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The New England Journal of Medicine Feb 2022NVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
NVX-CoV2373 is an adjuvanted, recombinant spike protein nanoparticle vaccine that was shown to have clinical efficacy for the prevention of coronavirus disease 2019 (Covid-19) in phase 2b-3 trials in the United Kingdom and South Africa, but its efficacy had not yet been tested in North America.
METHODS
We conducted a phase 3, randomized, observer-blinded, placebo-controlled trial in the United States and Mexico during the first half of 2021 to evaluate the efficacy and safety of NVX-CoV2373 in adults (≥18 years of age) who had not had severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Participants were randomly assigned in a 2:1 ratio to receive two doses of NVX-CoV2373 or placebo 21 days apart. The primary objective was to determine vaccine efficacy against reverse-transcriptase-polymerase-chain-reaction-confirmed Covid-19 occurring at least 7 days after the second dose. Vaccine efficacy against moderate-to-severe disease and against different variants was also assessed.
RESULTS
Of the 29,949 participants who underwent randomization between December 27, 2020, and February 18, 2021, a total of 29,582 (median age, 47 years; 12.6% ≥65 years of age) received at least one dose: 19,714 received vaccine and 9868 placebo. Over a period of 3 months, 77 cases of Covid-19 were noted - 14 among vaccine recipients and 63 among placebo recipients (vaccine efficacy, 90.4%; 95% confidence interval [CI], 82.9 to 94.6; P<0.001). Ten moderate and 4 severe cases occurred, all in placebo recipients, yielding vaccine efficacy against moderate-to-severe disease of 100% (95% CI, 87.0 to 100). Most sequenced viral genomes (48 of 61, 79%) were variants of concern or interest - largely B.1.1.7 (alpha) (31 of the 35 genomes for variants of concern, 89%). Vaccine efficacy against any variant of concern or interest was 92.6% (95% CI, 83.6 to 96.7). Reactogenicity was mostly mild to moderate and transient but was more frequent among NVX-CoV2373 recipients than among placebo recipients and was more frequent after the second dose than after the first dose.
CONCLUSIONS
NVX-CoV2373 was safe and effective for the prevention of Covid-19. Most breakthrough cases were caused by contemporary variant strains. (Funded by Novavax and others; PREVENT-19 ClinicalTrials.gov number, NCT04611802.).
Topics: Adolescent; Adult; Aged; COVID-19; COVID-19 Nucleic Acid Testing; COVID-19 Vaccines; Humans; Incidence; Male; Mexico; Middle Aged; SARS-CoV-2; Single-Blind Method; United States; Vaccine Efficacy
PubMed: 34910859
DOI: 10.1056/NEJMoa2116185 -
Cureus Jun 2021Objectives Rett syndrome is a rare disorder characterised by severe scoliosis in 80% of cases. In this retrospective case series, we analysed the radiographic, clinical,...
Objectives Rett syndrome is a rare disorder characterised by severe scoliosis in 80% of cases. In this retrospective case series, we analysed the radiographic, clinical, and functional outcomes of consecutive patients treated for scoliosis associated with Rett syndrome. We sought to understand the results of the treatment of scoliosis in Rett syndrome and evaluate the need to fuse to the pelvis. Methods A retrospective case series was used to analyse the radiographic, clinical, and functional outcomes of consecutive patients treated for Rett syndrome scoliosis between the ages of 10 and 8 years in a single tertiary paediatric spinal unit. Cases were identified through departmental and neurophysiological records, and patients were excluded if the diagnosis of Rett syndrome was not confirmed. Results Seven eligible cases were identified. At presentation, the mean coronal Cobb angle was 90.9°, mean sagittal Cobb 72.0°, and pelvic obliquity 24.5°. The mean post-operative improvement in coronal Cobb was 53.2° and pelvic obliquity reduced to 5.8°. These did not change during a mean follow up of 3.5 years. None showed any post-operative complications. Three patients with a mean 16.1° pelvic obliquity underwent a fusion to L5. The postoperative result in those cases remained stable at 3.5 years mean follow-up and full skeletal maturity. Conclusion Our data suggests that with modern technology, severe curves can be safely treated. Fusion to the pelvis is not necessary in patients with mild, flexible pelvic obliquity.
