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BACKGROUND Mohs micrographic surgery (MMS) for cutaneous melanoma is becoming more prevalent, but surgical technique varies. OBJECTIVE To define variations in published techniques for MMS for melanoma. METHODS AND MATERIALS A systematic review was performed of PubMed, EMBASE, and Scopus databases to identify all articles describing surgical techniques for MMS for melanoma. Technical details were recorded for the preoperative, intraoperative, and postoperative phases of MMS. RESULTS Twenty-four articles were included. Mohs surgeons vary in how they assess clinical margins, how wide a margin they excise on the first MMS layer, and how they process tissue to determine tumor stage and margin clearance during MMS for melanoma. CONCLUSION Mohs micrographic surgery for melanoma is performed with varied surgical techniques. To establish best practices, additional research is necessary to determine how different techniques affect outcomes.

CE Information Activity Available Online: To access the article, post-test, and evaluation online, go to https://www.highmarksce.com/mscare. Target Audience: The target audience for this activity is physicians, physician assistants, nursing professionals, pharmacists, and other health care providers involved in the management of patients with multiple sclerosis (MS). Learning Objectives: 1) Describe the characteristic factors of MS disease that can confound the identification of symptomatic urinary tract infection (UTI). 2) Distinguish appropriate, potentially appropriate, and inappropriate testing and treatment practices for the diagnosis and treatment of UTIs in patients with MS. Accreditation Statement: In support of improving patient care, this activity has been planned and implemented by the Consortium of Multiple Sclerosis Centers (CMSC) and Delaware Media Group. The CMSC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team. Physician Credit: The CMSC designates this journal-based activity for a maximum of 0.5 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Nurse Credit: The CMSC designates this enduring material for 0.5 contact hour of nursing continuing professional development (NCPD) (none in the area of pharmacology). Pharmacist Credit: This knowledge-based activity (UAN # JA4008165-9999-21-021-H01-P) qualifies for 0.5 contact hour (0.05 CEUs) of continuing pharmacy education credit. Disclosures: Francois Bethoux, MD, Editor in Chief of the International Journal of MS Care (IJMSC), has served as Physician Planner for this activity. He has disclosed relationships with Springer Publishing (royalty); Qr8 (receipt of intellectual property rights/patent holder); Biogen (receipt of intellectual property rights/patent holder, speakers' bureau); MedRhythms (consulting fee, contracted research); GW Pharmaceuticals, Genentech, Helius Medical Technologies, Osmotica, Ipsen (consulting fee); and Adamas Pharmaceuticals (contracted research). Alissa Mary Willis, MD, Associate Editor of IJMSC, has disclosed relationships with Greenwich Biosciences (consulting fee); Alexion (consulting fee, speakers' bureau, contracted research); Genentech (consulting fee, speakers' bureau); and Biogen, Bristol Myers Squibb (speakers' bureau). Nicole C. Griffith, PharmD, has disclosed no relevant financial relationships. Brandon K. Hill, PharmD, has disclosed no relevant financial relationships. Myla D. Goldman, MD, has disclosed relationships with Adamas Pharmaceuticals, Biogen, Brainstorm Cell Therapeutics Ltd, EMD Serono, Genentech, Greenwich Biosciences, Immunic, MedDay, and Sanofi Genzyme (consulting fees). S. Ross Tingen, PharmD, has disclosed a relationship with Novartis (advisory board). The staff at IJMSC, CMSC, and Delaware Media Group who are in a position to influence content have disclosed no relevant financial relationships. Laurie Scudder, DNP, NP, Continuing Education Director CMSC, has served as Reviewer for this activity. She has disclosed no relevant financial relationships. One peer reviewer for IJMSC has disclosed relationships with EMD Serono, Novartis, Bristol Myers Squibb, and Genentech (consulting fees). The other peer reviewer has disclosed no relevant financial relationships. Note: Financial relationships may have changed in the interval between listing these disclosures and publication of the article. Method of Participation: Release Date: October 1, 2021 Valid for Credit Through: October 1, 2022 In order to receive CME/NCPD/CPE credit, participants must: 1) Review the continuing education information, including learning objectives and author disclosures.2) Study the educational content.3) Complete the post-test and evaluation, which are available at https://www.highmarksce.com/mscare. Statements of Credit are awarded upon successful completion of the evaluation and the post-test with a passing score of >70%. The post-test may be retaken if necessary. There is no fee to participate in this activity. Disclosure of Unlabeled Use: This educational activity may contain discussion of published and/or investigational uses of agents that are not approved by the FDA. The CMSC and Delaware Media Group do not recommend the use of any agent outside of the labeled indications. The opinions expressed in the educational activity are those of the faculty and do not necessarily represent the views of the CMSC or Delaware Media Group. Disclaimer: Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and their own professional development. The information presented in this activity is not meant to serve as a guideline for patient management. Any medications, diagnostic procedures, or treatments discussed in this publication should not be used by clinicians or other health care professionals without first evaluating their patients' conditions, considering possible contraindications or risks, reviewing any applicable manufacturer's product information, and comparing any therapeutic approach with the recommendations of other authorities.

