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JAMA Sep 2020Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Remdesivir demonstrated clinical benefit in a placebo-controlled trial in patients with severe coronavirus disease 2019 (COVID-19), but its effect in patients with moderate disease is unknown.
OBJECTIVE
To determine the efficacy of 5 or 10 days of remdesivir treatment compared with standard care on clinical status on day 11 after initiation of treatment.
DESIGN, SETTING, AND PARTICIPANTS
Randomized, open-label trial of hospitalized patients with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and moderate COVID-19 pneumonia (pulmonary infiltrates and room-air oxygen saturation >94%) enrolled from March 15 through April 18, 2020, at 105 hospitals in the United States, Europe, and Asia. The date of final follow-up was May 20, 2020.
INTERVENTIONS
Patients were randomized in a 1:1:1 ratio to receive a 10-day course of remdesivir (n = 197), a 5-day course of remdesivir (n = 199), or standard care (n = 200). Remdesivir was dosed intravenously at 200 mg on day 1 followed by 100 mg/d.
MAIN OUTCOMES AND MEASURES
The primary end point was clinical status on day 11 on a 7-point ordinal scale ranging from death (category 1) to discharged (category 7). Differences between remdesivir treatment groups and standard care were calculated using proportional odds models and expressed as odds ratios. An odds ratio greater than 1 indicates difference in clinical status distribution toward category 7 for the remdesivir group vs the standard care group.
RESULTS
Among 596 patients who were randomized, 584 began the study and received remdesivir or continued standard care (median age, 57 [interquartile range, 46-66] years; 227 [39%] women; 56% had cardiovascular disease, 42% hypertension, and 40% diabetes), and 533 (91%) completed the trial. Median length of treatment was 5 days for patients in the 5-day remdesivir group and 6 days for patients in the 10-day remdesivir group. On day 11, patients in the 5-day remdesivir group had statistically significantly higher odds of a better clinical status distribution than those receiving standard care (odds ratio, 1.65; 95% CI, 1.09-2.48; P = .02). The clinical status distribution on day 11 between the 10-day remdesivir and standard care groups was not significantly different (P = .18 by Wilcoxon rank sum test). By day 28, 9 patients had died: 2 (1%) in the 5-day remdesivir group, 3 (2%) in the 10-day remdesivir group, and 4 (2%) in the standard care group. Nausea (10% vs 3%), hypokalemia (6% vs 2%), and headache (5% vs 3%) were more frequent among remdesivir-treated patients compared with standard care.
CONCLUSIONS AND RELEVANCE
Among patients with moderate COVID-19, those randomized to a 10-day course of remdesivir did not have a statistically significant difference in clinical status compared with standard care at 11 days after initiation of treatment. Patients randomized to a 5-day course of remdesivir had a statistically significant difference in clinical status compared with standard care, but the difference was of uncertain clinical importance.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT04292730.
Topics: Adenosine Monophosphate; Administration, Intravenous; Aged; Alanine; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Drug Administration Schedule; Female; Hospitalization; Humans; Male; Middle Aged; Odds Ratio; Pandemics; Patient Acuity; Pneumonia, Viral; SARS-CoV-2; Treatment Outcome; COVID-19 Drug Treatment
PubMed: 32821939
DOI: 10.1001/jama.2020.16349 -
Molecular and Clinical Oncology Mar 2017Proteus syndrome is a rare complex syndrome involving clinical presentation with atypical skeletal growth. Only a limited number of cases with this syndrome have been...
Proteus syndrome is a rare complex syndrome involving clinical presentation with atypical skeletal growth. Only a limited number of cases with this syndrome have been reported in the literature to date. We herein report the case of a Chinese male patient with Proteus syndrome and review the clinical and molecular characteristics of this disease. The patient was a 34-year-old man with clinical manifestations suggestive of the Proteus syndrome, including mosaic distribution of the lesions, sporadic occurrence, progressive course, disproportionate overgrowth of the legs, epidermal nevi, lipomas, venous malformations and characteristic facial phenotype. Genetic mosaicism, such as mutations involving the phosphoinositide 3 kinase-AKT pathway in the affected tissues, may be important causes of Proteus syndrome. In the present case, samples from the affected tissues were collected from the patient and were further analyzed using whole-exome sequencing. However, no mutation of the genes reportedly associated with Proteus syndrome was identified in the affected tissues. Proteus syndrome is a complex mosaic disorder with a number of variable characteristics. Although activating AKT1 mutations have been found to be associated with this disorder, the molecular etiology remains to be fully elucidated and diagnostic criteria must be established in the clinical setting.
