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The cell wall is a critical extracellular barrier for bacteria and many other organisms. In bacteria, this structural layer consists of peptidoglycan, which maintains cell shape and structural integrity and provides a scaffold for displaying various protein factors. To attach proteins to the cell wall, Gram-positive bacteria utilize sortase enzymes, which are cysteine transpeptidases that recognize and cleave a specific sorting signal, followed by ligation of the sorting signal-containing protein to the peptidoglycan precursor lipid II (LII). This mechanism is the subject of considerable interest as a target for therapeutic intervention and as a tool for protein engineering, where sortases have enabled sortase-mediated ligation or sortagging strategies. Despite these uses, there remains an incomplete understanding of the stereochemistry of substrate recognition and ligation product formation. Here, we solved the first structures of sortase A from Streptococcus pyogenes bound to two substrate sequences, LPATA and LPATS. In addition, we synthesized a mimetic of the product of sortase-mediated ligation involving LII (LPAT-LII) and solved the complex structure in two ligand conformations. These structures were further used as the basis for molecular dynamics simulations to probe sortase A-ligand dynamics and to construct a model of the acyl-enzyme intermediate, thus providing a structural view of multiple key states in the catalytic mechanism. Overall, this structural information provides new insights into the recognition of the sortase substrate motif and LII ligation partner and will support the continued development of sortases for protein engineering applications.
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Aminoaciltransferases , Aminoaciltransferases/química , Aminoaciltransferases/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/metabolismo , Ligantes , Peptidoglicano , Streptococcus pyogenes/enzimologiaRESUMO
Protein misfolding and aggregation is observed in many amyloidogenic diseases affecting either the central nervous system or a variety of peripheral tissues. Structural and dynamic characterization of all species along the pathways from monomers to fibrils is challenging by experimental and computational means because they involve intrinsically disordered proteins in most diseases. Yet understanding how amyloid species become toxic is the challenge in developing a treatment for these diseases. Here we review what computer, in vitro, in vivo, and pharmacological experiments tell us about the accumulation and deposition of the oligomers of the (Aß, tau), α-synuclein, IAPP, and superoxide dismutase 1 proteins, which have been the mainstream concept underlying Alzheimer's disease (AD), Parkinson's disease (PD), type II diabetes (T2D), and amyotrophic lateral sclerosis (ALS) research, respectively, for many years.
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Amiloide/química , Amiloide/metabolismo , Doenças Neurodegenerativas/metabolismo , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/metabolismo , Esclerose Lateral Amiotrófica/patologia , Animais , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Humanos , Polipeptídeo Amiloide das Ilhotas Pancreáticas/química , Polipeptídeo Amiloide das Ilhotas Pancreáticas/metabolismo , Modelos Moleculares , Doenças Neurodegenerativas/patologia , Doença de Parkinson/metabolismo , Doença de Parkinson/patologia , Agregação Patológica de Proteínas , Deficiências na Proteostase/metabolismo , Superóxido Dismutase-1/química , Superóxido Dismutase-1/metabolismo , alfa-Sinucleína/química , alfa-Sinucleína/metabolismo , Proteínas tau/química , Proteínas tau/metabolismoRESUMO
Coacervation is a common phenomenon in natural polymers and has been applied to synthetic materials systems for coatings, adhesives, and encapsulants. Single-component coacervates are formed when block polyampholytes exhibit self-coacervation, phase separating into a dense liquid coacervate phase rich in the polyampholyte coexisting with a dilute supernatant phase, a process implicated in the liquid-liquid phase separation of intrinsically disordered proteins. Using fully fluctuating field-theoretic simulations using complex Langevin sampling and complementary molecular-dynamics simulations, we develop molecular design principles to connect the sequenced charge pattern of a polyampholyte with its self-coacervation behavior in solution. In particular, the lengthscale of charged blocks and number of connections between oppositely charged blocks are shown to have a dramatic effect on the tendency to phase separate and on the accessible chain conformations. The field and particle-based simulation results are compared with analytical predictions from the random phase approximation (RPA) and postulated scaling relationships. The qualitative trends are mostly captured by the RPA, but the approximation fails catastrophically at low concentration.
