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1.
Cell ; 185(25): 4826-4840.e17, 2022 Dec 08.
Artículo en Inglés | MEDLINE | ID: mdl-36402135

RESUMEN

Congenital Zika virus (ZIKV) infection results in neurodevelopmental deficits in up to 14% of infants born to ZIKV-infected mothers. Neutralizing antibodies are a critical component of protective immunity. Here, we demonstrate that plasma IgM contributes to ZIKV immunity in pregnancy, mediating neutralization up to 3 months post-symptoms. From a ZIKV-infected pregnant woman, we isolated a pentameric ZIKV-specific IgM (DH1017.IgM) that exhibited ultrapotent ZIKV neutralization dependent on the IgM isotype. DH1017.IgM targets an envelope dimer epitope within domain II. The epitope arrangement on the virion is compatible with concurrent engagement of all ten antigen-binding sites of DH1017.IgM, a solution not available to IgG. DH1017.IgM protected mice against viremia upon lethal ZIKV challenge more efficiently than when expressed as an IgG. Our findings identify a role for antibodies of the IgM isotype in protection against ZIKV and posit DH1017.IgM as a safe and effective candidate immunotherapeutic, particularly during pregnancy.


Asunto(s)
Inmunoglobulina M , Embarazo , Infección por el Virus Zika , Virus Zika , Animales , Femenino , Ratones , Embarazo/inmunología , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Epítopos , Pruebas de Neutralización , Infección por el Virus Zika/inmunología , Inmunoglobulina M/inmunología , Inmunoglobulina M/aislamiento & purificación
2.
Cell ; 162(3): 493-504, 2015 Jul 30.
Artículo en Inglés | MEDLINE | ID: mdl-26189681

RESUMEN

Dengue is the most common vector-borne viral disease, causing nearly 400 million infections yearly. Currently there are no approved therapies. Antibody epitopes that elicit weak humoral responses may not be accessible by conventional B cell panning methods. To demonstrate an alternative strategy to generating a therapeutic antibody, we employed a non-immunodominant, but functionally relevant, epitope in domain III of the E protein, and engineered by structure-guided methods an antibody directed to it. The resulting antibody, Ab513, exhibits high-affinity binding to, and broadly neutralizes, multiple genotypes within all four serotypes. To assess therapeutic relevance of Ab513, activity against important human clinical features of dengue was investigated. Ab513 mitigates thrombocytopenia in a humanized mouse model, resolves vascular leakage, reduces viremia to nearly undetectable levels, and protects mice in a maternal transfer model of lethal antibody-mediated enhancement. The results demonstrate that Ab513 may reduce the public health burden from dengue.


Asunto(s)
Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/química , Virus del Dengue/fisiología , Dengue/terapia , Epítopos Inmunodominantes/química , Secuencia de Aminoácidos , Animales , Dengue/inmunología , Dengue/virología , Virus del Dengue/inmunología , Modelos Animales de Enfermedad , Ratones , Modelos Moleculares , Datos de Secuencia Molecular , Fagocitosis , Ingeniería de Proteínas , Receptores Fc/inmunología , Alineación de Secuencia
4.
PLoS Biol ; 21(11): e3002351, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37934720

RESUMEN

The COVID-19 pandemic has accelerated the development of vaccines for viral infections. However, a failure to integrate T cell immunity as a determinant of vaccine efficacy could curtail advancement of newer vaccines for pandemic preparedness.


Asunto(s)
COVID-19 , Vacunas , Vacunas Virales , Humanos , Vacunas contra la COVID-19 , Pandemias/prevención & control , SARS-CoV-2 , COVID-19/epidemiología , COVID-19/prevención & control
5.
Nature ; 584(7821): 457-462, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32668444

RESUMEN

Memory T cells induced by previous pathogens can shape susceptibility to, and the clinical severity of, subsequent infections1. Little is known about the presence in humans of pre-existing memory T cells that have the potential to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease 2019 (COVID-19) (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2. We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein. Epitope characterization of NSP7-specific T cells showed the recognition of protein fragments that are conserved among animal betacoronaviruses but have low homology to 'common cold' human-associated coronaviruses. Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic.


