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The Lancet. Child & Adolescent Health Mar 2024Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged... (Randomized Controlled Trial)
Randomized Controlled Trial
Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial.
BACKGROUND
Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged in April, 2020. The paediatric comparisons within the RECOVERY trial aimed to assess the effect of intravenous immunoglobulin or corticosteroids compared with usual care on duration of hospital stay for children with PIMS-TS and to compare tocilizumab (anti-IL-6 receptor monoclonal antibody) or anakinra (anti-IL-1 receptor antagonist) with usual care for those with inflammation refractory to initial treatment.
METHODS
We did this randomised, controlled, open-label, platform trial in 51 hospitals in the UK. Eligible patients were younger than 18 years and had been admitted to hospital for PIMS-TS. In the first randomisation, patients were randomly assigned (1:1:1) to usual care (no additional treatments), usual care plus methylprednisolone (10mg/kg per day for 3 consecutive days), or usual care plus intravenous immunoglobulin (a single dose of 2 g/kg). If further anti-inflammatory treatment was considered necessary, children aged at least 1 year could be considered for a second randomisation, in which patients were randomly assigned (1:2:2) to usual care, intravenous tocilizumab (12 mg/kg in patients <30 kg; 8mg/kg in patients ≥30 kg, up to a maximum dose of 800 mg), or subcutaneous anakinra (2 mg/kg once per day in patients ≥10 kg). Randomisation was by use of a web-based simple (unstratified) randomisation with allocation concealment. The primary outcome was duration of hospital stay. Analysis was by intention to treat. For treatments assessed in each randomisation, a single Bayesian framework assuming uninformative priors for treatment was used to jointly assess the efficacy of each intervention compared with usual care. The trial was registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936).
FINDINGS
Between May 18, 2020, and Jan 20, 2022, 237 children with PIMS-TS were enrolled and included in the intention-to-treat analysis. Of the 214 patients who entered the first randomisation, 73 were assigned to receive intravenous immunoglobulin, 61 methylprednisolone, and 80 usual care. Of the 70 children who entered the second randomisation (including 23 who did not enter the first randomisation), 28 were assigned to receive tocilizumab, 14 anakinra, and 28 usual care. Mean age was 9·5 years (SD 3·8) in the randomisation and 9·6 years (3·6) in the second randomisation. 118 (55%) of 214 patients in the first randomisation and 39 (56%) of 70 patients in the second randomisation were male. 130 (55%) of 237 patients were Black, Asian, or minority ethnic, and 105 (44%) were White. Mean duration of hospital stay was 7·4 days (SD 0·4) in children assigned to intravenous immunoglobulin and 7·6 days (0·4) in children assigned to usual care (difference -0·1 days, 95% credible interval [CrI] -1·3 to 1·0; posterior probability 59%). Mean duration of hospital stay was 6·9 days (SD 0·5) in children assigned to methylprednisolone (difference from usual care -0·7 days, 95% CrI -1·9 to 0·6; posterior probability 87%). Mean duration of hospital stay was 6·6 days (SD 0·7) in children assigned to second-line tocilizumab and 9·9 days (0·9) in children assigned to usual care (difference -3·3 days, 95% CrI -5·6 to -1·0; posterior probability >99%). Mean duration of hospital stay was 8·5 days (SD 1·2) in children assigned to anakinra (difference from usual care -1·4 days, 95% CrI -4·3 to 1·8; posterior probability 84%). Two persistent coronary artery aneurysms were reported among patients assigned to usual care in the first randomisation. There were few cardiac arrythmias, bleeding, or thrombotic events in any group. Two children died; neither was considered related to study treatment.
INTERPRETATION
Moderate evidence suggests that, compared with usual care, first-line intravenous methylprednisolone reduces duration of hospital stay for children with PIMS-TS. Good evidence suggests that second-line tocilizumab reduces duration of hospital stay for children with inflammation refractory to initial treatment. Neither intravenous immunoglobulin nor anakinra had any effect on duration of hospital stay compared with usual care.
FUNDING
Medical Research Council and National Institute of Health Research.