PubMed: 34249558
DOI: 10.7759/cureus.15411 -
Science (New York, N.Y.) Feb 2007Rett syndrome is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. However, neurons do not die, which...
Rett syndrome is an autism spectrum disorder caused by mosaic expression of mutant copies of the X-linked MECP2 gene in neurons. However, neurons do not die, which suggests that this is not a neurodegenerative disorder. An important question for future therapeutic approaches to this and related disorders concerns phenotypic reversibility. Can viable but defective neurons be repaired, or is the damage done during development without normal MeCP2 irrevocable? Using a mouse model, we demonstrate robust phenotypic reversal, as activation of MeCP2 expression leads to striking loss of advanced neurological symptoms in both immature and mature adult animals.
Topics: Animals; Brain; Chimera; Disease Models, Animal; Female; Gene Expression Regulation; Gene Targeting; Long-Term Potentiation; Male; Methyl-CpG-Binding Protein 2; Mice; Mice, Inbred C57BL; Neurons; Phenotype; Rett Syndrome; Synaptic Transmission; Tamoxifen; Transgenes
PubMed: 17289941
DOI: 10.1126/science.1138389 -
Proceedings of the National Academy of... Jun 2023The protein kinase WNK1 (with-no-lysine 1) influences trafficking of ion and small-molecule transporters and other membrane proteins as well as actin polymerization...
The protein kinase WNK1 (with-no-lysine 1) influences trafficking of ion and small-molecule transporters and other membrane proteins as well as actin polymerization state. We investigated the possibility that actions of WNK1 on both processes are related. Strikingly, we identified the E3 ligase tripartite motif-containing 27 (TRIM27) as a binding partner for WNK1. TRIM27 is involved in fine tuning the WASH (Wiskott-Aldrich syndrome protein and SCAR homologue) regulatory complex which regulates endosomal actin polymerization. Knockdown of WNK1 reduced the formation of the complex between TRIM27 and its deubiquitinating enzyme USP7 (ubiquitin-specific protease 7), resulting in significantly diminished TRIM27 protein. Loss of WNK1 disrupted WASH ubiquitination and endosomal actin polymerization, which are necessary for endosomal trafficking. Sustained receptor tyrosine kinase (RTK) expression has long been recognized as a key oncogenic signal for the development and growth of human malignancies. Depletion of either WNK1 or TRIM27 significantly increased degradation of the epidermal growth factor receptor (EGFR) following ligand stimulation in breast and lung cancer cells. Like the EGFR, the RTK AXL was also affected similarly by WNK1 depletion but not by inhibition of WNK1 kinase activity. This study uncovers a mechanistic connection between WNK1 and the TRIM27-USP7 axis and extends our fundamental knowledge about the endocytic pathway regulating cell surface receptors.
Topics: Humans; Actins; Ubiquitin-Specific Peptidase 7; Endosomes; Transcription Factors; ErbB Receptors; Receptor Protein-Tyrosine Kinases; DNA-Binding Proteins; Nuclear Proteins; WNK Lysine-Deficient Protein Kinase 1
PubMed: 37307465
DOI: 10.1073/pnas.2300310120 -
The New England Journal of Medicine Nov 2021At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
At interim analysis in a phase 3, observer-blinded, placebo-controlled clinical trial, the mRNA-1273 vaccine showed 94.1% efficacy in preventing coronavirus disease 2019 (Covid-19). After emergency use of the vaccine was authorized, the protocol was amended to include an open-label phase. Final analyses of efficacy and safety data from the blinded phase of the trial are reported.