Asunto(s)
Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Neumonía Viral/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Linfocitos T/inmunología , Betacoronavirus/química , COVID-19 , Estudios de Casos y Controles , Infecciones por Coronavirus/virología , Proteínas de la Nucleocápside de Coronavirus , Reacciones Cruzadas/inmunología , Humanos , Epítopos Inmunodominantes/inmunología , Proteínas de la Nucleocápside/química , Proteínas de la Nucleocápside/inmunología , Pandemias , Fosfoproteínas , Neumonía Viral/virología , SARS-CoV-2
6.
PLoS Biol ; 20(5): e3001643, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35639676

RESUMEN

Ensuring high vaccination and even booster vaccination coverage is critical in preventing severe Coronavirus Disease 2019 (COVID-19). Among the various COVID-19 vaccines currently in use, the mRNA vaccines have shown remarkable effectiveness. However, systemic adverse events (AEs), such as postvaccination fatigue, are prevalent following mRNA vaccination, and the underpinnings of which are not understood. Herein, we found that higher baseline expression of genes related to T and NK cell exhaustion and suppression were positively correlated with the development of moderately severe fatigue after Pfizer-BioNTech BNT162b2 vaccination; increased expression of genes associated with T and NK cell exhaustion and suppression reacted to vaccination were associated with greater levels of innate immune activation at 1 day postvaccination. We further found, in a mouse model, that altering the route of vaccination from intramuscular (i.m.) to subcutaneous (s.c.) could lessen the pro-inflammatory response and correspondingly the extent of systemic AEs; the humoral immune response to BNT162b2 vaccination was not compromised. Instead, it is possible that the s.c. route could improve cytotoxic CD8 T-cell responses to BNT162b2 vaccination. Our findings thus provide a glimpse of the molecular basis of postvaccination fatigue from mRNA vaccination and suggest a readily translatable solution to minimize systemic AEs.


Asunto(s)
COVID-19 , Animales , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Fatiga/etiología , Humanos , Células Asesinas Naturales , Ratones , ARN Mensajero/genética , Vacunación/efectos adversos
7.
J Transl Med ; 22(1): 126, 2024 02 02.
Artículo en Inglés | MEDLINE | ID: mdl-38308299

RESUMEN

Glioblastoma multiforme (GBM) is the most common malignant primary brain cancer affecting the adult population. Median overall survival for GBM patients is poor (15 months), primarily due to high rates of tumour recurrence and the paucity of treatment options. Oncolytic virotherapy is a promising treatment alternative for GBM patients, where engineered viruses selectively infect and eradicate cancer cells by inducing cell lysis and eliciting robust anti-tumour immune response. In this study, we evaluated the oncolytic potency of live-attenuated vaccine strains of Zika virus (ZIKV-LAV) against human GBM cells in vitro. Our findings revealed that Axl and integrin αvß5 function as cellular receptors mediating ZIKV-LAV infection in GBM cells. ZIKV-LAV strains productively infected and lysed human GBM cells but not primary endothelia and terminally differentiated neurons. Upon infection, ZIKV-LAV mediated GBM cell death via apoptosis and pyroptosis. This is the first in-depth molecular dissection of how oncolytic ZIKV infects and induces death in tumour cells.


Asunto(s)
Glioblastoma , Viroterapia Oncolítica , Virus Oncolíticos , Infección por el Virus Zika , Virus Zika , Humanos , Virus Zika/fisiología , Infección por el Virus Zika/prevención & control , Glioblastoma/terapia , Vacunas Atenuadas , Recurrencia Local de Neoplasia/terapia
8.
PLoS Pathog ; 18(8): e1010763, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35939522

RESUMEN

Transmembrane Protein 41B (TMEM41B) and Vacuole Membrane Protein 1 (VMP1) are two ER-associated lipid scramblases that play a role in autophagosome formation and cellular lipid metabolism. TMEM41B is also a recently validated host factor required by flaviviruses and coronaviruses. However, the exact underlying mechanism of TMEM41B in promoting viral infections remains an open question. Here, we validated that both TMEM41B and VMP1 are essential host dependency factors for all four serotypes of dengue virus (DENV) and human coronavirus OC43 (HCoV-OC43), but not chikungunya virus (CHIKV). While HCoV-OC43 failed to replicate entirely in both TMEM41B- and VMP1-deficient cells, we detected diminished levels of DENV infections in these cell lines, which were accompanied by upregulation of the innate immune dsRNA sensors, RIG-I and MDA5. Nonetheless, this upregulation did not correspondingly induce the downstream effector TBK1 activation and Interferon-beta expression. Despite low levels of DENV replication, classical DENV replication organelles were undetectable in the infected TMEM41B-deficient cells, suggesting that the upregulation of the dsRNA sensors is likely a consequence of aberrant viral replication rather than a causal factor for reduced DENV infection. Intriguingly, we uncovered that the inhibitory effect of TMEM41B deficiency on DENV replication, but not HCoV-OC43, can be partially reversed using exogenous fatty acid supplements. In contrast, VMP1 deficiency cannot be rescued using the metabolite treatment. In line with the observed phenotypes, we found that both TMEM41B- and VMP1-deficient cells harbor higher levels of compromised mitochondria, especially in VMP1 deficiency which results in severe dysregulations of mitochondrial beta-oxidation. Using a metabolomic profiling approach, we revealed distinctive global dysregulations of the cellular metabolome, particularly lipidome, in TMEM41B- and VMP1-deficient cells. Our findings highlight a central role for TMEM41B and VMP1 in modulating multiple cellular pathways, including lipid mobilization, mitochondrial beta-oxidation, and global metabolic regulations, to facilitate the replication of flaviviruses and coronaviruses.


