Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44
Filtrar
1.
Nature ; 616(7957): 525-533, 2023 04.
Artigo em Inglês | MEDLINE | ID: mdl-37046096

RESUMO

Lung cancer is the leading cause of cancer-associated mortality worldwide1. Here we analysed 1,644 tumour regions sampled at surgery or during follow-up from the first 421 patients with non-small cell lung cancer prospectively enrolled into the TRACERx study. This project aims to decipher lung cancer evolution and address the primary study endpoint: determining the relationship between intratumour heterogeneity and clinical outcome. In lung adenocarcinoma, mutations in 22 out of 40 common cancer genes were under significant subclonal selection, including classical tumour initiators such as TP53 and KRAS. We defined evolutionary dependencies between drivers, mutational processes and whole genome doubling (WGD) events. Despite patients having a history of smoking, 8% of lung adenocarcinomas lacked evidence of tobacco-induced mutagenesis. These tumours also had similar detection rates for EGFR mutations and for RET, ROS1, ALK and MET oncogenic isoforms compared with tumours in never-smokers, which suggests that they have a similar aetiology and pathogenesis. Large subclonal expansions were associated with positive subclonal selection. Patients with tumours harbouring recent subclonal expansions, on the terminus of a phylogenetic branch, had significantly shorter disease-free survival. Subclonal WGD was detected in 19% of tumours, and 10% of tumours harboured multiple subclonal WGDs in parallel. Subclonal, but not truncal, WGD was associated with shorter disease-free survival. Copy number heterogeneity was associated with extrathoracic relapse within 1 year after surgery. These data demonstrate the importance of clonal expansion, WGD and copy number instability in determining the timing and patterns of relapse in non-small cell lung cancer and provide a comprehensive clinical cancer evolutionary data resource.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Adenocarcinoma de Pulmão/etiologia , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Carcinoma Pulmonar de Células não Pequenas/etiologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mutação , Recidiva Local de Neoplasia/genética , Filogenia , Resultado do Tratamento , Fumar/genética , Fumar/fisiopatologia , Mutagênese , Variações do Número de Cópias de DNA
4.
Emerg Med J ; 34(5): 302-307, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28143813

RESUMO

OBJECTIVE: To identify the injury history features reported by patients with anterior cruciate ligament (ACL) injuries and determine whether history may be used to identify patients requiring follow-up appointments from acute trauma services. METHODS: Multisite cross-sectional service evaluation using a survey questionnaire design conducted in the UK. The four injury history features investigated were 'leg giving way at the time of injury', 'inability to continue activity immediately following injury', 'marked effusion' and 'pop (heard or felt) at the time of injury'(LIMP). RESULTS: 194 patients with ACL injury were identified, of which 165 (85.5%) attended an acute trauma service. Data on delay was available for 163 (98.8%) of these patients of which 120 (73.6%) had a follow-up appointment arranged. Patients who had a follow-up appointment arranged waited significantly less time for a correct diagnosis (geometric mean 29 vs 198 days; p<0.001) and to see a specialist consultant (geometric mean 61 vs 328 days; p<0.001). Using a referral threshold of any two of the four LIMP injury history features investigated, 95.8% of patients would have had a follow-up appointment arranged. CONCLUSIONS: Findings support the value of questioning patients on specific injury history features in identifying patients who may have suffered ACL injury. Using a threshold of two or more of the four LIMP history features investigated would have reduced the percentage of patients inappropriately discharged by 22.2%. Evidence presented suggests that this would significantly reduce the time to diagnosis and specialist consultation minimising the chance of secondary complications.


Assuntos
Lesões do Ligamento Cruzado Anterior/diagnóstico , Diagnóstico Tardio/estatística & dados numéricos , Ferimentos e Lesões/diagnóstico , Adulto , Assistência ao Convalescente/estatística & dados numéricos , Ligamento Cruzado Anterior/anormalidades , Ligamento Cruzado Anterior/fisiopatologia , Estudos Transversais , Feminino , Humanos , Masculino , Encaminhamento e Consulta/estatística & dados numéricos , Medicina Estatal/organização & administração , Inquéritos e Questionários , Reino Unido
5.
Pediatr Nephrol ; 29(10): 1873-81, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25125229