METHODS
We enrolled volunteers who were at high risk for Covid-19 or its complications; participants were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo, 28 days apart, at 99 centers across the United States. The primary end point was prevention of Covid-19 illness with onset at least 14 days after the second injection in participants who had not previously been infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The data cutoff date was March 26, 2021.
RESULTS
The trial enrolled 30,415 participants; 15,209 were assigned to receive the mRNA-1273 vaccine, and 15,206 to receive placebo. More than 96% of participants received both injections, 2.3% had evidence of SARS-CoV-2 infection at baseline, and the median follow-up was 5.3 months in the blinded phase. Vaccine efficacy in preventing Covid-19 illness was 93.2% (95% confidence interval [CI], 91.0 to 94.8), with 55 confirmed cases in the mRNA-1273 group (9.6 per 1000 person-years; 95% CI, 7.2 to 12.5) and 744 in the placebo group (136.6 per 1000 person-years; 95% CI, 127.0 to 146.8). The efficacy in preventing severe disease was 98.2% (95% CI, 92.8 to 99.6), with 2 cases in the mRNA-1273 group and 106 in the placebo group, and the efficacy in preventing asymptomatic infection starting 14 days after the second injection was 63.0% (95% CI, 56.6 to 68.5), with 214 cases in the mRNA-1273 group and 498 in the placebo group. Vaccine efficacy was consistent across ethnic and racial groups, age groups, and participants with coexisting conditions. No safety concerns were identified.
CONCLUSIONS
The mRNA-1273 vaccine continued to be efficacious in preventing Covid-19 illness and severe disease at more than 5 months, with an acceptable safety profile, and protection against asymptomatic infection was observed. (Funded by the Biomedical Advanced Research and Development Authority and the National Institute of Allergy and Infectious Diseases; COVE ClinicalTrials.gov number, NCT04470427.).
Topics: 2019-nCoV Vaccine mRNA-1273; Adolescent; Adult; Aged; COVID-19; COVID-19 Vaccines; Follow-Up Studies; Humans; Immunization, Secondary; Immunogenicity, Vaccine; Incidence; Intention to Treat Analysis; Male; Middle Aged; Patient Acuity; Single-Blind Method; Treatment Outcome; Young Adult
PubMed: 34551225
DOI: 10.1056/NEJMoa2113017 -
PLoS Neglected Tropical Diseases Mar 2016Reports of high rates of primary microcephaly and Guillain-Barré syndrome associated with Zika virus infection in French Polynesia and Brazil have raised concerns that... (Review)
Review
INTRODUCTION
Reports of high rates of primary microcephaly and Guillain-Barré syndrome associated with Zika virus infection in French Polynesia and Brazil have raised concerns that the virus circulating in these regions is a rapidly developing neuropathic, teratogenic, emerging infectious public health threat. There are no licensed medical countermeasures (vaccines, therapies or preventive drugs) available for Zika virus infection and disease. The Pan American Health Organization (PAHO) predicts that Zika virus will continue to spread and eventually reach all countries and territories in the Americas with endemic Aedes mosquitoes. This paper reviews the status of the Zika virus outbreak, including medical countermeasure options, with a focus on how the epidemiology, insect vectors, neuropathology, virology and immunology inform options and strategies available for medical countermeasure development and deployment.
METHODS
Multiple information sources were employed to support the review. These included publically available literature, patents, official communications, English and Lusophone lay press. Online surveys were distributed to physicians in the US, Mexico and Argentina and responses analyzed. Computational epitope analysis as well as infectious disease outbreak modeling and forecasting were implemented. Field observations in Brazil were compiled and interviews conducted with public health officials.
Topics: Aedes; Americas; Animals; Communicable Disease Control; Disease Transmission, Infectious; Humans; Pandemics; Polynesia; Zika Virus Infection
PubMed: 26934531
DOI: 10.1371/journal.pntd.0004530 -
BMJ Case Reports Feb 2022Cobb syndrome is a rare neurocutaneous disorder characterised by spinal and cutaneous vascular malformations in a metameric distribution. Managing such cases is a...
