and B-type nuclear lamin isoforms distinctively modulate both nuclear and cellular volume and selectively stabilize the linker of nucleoskeleton and cytoskeleton (LINC) complexes that couple the nucleus to cytoskeletal actin and vimentin. We reveal, further, that loss of each of the four-known lamin isoforms in the mouse embryonic fibroblasts differentially affects cortical and cytoplasmic stiffness as well as cellular contractility, and then propose a LINC complex mediated model that explains these impaired mechanical phenotypes. Finally, we demonstrate that loss of each lamin isoform softens the nucleus in a manner that correlates with loss of heterochromatin. Together, these findings uncover distinctive roles for each lamin isoform in maintaining cellular and nuclear mechanics.

AIMS OF THE STUDY The COVID-19 pandemic is likely to overlap with the seasonal influenza epidemic, increasing the risk of overextending the health system capacity in Switzerland. Influenza vaccine uptake has remained low in most countries, including Switzerland. The aim of the study was to determine parents’ intentions towards influenza vaccination of their children, as well as themselves, and to assess regional differences. METHODS Parents presenting to four paediatric emergency departments (Zurich, Bern, Bellinzona, Geneva) were asked to complete an online survey during and after the first lockdown of the COVID-19 pandemic (April to June 2020). The anonymised survey included demographic information, vaccination history and intentions to vaccinate against influenza, as well as attitudes towards future vaccination against COVID-19. RESULTS The majority of children (92%; 602/654) were up-to-date on their vaccination schedule. In 2019/2020, 7.2% (47/654) were vaccinated against influenza. Children with chronic illnesses were more frequently vaccinated than healthy children (19.2% vs 5.6%; p = 0.002). For the coming winter season, 111 (17%) parents stated they plan to vaccinate their children against influenza, more than double the rate from last year, and 383 (59.2%) parents suggested they will vaccinate against COVID-19 once a vaccine is available. Regional differences between “German” and “Latin” Switzerland were found for parents’ intent to have their children vaccinated against influenza next season (Zurich and Bern 14.3%, Bellinzona and Geneva 27.2%, p