RESUMO

BACKGROUND: To compare the efficacy of the Newcastle infant dialysis and ultrafiltration system (Nidus) with peritoneal dialysis (PD) and conventional haemodialysis (HD) in infants weighing <8 kg. METHODS: We compared the urea, creatinine and phosphate clearances, the ultrafiltration precision, and the safety of the Nidus machine with PD in 7 piglets weighing 1-8 kg, in a planned randomised cross-over trial in babies, and in babies for whom no other therapy existed, some of whom later graduated to conventional HD. RESULTS: Two babies entered the randomised trial; 1 recovered rapidly on PD, the other remained on the Nidus as PD failed. Additionally, 9 babies were treated on the Nidus on humanitarian grounds: 3 because of failed PD, and 3 with permanent kidney failure later converted to conventional HD. We haemodialysed 10 babies weighing between 1.8 and 5.9 kg for 2,475 h during 354 Nidus sessions without any clinically important incidents, and without detectable haemolysis. Single-lumen vascular access was used with no blood priming of circuits. The urea, creatinine and phosphate clearances using the Nidus were around 1.5 to 2.0 ml/min in piglets and babies, and were consistently higher than PD clearances, which ranged from about 0.2 to 0.8 ml/min (p ≤ 0.0002 for each chemical). Ultrafiltration was achieved to microlitre precision by the Nidus, but varied widely with PD. Fluid removal using conventional HD was imprecise and resulted in some hypovolaemic episodes requiring correction. CONCLUSION: The Nidus can provide HD in the Pediatric Intensive Care Unit (PICU) and outpatient intermittent HD without blood priming for babies weighing <8 kg, It generates higher dialysis clearances than PD, and delivers more precise ultrafiltration control than either PD or conventional HD.


Assuntos
Injúria Renal Aguda/terapia , Hemodiafiltração/instrumentação , Hemodiafiltração/métodos , Animais , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Diálise Peritoneal/métodos , Diálise Renal/métodos , Suínos
6.
Paediatr Anaesth ; 23(2): 111-6, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23061742

RESUMO

BACKGROUND: When intubating a child's trachea with an uncuffed tracheal tube (TT), it is current practice in anesthesia and intensive care to use the leak test to assess TT fit. The aim of this study is to compare three measures of assessing leak around uncuffed tracheal tubes in the PICU. METHODS: We obtained institutional ethical permission and written informed consent, prior to any clinical investigation, from the parents of 135 children who had surgery for cardiac defects. On admission to the PICU, we measured leak by audible assessment, fractional volume loss, and leak conductance for each patient. Measurements of fractional volume loss and leak conductance were repeated every 4 h thereafter until extubation. RESULTS: On admission to the PICU, calculated values of leak conductance were significantly different between each grade of audible leak (P < 0.001). Values of fractional volume loss were not significantly different between 'no leak' and 'small leak' grades of leak. Throughout the PICU stay, a significant correlation between mean leak conductance and mean fractional volume loss was found (0.86, 95% CI, 0.81-0.90). Significant agreement within time series of leak conductance and fractional volume recorded for each patient occurred in 47/128 cases (37%). CONCLUSIONS: On admission to the PICU, values of leak conductance are more strongly associated with audible assessment than with fractional volume loss. Throughout PICU stay, leak conductance is associated with fractional volume loss. This study demonstrates that leak conductance, calculated from routinely available pressure and flow signals, has the potential to represent the characteristics of the leak interface between a TT and the trachea.


Assuntos
Manuseio das Vias Aéreas/métodos , Análise de Falha de Equipamento , Intubação Intratraqueal/métodos , Procedimentos Cirúrgicos Cardíacos , Pré-Escolar , Falha de Equipamento , Feminino , Cardiopatias Congênitas/cirurgia , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Prospectivos
7.
Rural Remote Health ; 13(3): 2497, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23895494

RESUMO

INTRODUCTION: The US Health Care and Social Services sector (North American Industrial Classification System 'sector 62') has become an extremely important component of the nation's economy, employing approximately 18 million workers and generating almost $753 billion in annual payrolls. At the county level, the health care and social services sector is typically the largest or second largest employer. Hospital employment is often the largest component of the sector's total employment. Hospital employment is particularly important to non-metropolitan or rural communities. A high quality healthcare sector serves to promote economic development and attract new businesses and to provide stability in economic downturns. The purpose of this study was to examine the intensity of hospital employment in rural counties relative to the nation as a whole using location quotients and to draw conclusions regarding how potential changes in Medicare and Medicaid might affect rural populations. METHODS: Estimates for county-level hospital employment are not commonly available. Estimates of county-level hospital employment were therefore generated for all counties in the USA the Census Bureau's County Business Pattern Data for 2010. These estimates were used to generate location quotients for each county which were combined with demographic data to generate a profile of factors that are related to the magnitude of location quotients. The results were then used to draw inferences regarding the possible impact of the Patient Protection and Affordable Care Act 2010 (ACA) and the possible imposition of aspects of the Budget Control Act 2011 (BCA). RESULTS: Although a very high percentage of rural counties contain medically underserved areas, an examination of location quotients indicates that the percentage of the county workforce employed by hospitals in the most rural counties tends to be higher than for the nation as a whole, a counterintuitive finding. Further, when location quotients are regressed upon data related to poverty, county demographics, and the percentage of the population insured, a relationship between the proportion of the population over 65 years, the percentage of the population living in poverty, the percentage of the population without insurance and county density was found. CONCLUSION: The results of the analysis suggest that hospital employment in rural communities is higher than would be expected in the absence of programs that provide external funding to support hospital hiring. The most important public programs providing this support are Medicare and Medicaid. Social Security is another source of federal funding important for rural populations. Sequestration and other cuts in funding could impact rural communities significantly. This can be even worse in states that fail to expand Medicaid and in states that fail to increase Medicaid reimbursements for services important in rural communities.