Asunto(s)
Infecciones por Coronavirus , Coronavirus , Dengue , Metabolismo Energético , Humanos , Lípidos , Proteínas de la Membrana/genética , Replicación Viral
9.
Artículo en Inglés | MEDLINE | ID: mdl-38985201

RESUMEN

BACKGROUND: Service delivery of post-treatment surveillance in head and neck cancer (HNC) varies across institutions in Australia. To better understand current practices and develop protocols that maximize service capacity or incorporate emerging technologies, especially in under-resourced regional and remote communities, it is important to obtain the perspectives of clinicians that regularly manage patients with HNC. DESIGN: This cross-sectional study utilized an online survey distributed via email to specialists recruited from HNC-associated networks across Australia. The survey captured information on current practices and explored clinician perspectives towards re-designing the current surveillance model to incorporate telehealth or patient-reported outcome measures (PROMs). Quantitative data was analyzed using descriptive statistics while open-ended survey comments were analyzed using a content analysis approach. RESULTS: Forty participants completed the survey (25 surgeons, 9 medical oncologists, 5 radiation oncologists and 1 oral medicine specialist). Most clinicians used either institution-specific guidelines (44%) or National Comprehensive Cancer Network guidelines (39%), with the remaining 17% using surveillance intervals based on patient symptoms. Following treatment, 53% of participants imaged patients only when there was clinical suspicion of recurrence or new symptoms. Planned surveillance imaging was conducted at 6 or 12-monthly intervals based on the HNC subtype. Fifty-seven percent of clinicians were open to redesigning the surveillance model, specifically in low-risk patients who did not require nasoendoscopic examination. Seventy-one percent had concerns regarding the feasibility of telehealth appointments, citing disparities in digital health equity. Additionally, 61% felt PROMs are currently underutilized and were open to incorporating HNC-specific PROMS into surveillance. Open-ended responses indicated that within the current surveillance model, "fragmented service provision" and "administration issues" were significantly impacting on timing of care. CONCLUSION: Surveyed HNC clinicians feel that current post-treatment surveillance can be fragmented and potentially lead to delayed care. They are open to incorporating PROMS to assist in surveillance scheduling, especially in low-risk patients.

10.
N Engl J Med ; 383(5): 452-459, 2020 07 30.
Artículo en Inglés | MEDLINE | ID: mdl-32726531

RESUMEN

BACKGROUND: Insufficient vaccine doses and the lack of therapeutic agents for yellow fever put global health at risk, should this virus emerge from sub-Saharan Africa and South America. METHODS: In phase 1a of this clinical trial, we assessed the safety, side-effect profile, and pharmacokinetics of TY014, a fully human IgG1 anti-yellow fever virus monoclonal antibody. In a double-blind, phase 1b clinical trial, we assessed the efficacy of TY014, as compared with placebo, in abrogating viremia related to the administration of live yellow fever vaccine (YF17D-204; Stamaril). The primary safety outcomes were adverse events reported 1 hour after the infusion and throughout the trial. The primary efficacy outcome was the dose of TY014 at which 100% of the participants tested negative for viremia within 48 hours after infusion. RESULTS: A total of 27 healthy participants were enrolled in phase 1a, and 10 participants in phase 1b. During phase 1a, TY014 dose escalation to a maximum of 20 mg per kilogram of body weight occurred in 22 participants. During phases 1a and 1b, adverse events within 1 hour after infusion occurred in 1 of 27 participants who received TY014 and in none of the 10 participants who received placebo. At least one adverse event occurred during the trial in 22 participants who received TY014 and in 8 who received placebo. The mean half-life of TY014 was approximately 12.8 days. At 48 hours after the infusion, none of the 5 participants who received the starting dose of TY014 of 2 mg per kilogram had detectable YF17D-204 viremia; these participants remained aviremic throughout the trial. Viremia was observed at 48 hours after the infusion in 2 of 5 participants who received placebo and at 72 hours in 2 more placebo recipients. Symptoms associated with yellow fever vaccine were less frequent in the TY014 group than in the placebo group. CONCLUSIONS: This phase 1 trial of TY014 did not identify worrisome safety signals and suggested potential clinical benefit, which requires further assessment in a phase 2 trial. (Funded by Tysana; ClinicalTrials.gov number, NCT03776786.).