Topics: Humans; Male; Child; Female; COVID-19; SARS-CoV-2; Interleukin 1 Receptor Antagonist Protein; Immunoglobulins, Intravenous; Bayes Theorem; Treatment Outcome; Methylprednisolone; Inflammation; Immunomodulation; Systemic Inflammatory Response Syndrome
PubMed: 38272046
DOI: 10.1016/S2352-4642(23)00316-4 -
Biology Oct 2023The liver is a major metabolic organ that performs many essential biological functions such as detoxification and the synthesis of proteins and biochemicals necessary... (Review)
Review
The liver is a major metabolic organ that performs many essential biological functions such as detoxification and the synthesis of proteins and biochemicals necessary for digestion and growth. Any disruption in normal liver function can lead to the development of more severe liver disorders. Overall, about 3 million Americans have some type of liver disease and 5.5 million people have progressive liver disease or cirrhosis, in which scar tissue replaces the healthy liver tissue. An estimated 20% to 30% of adults have excess fat in their livers, a condition called steatosis. The most common etiologies for steatosis development are (1) high caloric intake that causes non-alcoholic fatty liver disease (NAFLD) and (2) excessive alcohol consumption, which results in alcohol-associated liver disease (ALD). NAFLD is now termed "metabolic-dysfunction-associated steatotic liver disease" (MASLD), which reflects its association with the metabolic syndrome and conditions including diabetes, high blood pressure, high cholesterol and obesity. ALD represents a spectrum of liver injury that ranges from hepatic steatosis to more advanced liver pathologies, including alcoholic hepatitis (AH), alcohol-associated cirrhosis (AC) and acute AH, presenting as acute-on-chronic liver failure. The predominant liver cells, hepatocytes, comprise more than 70% of the total liver mass in human adults and are the basic metabolic cells. Mitochondria are intracellular organelles that are the principal sources of energy in hepatocytes and play a major role in oxidative metabolism and sustaining liver cell energy needs. In addition to regulating cellular energy homeostasis, mitochondria perform other key physiologic and metabolic activities, including ion homeostasis, reactive oxygen species (ROS) generation, redox signaling and participation in cell injury/death. Here, we discuss the main mechanism of mitochondrial dysfunction in chronic liver disease and some treatment strategies available for targeting mitochondria.
PubMed: 37887021
DOI: 10.3390/biology12101311 -
Case Reports in Pediatrics 2023Donohue syndrome (DS) is a rare recessively inherited disorder characterized by severe insulin resistance caused by genetic defects affecting the insulin receptor. The...
Donohue syndrome (DS) is a rare recessively inherited disorder characterized by severe insulin resistance caused by genetic defects affecting the insulin receptor. The classical clinical characteristics include severe intrauterine growth restriction, craniofacial dysmorphic features, body and skin features, and soft tissue overgrowth. Postnatal growth retardation, cardiac, gastrointestinal, and renal complications, and infection susceptibility develop within the first few months of life, leading to a short life expectancy (<2 years). The classical metabolic abnormalities vary from fasting hypoglycemia to postprandial hyperglycemia with severe hyperinsulinemia. We present the case of a 14-week-old infant with DS who developed cardiac, renal, hepatic, pancreatic, and gastrointestinal features, all of them previously reported in infants with DS. The gastrointestinal features started during the first week of life and included abdominal distension, feeding difficulties, intermittent vomiting, and two episodes of intestinal obstruction. The diagnosis of duodenogastric intussusception was made, and this previously unreported complication tragically resulted in mortality. We discuss how basic mechanisms of cross-talk between insulin and insulin-growth factor 1 receptors could be linked to hyperinsulinemia and its associated comorbidities.
PubMed: 37885901
DOI: 10.1155/2023/7799234 -
Med (New York, N.Y.) Nov 2023Individuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease that requires hospitalization. It...
BACKGROUND
Individuals vaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), when infected, can still develop disease that requires hospitalization. It remains unclear whether these patients differ from hospitalized unvaccinated patients with regard to presentation, coexisting comorbidities, and outcomes.