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Misturas Anfolíticas/química , Conformação Molecular , Polímeros/química , Engenharia Química , Fenômenos Químicos , Simulação de Dinâmica MolecularRESUMO
The process of freezing proteins is widely used in applications ranging from processing and storage of biopharmaceuticals to cryo-EM analysis of protein complexes. The formation of an ice-water interface is a critical destabilization factor for the protein, which can be offset by the use of cryo-protectants. Using molecular dynamics simulation, we demonstrate that the presence of the ice-water interface leads to a lowering of the free-energy barrier for unfolding, resulting in rapid unfolding of the protein. The unfolding process does not require direct adsorption of the protein to the surface, but is rather mediated by nearby liquid molecules that show an increased tendency for hydrating nonpolar groups. The observed enhancement in the cold denaturation process upon ice formation can be mitigated by addition of glucose, which acts as a cryoprotectant through preferential exclusion from side chains of the protein.
Assuntos
Proteínas de Bactérias/química , Gelo , Desnaturação Proteica , Água/química , Sequência de Aminoácidos , Firmicutes/química , Glucose/química , Cinética , Simulação de Dinâmica MolecularRESUMO
BACKGROUND: The anatomic course of the phrenic nerve runs in the fascia covering the anterior scalene muscle. Interscalene blocks are commonly performed by an anesthesiologist for shoulder surgery, such as a rotator cuff repair, total shoulder replacement, humeral fracture, or other arm surgery. Phrenic nerve palsy or paralysis is a known complication from interscalene block and is covered in multiple case reports and series in both Anesthesia and Neurosurgical literature, but only one case report in the Emergency Medicine literature. CASE REPORT: This case involves a 57-year-old man who had an uncomplicated arthroscopic rotator cuff repair with placement of interscalene block under care of anesthesia. He was discharged with a pain pump in place and then subsequently presented to the Emergency Department (ED) later that same day for evaluation of dyspnea. Using point-of-care ultrasound, his right diaphragm did not appear to be moving. Chest x-ray study revealed an elevated right hemidiaphragm. He was diagnosed with iatrogenic right phrenic nerve paralysis from interscalene block. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergent diagnosis of phrenic nerve paralysis in the ED is complicated by a distressed patient and need for quick intervention. Most formal tests for this diagnosis are not immediately available to emergency physicians. Ultrasound is a rapid and reproducible, noninvasive resource with high sensitivity and specificity, making it an ideal imaging modality for the emergent evaluation of possible phrenic nerve palsy or paralysis.
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Bloqueio do Plexo Braquial , Plexo Braquial , Doenças do Sistema Nervoso Periférico , Paralisia Respiratória , Humanos , Masculino , Pessoa de Meia-Idade , Paralisia/etiologia , Nervo Frênico , Paralisia Respiratória/diagnóstico , Paralisia Respiratória/etiologiaRESUMO
Self-coacervation is a phenomenon in which a solution of polyampholytes spontaneously phase separates into a dense liquid coacervate phase, rich in the polyampholyte, coexisting with a dilute supernatant phase. Such coacervation results in the formation of membraneless organelles in vivo and has further been applied industrially as synthetic encapsulants and coatings. It has been suggested that coacervation is primarily driven by the entropy gain from releasing counter-ions upon complexation. Using fully fluctuating field-theoretic simulations employing complex Langevin sampling and complementary molecular dynamics simulations, we have determined that the small ions contribute only weakly to the self-coacervation behavior of charge-symmetric block polyampholytes in solution. Salt partitioning between the supernatant and coacervate is also found to be negligible in the weak-binding regime at low electrostatic strengths. Asymmetries in charge distribution along the polyampholytes can cause net-charges that lead to "tadpole" configurations in dilute solution and the suppression of phase separation at low salt content. The field and particle-based simulation results are compared with analytical predictions from the random phase approximation (RPA) and postulated scaling relationships. The qualitative trends are mostly captured by the RPA, but the approximation fails at low concentration.