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Vacuna contra la Fiebre Amarilla , Fiebre Amarilla/tratamiento farmacológico , Virus de la Fiebre Amarilla/inmunología , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Semivida , Humanos , Estimación de Kaplan-Meier , Viremia/tratamiento farmacológico , Fiebre Amarilla/virología , Virus de la Fiebre Amarilla/efectos de los fármacos
11.
J Virol ; 96(3): e0173721, 2022 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-34851147

RESUMEN

The expansion of the geographical footprint of dengue viruses (DENVs) and their mosquito vectors have affected more than half of the global population, including older adults who appear to show elevated risk of severe dengue. Despite this epidemiological trend, how aging contributes to increased dengue pathogenesis is poorly understood. A limitation has been the lack of useful in vitro experimental approaches; cell lines commonly used for infection studies are immortal and hence do not age. Cell strains such as WI-38 and MRC-5 with diploid genomes do age with in vitro passaging, but these cell strains were isolated decades ago and are now mostly highly passaged. Here, we show that reprogramming of cell strains with finite life span into induced pluripotent stem cells (iPSCs), followed by conversion back into terminally differentiated cells, can be an approach to derive genetically identical cells at different stages of aging. The iPSC-derived differentiated cells were susceptible to wild-type DENV infection and produced greater levels of type I interferon expression with increased passaging, despite similar levels of infection. In contrast, infection with the attenuated DENV-2 PDK53 and YF17D-204 strains showed reduced and increased levels of infection with increasing passages, respectively; the latter could be clinically pertinent, as YF17D-204 vaccination in older adults is associated with increased risk of severe adverse outcome. The differences in infection susceptibility and host response collectively suggest the potential of iPSC-derived cell strains as a genetically controlled approach to understanding how aging impacts viral pathogenesis. IMPORTANCE Aging has been a risk factor for poor clinical outcome in several infectious diseases, including dengue. However, age-dependent responses to dengue and other flaviviral infection or vaccination have remained incompletely understood due partly to lack of suitable laboratory tools. We thus developed an in vitro approach to examine age-related changes in host response to flaviviral infection. Notably, this approach uses cell strains with diploid rather than aneuploidic genomes, which are unstable. Conversion of these cells into iPSCs ensures sustainability of this resource, and reprogramming back into terminally differentiated cells would, even with a limited number of passages, produce cells at different stages of aging for infection studies. Our findings suggest that this in vitro system has the potential to serve as a genetically controlled approach to define the age-related response to flavivirus infection.


Asunto(s)
Infecciones por Flavivirus/metabolismo , Infecciones por Flavivirus/virología , Flavivirus/fisiología , Interacciones Huésped-Patógeno , Células Madre Pluripotentes Inducidas/metabolismo , Células Madre Pluripotentes Inducidas/virología , Factores de Edad , Diferenciación Celular , Células Cultivadas , Senescencia Celular/genética , Senescencia Celular/inmunología , Dengue/virología , Virus del Dengue , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Interacciones Huésped-Patógeno/genética , Interacciones Huésped-Patógeno/inmunología , Humanos , Masculino
12.
Proc Natl Acad Sci U S A ; 117(20): 11038-11047, 2020 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-32366663