Background Virtual reality has been used to alleviate pain and anxiety in a variety of medical procedures. The authors sought to explore the effects of virtual reality in common awake minor plastic surgery procedures where children may experience discomfort. Methods A randomized controlled trial compared virtual reality to standard-of-care distraction among children aged 6 to 16 years undergoing awake minor plastic surgery procedures at a quaternary children's hospital. Primary outcome was change in Faces Pain Scale-Revised pain score, and secondary outcomes included change in Venham Situational Anxiety Scale score, procedure duration, administration of local anesthetic, and pain/anxiety management satisfaction. Results Mean pain and anxiety scores were similar in both groups (p = 0.60 and p = 0.18, respectively), and procedure duration was shorter with virtual reality (22 minutes versus 29 minutes; p = 0.002). Duration remained shorter in a linear regression model accounting for procedure type (p = 0.01). Similar proportions of children received additional local anesthetic after the initial dose (virtual reality, n = 6; standard of care, n = 9; p = 0.19) and median pain management satisfaction was similar (virtual reality, 9 of 10; standard of care, 9 of 10; p = 0.41). Median anxiety management satisfaction was similar (virtual reality, 9 of 10; standard of care, 9 of 10; p = 0.05). Younger children reported more "fun" than older children with virtual reality (p = 0.02). Surgeons reported interest "using virtual reality again" in 83 percent of cases. Conclusions The use of virtual reality for awake pediatric plastic surgery reduced procedure time but not pain or anxiety compared to standard of care in children aged 6 to 16 years. Virtual reality was safe and well-liked and should be considered as an additional tool. Increased efficiency may allow more cases to be performed. Clinical question/level of evidence Therapeutic, II.

In recent years, the number of patients presenting to the emergency department with mental health complaints has been growing, alongside an increase in second-generation antipsychotic (SGAs) prescriptions for a variety of mental health conditions. Children treated with SGAs may have abnormalities, such as rapid weight gain and central adiposity, glucose intolerance, dyslipidemia, and hypertension; they may present to the pediatric emergency department with components of metabolic syndrome or type 2 diabetes, and a subsequent significant risk for cardiovascular complications later in life. Pediatric emergency department providers may serve as a safety net for patients to detect SGA-related metabolic complications, especially among vulnerable populations lacking access to primary care or psychiatric services.

Summary Background Baricitinib is an oral selective Janus kinase 1/2 inhibitor with known anti-inflammatory properties. This study evaluates the efficacy and safety of baricitinib in combination with standard of care for the treatment of hospitalised adults with COVID-19. Methods In this phase 3, double-blind, randomised, placebo-controlled trial, participants were enrolled from 101 centres across 12 countries in Asia, Europe, North America, and South America. Hospitalised adults with COVID-19 receiving standard of care were randomly assigned (1:1) to receive once-daily baricitinib (4 mg) or matched placebo for up to 14 days. Standard of care included systemic corticosteroids, such as dexamethasone, and antivirals, including remdesivir. The composite primary endpoint was the proportion who progressed to high-flow oxygen, non-invasive ventilation, invasive mechanical ventilation, or death by day 28, assessed in the intention-to-treat population. All-cause mortality by day 28 was a key secondary endpoint, and all-cause mortality by day 60 was an exploratory endpoint; both were assessed in the intention-to-treat population. Safety analyses were done in the safety population defined as all randomly allocated participants who received at least one dose of study drug and who were not lost to follow-up before the first post-baseline visit. This study is registered with ClinicalTrials.gov , NCT04421027 . Findings Between June 11, 2020, and Jan 15, 2021, 1525 participants were randomly assigned to the baricitinib group (n=764) or the placebo group (n=761). 1204 (79·3%) of 1518 participants with available data were receiving systemic corticosteroids at baseline, of whom 1099 (91·3%) were on dexamethasone; 287 (18·9%) participants were receiving remdesivir. Overall, 27·8% of participants receiving baricitinib and 30·5% receiving placebo progressed to meet the primary endpoint (odds ratio 0·85 [95% CI 0·67 to 1·08], p=0·18), with an absolute risk difference of −2·7 percentage points (95% CI −7·3 to 1·9). The 28-day all-cause mortality was 8% (n=62) for baricitinib and 13% (n=100) for placebo (hazard ratio [HR] 0·57 [95% CI 0·41–0·78]; nominal p=0·0018), a 38·2% relative reduction in mortality; one additional death was prevented per 20 baricitinib-treated participants. The 60-day all-cause mortality was 10% (n=79) for baricitinib and 15% (n=116) for placebo (HR 0·62 [95% CI 0·47–0·83]; p=0·0050). The frequencies of serious adverse events (110 [15%] of 750 in the baricitinib group vs 135 [18%] of 752 in the placebo group), serious infections (64 [9%] vs 74 [10%]), and venous thromboembolic events (20 [3%] vs 19 [3%]) were similar between the two groups. Interpretation Although there was no significant reduction in the frequency of disease progression overall, treatment with baricitinib in addition to standard of care (including dexamethasone) had a similar safety profile to that of standard of care alone, and was associated with reduced mortality in hospitalised adults with COVID-19. Funding Eli Lilly and Company. Translations For the French, Japanese, Portuguese, Russian and Spanish translations of the abstract see Supplementary Materials section.