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In this paper, we combine two powerful computational techniques, well-tempered metadynamics and time-lagged independent component analysis. The aim is to develop a new tool for studying rare events and exploring complex free energy landscapes. Metadynamics is a well-established and widely used enhanced sampling method whose efficiency depends on an appropriate choice of collective variables. Often the initial choice is not optimal leading to slow convergence. However by analyzing the dynamics generated in one such run with a time-lagged independent component analysis and the techniques recently developed in the area of conformational dynamics, we obtain much more efficient collective variables that are also better capable of illuminating the physics of the system. We demonstrate the power of this approach in two paradigmatic examples.
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We propose a new method to obtain kinetic properties of infrequent events from molecular dynamics simulation. The procedure employs a recently introduced variational approach [Valsson and Parrinello, Phys. Rev. Lett. 113, 090601 (2014)] to construct a bias potential as a function of several collective variables that is designed to flood the associated free energy surface up to a predefined level. The resulting bias potential effectively accelerates transitions between metastable free energy minima while ensuring bias-free transition states, thus allowing accurate kinetic rates to be obtained. We test the method on a few illustrative systems for which we obtain an order of magnitude improvement in efficiency relative to previous approaches and several orders of magnitude relative to unbiased molecular dynamics. We expect an even larger improvement in more complex systems. This and the ability of the variational approach to deal efficiently with a large number of collective variables will greatly enhance the scope of these calculations. This work is a vindication of the potential that the variational principle has if applied in innovative ways.
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The yeast cytosine deaminase (yCD) enzyme/5-fluorocytosine prodrug system is a promising candidate for targeted chemotherapeutics. After conversion of the prodrug into the toxic chemotherapeutic drug, 5-fluorouracil (5-FU), the slow product release from the enzyme limits the overall catalytic efficiency of the enzyme/prodrug system. Here, we present a computational study of the product release of the anticancer drug, 5-FU, from yCD using metadynamics. We present a comparison of the 5-FU drug to the natural enzyme product, uracil. We use volume-based metadynamics to compute the free energy landscape for product release and show a modest binding affinity for the product to the enzyme, consistent with experiments. Next, we use infrequent metadynamics to estimate the unbiased release rate from Kramers time-dependent rate theory and find a favorable comparison to experiment with a slower rate of product release for the 5-FU system. Our work demonstrates how adaptive sampling methods can be used to study the protein-ligand unbinding process for engineering enzyme/prodrug systems and gives insights into the molecular mechanism of product release for the yCD/5-FU system.
Assuntos
Antineoplásicos , Pró-Fármacos , Saccharomyces cerevisiae , Citosina Desaminase/química , Citosina Desaminase/metabolismo , Fluoruracila/metabolismo , Flucitosina/química , Flucitosina/metabolismo , Pró-Fármacos/químicaRESUMO
BACKGROUND: Coccidioidomycosis is a spectrum of diseases caused by the dimorphic fungi Coccidioides. Current regimens for severe or disseminated disease include fluconazole, itraconazole, or amphotericin; newer triazoles (ie, voriconazole, posaconazole) have been demonstrated to be useful in refractory disease. Previous reported experience with combination triazole and caspofungin therapy has been very limited; however, the utility of this combination for treatment of other invasive fungal diseases suggests potential benefit in refractory coccidioidomycosis. METHODS: We conducted a retrospective review of 9 pediatric patients treated with combination voriconazole and caspofungin (V/C) salvage therapy for refractory coccidioidomycosis at two children's hospitals between January 2000 and June 2012. RESULTS: Nine children with refractory coccidioidomycosis were treated with V/C salvage therapy after failing conventional therapy consisting of a triazole, amphotericin B, or a combination of both. Eight of the 9 patients are currently in remission; 1 patient with central nervous system involvement continues to progress. CONCLUSIONS: We report our positive clinical experience treating medically refractory coccidioidomycosis in the pediatric population with concurrent voriconazole and caspofungin therapy. Additional in vitro and in vivo evaluations are warranted to support the role of V/C salvage therapy for refractory coccidioidomycosis.