RESUMEN

Dengue virus (DENV) is a global health threat, causing repeated epidemics throughout the tropical world. While low herd immunity levels to any one of the four antigenic types of DENV predispose populations to outbreaks, viral genetic determinants that confer greater fitness for epidemic spread is an important but poorly understood contributor of dengue outbreaks. Here we report that positive epistasis between the coding and noncoding regions of the viral genome combined to elicit an epidemiologic fitness phenotype associated with the 1994 DENV2 outbreak in Puerto Rico. We found that five amino acid substitutions in the NS5 protein reduced viral genomic RNA (gRNA) replication rate to achieve a more favorable and relatively more abundant subgenomic flavivirus RNA (sfRNA), a byproduct of host 5'-3' exoribonuclease activity. The resulting increase in sfRNA relative to gRNA levels not only inhibited type I interferon (IFN) expression in infected cells through a previously described mechanism, but also enabled sfRNA to compete with gRNA for packaging into infectious particles. We suggest that delivery of sfRNA to new susceptible cells to inhibit type I IFN induction before gRNA replication and without the need for further de novo sfRNA synthesis could form a "preemptive strike" strategy against DENV.


Asunto(s)
Regiones no Traducidas 3'/genética , Virus del Dengue/genética , Dengue/virología , Proteínas no Estructurales Virales/genética , Células A549 , Dengue/epidemiología , Epistasis Genética , Exorribonucleasas , Técnicas de Inactivación de Genes , Genoma Viral , Células HEK293 , Interacciones Huésped-Patógeno , Humanos , Interferón Tipo I/metabolismo , Proteínas Asociadas a Microtúbulos , Mutación , Puerto Rico/epidemiología , ARN Guía de Kinetoplastida/metabolismo , Replicación Viral
13.
Eur Arch Otorhinolaryngol ; 280(2): 885-890, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36136151

RESUMEN

PURPOSE: To investigate parental perceptions of the effects of tonsillectomy on their child's quality of life while awaiting and following surgery in an Australian public health system. METHODS: An observational pragmatic study was undertaken at a tertiary Australian hospital. Parents of paediatric patients (2-16 years of age) listed for tonsillectomy completed a validated quality-of-life questionnaire (T-14 Paediatric Throat Disorders Outcome Test) at the initial consultation, on day of surgery, 6 weeks post-operatively and 6 months post-operatively. T-14 scores were compared using the Related-Samples Wilcoxon Signed Rank Test. RESULTS: Parents of 167 children participated in this study. There was a median wait time of 174 days (IQR 108-347) from the initial consultation until the day of surgery, with no significant change in median T-14 scores (35 [IQR 22-42] vs 36 [IQR 22-42]; n = 63; p > 0.05). There was a significant decrease from pre-operative T-14 scores to 6 weeks post-operatively (33.5 [IQR 22-42] vs 2 [IQR 0-5]; n = 160; p < 0.001), and this was sustained with a minor improvement at 6 months post-operatively (6 weeks 2 [IQR 0-5] vs 6 months 0 [IQR 0-2]; n = 148; p < 0.001). CONCLUSIONS: Paediatric tonsillectomy improves quality of life with a sustained benefit in the long term. There is no improvement to the patient's quality of life while awaiting tonsillectomy, thus patient welfare can be improved through reducing waiting times for surgery.


Asunto(s)
Tonsilectomía , Niño , Humanos , Recién Nacido , Adenoidectomía , Calidad de Vida , Australia , Faringe
14.
Cleft Palate Craniofac J ; : 10556656221148368, 2023 Jan 04.
Artículo en Inglés | MEDLINE | ID: mdl-36600676

RESUMEN

OBJECTIVE: To compare the effectiveness of short-term ventilation tubes compared to surveillance on conductive hearing loss in children with non-syndromic orofacial clefting involving the muscular palate. INTRODUCTION: Chronic otitis media with effusion is a common finding in children with cleft palate. The accepted convention is insertion of short-term ventilation tubes at the time of palate repair, but some centres are choosing conservative management. Each approach has its advantages but there is currently no consensus on the most appropriate management in children with non-syndromic cleft palate. INCLUSION CRITERIA: Children <18 years with cleft lip and palate, or isolated cleft palate, not associated with a genetic syndrome, who have been diagnosed with chronic otitis media with effusion. METHODS: A systematic search of MEDLINE, CINAHL, Embase and Scopus databases was conducted. Grey literature searches were conducted through Central Register of Controlled Trials, Clinicaltrials.gov and ProQuest. Two reviewers screened the studies, conducted critical appraisal, assessed the methodological quality, and extracted the data. Where possible, studies were pooled in statistical meta-analysis with heterogeneity being assessed using the standard Chi-squared and I2 tests. RESULTS: Four studies met the inclusion criteria but were of low quality with a moderate risk of bias. Only data on hearing thresholds could be pooled for analysis which found no statistically significant difference. Other outcomes were presented in narrative form. Certainty of evidence for all outcomes was deemed low to very low using GRADE criteria. CONCLUSIONS: No definitive conclusions can be drawn regarding most effective management at improving conductive hearing loss. Missing data and inconsistent reporting of outcomes limited capacity for pooled analysis.