METHODS
Here, we use data from an international consortium to study this question and assess whether differences between these groups are context specific. Data from 83,163 hospitalized COVID-19 patients (34,843 vaccinated, 48,320 unvaccinated) from 38 countries were analyzed.
FINDINGS
While typical symptoms were more often reported in unvaccinated patients, comorbidities, including some associated with worse prognosis in previous studies, were more common in vaccinated patients. Considerable between-country variation in both in-hospital fatality risk and vaccinated-versus-unvaccinated difference in this outcome was observed.
CONCLUSIONS
These findings will inform allocation of healthcare resources in future surges as well as design of longer-term international studies to characterize changes in clinical profile of hospitalized COVID-19 patients related to vaccination history.
FUNDING
This work was made possible by the UK Foreign, Commonwealth and Development Office and Wellcome (215091/Z/18/Z, 222410/Z/21/Z, 225288/Z/22/Z, and 220757/Z/20/Z); the Bill & Melinda Gates Foundation (OPP1209135); and the philanthropic support of the donors to the University of Oxford's COVID-19 Research Response Fund (0009109). Additional funders are listed in the "acknowledgments" section.
Topics: Humans; COVID-19; SARS-CoV-2; Hospitalization; Hospitals; Vaccination
PubMed: 37738979
DOI: 10.1016/j.medj.2023.08.005 -
Neurotherapeutics : the Journal of the... Oct 2023Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules...
Patients with Lafora disease have a mutation in EPM2A or EPM2B, resulting in dysregulation of glycogen metabolism throughout the body and aberrant glycogen molecules that aggregate into Lafora bodies. Lafora bodies are particularly damaging in the brain, where the aggregation drives seizures with increasing severity and frequency, coupled with neurodegeneration. Previous work employed mouse genetic models to reduce glycogen synthesis by approximately 50%, and this strategy significantly reduced Lafora body formation and disease phenotypes. Therefore, an antisense oligonucleotide (ASO) was developed to reduce glycogen synthesis in the brain by targeting glycogen synthase 1 (Gys1). To test the distribution and efficacy of this drug, the Gys1-ASO was administered to Epm2b-/- mice via intracerebroventricular administration at 4, 7, and 10 months. The mice were then sacrificed at 13 months and their brains analyzed for Gys1 expression, glycogen aggregation, and neuronal excitability. The mice treated with Gys1-ASO exhibited decreased Gys1 protein levels, decreased glycogen aggregation, and reduced epileptiform discharges compared to untreated Epm2b-/- mice. This work provides proof of concept that a Gys1-ASO halts disease progression of EPM2B mutations of Lafora disease.
Topics: Humans; Mice; Animals; Lafora Disease; Glycogen Synthase; Disease Models, Animal; Mutation; Oligonucleotides, Antisense; Glycogen; Ubiquitin-Protein Ligases
PubMed: 37700152
DOI: 10.1007/s13311-023-01434-9 -
Open Forum Infectious Diseases Aug 2023The influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA level and presence of infectious virus on symptom occurrence is poorly understood,...
BACKGROUND
The influence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA level and presence of infectious virus on symptom occurrence is poorly understood, particularly among nonhospitalized individuals.
METHODS
The study included 85 nonhospitalized, symptomatic adults, who were enrolled from September 2020 to November 2021. Data from a longitudinal cohort studied over 28 days was used to analyze the association of individual symptoms with SARS-CoV-2 viral RNA load, or the presence or level of infectious (culturable) virus. Presence of infectious virus and viral RNA load were assessed daily, depending on specimen availability, and amount of infectious virus was assessed on the day of maximum RNA load. Participants were surveyed for the start and end dates of 31 symptoms at enrollment and at days 9, 14, 21, and 28; daily symptom presence was determined analytically. We describe symptoms and investigate their possible association with viral determinants through a series of single or pooled (multiple days across acute period) cross-sectional analyses.
RESULTS
There was an association between viral RNA load and the same-day presence of many individual symptoms. Additionally, individuals with infectious virus were more than three times as likely to have a concurrent fever than individuals without infectious virus, and more than two times as likely to have concurrent myalgia, chills, headache, or sore throat.