Question An adolescent who smokes regularly came to my clinic for help quitting. While I am aware that bupropion is a first-line medication for smoking cessation among adults, is it effective and safe for adolescents? Answer Most adolescent smokers in Canada would like to quit, but more than 90% of the attempts are unsuccessful. Bupropion appears to be more effective than other pharmacologic options in improving abstinence among adolescents who smoke in the short term; however, it is not approved by Health Canada for those younger than 18 years. Bupropion has not been associated with an increase in adverse events in smoking cessation trials. More research is needed on the long-term effectiveness and safety of bupropion in this population.

Primary Subject area Public Health and Preventive Medicine Background Visits to pediatric emergency departments have decreased up to 75% during the pandemic, with corresponding increases in high acuity visits, inpatient admissions, and intensive care unit admissions compared to historical cohorts. Objectives To determine if caregivers of children presenting to pediatric emergency departments (EDs) during the COVID-19 pandemic are delaying presenting to care for fear of contracting COVID-19. Secondary objectives were to: a) evaluate potential predictors of delay; b) describe the proportion of children whose symptoms worsened during time to presentation. Design/Methods A multicentre cross-sectional survey study of caregivers accompanying their children aged 0-19 years old to 16 pediatric EDs in 6 countries, from May-June 2020. An anonymous online survey, completed by caregivers via RedCAP, included caregiver and child demographics, presenting complaints, if they delayed presentation and whether symptoms worsened during this interval, as well as caregiver concerns about the child or caregiver having COVID-19 at the time of ED visit. Results Of 1543 caregivers completing the survey, 287 (18.6%) reported a delay in seeking ED care due to concerns of contracting COVID-19 in the hospital. Of those, 124 (43.2%) stated their child’s symptoms worsened during the waiting interval. Caregiver relationship to child [mother] (OR 1.85, 95% CI 1.27-2.76), presence of chronic illness in child (OR 1.78. 95% CI 1.14-2.79), younger age of caregiver (OR 0.965, 95% CI 0.943-0.986), and caregiver concerns about lost work during the pandemic (OR 1.08, 95% CI 1.04-1.12), were independently associated with a COVID-19-related delayed presentation in multivariate regression analysis. Conclusion Almost one in five caregivers reported delaying ED presentation for their ill or injured child, specifically due to fear of contracting COVID-19 while in hospital. Mothers, younger caregivers, caregivers of children with chronic illness, and those concerned about lost work were at highest risk for delay.

Question As a family physician caring for a large pediatric population, I evaluate numerous adolescents with testicular pain. Given the gravity of prognosis for late treatment of children with testicular torsion, what are best practices for its assessment and management? Answer The Testicular Workup for Ischemia and Suspected Torsion (TWIST) score has been developed and validated to identify children at risk of testicular torsion. If the TWIST score is 0 and clinical suspicion is low in the office setting, a referral to urology for urgent consultation is not needed. If the TWIST score is 1 or higher or if the clinical presentation suggests torsion, manual detorsion should be attempted and the patient should be urgently sent to the nearest emergency department.

Management of multiple sclerosis and neuroimmunologic disorders has become increasingly complex because of the expanding number of recognized neuroimmune disorders, increased number of therapeutic options, and multidisciplinary care management needs of people with multiple sclerosis and neuroimmunologic disorders. More subspecialists are needed to optimize care of these patients, and many fellowship programs have been created or expanded to increase the subspecialty workforce. Consequently, defining the scope and standardizing fellowship training is essential to ensure that trainees receive high-quality training. A workgroup was created to develop a consensus fellowship curriculum to serve as a resource for all current and future training programs. This curriculum may also serve as a basis for future accreditation efforts.