15.
Clin Otolaryngol ; 48(4): 672-679, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37129013

RESUMEN

OBJECTIVE: To determine primary and secondary post-tonsillectomy haemorrhage (PTH) rates and identify predictive factors in a cohort of consecutive adult and paediatric BiZact™ tonsillectomy cases. SETTING: Retrospective cohort study. Patients from Flinders Medical Centre, Noarlunga Hospital and private otolaryngology practices who underwent BiZact™ tonsillectomy from 2017 to 2020. DATA COLLECTED: patient age, indication for tonsillectomy, surgeon experience, time and severity of PTH, including return to theatre. Each secondary PTH was graded using the Stammberger classification. Logistic regression was utilised to identify predictors of secondary PTH. RESULTS: One thousand seven hundred and seventeen patient medical records were assessed (658 adults and 1059 children). The primary PTH rate was 0.1%, and secondary PTH rate was 5.9%. The majority of secondary PTH cases were Stammberger grade A (80/102, 78.4%) requiring observation only. Few secondary PTH required medical intervention (grade B; 9/102, 8.8%), return to theatre (grade C; 12/102, 11.8%), or blood transfusion (grade D; 1/102, 1.0%), with no death reported (grade E; 0/102, 0.0%). Recurrent secondary PTH occurred in 8 patients (0.5%). Predictive factors of secondary PTH in children were surgeon experience with trainees having greater chance of PTH (OR 2.502, 95% CI 1.345-4.654; p = .004) and age of child (OR 1.095, 95% CI 1.025-1.170; p = .007). Surgeon experience was a predictive factor for adults (OR 3.804, 95% CI 2.139-6.674; p < .001). CONCLUSIONS: BiZact™ tonsillectomy has a low primary PTH rate, with a secondary PTH rate comparable to other 'hot tonsillectomy' techniques. The majority of PTH events were minor and self-reported. There appears to be a learning curve for trainee surgeons.


Asunto(s)
Cirujanos , Tonsilectomía , Adulto , Niño , Humanos , Tonsilectomía/métodos , Estudios Retrospectivos , Hemorragia Posoperatoria/cirugía
16.
J Infect Dis ; 226(8): 1338-1347, 2022 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-35267010

RESUMEN

BACKGROUND: Severe dengue, characterized by shock and organ dysfunction, is driven by an excessive host immune response. We investigated the role of hyperinflammation in dengue pathogenesis. METHODS: Patients recruited into an observational study were divided into 3 plasma leak severity grades. Hyperinflammatory biomarkers were measured at 4 time points. Frequencies, activation, and cytotoxic potential of natural killer (NK) cells were analyzed by flow cytometry. RNA was extracted from sorted CD56+ NK cells and libraries were prepared using SMART-Seq and sequenced using HiSeq3000 (Illumina). RESULTS: Sixty-nine patients were included (grade 0, 42 patients; grade 1, 19 patients; grade 2, 8 patients). Patients with grade 2 leakage had higher biomarkers than grade 0, including higher peak ferritin levels (83.3% vs 45.2%) and H-scores (median, 148.5 vs 105.5). NK cells from grade 2 patients exhibited decreased expression of perforin and granzyme B and activation markers. RNA sequencing revealed 3 single-nucleotide polymorphisms in NK cell functional genes associated with more severe leakage-NK cell lectin-like receptor K1 gene (KLRK1) and perforin 1 (PRF1). CONCLUSIONS: Features of hyperinflammation are associated with dengue severity, including higher biomarkers, impaired NK cell function, and polymorphisms in NK cell cytolytic function genes (KLRK1 and PRF1). Trials of immunomodulatory therapy in these patients is now warranted.