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Antifúngicos/uso terapêutico , Coccidioidomicose/tratamento farmacológico , Equinocandinas/uso terapêutico , Pirimidinas/uso terapêutico , Triazóis/uso terapêutico , Adolescente , Caspofungina , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Lipopeptídeos , Masculino , Estudos Retrospectivos , Terapia de Salvação , Resultado do Tratamento , VoriconazolRESUMO
BACKGROUND: Coccidioidomycosis, an endemic fungal infection seen throughout the southwestern United States, is not well described in children. METHODS: We performed a retrospective observational study of all children admitted to Children's Hospital Central California with coccidioidomycosis from 1 January 2010 to 1 September 2011. RESULTS: Thirty-three children, aged 6 months to 17 years, were hospitalized during the study period. These included patients with pneumonia (n = 28), pleural effusion (n = 13), pleural empyema (n = 4), lung abscess (n = 7), pericarditis (n = 2), osteomyelitis (n = 5), meningitis/cerebritis (n = 2), and vocal cord infection (n = 1). Mediastinitis, with radiographic evidence of purulence and necrotic/abscessed lymph nodes in the mediastinum, was present in 7 patients (21%) and tended to occur more often in younger children (median age, 3 years [range, 0.5-11 years] vs 7 years [range, 0.6-17 years] for non-mediastinitis patients; P = .10). Seven patients were admitted to the intensive care unit and 10 required surgical intervention. One patient died of meningitis. Hospitalizations were longer for patients with mediastinitis (median, 130 days [range, 58-200 days] vs 43 days [range, 3-273 days for non-mediastinitis patients]; P < .01) and those with maximum coccidioidal complement fixing antibody titers ≥1:128 (median, 174 days [range, 53-273 days] vs 33 days [range, 3-200 days] for those with maximum titers <1:128; P < .01). CONCLUSIONS: Coccidioidomycosis causes a substantial disease burden in the children of central California. Mediastinitis is common and tends to occur in younger children. Patients with mediastinitis or elevated coccidioidal complement fixation titers require longer hospitalizations. Further research is needed on the prevention and treatment of this disease.
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Coccidioidomicose/diagnóstico , Coccidioidomicose/tratamento farmacológico , Adolescente , Anticorpos Antifúngicos/sangue , Antifúngicos/uso terapêutico , California , Criança , Pré-Escolar , Coccidioidomicose/fisiopatologia , Feminino , Humanos , Lactente , Masculino , Radiografia Torácica , Estudos Retrospectivos , Estatísticas não Paramétricas , Resultado do TratamentoRESUMO
The surgical correction of hammer digits offers a variety of surgical treatments ranging from arthroplasty to arthrodesis, with many options for fixation. In the present study, we compared 2 buried implants for arthrodesis of lesser digit deformities: a Smart Toe® implant and a buried Kirschner wire. Both implants were placed in a prepared interphalangeal joint, did not violate other digital or metatarsal joints, and were not exposed percutaneously. A retrospective comparative study was performed of 117 digits with either a Smart Toe® implant or a buried Kirschner wire, performed from January 1, 2007 to December 31, 2010. Of the 117 digits, 31 were excluded because of a lack of 90-day radiographic follow-up. The average follow-up was 94 to 1130 days. The average patient age was 61.47 (range 43 to 84) years. Of the 86 included digits, 48 were left digits and 38 were right. Of the digits corrected, 54 were second digits, 24 were third digits and 8 were fourth digits. Fifty-eight Smart Toe® implants were found (15 with 19-mm straight; 2 with 19-mm angulated; 34 with 16-mm straight; and 7 with 16-mm angulated). Twenty-eight buried Kirschner wires were evaluated. No statistically significant difference was found between the Smart Toe® implants and the buried Kirschner wires, including the rate of malunion, nonunion, fracture of internal fixation, and the need for revision surgery. Of the 86 implants, 87.9% of the Smart Toe® implants and 85.7% of the buried Kirschner wires were in good position (0° to 10° of transverse angulation on radiographs). Osseous union was achieved in 68.9% of Smart Toe® implants and 82.1% of buried Kirschner wires. Fracture of internal fixation occurred in 12 of the Smart Toe® implants (20.7%) and 2 of the buried Kirschner wires (7.1%). Most of the fractured internal fixation and malunions or nonunions were asymptomatic, leading to revision surgery in only 8.6% of the Smart Toe® implants and 10.7% of the buried Kirschner wires. Both the Smart Toe® implant and the buried Kirschner wire offer a viable choice for internal fixation of an arthrodesis of the digit compared with other studies using other techniques.