Background Neurodevelopmental outcomes of asymptomatic children exposed to Zika virus (ZIKV) in utero are not well characterized. Methods We prospectively followed 129 newborns without evidence of congenital Zika syndrome (CZS) up to 24 months of age. Participants were classified as ZIKV exposed or ZIKV unexposed. The Mullen Scales of Early Learning (MSEL) was administered in the participants’ homes at 6, 12, 15, 18, 21, and 24 months of age by trained psychologists. Sociodemographic data, medical history, and infant anthropometry at birth were collected at each home visit. Our primary outcome was the Mullen Early Learning Composite Score (ECL) at 24 months of age between our 2 exposure groups. Secondary outcomes were differences in MSEL subscales over time and at 24 months. Results Of 129 infants in whom exposure status could be ascertained, 32 (24.8%) met criteria for in utero ZIKV exposure and 97 (75.2%) did not. There were no differences in maternal age, maternal educational attainment, birthweight, or gestational age at birth between the 2 exposure groups. The adjusted means and standard errors (SEs) for the ELC score between the ZIKV-exposed children compared to ZIKV-unexposed children were 91.4 (SE, 3.1) vs 96.8 (SE, 2.4) at 12 months and 93.3 (SE, 2.9) vs 95.9 (SE, 2.3) at 24 months. In a longitudinal mixed model, infants born to mothers with an incident ZIKV infection (P = .01) and low-birthweight infants (, Children with in utero Zika virus exposure and without congenital Zika syndrome in Nicaragua had lower neurocognitive scores at 24 months. Our study includes multiple evaluations over time and a contemporary nonexposed comparator group of children, which is currently lacking in the literature.

The coronavirus disease 2019 (COVID-19) pandemic has taken an unprecedented global toll and vaccination is needed to restore healthy living. Timely inclusion of children in vaccination trials is critical. We surveyed caregivers of children seeking care in 17 Emergency Departments (ED) across 6 countries during the peak of the pandemic to identify factors associated with intent to participate in COVID-19 vaccine trials. Questions about child and parent characteristics, COVID-19 expressed concerns and parental attitudes toward participation in a trial were asked. Of 2768 completed surveys, 18.4% parents stated they would enroll their child in a clinical trial for a COVID-19 vaccine and 14.4% would agree to a randomized placebo-controlled study. Factors associated with willingness to participate were parents agreeing to enroll in a COVID-19 vaccine trial themselves (Odds Ratio (OR) 32.9, 95% Confidence Interval (CI) (21.9–51.2)) having an older child (OR 1.0 (1.0–1.01)), having children who received all vaccinations based on their country schedule (OR 2.67 (1.35–5.71)) and parents with high school education or lower (OR 1.79 (1.18–2.74)). Mothers were less likely to enroll their child in a trial (OR 0.68 (0.47–0.97)). Only one fifth of families surveyed will consider enrolling their child in a vaccine trial. Parental interest in participation, history of vaccinating their child, and the child being older all are associated with parents allowing their child to participate in a COVID vaccine trial. This information may help decision-makers and researchers shape their strategies for trial design and participation engagement in upcoming COVID19 vaccination trials.

The modern ethical framework demands informed consent for research participation that includes disclosure of material information, as well as alternatives. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic (COVID-19) results in illness that often involves rapid deterioration. Despite the urgent need to find therapy, obtaining informed consent for COVID-19 research is needed. The current pandemic presents three types of challenges for investigators faced with obtaining informed consent for research participation: (1) uncertainty over key information to informed consent, (2) time and pressure constraints, and (3) obligations regarding disclosure of new alternative therapies and re-consent. To mitigate consenting challenges, primary investigators need to work together to jointly promote urgent care and research into COVID-19. Actions they can take include (1) prior plan addressing ways to incorporate clinical research into clinical practice in emergency, (2) consider patients vulnerable with early deliberation on the consent process, (3) seek Legally Authorized Representatives (LARs), (4) create a collaborative research teams, (5) aim to consent once, despite evolving information during the pandemic, and (6) aim to match patients to a trial that will most benefit them. The COVID-19 pandemic both exacerbates existing challenges and raises unique obstacles for consent that require forethought and mindfulness to overcome. While research teams and clinician-investigators will need to be sensitive to their own contexts and adapt solutions accordingly, they can meet the challenge of obtaining genuinely informed consent during the current pandemic.