BackgroundThe efficacy and safety of baricitinib, an oral selective Janus kinase 1/2 inhibitor, in addition to standard of care (SOC) in hospitalised adults with COVID-19 is unknown.MethodsIn this phase 3, global, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America (ClinicalTrials.govNCT04421027). Hospitalised adults with COVID-19 receiving SOC were randomly assigned (1:1) to once-daily baricitinib 4-mg or placebo for up to 14 days. SOC included systemic corticosteroids in 79·3% of participants (dexamethasone ∼90%). The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28. All-cause mortality by days 28 and 60 were key secondary and exploratory endpoints, respectively. Efficacy and safety analyses included the intent-to-treat and safety populations, respectively.FindingsBetween June 11, 2020 and January 15, 2021, 1525 participants were randomly assigned to baricitinib 4-mg (n=764) or matched placebo (n=761). Overall, 27·8% of participants receiving baricitinib vs 30·5% receiving placebo progressed (primary endpoint, odds ratio 0·85, 95% CI 0·67-1·08; p=0·18). The 28-day all-cause mortality was 8·1% (n=62) for baricitinib and 13·1% (n=100) for placebo, corresponding to a 38·2% reduction in mortality (hazard ratio [HR] 0·57, 95% CI 0·41-0·78; nominal p=0·0018). The 60-day all-cause mortality was 10·3% (n=79) for baricitinib and 15·2% (n=116) for placebo (HR 0·62, 95% CI 0·47-0·83; p=0·0050). Frequency of serious adverse events (14·7% [n=110] vs 18·0% [n=135]), serious infections (8·5% [n=64] vs 9·8% [n=74]), and venous thromboembolic events (2·7% [n=20] vs 2·5% [n=19]) was similar between baricitinib and placebo, respectively.InterpretationWhile reduction of disease progression did not achieve statistical significance, treatment with baricitinib in addition to SOC (including dexamethasone) significantly reduced mortality, with a similar safety profile to SOC, in hospitalised COVID-19 participants.FundingEli Lilly and Company.Research in contextEvidence before this studyWe searched PubMed using the terms “COVID-19”, “SARS-CoV-2”, “treatment”, “baricitinib” and “JAK inhibitor” for articles in English published up to April 31, 2020, regardless of article type. We considered previous and current clinical trials of investigational medications in COVID-19, as well as previous clinical trials of the Janus kinase (JAK)1 and JAK2 inhibitor, baricitinib, before undertaking this study. At the time the COV-BARRIER study was designed, there were no approved therapies for the treatment of COVID-19. Management of COVID-19 was supportive, and limited phase 3 randomised placebo-controlled studies had been completed. Limited phase 2 and 3 data on the antimalarial hydroxychloroquine and protease inhibitor lopinavir/ritonavir were available, and trials investigating the use of the antiviral remdesivir were ongoing. Baricitinib’s mechanism of action as a JAK1 and JAK2 inhibitor was identified as a potential intervention for the treatment of COVID-19 given its known anti-cytokine properties and potential for targeting host proteins for its antiviral mechanism. Additionally, early case series evaluating the efficacy and safety of baricitinib in the hospitalised patient population supported further evaluation of baricitinib as a potential treatment option for hospitalised patients with COVID-19. While COV-BARRIER was enrolling, ACTT-2, a phase 3 study evaluating baricitinib plus remdesivir was completed showing that baricitinib added to remdesivir improved time to recovery and other outcomes.Added value of this studyThis was the first phase 3 study to evaluate baricitinib in addition to the current standard of care (SOC) and included antivirals, anticoagulants, and corticosteroids. After the earliest publication of the RECOVERY study in June 2020, the treatment of hospitalised patients with COVID-19 changed with the adoption of dexamethasone as SOC. As a result of its design, COV-BARRIER became the first trial to evaluate the benefit/risk of baricitinib when added to the most current SOC (dexamethasone) in these patients. This was a randomised, double-blind, placebo-controlled trial conducted globally in regions with high COVID-19 hospitalisation rates. The reduction in the composite primary endpoint of progression to non-invasive ventilation, high flow oxygen, invasive mechanical ventilation, or death for baricitinib plus SOC (including dexamethasone) compared to placebo plus SOC did not reach statistical significance. However, in a pre-specified key secondary endpoint, treatment with baricitinib reduced 28-day all-cause mortality by 38·2% compared to placebo (HR 0·57, 95% CI 0·41-0·78; nominal p=0·0018); one additional death was prevented per 20 baricitinib-treated participants. The reduction of all-cause mortality with baricitinib was maintained by day 60 in an exploratory analysis. The frequency of serious adverse events, serious infections, and venous thromboembolic events was similar between baricitinib and placebo, respectively.Implications of all the available evidenceIn this phase 3 trial, baricitinib given in addition to SOC (which predominantly included dexamethasone) did not reduce a composite endpoint of disease progression, but showed a strong effect on reducing mortality by 28 days, an effect which was maintained by 60 days. In the ACTT-2 study, baricitinib further reduced time to recovery above the background use of remdesivir. Taken together, these findings suggest that baricitinib has synergistic effects to other SOC treatment modalities including remdesivir and dexamethasone. Based on all available evidence, baricitinib is a potentially effective oral treatment option to decrease mortality in hospitalised patients with COVID-19.

QUESTION: With the approval of coronavirus disease 2019 (COVID-19) vaccine for children 5 to 11 years of age and concerns among parents in the past year following reported cases of myocarditis and pericarditis in adolescents, should my office continue to encourage all children and young adults to receive the COVID-19 messenger RNA vaccine? ANSWER: Since April 2021 reports have documented cases of myocarditis and pericarditis in adolescents and young adults after messenger RNA COVID-19 vaccination, and several hundred such reports were documented in Canada. Clinical presentations were mostly mild, with rare instances of admission to the hospital, and were typically among male adolescents 16 years of age and older within several days after the second dose of the vaccine. After vaccination, children and adolescents with symptoms of chest pain, shortness of breath, or palpitations should be evaluated with a physical examination, an electrocardiogram, and measurement of cardiac troponin levels. If results are abnormal, an echocardiogram or cardiac magnetic resonance imaging should be considered. Myocarditis and pericarditis after vaccination are much less common, and much milder, than cardiac complications of COVID-19 infection, and vaccines should continue to be recommended to all those eligible.