Assuntos
Emprego/estatística & dados numéricos , Hospitais Rurais/estatística & dados numéricos , Área Carente de Assistência Médica , População Rural/estatística & dados numéricos , Humanos , Medicaid/estatística & dados numéricos , Medicare/estatística & dados numéricos , Fatores Socioeconômicos , Estados Unidos
8.
Lancet ; 378(9789): 428-38, 2011 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-21664680

RESUMO

For human vaccines to be available on a global scale, complex production methods, meticulous quality control, and reliable distribution channels are needed to ensure that the products are potent and effective at the point of use. The technologies used to manufacture different types of vaccines can strongly affect vaccine cost, ease of industrial scale-up, stability, and, ultimately, worldwide availability. The complexity of manufacturing is compounded by the need for different formulations in different countries and age-groups. Reliable vaccine production in appropriate quantities and at affordable prices is the cornerstone of developing global vaccination policies. However, to ensure optimum access and uptake, strong partnerships are needed between private manufacturers, regulatory authorities, and national and international public health services. For vaccines whose supply is insufficient to meet demand, prioritisation of target groups can increase the effect of these vaccines. In this report, we draw from our experience of vaccine development and focus on influenza vaccines as an example to consider production, distribution, access, and other factors that affect vaccine uptake and population-level effectiveness.


Assuntos
Tecnologia Farmacêutica , Vacinas/provisão & distribuição , Vacinas Bacterianas/provisão & distribuição , Vacinas Bacterianas/uso terapêutico , Indústria Farmacêutica , Humanos , Programas de Imunização , Vacinas contra Influenza/provisão & distribuição , Vacinas contra Influenza/uso terapêutico , Vacinas/uso terapêutico
9.
Eur J Pediatr ; 171(2): 281-7, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21748291

RESUMO

UNLABELLED: Cardiovascular malformations are an important cause of infant death and the major cause of death due to malformation. Our aims were to analyse and categorise all deaths in infants with cardiovascular malformations, and to analyse trends in mortality over time and influences on mortality. We obtained details of infant deaths and cardiovascular malformations from the population of one health region for 1987-2006. We categorised deaths by cause and by presence of additional chromosomal or genetic abnormalities or non-cardiac malformations. In 676,927 live births the total infant mortality was 4,402 (6.5 per 1,000). A total of 4,437 infants had cardiovascular malformations (6.6 per 1000) of whom 458 (10.3%) died before 1 year of age. Of this number, 151 (33%) deaths had non-cardiac causes, 128 (28%) were cardiac without surgery and 179 (39%) occurred from cardiac causes after surgery. Death was unrelated to the cardiovascular malformation in 57% of infants with an additional chromosomal or genetic abnormality, in 76% of infants with a major non-cardiac malformation and in 16% of infants with an isolated cardiovascular malformation. Terminations of pregnancies affected by cardiovascular malformations increased from 20 per 100,000 registered births in the first 5 years to 78 per 100,000 in the last 5 years. A total of 2,067 infants (47%) underwent surgery and of these 216 (10%) died before 1 year of age. CONCLUSIONS: A total of 10.4% of infants who died had a cardiovascular malformation and two-thirds of deaths were due to the malformation or its treatment. Mortality declined due to increasing termination of pregnancy and improved survival after operation.