Kawasaki disease (KD) is one of the most common vasculitides of childhood and frequently presents to the emergency department. Although the diagnosis of KD is based on clinical criteria, children who do not fulfill the criteria but have sufficient supportive features of KD are diagnosed as having incomplete KD and warrant the same course of therapy as children with classic KD. The diagnosis of incomplete KD is challenging and requires a high index of suspicion. The purpose of this article is to review presenting features of incomplete KD and the diagnostic approach and management of children in the emergency department.

The cytoskeleton of eukaryotic cells is primarily composed of networks of filamentous proteins, F-actin, microtubules, and intermediate filaments. Interactions among the cytoskeletal components are important in determining cell structure and in regulating cell functions. For example, F-actin and microtubules work together to control cell shape and polarity, while the subcellular organization and transport of vimentin intermediate filament (VIF) networks depend on their interactions with microtubules. However, it is generally thought that F-actin and VIFs form two coexisting but separate networks that are independent due to observed differences in their spatial distribution and functions. In this paper, we present a closer investigation of both the structural and functional interplay between the F-actin and VIF cytoskeletal networks. We characterize the structure of VIFs and F-actin networks within the cell cortex using structured illumination microscopy and cryo-electron tomography. We find that VIFs and F-actin form an interpenetrating network (IPN) with interactions at multiple length scales, and VIFs are integral components of F-actin stress fibers. From measurements of recovery of cell contractility after transient stretching, we find that the IPN structure results in enhanced contractile forces and contributes to cell resilience. Studies of reconstituted networks and dynamic measurements in cells suggest direct and specific associations between VIFs and F-actin. From these results, we conclude that VIFs and F-actin work synergistically, both in their structure and in their function. These results profoundly alter our understanding of the contributions of the components of the cytoskeleton, particularly the interactions between intermediate filaments and F-actin.

Question A 2-year-old boy presented to my clinic after a caregiver witnessed him swallow a foreign body. The caregiver recalls seeing a small metallic object but is unsure exactly what was ingested. The child was asymptomatic upon examination. How should I identify and localize the foreign body? Do metal foreign bodies need to be removed endoscopically? Answer Foreign body ingestion is very common in children. Considerations must be made for the type of foreign body and site of impaction. A clear patient history and radiographs should be used to localize and identify the object. Handheld metal detectors can also be used to localize known metallic foreign bodies. Most metallic objects that pass the esophagus and reach the stomach will continue to pass without complication. Bowel perforation, sepsis, and even death have been documented in extremely rare cases of multiple magnets, button batteries, and long, angular, or 2-pointed sharp objects. These objects must be removed. Other metallic foreign bodies including coins and single magnets can be managed conservatively with stool monitoring.

Question A child came to my clinic complaining of recurrent epistaxis with several episodes occurring every year since he was a toddler. The nosebleeds affect both nostrils, often lasting for an extended period of time and occurring in no apparent seasonal pattern. What interventions are safe and effective for recurrent epistaxis in children, and which patients warrant hematologic testing? Answer Epistaxis affects more than half of children by the time they are 10 years old, with 9% of children reported to have recurrent episodes. Most cases are of benign origin and will not require further workup. For those seeking intervention, nasal mucosal hydration, such as emollient application, or humidification resolves up to 65% of cases, and many novel interventions have shown promise in their respective initial studies. Standardized bleeding questionnaires have demonstrated usefulness in decision making for further coagulation studies, taking into account historical features including frequency, duration, bleeding site, seasonal correlation, and severity.

Question Un enfant vient a ma clinique et se plaint d’une epistaxis recurrente, notamment de plusieurs episodes par annee depuis qu’il est tout petit. Les saignements de nez se produisent dans les 2 narines et durent souvent longtemps, sans qu’il y ait de tendances saisonnieres apparentes. Quelles sont les interventions sures et efficaces pour l’epistaxis chez les enfants, et chez quels patients des analyses hematologiques s’imposeraient-elles? Reponse L’epistaxis se produit chez plus de la moitie des enfants avant qu’ils aient atteint l’âge de 10 ans, et on rapporte que chez 9 % des enfants, les episodes sont recurrents. Dans la plupart des cas, l’affection est d’origine benigne et ne necessitera pas d’investigation plus poussee. Pour ceux qui demandent une intervention, l’hydratation des muqueuses nasales, comme l’application d’emollients ou l’humidification, regle jusqu’a 65 % des cas, et de nombreuses nouvelles interventions se sont revelees prometteuses dans leurs etudes initiales respectives. Il a ete demontre que des questionnaires normalises sur les saignements sont utiles dans la prise de decisions sur la poursuite d’autres analyses de la coagulation, en tenant compte des caracteristiques historiques comme la frequence, la duree, le site des saignements, les correlations saisonnieres et la gravite.

