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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 -
Diabetology International Apr 2022This report of a working group established by the Japan Diabetes Society proposes a new classification and diagnostic criteria for insulin resistance syndrome. Insulin...
This report of a working group established by the Japan Diabetes Society proposes a new classification and diagnostic criteria for insulin resistance syndrome. Insulin resistance syndrome is defined as a condition characterized by severe attenuation of insulin action due to functional impairment of the insulin receptor or its downstream signaling molecules. This syndrome is classified into two types: genetic insulin resistance syndrome, caused by gene abnormalities, and type B insulin resistance syndrome, caused by autoantibodies to the insulin receptor. Genetic insulin resistance syndrome includes type A insulin resistance as well as Donohue and Rabson-Mendenhall syndromes, all of which are caused by abnormalities of the insulin receptor gene; conditions such as SHORT syndrome caused by abnormalities of , which encodes a regulatory subunit of phosphatidylinositol 3-kinase; conditions caused by abnormalities of , , or ; and conditions in which a causative gene has not yet been identified. Type B insulin resistance syndrome is characterized by severe impairment of insulin action due to the presence of insulin receptor autoantibodies. Cases in which hypoglycemia alone is induced by autoantibodies that stimulate insulin receptor were not included in Type B insulin resistance syndrome.
PubMed: 35463863
DOI: 10.1007/s13340-022-00570-5 -
The New England Journal of Medicine Dec 2021In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern.
METHODS
In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated.
RESULTS
Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups.
CONCLUSIONS
REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).
Topics: Adolescent; Adult; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; Antiviral Agents; COVID-19; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Female; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Pregnancy; Pregnancy Complications, Infectious; Proportional Hazards Models; Viral Load; Young Adult; COVID-19 Drug Treatment
PubMed: 34587383
DOI: 10.1056/NEJMoa2108163 -
Proceedings of the National Academy of... Jul 2022The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly...
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) readily infects a variety of cell types impacting the function of vital organ systems, with particularly severe impact on respiratory function. Neurological symptoms, which range in severity, accompany as many as one-third of COVID-19 cases, indicating a potential vulnerability of neural cell types. To assess whether human cortical cells can be directly infected by SARS-CoV-2, we utilized stem-cell-derived cortical organoids as well as primary human cortical tissue, both from developmental and adult stages. We find significant and predominant infection in cortical astrocytes in both primary tissue and organoid cultures, with minimal infection of other cortical populations. Infected and bystander astrocytes have a corresponding increase in inflammatory gene expression, reactivity characteristics, increased cytokine and growth factor signaling, and cellular stress. Although human cortical cells, particularly astrocytes, have no observable ACE2 expression, we find high levels of coronavirus coreceptors in infected astrocytes, including CD147 and DPP4. Decreasing coreceptor abundance and activity reduces overall infection rate, and increasing expression is sufficient to promote infection. Thus, we find tropism of SARS-CoV-2 for human astrocytes resulting in inflammatory gliosis-type injury that is dependent on coronavirus coreceptors.
Topics: Angiotensin-Converting Enzyme 2; Astrocytes; Cerebral Cortex; Humans; Organoids; Primary Cell Culture; SARS-CoV-2; Viral Tropism
PubMed: 35858406
DOI: 10.1073/pnas.2122236119 -
BMJ Paediatrics Open Oct 2022The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought...
BACKGROUND
The impact of the COVID-19 pandemic on paediatric populations varied between high-income countries (HICs) versus low-income to middle-income countries (LMICs). We sought to investigate differences in paediatric clinical outcomes and identify factors contributing to disparity between countries.
METHODS
The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) COVID-19 database was queried to include children under 19 years of age admitted to hospital from January 2020 to April 2021 with suspected or confirmed COVID-19 diagnosis. Univariate and multivariable analysis of contributing factors for mortality were assessed by country group (HICs vs LMICs) as defined by the World Bank criteria.