Assuntos
Anormalidades Cardiovasculares/mortalidade , Mortalidade Infantil/tendências , Aborto Eugênico/estatística & dados numéricos , Anormalidades Cardiovasculares/complicações , Anormalidades Cardiovasculares/genética , Anormalidades Cardiovasculares/cirurgia , Procedimentos Cirúrgicos Cardiovasculares/mortalidade , Causas de Morte , Anormalidades Congênitas/epidemiologia , Inglaterra/epidemiologia , Feminino , Doenças Genéticas Inatas/epidemiologia , Humanos , Lactente , Recém-Nascido , Gravidez
10.
Proc Natl Acad Sci U S A ; 106(42): 17655-60, 2009 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-19805060

RESUMO

Soil organisms, as recorded by trace fossils in paleosols of the Willwood Formation, Wyoming, show significant body-size reductions and increased abundances during the Paleocene-Eocene Thermal Maximum (PETM). Paleobotanical, paleopedologic, and oxygen isotope studies indicate high temperatures during the PETM and sharp declines in precipitation compared with late Paleocene estimates. Insect and oligochaete burrows increase in abundance during the PETM, suggesting longer periods of soil development and improved drainage conditions. Crayfish burrows and molluscan body fossils, abundant below and above the PETM interval, are significantly less abundant during the PETM, likely because of drier floodplain conditions and lower water tables. Burrow diameters of the most abundant ichnofossils are 30-46% smaller within the PETM interval. As burrow size is a proxy for body size, significant reductions in burrow diameter suggest that their tracemakers were smaller bodied. Smaller body sizes may have resulted from higher subsurface temperatures, lower soil moisture conditions, or nutritionally deficient vegetation in the high-CO(2) atmosphere inferred for the PETM. Smaller soil fauna co-occur with dwarf mammal taxa during the PETM; thus, a common forcing mechanism may have selected for small size in both above- and below-ground terrestrial communities. We predict that soil fauna have already shown reductions in size over the last 150 years of increased atmospheric CO(2) and surface temperatures or that they will exhibit this pattern over the next century. We retrodict also that soil fauna across the Permian-Triassic and Triassic-Jurassic boundary events show significant size decreases because of similar forcing mechanisms driven by rapid global warming.


Assuntos
Biodiversidade , Evolução Biológica , Tamanho Corporal , Fósseis , Animais , Astacoidea/anatomia & histologia , Clima , Aquecimento Global , Insetos/anatomia & histologia , Moluscos/anatomia & histologia , Oligoquetos/anatomia & histologia , Solo
11.
Pediatr Cardiol ; 32(2): 139-44, 2011 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21140261

RESUMO

Severe heart failure in children is uncommon. The anesthetic management of children with this condition is challenging. The authors aimed to identify the frequency with which anesthesia for short noncardiac surgical procedures or investigations was complicated by life-threatening hemodynamic instability and to describe the anesthetic techniques used. This study retrospectively reviewed the anesthetic charts and notes of children admitted acutely with a diagnosis of severe heart failure (fractional shortening of 15% or less) who received general anesthesia for noncardiac surgical or diagnostic interventions during the 3-year period from September 2005 to September 2008. In this study, 21 children received a total of 28 general anesthetics. Two patients (10%) experienced a cardiac arrest, and both required unplanned admission to the authors' pediatric intensive care unit (PICU) postoperatively. A variety of anesthetic techniques was used. In 27 (96%) of the 28 cases, perioperative inotropic support was required. General anesthesia for children with severe heart failure is associated with a significant complication rate and should be administered by anesthetists familiar with managing all aspects of circulatory support for children in an appropriate setting.


Assuntos
Anestesia Geral/efeitos adversos , Parada Cardíaca/prevenção & controle , Insuficiência Cardíaca/patologia , Pediatria , Adolescente , Anestesia Geral/métodos , Anestésicos Dissociativos , Criança , Pré-Escolar , Feminino , Indicadores Básicos de Saúde , Hemodinâmica , Humanos , Lactente , Unidades de Terapia Intensiva Pediátrica , Intubação Intratraqueal/métodos , Ketamina/uso terapêutico , Masculino , Bloqueadores Neuromusculares/uso terapêutico , Respiração Artificial/métodos , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença , Estatística como Assunto
12.
Lancet Infect Dis ; 21(9): 1257-1270, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33887209