In many developmental and pathological processes, including cellular migration during normal development and invasion in cancer metastasis, cells are required to withstand severe deformations. The structural integrity of eukaryotic cells under small deformations has been known to depend on the cytoskeleton including actin filaments (F-actin), microtubules (MT), and intermediate filaments (IFs). However, it remains unclear how cells resist severe deformations since both F-actin and microtubules yield or disassemble under moderate strains. Using vimentin containing IFs (VIFs) as a model for studying the large family of IF proteins, we demonstrate that they dominate cytoplasmic mechanics and maintain cell viability at large deformations. Our results show that cytoskeletal VIFs form a stretchable, hyperelastic network in living cells. This network works synergistically with other cytoplasmic components, substantially enhancing the strength, stretchability, resilience, and toughness of cells. Moreover, we find the hyperelastic VIF network, together with other quickly recoverable cytoskeletal components, forms a mechanically robust structure which can mechanically recover after damage.

The nucleus houses, organizes, and protects chromatin to ensure genome integrity and proper gene expression, but how the nucleus adapts mechanically to changes in the extracellular environment is poorly understood. Recent studies have revealed that extracellular physical stresses induce chromatin compaction via mechanotransductive processes. We report that increased extracellular multivalent cations lead to increased heterochromatin levels through activation of mechanosensitive ion channels, without large-scale cell stretching. In cells with perturbed chromatin or lamins, this increase in heterochromatin suppresses nuclear blebbing associated with nuclear rupture and DNA damage. Through micromanipulation force measurements, we show that this increase in heterochromatin increases chromatin-based nuclear rigidity, which protects nuclear morphology and function. In addition, transduction of elevated extracellular cations rescues nuclear morphology in model and patient cells of human diseases, including progeria and the breast cancer model cell line MDA-MB-231. We conclude that nuclear mechanics, morphology, and function can be modulated by cell sensing of the extracellular environment through mechanosensitive ion channels and consequent changes to histone modification state and chromatin-based nuclear rigidity.

Cortical structure has been consistently related to cognitive abilities in children and adults, yet we know little about how the cortex develops to support emergent cognition in infancy and toddlerhood when cortical thickness (CT) and surface area (SA) are maturing rapidly. In this report, we assessed how regional and global measures of CT and SA in a sample (N = 487) of healthy neonates, 1-year-olds, and 2-year-olds related to motor, language, visual reception, and general cognitive ability. We report novel findings that thicker cortices at ages 1 and 2 and larger SA at birth, age 1, and age 2 confer a cognitive advantage in infancy and toddlerhood. While several expected brain–cognition relationships were observed, overlapping cortical regions were also implicated across cognitive domains, suggesting that infancy marks a period of plasticity and refinement in cortical structure to support burgeoning motor, language, and cognitive abilities. CT may be a particularly important morphological indicator of ability, but its impact on cognition is relatively weak when compared with gestational age and maternal education. Findings suggest that prenatal and early postnatal cortical developments are important for cognition in infants and toddlers but should be considered in relation to other child and demographic factors.

Background In Japan, blood cultures for children are performed by pediatric residents, and povidone-iodine (PI) is the recommended solution for skin preparation. Given that PI needs to be applied for 1.5-2 min before venipuncture, skin preparation may be suboptimal if this is not followed. In this study, we investigated the blood culture contamination rate after skin preparation with only 70% isopropyl alcohol (IPA) or IPA plus PI. Methods We performed a retrospective study of patients aged ≤6 years who provided blood cultures in the emergency department or pediatric ward. Patients with indwelling central venous catheter were excluded. We evaluated the impact of changing the method of skin preparation, comparing the traditional method using IPA plus PI between 2008 and 2010 (IPA + PI group) with the simplified method using only IPA between 2015 and 2017 (IPA group). Results A total of 5,365 blood culture samples were eligible for this study. Of these, 171 (3.2%) had an organism identified in blood culture. Of the blood culture-positive samples, 68 (1.3%) were true positive and 103 (1.9%) were contaminated. Thirty-eight (1.6%) of 2,407 cultures in the IPA group were contaminated, whereas 65 (2.2%) of 2,958 cultures in the IPA + PI group were contaminated (OR, 0.72; 95%CI: 0.48-1.07; P = 0.1). Coagulase-negative Staphylococcus grew significantly less in the IPA group (1.7% vs 1.0%, P = 0.02). Conclusions A single application of 70% IPA may be the optimal skin preparation method for obtaining peripheral blood cultures from children in Japan.