Asunto(s)
Dengue Grave , Humanos , Biomarcadores/metabolismo , Ferritinas , Granzimas/genética , Granzimas/metabolismo , Células Asesinas Naturales , Perforina/genética , Perforina/metabolismo , Polimorfismo Genético , Receptores Similares a Lectina de Células NK/genética , Receptores Similares a Lectina de Células NK/metabolismo , ARN
17.
Clin Infect Dis ; 74(1): 144-148, 2022 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-32604407

RESUMEN

We are learning that the host response to severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2) infection is complex and highly dynamic. Effective initial host defense in the lung is associated with mild symptoms and disease resolution. Viral evasion of the immune response can lead to refractory alveolar damage, ineffective lung repair mechanisms, and systemic inflammation with associated organ dysfunction. The immune response in these patients is highly variable and can include moderate to severe systemic inflammation and/or marked systemic immune suppression. There is unlikely to be a "one size fits all" approach to immunomodulation in patients with coronavirus disease 2019 (COVID-19). We believe that a personalized, immunophenotype-driven approach to immunomodulation that may include anticytokine therapy in carefully selected patients and immunostimulatory therapies in others is the shortest path to success in the study and treatment of patients with critical illness due to COVID-19.


Asunto(s)
COVID-19 , Inmunomodulación , Medicina de Precisión , COVID-19/inmunología , COVID-19/terapia , Citocinas , Humanos , Inmunidad , Pulmón , SARS-CoV-2
18.
BMC Microbiol ; 22(1): 24, 2022 01 13.
Artículo en Inglés | MEDLINE | ID: mdl-35026986

RESUMEN

BACKGROUND: Otitis media (OM) is a major disease burden in Australian Aboriginal children, contributing to serious long-term health outcomes. We report a pilot analysis of OM in children attending an outreach ear and hearing clinic in a remote south Australian community over a two-year period. Our study focuses on longitudinal relationships between ear canal microbiota characteristics with nasopharyngeal microbiota, and clinical and treatment variables. RESULTS: Middle ear health status were assessed in 19 children (aged 3 months to 8 years) presenting in remote western South Australia and medical interventions were recorded. Over the two-year study period, chronic suppurative OM was diagnosed at least once in 7 children (37%), acute OM with perforation in 4 children (21%), OM with effusion in 11 children (58%), while only 1 child had no ear disease. Microbiota analysis of 19 children (51 sets of left and right ear canal swabs and nasopharyngeal swabs) revealed a core group of bacterial taxa that included Corynebacterium, Alloiococcus, Staphylococcus, Haemophilus, Turicella, Streptococcus, and Pseudomonas. Within-subject microbiota similarity (between ears) was significantly greater than inter-subject similarity, regardless of differences in ear disease (p = 0.0006). Longitudinal analysis revealed changes in diagnosis to be associated with more pronounced changes in microbiota characteristics, irrespective of time interval. Ear microbiota characteristics differed significantly according to diagnosis (P (perm) = 0.0001). Diagnoses featuring inflammation with tympanic membrane perforation clustering separately to those in which the tympanic membrane was intact, and characterised by increased Proteobacteria, particularly Haemophilus influenzae, Moraxella catarrhalis, and Oligella. While nasopharyngeal microbiota differed significantly in composition to ear microbiota (P (perm) = 0.0001), inter-site similarity was significantly greater in subjects with perforated tympanic membranes, a relationship that was associated with the relative abundance of H. influenzae in ear samples (rs = - 0.71, p = 0.0003). Longitudinal changes in ear microbiology reflected changes in clinical signs and treatment. CONCLUSIONS: Children attending the ear and hearing clinic in a remote Aboriginal community present with a broad spectrum of OM conditions and severities, consistent with other remote Aboriginal communities. Ear microbiota characteristics align with OM diagnosis and change with disease course. Nasopharyngeal microbiota characteristics are consistent with the contribution of acute upper respiratory infection to OM aetiology.


Asunto(s)
Bacterias/aislamiento & purificación , Oído Medio/microbiología , Oído Medio/patología , Microbiota , Nativos de Hawái y Otras Islas del Pacífico/estadística & datos numéricos , Otitis Media/microbiología , Australia/epidemiología , Bacterias/clasificación , Bacterias/genética , Bacterias/patogenicidad , Niño , Preescolar , Femenino , Humanos , Lactante , Estudios Longitudinales , Masculino , Nasofaringe/microbiología , Otitis Media/epidemiología , Proyectos Piloto , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/microbiología , Población Rural/estadística & datos numéricos
19.
Mol Ther ; 29(6): 1970-1983, 2021 06 02.
Artículo en Inglés | MEDLINE | ID: mdl-33823303