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Artrodese/instrumentação , Fios Ortopédicos , Dispositivos de Fixação Ortopédica , Articulação do Dedo do Pé/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Síndrome do Dedo do Pé em Martelo/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Dispositivos de Fixação Ortopédica/efeitos adversos , Osseointegração , Radiografia , Reoperação , Estudos Retrospectivos , Articulação do Dedo do Pé/diagnóstico por imagemRESUMO
In a phase 4, placebo-controlled, double-blind, multi-center study performed to assess the immunogenicity of a single oral dose of live, attenuated cholera vaccine, volunteers aged 2-17 years were randomized 6:1 to receive 1 × 109 colony forming units of PXVX0200 or placebo. In the subset of subjects who consumed < 80 % of the vaccine dose, seroconversion rates were calculated and stratified by amount consumed. Of 468 subjects dosed, a subset of 33 (7 %) received < 80 % of the vaccine dose. SVA seroconversion occurred in 75.8 % of these subjects, including 100 % (7/7) of those who took 50-80 % and 69.2 % (18/26) of those who took < 50 %, versus 98.5 % of those who consumed 80 % or more. Vaccination with PXVX0200 produced an immune response in most children who received partial dosing. Since SVA seroconversion is a strong correlate of protection, PXVX0200 may protect against cholera infection in children who ingest only part of the vaccine dose.
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Vacinas contra Cólera , Cólera , Humanos , Criança , Estados Unidos , Administração Oral , Anticorpos Antibacterianos , Cólera/prevenção & controle , Vacinas Atenuadas , Método Duplo-Cego , Imunogenicidade da VacinaRESUMO
Liquid-liquid phase separation (LLPS) is a process that results in the formation of a polymer-rich liquid phase coexisting with a polymer-depleted liquid phase. LLPS plays a critical role in the cell through the formation of membrane-less organelles, but it also has a number of biotechnical and biomedical applications such as drug confinement and its targeted delivery. In this chapter, we present a computational efficient methodology that uses field-theoretic simulations (FTS) with complex Langevin (CL) sampling to characterize polymer phase behavior and delineate the LLPS phase boundaries. This approach is a powerful complement to analytical and explicit-particle simulations, and it can serve to inform experimental LLPS studies. The strength of the method lies in its ability to properly sample a large ensemble of polymers in a saturated solution while including the effect of composition fluctuations on LLPS. We describe the approaches that can be used to accurately construct phase diagrams of a variety of molecularly designed polymers and illustrate the method by generating an approximation-free phase diagram for a classical symmetric diblock polyampholyte.