RESULTS
A total of 12 860 children (3819 from 21 HICs and 9041 from 15 LMICs) participated in this study. Of these, 8961 were laboratory-confirmed and 3899 suspected COVID-19 cases. About 52% of LMICs children were black, and more than 40% were infants and adolescent. Overall in-hospital mortality rate (95% CI) was 3.3% [=(3.0% to 3.6%), higher in LMICs than HICs (4.0% (3.6% to 4.4%) and 1.7% (1.3% to 2.1%), respectively). There were significant differences between country income groups in intervention profile, with higher use of antibiotics, antivirals, corticosteroids, prone positioning, high flow nasal cannula, non-invasive and invasive mechanical ventilation in HICs. Out of the 439 mechanically ventilated children, mortality occurred in 106 (24.1%) subjects, which was higher in LMICs than HICs (89 (43.6%) vs 17 (7.2%) respectively). Pre-existing infectious comorbidities (tuberculosis and HIV) and some complications (bacterial pneumonia, acute respiratory distress syndrome and myocarditis) were significantly higher in LMICs compared with HICs. On multivariable analysis, LMIC as country income group was associated with increased risk of mortality (adjusted HR 4.73 (3.16 to 7.10)).
CONCLUSION
Mortality and morbidities were higher in LMICs than HICs, and it may be attributable to differences in patient demographics, complications and access to supportive and treatment modalities.
Topics: Adolescent; Humans; Child; COVID-19 Testing; Pandemics; COVID-19; Tuberculosis; Health Resources
PubMed: 36645791
DOI: 10.1136/bmjpo-2022-001657 -
Problemy Endokrinologii Jun 2022Donohue syndrome (DS), also called Leprechaunism, is the most severe form of insulin resistance associated with biallelic mutations in INSR gene (OMIM: 147670). The...
Donohue syndrome (DS), also called Leprechaunism, is the most severe form of insulin resistance associated with biallelic mutations in INSR gene (OMIM: 147670). The approximate incidence of this syndrome is 1 per 1000000 births. Patients are present with typical clinical features such as intrauterine growth retardation, facial dysmorphism, severe metabolic disturbances, hepatomegaly and hypertrophic cardiomyopathy. Most DS patients die within the first two years of life due to respiratory infections, severe hypoglycemia or progressive cardiomyopathy. Treatment options are limited and no specific therapy exist for DS. Given the similarities between insulin and insulin-like growth factor 1 (IGF-1) receptors, recombinant human IGF-1 (rhIGF-1) has been used to treat severe insulin resistance including DS.We report the case of a male patient with genetically confirmed Donohue syndrome, successfully treated with continuous subcutaneous IGF1 infusion via insulin pump. We observed improvement of glycemic control, liver function and cardiac hypertrophy regression following 15-month IGF1 therapy.
Topics: Humans; Male; Donohue Syndrome; Insulin-Like Growth Factor I; Insulin Resistance; Receptor, Insulin; Insulin
PubMed: 36337021
DOI: 10.14341/probl13121 -
Journal of Diabetes Investigation May 2020Insulin resistance syndrome (IRS) of type A or B is triggered by gene abnormalities of or autoantibodies to the insulin receptor, respectively....
AIMS/INTRODUCTION
Insulin resistance syndrome (IRS) of type A or B is triggered by gene abnormalities of or autoantibodies to the insulin receptor, respectively. Rabson-Mendenhall/Donohue syndrome is also caused by defects of the insulin receptor gene (INSR), but is more serious than type A IRS. Here, we carried out a nationwide survey of these syndromes in Japan.
MATERIALS AND METHODS
We sent questionnaires to a total of 1,957 academic councilors or responsible individuals at certified facilities of the Japan Diabetes Society, as well as at the department pediatrics or neonatology in medical centers with >300 beds.