CONCLUSIONS
We found evidence to support the association of viral RNA load and infectious virus on some, but not all symptoms. Fever was most strongly associated with the presence of infectious virus; this may support the potential for symptom-based isolation guidance for COVID-19.
PubMed: 37636517
DOI: 10.1093/ofid/ofad396 -
Pediatrics Sep 2023Neurodevelopmental evaluation of toddlers with complex congenital heart disease is recommended but reported frequency is low. Data on barriers to attending...
BACKGROUND AND OBJECTIVES
Neurodevelopmental evaluation of toddlers with complex congenital heart disease is recommended but reported frequency is low. Data on barriers to attending neurodevelopmental follow-up are limited. This study aims to estimate the attendance rate for a toddler neurodevelopmental evaluation in a contemporary multicenter cohort and to assess patient and center level factors associated with attending this evaluation.
METHODS
This is a retrospective cohort study of children born between September 2017 and September 2018 who underwent cardiopulmonary bypass in their first year of life at a center contributing data to the Cardiac Neurodevelopmental Outcome Collaborative and Pediatric Cardiac Critical Care Consortium clinical registries. The primary outcome was attendance for a neurodevelopmental evaluation between 11 and 30 months of age. Sociodemographic and medical characteristics and center factors specific to neurodevelopmental program design were considered as predictors for attendance.
RESULTS
Among 2385 patients eligible from 16 cardiac centers, the attendance rate was 29.0% (692 of 2385), with a range of 7.8% to 54.3% across individual centers. In multivariable logistic regression models, hospital-initiated (versus family-initiated) scheduling for neurodevelopmental evaluation had the largest odds ratio in predicting attendance (odds ratio = 4.24, 95% confidence interval, 2.74-6.55). Other predictors of attendance included antenatal diagnosis, absence of Trisomy 21, higher Society of Thoracic Surgeons-European Association for Cardio-Thoracic Surgery mortality category, longer postoperative length of stay, private insurance, and residing a shorter distance from the hospital.
CONCLUSIONS
Attendance rates reflect some improvement but remain low. Changes to program infrastructure and design and minimizing barriers affecting access to care are essential components for improving neurodevelopmental care and outcomes for children with congenital heart disease.
Topics: Pregnancy; Humans; Female; Child; Retrospective Studies; Heart; Cardiopulmonary Bypass; Critical Care; Down Syndrome
PubMed: 37593818
DOI: 10.1542/peds.2022-060995 -
BioRxiv : the Preprint Server For... Jul 2023The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the...
UNLABELLED
The renin-angiotensin-aldosterone system (RAAS) plays a well-characterized role regulating blood pressure in mammals. Pharmacological and genetic manipulation of the RAAS has been shown to extend lifespan in , , and rodents, but its mechanism is not well defined. Here we investigate the angiotensin-converting enzyme (ACE) inhibitor drug captopril, which extends lifespan in worms and mice. To investigate the mechanism, we performed a forward genetic screen for captopril hypersensitive mutants. We identified a missense mutation that causes a partial loss-of-function of the receptor tyrosine kinase gene, a powerful regulator of aging. The homologous mutation in the human insulin receptor causes Donohue syndrome, establishing these mutant worms as an invertebrate model of this disease. Captopril functions in by inhibiting ACN-1, the worm homolog of ACE. Reducing the activity of via captopril or RNAi promoted dauer larvae formation, suggesting is a gene. Captopril-mediated lifespan extension xwas abrogated by and mutations. Our results indicate that captopril and control aging by modulating dauer formation pathways. We speculate that this represents a conserved mechanism of lifespan control.
SUMMARY STATEMENT
Captopril and control aging. By demonstrating they regulate dauer formation and interact with genes, including a new DAF-2(A261V) mutant corresponding to a human disease variant, we clarified the mechanism.
PubMed: 37502959
DOI: 10.1101/2023.07.17.549402 -
Cardiology in the Young Feb 2024The National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) lacks a rigorous enrollment audit process, unlike other collaborative networks. Most...
