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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 -
Cardiology in the Young Apr 2016We report the case of a patient with Donohue syndrome who died of heart failure due to obstructive hypertrophic cardiomyopathy. A literature survey revealed that...
We report the case of a patient with Donohue syndrome who died of heart failure due to obstructive hypertrophic cardiomyopathy. A literature survey revealed that hypertrophic cardiomyopathy was present in 30% of these patients and was often fatal. Therefore, every patient with Donohue syndrome should be screened for hypertrophic cardiomyopathy.
Topics: Cardiomyopathy, Hypertrophic; Donohue Syndrome; Humans; Infant, Newborn; Male
PubMed: 26555333
DOI: 10.1017/S1047951115002437 -
BMJ Case Reports Oct 2015Donohue syndrome is a rare autosomal recessive condition caused by severe loss-of-function mutations in the insulin receptor (INSR) gene. The diagnosis is made on...
Donohue syndrome is a rare autosomal recessive condition caused by severe loss-of-function mutations in the insulin receptor (INSR) gene. The diagnosis is made on clinical, biochemical and genetic grounds. Mutations are found on chromosome 19p13.2, and code for mutations in the INSR gene. Treatment is challenging and often unsuccessful, and relies on maintaining normoglycaemia and avoiding fasting; in some patients, recombinant human insulin-like growth factor (rhIGF-1) has been trialled. The prognosis is poor, with most babies dying in infancy. Ethically, it is important to consider the benefit versus burden of treatment, the quality of life of the surviving patient and the parents' wishes, when making decisions regarding withholding or withdrawing care.
Topics: Clinical Decision-Making; Donohue Syndrome; Humans; Hyperglycemia; Infant, Newborn; Insulin Infusion Systems; Male; Mutation; Palliative Care; Prognosis; Quality of Life; Receptor, Insulin
PubMed: 26508115
DOI: 10.1136/bcr-2015-210019 -
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 -
Medicine Feb 2016Donohue syndrome ([DS]; leprechaunism) describes a genetic autosomal recessive disorder that results from the presence of homozygous or compound heterozygous mutations...
Donohue syndrome ([DS]; leprechaunism) describes a genetic autosomal recessive disorder that results from the presence of homozygous or compound heterozygous mutations in the insulin receptor gene (INSR; 19p13.3-p13.2).Donohue syndrome is associated with a fatal congenital form of dwarfism with features of intrauterine and postnatal growth retardation, exaggerated hyperglycemia with hyperinsulinism and dysmorphic abnormalities.We present a case of DS owing to the rarity of this syndrome (1 case in every million births). We discuss how the disease presents, its genetic underpinning, and its prevention.The case was encountered in an Arab male born on 1 September, 2014, for consanguineous parents. The delivery was via cesarean section at 37 weeks gestation due to severe intrauterine growth restriction and nonprogress labor term. The patient was admitted to the Neonatal Intensive Care Unit due to infection, and jaundice. Dysmorphic features, abnormalities of the craniofacial region, low birth weight, skin abnormalities, abdominal distension and hypertrichosis were observed. Laboratory examinations showed, hyperinsulinism, increased C-peptide, thrombocytopenia, leucopenia, and anemia.The diagnosis of DS was done based on the combinations of typical dysmorphic characteristics, clinical evaluation, supported by genetic analysis and exaggerated biochemical results. Genetic diagnosis of DS was performed through analysis of DNA via polymerase chain reaction (PCR). A qualitative real-time PCR was used, to monitor the amplification of a targeted DNA molecule during the PCR. Other technique using sequencing of the INSR gene, which permits genetic diagnosis, counseling, and antenatal diagnoses in subsequent pregnancies, were also performed.Treatment of DS is supportive and requires the combined efforts of a multidisciplinary team, which include pediatricians, endocrinologists, dermatologists, and other health care professionals. Currently, treatment with recombinant insulin-like growth factor 1 demonstrates effectiveness, and a combination treatment with insulin-like growth factor binding protein 3 resulted in an increased lifespan.There is a scarcity of genetic information on DS among the Arab population. Consanguinity is one of underlying reasons for the appearance of rare genetic disorders. Inbreeding has long been considered a controversial phenomenon. Genetic counseling and overwhelming the alertness of the negative consequences of consanguinity on public health are warranted.
Topics: Consanguinity; Donohue Syndrome; Fatal Outcome; Humans; Infant; Infant, Newborn; Male
PubMed: 26871809
DOI: 10.1097/MD.0000000000002710 -
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 -
Cell Stem Cell Mar 2024Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2...
Thalamic dysfunction has been implicated in multiple psychiatric disorders. We sought to study the mechanisms by which abnormalities emerge in the context of the 22q11.2 microdeletion, which confers significant genetic risk for psychiatric disorders. We investigated early stages of human thalamus development using human pluripotent stem cell-derived organoids and show that the 22q11.2 microdeletion underlies widespread transcriptional dysregulation associated with psychiatric disorders in thalamic neurons and glia, including elevated expression of FOXP2. Using an organoid co-culture model, we demonstrate that the 22q11.2 microdeletion mediates an overgrowth of thalamic axons in a FOXP2-dependent manner. Finally, we identify ROBO2 as a candidate molecular mediator of the effects of FOXP2 overexpression on thalamic axon overgrowth. Together, our study suggests that early steps in thalamic development are dysregulated in a model of genetic risk for schizophrenia and contribute to neural phenotypes in 22q11.2 deletion syndrome.
Topics: Humans; Schizophrenia; DiGeorge Syndrome; Phenotype
PubMed: 38382530
DOI: 10.1016/j.stem.2024.01.010 -
Neuropsychology Feb 2023Sport concussion is a common injury, and athletes with attention-deficit/hyperactivity disorder (ADHD) and/or learning disorder (LD) are at increased risk and require... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Sport concussion is a common injury, and athletes with attention-deficit/hyperactivity disorder (ADHD) and/or learning disorder (LD) are at increased risk and require specialized attention in clinical settings. Although systematic reviews of the relationship between ADHD/LD and concussion are reported in the literature, these reviews do not include quantitative syntheses. Additionally, no reviews have focused on the most commonly utilized concussion assessment, Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT). The current review provides an update of sport concussion assessment in athletes with ADHD and/or LD from 2000 to 2021 on these topics: baseline and postconcussion performance on ImPACT, baseline and postconcussion symptom reporting using the Postconcussion Symptom Scale, invalid baseline classification on ImPACT, and self-reported history of concussion.
METHOD
Meta-analyses were conducted on baseline ImPACT performance, symptom reporting, invalid baseline classification, and concussion rates. Thirty-four studies were included in systematic review and 19 were included in meta-analyses.
RESULTS
Decreased baseline performance was found for athletes with ADHD (trivial to small effects), LD (small-to-medium effects), and ADHD/LD (small-to-medium effects). Increased baseline symptom reporting was found for athletes with ADHD (small effect). Increased odds of invalid baseline performance (trivial effect) and self-reported concussion history (small effect) were found in ADHD.
CONCLUSIONS
These results provide the first quantitative synthesis of the literature in this area. It is recommended that future research further examines these topics in athletes with LD and co-occurring ADHD/LD (given the focus on ADHD), as well as the effects that all of these conditions may have on concussion recovery and return-to-play decision-making. (PsycInfo Database Record (c) 2023 APA, all rights reserved).
Topics: Humans; Attention Deficit Disorder with Hyperactivity; Athletic Injuries; Self Report; Brain Concussion; Learning Disabilities; Athletes; Neuropsychological Tests; Schools; Post-Concussion Syndrome
PubMed: 36442003
DOI: 10.1037/neu0000870