Question We engage parents on a daily basis in the office to discuss immunization for their children, and some of them are hesitant about vaccination. Discussing the importance of vaccines for the child and the public, and reviewing the safety of vaccines has not led to substantial increases in acceptance in our office. What factors influence a parent’s views of vaccines, and how can we effectively address them in practice? Answer Despite medical acceptance of vaccines and widespread accessibility, many Canadian children do not receive all their vaccines, and parental hesitancy has increased in the past 30 years. Thus, family physicians play an important role in addressing concerns that parents might have about vaccines and in increasing vaccine uptake. Determinants of vaccine hesitancy are heterogeneous and multifactorial. Factors that affect vaccine decision making include the perceived risks of vaccines, the relationship between parents and health care providers, and the social norm of vaccination. Communication strategies such as motivational interviewing and using presumptive language are valuable tools to increase vaccine uptake in children with vaccine-hesitant parents.

This study sought to determine whether adding virtual reality (VR) was superior to standard of care alone in facilitating reduction in pain and anxiety among children who underwent intravenous catheterization in the emergency department (ED). Sixty-six children aged 6-16 years who needed intravenous placement received VR, or standard of care in the ED (videos, television, iPad, child life specialist). Outcome measures included change in pain score, level of anxiety, patient and parent satisfaction (pain and anxiety), number of trials, and procedure time. Compared with controls, the intervention group had similar age, sex, number of trials, and anesthetic use. Time of procedure was shorter in the VR group (median 5 min) but this was not statistically significant compared with 7 min for the control group. Pain in the intervention group was lower, even before the procedure. Difference in pain (before and after) and anxiety (after the procedure) were similar in both groups. Satisfaction from anxiety management was higher for the VR group (p < 0.007) and children rated VR significantly more "fun" (p < 0.024).Conclusion: VR was an effective distraction tool and increased satisfaction from anxiety management for this common pediatric procedure, and should be incorporated in management of anxiety in children in the ED setting.Trial registration: clinicaltrials.gov ID NCT03681730, https://clinicaltrials.gov/ct2/show/NCT03681730 What is Known: • Virtual reality is an evolving computer technology that shows some promise in the areas of acute and chronic pain management due to its ability to create effective distraction. What is New: • We report that among children in the emergency setting with intravenous catheterization, satisfaction from the use of VR for anxiety management should support implementation of VR systems for this procedure.

Background Community transmission of coronavirus 2019 (Covid-19) was detected in the state of Washington in February 2020. Methods We identified patients from nine Seattle-area hospitals who were admitted to the intensive care unit (ICU) with confirmed infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Clinical data were obtained through review of medical records. The data reported here are those available through March 23, 2020. Each patient had at least 14 days of follow-up. Results We identified 24 patients with confirmed Covid-19. The mean (±SD) age of the patients was 64±18 years, 63% were men, and symptoms began 7±4 days before admission. The most common symptoms were cough and shortness of breath; 50% of patients had fever on admission, and 58% had diabetes mellitus. All the patients were admitted for hypoxemic respiratory failure; 75% (18 patients) needed mechanical ventilation. Most of the patients (17) also had hypotension and needed vasopressors. No patient tested positive for influenza A, influenza B, or other respiratory viruses. Half the patients (12) died between ICU day 1 and day 18, including 4 patients who had a do-not-resuscitate order on admission. Of the 12 surviving patients, 5 were discharged home, 4 were discharged from the ICU but remained in the hospital, and 3 continued to receive mechanical ventilation in the ICU. Conclusions During the first 3 weeks of the Covid-19 outbreak in the Seattle area, the most common reasons for admission to the ICU were hypoxemic respiratory failure leading to mechanical ventilation, hypotension requiring vasopressor treatment, or both. Mortality among these critically ill patients was high. (Funded by the National Institutes of Health.)

Diamond Blackfan anemia (DBA) is predominantly an autosomal dominant inherited red cell aplasia primarily caused by pathogenic germline variants in ribosomal protein genes. DBA due to pathogenic RPL35A variants has been associated with large 3q29 deletions and phenotypes not common in DBA. We conducted a multi-institutional genotype-phenotype study of 45 patients with DBA associated with pathogenic RPL35A germline variants and curated the variant data on 21 additional cases from the literature. Genotype-phenotype analyses were conducted comparing patients with large deletions versus all other pathogenic variants in RPL35A. Twenty-two of the 45 cases had large deletions in RPL35A. After adjusting for multiple tests, a statistically significant association was observed between patients with a large deletion and steroid-resistant anemia, neutropenia, craniofacial abnormalities, chronic gastrointestinal problems, and intellectual disabilities (p