Assessing enrollment of eligible infants in the national pediatric cardiology quality improvement collaborative (NPC-QIC) through linkage to the pediatric cardiac critical care consortium (PC4) registry.
BACKGROUND
The National Pediatric Cardiology Quality Improvement Collaborative (NPC-QIC) lacks a rigorous enrollment audit process, unlike other collaborative networks. Most centers require individual families to consent to participate. It is unknown whether there is variation across centers or biases in enrollment.
METHODS
We used the Pediatric Cardiac Critical Care Consortium (PC) registry to assess enrollment rates in NPC-QIC for those centers participating in both registries using indirect identifiers (date of birth, date of admission, gender, and center) to match patient records. All infants born 1/1/2018-12/31/2020 and admitted 30 days of life were eligible. In PC, all infants with a fundamental diagnosis of hypoplastic left heart or variant or who underwent a surgical or hybrid Norwood or variant were eligible. Standard descriptive statistics were used to describe the cohort and center match rates were plotted on a funnel chart.
RESULTS
Of 898 eligible NPC-QIC patients, 841 were linked to 1,114 eligible PC patients (match rate 75.5%) in 32 centers. Match rates were lower in patients of Hispanic/Latino ethnicity (66.1%, p = 0.005), and those with any specified chromosomal abnormality (57.4%, p = 0.002), noncardiac abnormality (67.8%, p = 0.005), or any specified syndrome (66.5%, p = 0.001). Match rates were lower for patients who transferred to another hospital or died prior to discharge. Match rates varied from 0 to 100% across centers.
CONCLUSIONS
It is feasible to match patients between the NPC-QIC and PC registries. Variation in match rates suggests opportunities for improvement in NPC-QIC patient enrollment.
Topics: Infant; Humans; Child; Quality Improvement; Norwood Procedures; Hypoplastic Left Heart Syndrome; Registries; Cardiology
PubMed: 37434511
DOI: 10.1017/S1047951123001671 -
PloS One 2023SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of...
IMPORTANCE
SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or other health effects after the acute phase of infection; termed post-acute sequelae of SARS-CoV-2 infection (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are ill-defined. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC in Adults (RECOVER-Adult) are to: (1) characterize PASC prevalence; (2) characterize the symptoms, organ dysfunction, natural history, and distinct phenotypes of PASC; (3) identify demographic, social and clinical risk factors for PASC onset and recovery; and (4) define the biological mechanisms underlying PASC pathogenesis.
METHODS
RECOVER-Adult is a combined prospective/retrospective cohort currently planned to enroll 14,880 adults aged ≥18 years. Eligible participants either must meet WHO criteria for suspected, probable, or confirmed infection; or must have evidence of no prior infection. Recruitment occurs at 86 sites in 33 U.S. states, Washington, DC and Puerto Rico, via facility- and community-based outreach. Participants complete quarterly questionnaires about symptoms, social determinants, vaccination status, and interim SARS-CoV-2 infections. In addition, participants contribute biospecimens and undergo physical and laboratory examinations at approximately 0, 90 and 180 days from infection or negative test date, and yearly thereafter. Some participants undergo additional testing based on specific criteria or random sampling. Patient representatives provide input on all study processes. The primary study outcome is onset of PASC, measured by signs and symptoms. A paradigm for identifying PASC cases will be defined and updated using supervised and unsupervised learning approaches with cross-validation. Logistic regression and proportional hazards regression will be conducted to investigate associations between risk factors, onset, and resolution of PASC symptoms.
DISCUSSION
RECOVER-Adult is the first national, prospective, longitudinal cohort of PASC among US adults. Results of this study are intended to inform public health, spur clinical trials, and expand treatment options.
REGISTRATION
NCT05172024.
Topics: Humans; COVID-19; Observational Studies as Topic; Post-Acute COVID-19 Syndrome; Prospective Studies; Retrospective Studies; SARS-CoV-2; Adolescent; Adult; Multicenter Studies as Topic
PubMed: 37352211
DOI: 10.1371/journal.pone.0286297