PubMed: 28451417
DOI: 10.3892/mco.2017.1140 -
Journal of Pediatric Genetics Sep 2015Numerous multiple malformation syndromes associated with pathologic overgrowth have been described and, for many, their molecular bases elucidated. This review describes... (Review)
Review
Numerous multiple malformation syndromes associated with pathologic overgrowth have been described and, for many, their molecular bases elucidated. This review describes the characteristic features of these overgrowth syndromes, as well as the current understanding of their molecular bases, intellectual outcomes, and cancer predispositions. We review syndromes such as Sotos, Malan, Marshall-Smith, Weaver, Simpson-Golabi-Behmel, Perlman, Bannayan-Riley-Ruvalcaba, PI3K-related, Proteus, Beckwith-Wiedemann, fibrous dysplasia, Klippel-Trenaunay-Weber, and Maffucci.
PubMed: 27617124
DOI: 10.1055/s-0035-1564440 -
Cold Spring Harbor Perspectives in... May 2020Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden... (Review)
Review
Germline alterations of the tumor suppressor PTEN have been extensively characterized in patients with PTEN hamartoma tumor syndromes, encompassing subsets of Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, Proteus and Proteus-like syndromes, as well as autism spectrum disorder. Studies have shown an increase in the risk of developing specific cancer types in the presence of a germline mutation. Furthermore, outside of the familial setting, somatic variants of occur in numerous malignancies. Here we introduce and discuss the prospect of moving toward a systems pathology approach for PTEN diagnostics, incorporating clinical and molecular pathology data with the goal of improving the clinical management of patients with a mutation. Detection of a germline mutation can inform cancer surveillance and in the case of somatic mutation, have value in predicting disease course. Given that PTEN functions in the PI3K/AKT/mTOR pathway, identification of a mutation may highlight new therapeutic opportunities and/or inform therapeutic choices.
Topics: Autism Spectrum Disorder; Biomarkers, Tumor; Genes, Tumor Suppressor; Genetic Testing; Germ-Line Mutation; Hamartoma Syndrome, Multiple; Molecular Targeted Therapy; Neoplasms; PTEN Phosphohydrolase; Phosphatidylinositol 3-Kinases
PubMed: 31615872
DOI: 10.1101/cshperspect.a037127 -
Turkish Journal of Anaesthesiology and... Dec 2022
PubMed: 36511499
DOI: 10.5152/TJAR.2021.21149 -
Experimental and Therapeutic Medicine Sep 2020Proteus syndrome (PS) is an extremely rare and sporadic disorder characterized by asymmetric and/or disproportionate overgrowth of limbs, hamartomas, and vascular...
Proteus syndrome (PS) is an extremely rare and sporadic disorder characterized by asymmetric and/or disproportionate overgrowth of limbs, hamartomas, and vascular malformations. The onset of overgrowth usually involves the skin, bone, fat, and other connective tissues in a patchy or mosaic pattern. Partial gigantism of the affected limb or digit is a pathognomonic sign of PS. Thus far, only a few cases of PS have been recorded in the literature. In the present report, a case of PS in a 35-year old woman with classic cerebriform plantar hyperplasia and macrodactyly of the left foot was documented. The clinical and molecular characteristics and differential diagnosis of PS are also discussed in this report.
PubMed: 32765766
DOI: 10.3892/etm.2020.8986 -
Cold Spring Harbor Molecular Case... Jun 2020Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively...
Proteus syndrome is a mosaic disorder that can cause progressive postnatal overgrowth of nearly any organ or tissue. To date, Proteus syndrome has been exclusively associated with the mosaic c.49G > A p.(Glu17Lys) pathogenic variant in , a variant that is also present in many cancers. Here we describe an individual with severe Proteus syndrome who died at 7.5 yr of age from combined parenchymal and restrictive pulmonary disease. Remarkably, this individual was found to harbor a mosaic c.49_50delinsAG p.(Glu17Arg) variant in at a variant allele fraction that ranged from <0.01 to 0.46 in fibroblasts established from an overgrown digit. This variant was demonstrated to be constitutively activating by phosphorylation of AKT(S473). These data document allelic heterogeneity for Proteus syndrome. We recommend that individuals with a potential clinical diagnosis of Proteus syndrome who are negative for the p.(Glu17Lys) variant be tested for other variants in .
Topics: Alleles; Allelic Imbalance; Amino Acid Substitution; Cervical Vertebrae; Genetic Association Studies; Genetic Heterogeneity; Genetic Predisposition to Disease; Genetic Testing; Humans; Infant; Magnetic Resonance Imaging; Male; Medical History Taking; Mutation; Phenotype; Proteus Syndrome; Proto-Oncogene Proteins c-akt; Radiography; Symptom Assessment
PubMed: 32327430
DOI: 10.1101/mcs.a005181