Background Neonates with hypoxic ischemic encephalopathy (HIE) on therapeutic hypothermia (TH) therapy may show persistent pulmonary hypertension of the newborn (PPHN). In Japan, reported mortality rate is lower than in the U.S., possibly due to treatment differences of newborns with moderate to severe HIE and PPHN. The objective of this study was to determine the feasibility and long term outcomes of Inhaled nitric oxide (iNO) and TH therapy in newborns with moderate to severe HIE with PPHN. Methods 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 developmental quotient (DQ) and gross motor function classification system (GMFCS) at 18 months old. Results 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 started for all six newborns with moderate to severe HIE with PPHN. In two neonates TH was discontinued because of an 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. Conclusion These initial findings suggest that monitoring hematologic and cardiovascular status is important with iNO for severe asphyxia infants with PPHN. We have to develop safer and more feasible protocols when we undergo iNO and TH therapy.

Consuming salad is one strategy with the potential to harmonize diets more closely with national dietary guidance. However, it is not known whether nutrient intake and diet quality differ between people who consume vegetable-based salad and those who do not.The objective of this study was to compare nutrient intake and diet quality between salad reporters and nonreporters.This study is a cross-sectional analysis of 1 day of dietary intake data collected via 24-hour recall.Adults 20 years and older (n=9,678) in What We Eat in America, National Health and Nutrition Examination Survey 2011-2014 were included. Respondents who ate salad on the intake day were considered salad reporters.This study estimated nutrient intake from all foods and beverages (excluding supplements) and evaluated diet quality using the Healthy Eating Index (HEI) 2015.Nutrient intake and HEI scores were compared between salad reporters and nonreporters using paired t tests with regression adjustment for confounding variables. Results were considered significant at P0.001.On the intake day, 23% of adults consumed salad. Energy, protein, and carbohydrate intakes did not differ between salad reporters and nonreporters. Salad reporters had higher intakes than nonreporters of dietary fiber, total fat, unsaturated fatty acids, vitamins A, B-6, C, E, K, folate, choline, magnesium, potassium, and sodium (P0.001). Total HEI 2015 scores were significantly higher for reporters (56 of a possible 100 points) than nonreporters (50 points) P0.001. Reporters also had significantly higher scores for eight of 13 HEI components: total vegetables, greens and beans, whole fruits, total protein foods, seafood and plant proteins, fatty acids, refined grains, and added sugars (P0.001).Incorporating vegetable-based salad into one's diet may be one effective way to increase nutrient intake and improve overall diet quality. Regardless of salad reporting status, HEI scores show that diets of US adults need improvement.

BACKGROUND Mohs surgery was developed for the treatment of advanced skin cancers. Advanced centrofacial tumors are among the most challenging lesions. OBJECTIVE The objective of the study was to review the most complex midface cases from our practice and to delineate how to plan the approach to these lesions, how to remove them in a step-by-step fashion, and how the patients were managed in a multidisciplinary manner when indicated. METHODS We reviewed 15 years of the most complex tumors to present to our practice for which Mohs micrographic surgery was performed. Follow-up for patients ranged from 3 to 13 years and is ongoing. RESULTS Twenty cases were identified in which tumors of the central face extended to bone and created extensive operative wounds. Eleven lesions were recurrent at presentation, and 9 had perineural disease. These cases are reviewed sequentially and demonstrate the challenges, successes, and pitfalls of Mohs micrographic surgery in the treatment of the most difficult tumors. Two patients died from disease. CONCLUSION Mohs surgery is an excellent technique for the removal of extensive midfacial lesions and allows for the surgical removal of lesions that might otherwise be considered inoperable. Approach to these lesions requires careful planning, meticulous surgical technique, excellence in histology, and an experienced reconstructive surgeon. Such tumors often require a multidisciplinary approach, imaging, and adjuvant therapy. All such cases require diligent follow-up. Although many such lesions will be cured, regional recurrence and metastasis may result, even when clear margins are achieved.

BACKGROUND Recent advances in diagnostic and therapeutic modalities have made oncologic care ever more challenging, and multidisciplinary tumor boards (MTBs) are increasingly being used as a forum to discuss and coordinate care for complex oncology patients. Literature on the use of MTBs specific to cutaneous oncology and dermatologic surgery remains limited. OBJECTIVE To share our experiences with cutaneous oncology MTBs at the University of Vermont Medical Center (UVMMC). METHODS We describe the formation, timing, participation, clinical discussion, case follow-up, and coordination of care of our MTBs. RESULTS A log of all cases discussed at cutaneous oncology MTBs from August 2018 to August 2019 is presented as an example. Five specific cases are described in further detail to demonstrate critical components of multidisciplinary care. CONCLUSION The MTBs at UVMMC has created a collaborative environment for providers in multiple specialties to jointly formulate and coordinate optimal treatment plans for difficult cases, particularly when treatment guidelines do not exist or are insufficient. Furthermore, MTBs can serve as an educational forum for all participants.