RESULTS
We received 904 responses with information on 23, 30 and 10 cases of type A or B IRS and Rabson-Mendenhall/Donohue syndrome, respectively. Eight cases with type A IRS-like clinical features, but without an abnormality of INSR, were tentatively designated type X IRS, with five of these cases testing positive for PIK3R1 mutations. Fasting serum insulin levels at diagnosis (mean ± standard deviation) were 132.0 ± 112.4, 1122.1 ± 3292.5, 2895.5 ± 3181.5 and 145.0 ± 141.4 μU/mL for type A IRS, type B IRS, Rabson-Mendenhall/Donohue syndrome and type X IRS, respectively. Type A and type X IRS, as well as Rabson-Mendenhall/Donohue syndrome were associated with low birthweight. Type B IRS was diagnosed most frequently in older individuals, and was often associated with concurrent autoimmune conditions and hypoglycemia.
CONCLUSIONS
Information yielded by this first nationwide survey should provide epidemiological insight into these rare conditions and inform better healthcare for affected patients.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antigens, CD; Asian People; Child; Child, Preschool; Donohue Syndrome; Female; Health Surveys; Humans; Infant; Infant, Newborn; Japan; Male; Metabolic Syndrome; Middle Aged; Receptor, Insulin; Young Adult
PubMed: 31677333
DOI: 10.1111/jdi.13171 -
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 -
Nature Immunology Apr 2024One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and...
One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.
Topics: Humans; Post-Acute COVID-19 Syndrome; COVID-19; Biomedical Research; Hospitalization; Immunoglobulin G
PubMed: 38589621
DOI: 10.1038/s41590-024-01778-0 -
The New England Journal of Medicine Jan 2021Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Recent data suggest that complications and death from coronavirus disease 2019 (Covid-19) may be related to high viral loads.
METHODS
In this ongoing, double-blind, phase 1-3 trial involving nonhospitalized patients with Covid-19, we investigated two fully human, neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, used in a combined cocktail (REGN-COV2) to reduce the risk of the emergence of treatment-resistant mutant virus. Patients were randomly assigned (1:1:1) to receive placebo, 2.4 g of REGN-COV2, or 8.0 g of REGN-COV2 and were prospectively characterized at baseline for endogenous immune response against SARS-CoV-2 (serum antibody-positive or serum antibody-negative). Key end points included the time-weighted average change in viral load from baseline (day 1) through day 7 and the percentage of patients with at least one Covid-19-related medically attended visit through day 29. Safety was assessed in all patients.
RESULTS
Data from 275 patients are reported. The least-squares mean difference (combined REGN-COV2 dose groups vs. placebo group) in the time-weighted average change in viral load from day 1 through day 7 was -0.56 log copies per milliliter (95% confidence interval [CI], -1.02 to -0.11) among patients who were serum antibody-negative at baseline and -0.41 log copies per milliliter (95% CI, -0.71 to -0.10) in the overall trial population. In the overall trial population, 6% of the patients in the placebo group and 3% of the patients in the combined REGN-COV2 dose groups reported at least one medically attended visit; among patients who were serum antibody-negative at baseline, the corresponding percentages were 15% and 6% (difference, -9 percentage points; 95% CI, -29 to 11). The percentages of patients with hypersensitivity reactions, infusion-related reactions, and other adverse events were similar in the combined REGN-COV2 dose groups and the placebo group.
CONCLUSIONS
In this interim analysis, the REGN-COV2 antibody cocktail reduced viral load, with a greater effect in patients whose immune response had not yet been initiated or who had a high viral load at baseline. Safety outcomes were similar in the combined REGN-COV2 dose groups and the placebo group. (Funded by Regeneron Pharmaceuticals and the Biomedical and Advanced Research and Development Authority of the Department of Health and Human Services; ClinicalTrials.gov number, NCT04425629.).
Topics: Adult; Antibodies, Monoclonal, Humanized; Antibodies, Neutralizing; COVID-19; Double-Blind Method; Drug Combinations; Female; Humans; Immunologic Factors; Least-Squares Analysis; Male; Middle Aged; Outpatients; Reverse Transcriptase Polymerase Chain Reaction; SARS-CoV-2; Viral Load; COVID-19 Drug Treatment
PubMed: 33332778
DOI: 10.1056/NEJMoa2035002