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Organelas , Polímeros , Fenômenos Químicos , Simulação por ComputadorRESUMO
BACKGROUND: Published literature on central nervous system (CNS) coccidioidomycosis in children is limited. Here we describe a large case series of pediatric CNS coccidioidomycosis from a tertiary care center in an endemic region. METHOD: This is a retrospective case review of patients ≤21 years old with a diagnosis of CNS coccidioidomycosis from January 1, 2000, to December 31, 2018. RESULTS: Thirty patients (median age 10.8 years) were identified and most (93%) were previously healthy. Fever (90%), headache (70%), vomiting (53%), and fatigue (57%) were the most common presenting clinical manifestations, with focal neurological signs/symptoms present in 14 (47%). The initial serum Coccidioides compliment fixation (CF) titer was ≤ 1:8 in 33%. Most patients had extra-axial brain involvement (83%) and seven (23%) had associated spinal cord disease. Shunt placement was required in 70% and 62% required revision. Fluconazole was the initial treatment in 22 (73%), with treatment failure occurring in 50%. Most patients (77%) stabilized and were maintained on suppressive therapy, 4 (13%) experienced relapses and/or progressive disease, and one (3%) died, while long-term neurological complications occurred in 17%. CONCLUSIONS: CNS coccidioidomycosis is an uncommon and sometimes devastating complication of disseminated coccidioidomycosis. Many patients present with relatively low CF titers and hydrocephalus is common. Fluconazole treatment failures are common, and management remains difficult despite recent advances in therapy. Most patients do well once the disease is stabilized and require lifelong therapy. Newer therapeutic agents are needed.
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Coccidioidomicose , Humanos , Criança , Adulto Jovem , Adulto , Coccidioidomicose/diagnóstico , Coccidioidomicose/tratamento farmacológico , Coccidioidomicose/epidemiologia , Fluconazol/uso terapêutico , Estudos Retrospectivos , Coccidioides , Sistema Nervoso Central , Antifúngicos/uso terapêuticoRESUMO
BACKGROUND: Laryngeal coccidioidomycosis is a rare but life-threatening manifestation of coccidioidomycosis. Data in children are sparse and limited to case reports. We conducted this study to review the characteristics of laryngeal coccidioidomycosis in children. METHODS: We performed a retrospective review of patients ≤21 years of age with laryngeal coccidioidomycosis who were treated from January 2010 to December 2017. We collected demographic data, clinical and laboratory studies and patient outcomes. RESULTS: Five cases of pediatric laryngeal coccidioidomycosis were reviewed. All children were Hispanic and 3 were female. The median age was 1.8 years and the median duration of symptoms before diagnosis was 24 days. The most common symptoms included fever (100%), stridor (60%), cough (100%) and vocal changes (40%). Airway obstruction requiring tracheostomy and/or intubation for airway management was present in 80%. The most frequent location of lesions was the subglottic area. Coccidioidomycosis complement fixation titers were frequently low and culture/histopathology of laryngeal tissue was necessary to make a definitive diagnosis. All patients required surgical debridement and were treated with antifungal agents. None of the patients had recurrence during the follow-up period. CONCLUSIONS: This study suggests that laryngeal coccidioidomycosis in children presents with refractory stridor or dysphonia and severe airway obstruction. Favorable outcomes can be achieved with a comprehensive diagnostic work-up and aggressive surgical and medical management. With the rise in cases of coccidioidomycosis, physicians should have a heightened awareness regarding the possibility of laryngeal coccidioidomycosis when encountering children who have visited or reside in endemic areas with stridor or dysphonia.
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Obstrução das Vias Respiratórias , Coccidioidomicose , Disfonia , Criança , Feminino , Humanos , Lactente , Masculino , Obstrução das Vias Respiratórias/tratamento farmacológico , Obstrução das Vias Respiratórias/etiologia , Antifúngicos/uso terapêutico , Coccidioidomicose/diagnóstico , Coccidioidomicose/tratamento farmacológico , Coccidioidomicose/epidemiologia , Disfonia/complicações , Disfonia/tratamento farmacológico , Sons Respiratórios , Estudos RetrospectivosRESUMO
In a phase 2 safety and immunogenicity study of a chikungunya virus virus-like particle (CHIKV VLP) vaccine in an endemic region, of 400 total participants, 78 were found to be focus reduction neutralizing antibody seropositive at vaccination despite being ELISA seronegative at screening, of which 39 received vaccine. This post hoc analysis compared safety and immunogenicity of CHIKV VLP vaccine in seropositive (n = 39) versus seronegative (n = 155) vaccine recipients for 72 weeks post-vaccination. There were no differences in solicited adverse events, except injection site swelling in 10.3% of seropositive versus 0.6% of seronegative recipients (p = 0.006). Baseline seropositive vaccine recipients had stronger post-vaccination luciferase neutralizing antibody responses versus seronegative recipients (peak geometric mean titer of 3594 and 1728, respectively) persisting for 72 weeks, with geometric mean fold increases of 3.1 and 13.2, respectively. In this small study, CHIKV VLP vaccine was well-tolerated and immunogenic in individuals with pre-existing immunity. ClinicalTrials.gov Identifier: NCT02562482.