Vaccinating children against COVID-19 is critical as a public health strategy in order to reach herd immunity and prevent illness among children and adults. The aim of the study was to identify correlation between willingness to vaccinate children under 12 years old, and vaccination rate for adult population in Canada, the United States, and Israel. This was a secondary analysis of a cross-sectional survey study (COVID-19 Parental Attitude Study) of parents of children 12 years and younger presenting to 12 pediatric emergency departments (EDs). Parental reports of willingness to vaccinate against COVID-19 when vaccines for children will be approved was correlated to country-specific rate of vaccination during December 2020-March 2021, obtained from ourworldindata.org. Logistic regression models were fit with covariates for week and the corresponding vaccine rate. A total of 720 surveys were analyzed. In Canada, administering mostly first dose to the adult population, willingness to vaccinate children was trending downward (correlation = -0.28), in the United States, it was trending upwards (correlation = 0.21) and in Israel, initially significant increase with decline shortly thereafter (correlation = 0.06). Odds of willingness to vaccinate in Canada, the United States, and Israel was OR = 0.82, 95% CI = 0.63-1.07, OR = 1.24, 95% CI = 0.99-1.56, and OR = 1.03, 95% CI = 0.95-1.12, respectively. A robust population-based vaccination program as in Israel, and to a lesser degree the United States, led to increasing willingness by parents to vaccinate their children younger than 12 years against COVID-19. In Canada, slow rate of vaccination of the adult population was associated with lower willingness to vaccinate children.

Purpose The goal of this study was to assess if caregivers’ attitudes toward the regulatory process of approving the vaccine against coronavirus disease 2019 (COVID-19) for children aged

Background Coronavirus 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). Methods We compared prevalence and levels of AT1R-Ab in COVID-19 cases with mild or severe disease to age and sex matched negative controls utilizing multivariate logistic and quantile regression adjusted for comorbidities including hypertension, diabetes, and heart disease. Results There were trends toward increased prevalence (50% vs. 33%, p = 0.1) and level of AT1R-Ab (median 9.8 vs. 6.1 U/mL, p = 0.06) in all cases versus controls. When considered by COVID-19 disease severity, there was a trend toward increased prevalence of AT1R-Ab (55% vs. 31%, p = 0.07), as well as significantly higher AT1R-Ab levels (median 10.7 vs. 5.9 U/mL, p = 0.03) amongst individuals with mild COVID-19 versus matched controls. In contrast, the prevalence (42% vs. 37%, p = 0.9) and level (both medians 6.7 U/mL, p = 0.9) of AT1R-Ab amongst those with severe COVID-19 did not differ from matched controls. Conclusions These findings support an association between COVID-19 and AT1R-Ab, emphasizing that vascular pathology may be present in individuals with mild COVID-19 as well as those with severe disease.

Complementary foods and beverages (CFBs) are key components of an infant's diet in the second 6 months of life. This article summarizes nutrition and feeding practices examined by the 2020 Dietary Guidelines Advisory Committees during the CFB life stage. Breastfeeding initiation is high (84%), but exclusive breastfeeding at 6 months (26%) is below the Healthy People 2030 goal (42%). Most infants (51%) are introduced to CFBs sometime before 6 months. The primary mode of feeding (ie, human milk fed [HMF]; infant formula or mixed formula and human milk fed [FMF]) at the initiation of CFBs is associated with the timing of introduction and types of CFBs reported. FMF infants (42%) are more likely to be introduced to CFBs before 4 months compared with HMF infants (19%). Different dietary patterns, such as higher prevalence of consumption and mean amounts, were observed, including fruit, grains, dairy, proteins, and solid fats. Compared with HMF infants of the same age, FMF infants consume more total energy (845 vs 631 kcal) and protein (22 vs 12 g) from all sources, and more energy (345 vs 204 kcal) and protein (11 vs 6 g) from CFBs alone. HMF infants have a higher prevalence of risk of inadequate intakes of iron (77% vs 7%), zinc (54% vs3%), and protein (27% vs3%). FMF infants are more likely to have an early introduction (12 months) to fruit juice (45% vs 20%) and cow's milk (36% vs 24%). Registered dietitian nutritionists and nutritional professionals should consider tailoring their advice to caregivers on dietary and complementary feeding practices, taking into account the primary mode of milk feeding during this life stage to support infants' nutrient adequacy. National studies that address the limitations of this analysis, including small sample sizes and imputed breast milk volume, could refine findings from this analysis.

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.

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.

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.

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.

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.

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 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.