Neutrophil (PMN) infiltration of the intestinal mucosa is a hallmark of tissue injury associated with inflammatory bowel diseases (IBDs). The pathological effects of PMNs are largely attributed to the release of soluble mediators and reactive oxygen species (ROS). We identified what we believe is a new, ROS-independent mechanism whereby activated tissue-infiltrating PMNs release microparticles armed with proinflammatory microRNAs (miR-23a and miR-155). Using IBD clinical samples, and in vitro and in vivo injury models, we show that PMN-derived miR-23a and miR-155 promote accumulation of double-strand breaks (DSBs) by inducing lamin B1-dependent replication fork collapse and inhibition of homologous recombination (HR) by targeting HR-regulator RAD51. DSB accumulation in injured epithelium led to impaired colonic healing and genomic instability. Targeted inhibition of miR-23a and miR-155 in cultured intestinal epithelial cells and in acutely injured mucosa decreased the detrimental effects of PMNs and enhanced tissue healing responses, suggesting that this approach can be used in therapies aimed at resolution of inflammation, in wound healing, and potentially to prevent neoplasia.

Recently, there has been a surge of interest in the possibility that microbial communities inhabiting the human gut could affect cognitive development and increase risk for mental illness via the “microbiome-gut-brain axis”. Infancy likely represents a critical period for the establishment of these relationships, as it is the most dynamic stage of postnatal brain development and a key period in the maturation of the microbiome. Indeed, recent reports indicate that characteristics of the infant gut microbiome are associated with both temperament and cognitive performance. The neural circuits underlying these relationships have not yet been delineated. To address this gap, resting-state fMRI scans were acquired from 39 one-year-old human infants who had provided fecal samples for identification and relative quantification of bacterial taxa. Measures of alpha diversity were generated and tested for associations with measures of functional connectivity. Primary analyses focused on the amygdala as manipulation of the gut microbiota in animal models alters the structure and neurochemistry of this brain region. Secondary analyses explored functional connectivity of nine canonical resting state functional networks. Alpha diversity was significantly associated with functional connectivity between the amygdala and thalamus and between the anterior cingulate cortex and anterior insula. These regions play an important role in processing/responding to threat. Alpha diversity was also associated with functional connectivity between the supplementary motor area (SMA, representing the sensorimotor network) and the inferior parietal lobule (IPL). Importantly, SMA-IPL connectivity also related to cognitive outcomes at 2 years of age, suggesting a potential pathway linking gut microbiome diversity and cognitive outcomes during infancy. These results provide exciting new insights into the gut-brain axis during early human development and should stimulate further studies into whether microbiome–associated changes in brain circuitry influence later risk for psychopathology.

OBJECTIVES Accurate assessment of pain in young children is challenging. An Emotion Application Programing Interface (API) can analyze and report 8 emotions from facial images. Each emotion ranges between 0 (no correlation) to 1 (greatest correlation). We evaluated correlation between the Emotion API with the FLACC scale (face, lets, activity, cry, and consolability) among children younger than 6 years old during blood sampling. METHODS Prospective pilot exploratory study in children during blood sampling. Pictures with facial expressions were uploaded to Emotion API program. Primary outcome was the correlation coefficient between FLACC scale and emotions. Secondary outcomes included maximal correlation of each emotion for 3 pictures-before, during and after needle penetration; and the average of each emotion for 9 pictures-4 before, 1 during and 4 after needle penetration to the skin. RESULTS A total of 77 children were included. During needle penetration, SADNESS was significantly correlated (0.887, P

Question Several children in my office have recurrent vomiting events and they usually end up in the emergency department for intravenous rehydration. One of them has been suffering from those attacks approximately once per month for the past 2 years, leading to a reduction in her quality of life. What is known about cyclic vomiting syndrome and can it be prevented? Answer Cyclic vomiting syndrome includes severe episodic vomiting lasting for hours or days, separated by symptom-free intervals. This gut-brain interaction is poorly understood and is difficult to diagnose. Children suffer from relentless vomiting, lethargy, abdominal pain, anorexia, and nausea. Half of the children require intravenous rehydration. Once diagnosis is made, supportive measures to reduce suffering are recommended and include administering fluids, encouraging sleep, promoting quiet environments, and administering antiemetics or sedatives. In adults, tricyclic antidepressants such as amitriptyline, as well as topiramate as second-line therapy, have been proposed for prophylactic treatment. However, pediatric data are very limited and evidence does not support any recommended course of prophylactic therapy for children with the condition.