RESUMEN

A self-transcribing and replicating RNA (STARR)-based vaccine (LUNAR-COV19) has been developed to prevent SARS-CoV-2 infection. The vaccine encodes an alphavirus-based replicon and the SARS-CoV-2 full-length spike glycoprotein. Translation of the replicon produces a replicase complex that amplifies and prolongs SARS-CoV-2 spike glycoprotein expression. A single prime vaccination in mice led to robust antibody responses, with neutralizing antibody titers increasing up to day 60. Activation of cell-mediated immunity produced a strong viral antigen-specific CD8+ T lymphocyte response. Assaying for intracellular cytokine staining for interferon (IFN)γ and interleukin-4 (IL-4)-positive CD4+ T helper (Th) lymphocytes as well as anti-spike glycoprotein immunoglobulin G (IgG)2a/IgG1 ratios supported a strong Th1-dominant immune response. Finally, single LUNAR-COV19 vaccination at both 2 µg and 10 µg doses completely protected human ACE2 transgenic mice from both mortality and even measurable infection following wild-type SARS-CoV-2 challenge. Our findings collectively suggest the potential of LUNAR-COV19 as a single-dose vaccine.


Asunto(s)
Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Antivirales/biosíntesis , Vacunas contra la COVID-19/administración & dosificación , COVID-19/prevención & control , SARS-CoV-2/efectos de los fármacos , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacunas Sintéticas/administración & dosificación , Alphavirus/genética , Alphavirus/inmunología , Enzima Convertidora de Angiotensina 2/genética , Enzima Convertidora de Angiotensina 2/inmunología , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/virología , COVID-19/inmunología , COVID-19/patología , COVID-19/virología , Vacunas contra la COVID-19/biosíntesis , Vacunas contra la COVID-19/genética , Vacunas contra la COVID-19/inmunología , Femenino , Expresión Génica , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Humoral/efectos de los fármacos , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-4/genética , Interleucina-4/inmunología , Ratones , Ratones Transgénicos , Replicón/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Células TH1/efectos de los fármacos , Células TH1/inmunología , Células TH1/virología , Transgenes , Resultado del Tratamiento , Vacunación/métodos , Vacunas Sintéticas/biosíntesis , Vacunas Sintéticas/genética , Vacunas Sintéticas/inmunología , Vacunas de ARNm
20.
Am J Otolaryngol ; 43(4): 103488, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35537230

RESUMEN

AIMS: The incidence of epistaxis-related admissions amongst elderly patients is rising due to the increasing use of anticoagulants and antiplatelet agents. This retrospective study evaluates the differences in outcomes for patients on warfarin, novel anticoagulants (NOACs) and antiplatelets over two different time periods. METHODOLOGY: Retrospective case-control study with data from patients admitted with epistaxis through the Flinders Medical Centre Emergency Department in the first six months of 2013 and compared to the same period in 2018. The latter coincides with integration of NOACs into Australian prescribing practices. Included participants were ≥50 years with spontaneous epistaxis which coincides with peak incidence in adults. Exclusion criteria were epistaxis due to trauma, intrinsic coagulopathy, or recent post-surgery. Linear regression and binary logistic regression models were the statistical methods used. RESULTS: Data from 85 patients were analysed for length of stay (LOS), readmission rates and method of haemostasis. In 2013, 41 patients were included compared to 44 in 2018, suggesting a 7% increase in admissions rates but this was not statistically significant (p = 0.96). The proportion of patients admitted with epistaxis while taking an anticoagulant or antiplatelet agent increased from 66% in 2013 to 93% in 2018. Thirty six percent of patients in 2018 were taking NOACs, however, LOS was 2 times shorter (mean ratio = 2.08 days, 95% CI: 1.03, 4.19). Seven percent of patients in 2018 had bleeding requiring surgery or interventional radiology, compared to 12% in 2013, but this was not statistically significant. There was no statistically significant difference in readmission rates (p = 0.82) or intervention required (p = 0.74) between the two time periods. CONCLUSIONS: Epistaxis admissions at our institution have increased since the introduction of NOACs. However, most patients can be managed successfully with intranasal packing and cautery alone. NOACs are not associated with increased rated of invasive haemostatic measures and patients have a shorter LOS.


Asunto(s)
Anticoagulantes , Warfarina , Administración Oral , Adulto , Anciano , Anticoagulantes/efectos adversos , Australia , Estudios de Casos y Controles , Epistaxis/etiología , Humanos , Inhibidores de Agregación Plaquetaria/efectos adversos , Estudios Retrospectivos , Warfarina/efectos adversos
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