Cobb syndrome is a rare neurocutaneous disorder characterised by spinal and cutaneous vascular malformations in a metameric distribution. Managing such cases is a challenge for the interventionists and neurosurgeons as the results are often suboptimal. We describe a case of Cobb syndrome in a young male child who presented clinically with acute paraparesis and lower backache. On radiological workup, an intradural perimedullary complex spinal arteriovenous fistula was seen with presence of subarachnoid haemorrhage in the spinal canal and compressive myelopathy. There was a haemangioma in paraspinal muscles and a maculopapular cutaneous lesion in the lower back. He was treated with combined endovascular embolisation and surgical intervention and showed significant clinical improvement on follow-up.
Topics: Arteriovenous Fistula; Arteriovenous Malformations; Central Nervous System Vascular Malformations; Child; Embolization, Therapeutic; Humans; Male; Spinal Cord; Spinal Cord Compression; Spine
PubMed: 35228229
DOI: 10.1136/bcr-2021-246821 -
Cell Proliferation Feb 2020Scoliosis, a complex three-dimensional deformity of the spine with the Cobb angle (a measure of the spinal lateral curvature) >10 degree, encompasses a spectrum of... (Review)
Review
Scoliosis, a complex three-dimensional deformity of the spine with the Cobb angle (a measure of the spinal lateral curvature) >10 degree, encompasses a spectrum of pathologies, including congenital, idiopathic, syndromic and neuromuscular aetiologies. The pathogenesis is multifactorial involving both environmental and genetic factors but the exact cellular and molecular mechanisms of disease development remain largely unknown. Emerging evidence showed that non-coding RNAs (ncRNAs), namely microRNAs, long ncRNAs and circular RNAs, are deregulated in many orthopaedic diseases, including scoliosis. Importantly, these deregulated ncRNAs functionally participate in the initiation and progression of scoliosis. Here, we review recent progress in ncRNA research on scoliosis.
Topics: Animals; Humans; RNA, Untranslated; Scoliosis
PubMed: 31828859
DOI: 10.1111/cpr.12736 -
Molecular Therapy. Nucleic Acids Sep 2023Neuromuscular junction (NMJ) dysfunction underlies several diseases, including congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular pathways...
Neuromuscular junction (NMJ) dysfunction underlies several diseases, including congenital myasthenic syndromes (CMSs) and motor neuron disease (MND). Molecular pathways governing NMJ stability are therefore of interest from both biological and therapeutic perspectives. Muscle-specific kinase (MuSK) is necessary for the formation and maintenance of post-synaptic elements of the NMJ, and downstream of tyrosine kinases 7 (DOK7) is crucial for activation of the MuSK pathway. Overexpression of DOK7 using AAV9 has been shown to ameliorate neuromuscular pathology in pre-clinical disease models of CMS and MND. However, long-term consequences of DOK7 expression have been sparsely investigated and targeted overexpression of DOK7 in skeletal muscle yet to be established. Here, we developed and characterized a novel AAV9-DOK7 facilitating forced expression of DOK7 under a skeletal muscle-specific promoter. AAV9-tMCK-DOK7 was systemically delivered to newborn mice that were monitored over 6 months. DOK7 overexpression was restricted to skeletal muscles. Body weight, blood biochemistry, and histopathological assessments were unaffected by AAV9-tMCK-DOK7 treatment. In contrast, forced expression of DOK7 resulted in enlargement of both the pre- and post-synaptic components of the NMJ, without causing denervation. We conclude that muscle-specific DOK7 overexpression can be achieved in a safe manner, with the capacity to target NMJs .
PubMed: 37637210
DOI: 10.1016/j.omtn.2023.07.036 -
Nature Reviews. Neurology Jan 2017In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein... (Review)
Review
In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families.
Topics: History, 20th Century; History, 21st Century; Humans; Rett Syndrome
PubMed: 27934853
DOI: 10.1038/nrneurol.2016.186