Evening eating has been associated with higher energy intake and lower nutrient density. However, these qualities may not characterize all late evening (LE) eating patterns.We sought to characterize US adults' LE eating patterns on a given day and identify differences, if any, in pattern-specific associations with, and impact on, daily energy intake and total diet quality.LE eating patterns, energy intakes, and Healthy Eating Index (HEI) scores were identified using Day-1 dietary recall data from the cross-sectional National Health and Nutrition Examination Survey 2013-2016.The sample included adults aged ≥ 20 years (n = 9,861). LE reporters were respondents who consumed foods/beverages between 20:00 and 23:59 on the intake day.Energy intake and HEI-2015 scores by LE status/pattern and the impact of LE consumption on these measures.Cluster analysis assigned individuals to LE eating patterns based on the LE energy contribution of food/beverage groups. Regression models estimated energy intake and HEI-2015 scores; estimates were compared between LE reporters and nonreporters. Similarly, LE's contribution to total energy and the difference in total HEI inclusive vs exclusive of LE consumption were estimated and compared among patterns.Among US adults, 64.4% were LE reporters. Eleven LE patterns were identified; the six most prevalent patterns (representing 89% of LE reporters) were further analyzed. Daily energy intake in all prevalent patterns except the fruit pattern exceeded that of nonreporters by ≥ 268 kcal (unadjusted; P0.001), varying by pattern. Conversely, total HEI score did not differ from that of nonreporters (51.0) in any pattern except the fruit pattern, where it was higher (57.4, unadjusted; P0.001). Generally, LE consumption's impact on energy was high and its impact on HEI scores was low.Late evening food/beverage consumption is common among US adults, and LE patterns are not monolithic in their associations with, and impact on, total energy intake and dietary quality.

There are limited data on direct‐acting antiviral (DAA) treatment options for previously treated patients with recurrent genotype 3 (GT3) hepatitis C virus (HCV) after liver transplantation. Sofosbuvir/velpatasvir/voxilaprevir (SOF/VEL/VOX) is currently approved for treatment of HCV in patients with prior treatment with DAAs. We report the first published experience using SOF/VEL/VOX after liver transplantation for a DAA‐experienced patient with severe hepatitis due to early recurrent GT3 HCV. The patient was treated with SOF/VEL/VOX that was extended to a total duration of 16 weeks and was intensified with ribavirin (RBV) starting at week 8 due to persistent viremia during treatment. Sustained virologic response at 12 weeks (SVR12) after treatment completion was achieved. SOF/VEL/VOX was well tolerated, and immediate drug–drug interaction (DDI) with tacrolimus (TAC) was not evident. Due to improvement in liver metabolic function with increasing TAC clearance, TAC dose adjustment was required throughout the treatment course. Conclusion: SOF/VEL/VOX can be considered for treatment of recurrent HCV after transplantation. Further study is needed to establish safety and efficacy and define treatment duration in difficult‐to‐treat populations.

BACKGROUND Benzodiazepine and antipsychotic use for acute management of agitation and aggression in the pediatric emergency department (ED) setting has not been well described. OBJECTIVES To describe medication utilization in the management of agitation and aggression in a pediatric ED and to assess the safety of their use. METHODS This was a retrospective observational study. Patients less than 20 years of age who presented to our pediatric ED and had agitation or aggression as part of their chief complaint were included if they received at least 1 dose of benzodiazepine or antipsychotic. Outcomes included frequency of benzodiazepine and antipsychotic use, dosing of medications, and reported adverse events. RESULTS During the 5-year study period, there were 128 visits of 120 patients who met the inclusion criteria. Lorazepam was most commonly given (70%), followed by chlorpromazine (20%). Most patients (82%) required a single dose of medication. Intoxication was associated with needing more than 1 dose of medication. Patients with autism or Asperger syndrome were more likely to receive an antipsychotic medication compared to not having these conditions (75% vs. 28%, respectively). Adverse events were documented in 6 visits: oxygen desaturation (n = 1), dizziness and nausea (n = 2), dizziness (n = 1), and paradoxical excitation (n = 2). The Naranjo Score indicated a probable adverse drug reaction for the cases of paradoxical excitation. CONCLUSIONS Benzodiazepine and antipsychotic drug therapy for acute agitation and aggression in children appears to be safe and well tolerated when used as a single agent and at the recommended doses in this setting.