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Febre de Chikungunya , Vírus Chikungunya , Vacinas de Partículas Semelhantes a Vírus , Vacinas Virais , Humanos , Febre de Chikungunya/prevenção & controle , Anticorpos Antivirais , Anticorpos Neutralizantes , Imunogenicidade da Vacina , Método Duplo-CegoRESUMO
Cholera remains endemic in >50 countries, putting millions at risk, especially young children for whom killed vaccines offer limited protection. An oral, live attenuated vaccine - CVD 103-HgR (Vaxchora vaccine) - was licensed by the US FDA in 2016 for adults aged 18-64 years traveling to endemic regions, based on clinical trials in human volunteers showing the vaccine was well tolerated and conferred 90% efficacy within 10 days. The evidence base for Vaxchora vaccine has expanded with additional clinical trial data, in older adults (aged 46-64 years) and children (aged 2-17 years), demonstrating that the vaccine produces a strong vibriocidal antibody response. Over 68,000 doses have been administered in the United States, with no new safety signals. The dose volume has been reduced in children to improve acceptability, and cold chain requirements are less st ringent, at +2°Câ+8°C. The vaccine has recently been licensed in the Untied States for children aged 2-17 years, in Europe for individuals aged ≥2 years, and for home administration in Europe. Next steps include a Phase 4 study in infants (6-23 months). Additional information is needed regarding duration of immunity, the need for and timing of revaccination, and efficacy data from lower-middle-income countries.
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Vacinas contra Cólera , Cólera , Vibrio cholerae , Administração Oral , Adolescente , Adulto , Idoso , Anticorpos Antibacterianos , Criança , Pré-Escolar , Cólera/prevenção & controle , Humanos , Lactente , Pessoa de Meia-Idade , Vacinas Atenuadas , Adulto JovemRESUMO
BACKGROUND: Published literature on musculoskeletal coccidioidomycosis is sparse and limited to case reports and case series. This is one of the largest case series to describe the clinical presentation, diagnosis, medical and surgical management and outcomes of pediatric musculoskeletal coccidioidomycosis at a tertiary care hospital. METHOD: A retrospective case review was performed on patients ≤ 21 years old who were followed at a tertiary care center with a diagnosis of musculoskeletal coccidioidomycosis from January 1, 2007, to December 31, 2020. Descriptive data are expressed as medians and interquartile range (IQR) for continuous variables or as frequency and percentage for categorical variables. Categorical values were compared using the χ2 test. RESULTS: Forty-one patients were identified. The median age was 12.8 years, and most were male (71%), Latinx (66%) and healthy (71%). Limb swelling (66%), bone pain (54%) and joint pain (46%) were the most common presenting symptoms. Multiple bone involvement was present in 29% while 12% had the joint disease, and craniofacial (n = 10) and metacarpal/metatarsal bones (n=9) were the most commonly involved sites. Elevated Coccidioides complement fixation (CF) titers ≥1:32 were seen in 90% of the patients. Thirty-three patients (81%) required surgical interventions and of these 16 (48%) required additional surgical procedures. Eleven patients (27%) had disease relapse. Children >13 years of age were more likely to have > 1 organ involvement (16 vs. 7, P = 0.04), multiple bone involvement (10 vs. 2, P = 0.004) and maximum Coccidioides CF titers >1:128 (13 vs. 6, P = 0.02). CONCLUSIONS: In endemic areas, musculoskeletal coccidioidomycosis causes a substantial disease burden in children and should be considered in the differential diagnosis of those presenting with bone and joint pain or swelling. Early diagnosis and treatment are essential to minimize long-term morbidity and mortality.