RESUMO

BACKGROUND: CoV2 preS dTM is a stabilised pre-fusion spike protein vaccine produced in a baculovirus expression system being developed against SARS-CoV-2. We present interim safety and immunogenicity results of the first-in-human study of the CoV2 preS dTM vaccine with two different adjuvant formulations. METHODS: This phase 1-2, randomised, double-blind study is being done in healthy, SARS-CoV-2-seronegative adults in ten clinical research centres in the USA. Participants were stratified by age (18-49 years and ≥50 years) and randomly assigned using an interactive response technology system with block randomisation (blocks of varying size) to receive one dose (on day 1) or two doses (on days 1 and 22) of placebo or candidate vaccine, containing low-dose (effective dose 1·3 µg) or high-dose (2·6 µg) antigen with adjuvant AF03 (Sanofi Pasteur) or AS03 (GlaxoSmithKline) or unadjuvanted high-dose antigen (18-49 years only). Primary endpoints were safety, assessed up to day 43, and immunogenicity, measured as SARS-C0V-2 neutralising antibodies (geometric mean titres), assessed on days 1, 22, and 36 serum samples. Safety was assessed according to treatment received in the safety analysis set, which included all randomly assigned participants who received at least one dose. Neutralising antibody titres were assessed in the per-protocol analysis set for immunogenicity, which included participants who received at least one dose, met all inclusion and exclusion criteria, had no protocol deviation, had negative results in the neutralisation test at baseline, and had at least one valid post-dose serology sample. This planned interim analysis reports data up to 43 days after the first vaccination; participants in the trial will be followed up for 12 months after the last study injection. This trial is registered with ClinicalTrials.gov, NCT04537208, and is ongoing. FINDINGS: Between Sept 3 and Sept 29, 2020, 441 individuals (299 aged 18-49 years and 142 aged ≥50 years) were randomly assigned to one of the 11 treatment groups. The interim safety analyses included 439 (>99%) of 441 randomly assigned participants (299 aged 18-49 years and 140 aged ≥50 years). Neutralising antibody titres were analysed in 326 (74%) of 441 participants (235 [79%] of 299 aged 18-49 years and 91 [64%] of 142 aged ≥50 years). There were no vaccine-related unsolicited immediate adverse events, serious adverse events, medically attended adverse events classified as severe, or adverse events of special interest. Among all study participants, solicited local and systemic reactions of any grade after two vaccine doses were reported in 81% (95% CI 61-93; 21 of 26) of participants in the low-dose plus AF03 group, 93% (84-97; 74 of 80) in the low-dose plus AS03 group, 89% (70-98; 23 of 26) in the high-dose plus AF03 group, 95% (88-99; 81 of 85) in the high-dose plus AS03 group, 29% (10-56; five of 17) in the unadjuvanted high-dose group, and 21% (8-40; six of 29) in the placebo group. A single vaccine dose did not generate neutralising antibody titres above placebo levels in any group at days 22 or 36. Among participants aged 18-49 years, neutralising antibody titres after two vaccine doses were 13·1 (95% CI 6·40-26·9) in the low-dose plus AF03 group, 20·5 (13·1-32·1) in the low-dose plus AS03 group, 43·2 (20·6-90·4) in the high-dose plus AF03 group, 75·1 (50·5-112·0) in the high-dose plus AS03 group, 5·00 (not calculated) in the unadjuvanted high-dose group, and 5·00 (not calculated) in the placebo group. Among participants aged 50 years or older, neutralising antibody titres after two vaccine doses were 8·62 (1·90-39·0) in the low-dose plus AF03 group, 12·9 (7·09-23·4) in the low-dose plus AS03 group, 12·3 (4·35-35·0) in the high-dose plus AF03 group, 52·3 (25·3-108·0) in the high-dose plus AS03 group, and 5·00 (not calculated) in the placebo group. INTERPRETATION: The lower than expected immune responses, especially in the older age groups, and the high reactogenicity after dose two were probably due to higher than anticipated host-cell protein content and lower than planned antigen doses in the formulations tested, which was discovered during characterisation studies on the final bulk drug substance. Further development of the AS03-adjuvanted candidate vaccine will focus on identifying the optimal antigen formulation and dose. FUNDING: Sanofi Pasteur and Biomedical Advanced Research and Development Authority.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Vacinas contra COVID-19/administração & dosagem , COVID-19/prevenção & controle , Imunogenicidade da Vacina , Proteínas Recombinantes/administração & dosagem , SARS-CoV-2/imunologia , Adulto , Anticorpos Neutralizantes/efeitos dos fármacos , Anticorpos Antivirais/efeitos dos fármacos , Vacinas contra COVID-19/imunologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes/imunologia , Glicoproteína da Espícula de Coronavírus , Estados Unidos/epidemiologia
13.
J Clin Invest ; 131(5)2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33529172

RESUMO

BACKGROUNDTo understand the features of a replicating vaccine that might drive potent and durable immune responses to transgene-encoded antigens, we tested a replication-competent adenovirus type 4 encoding influenza virus H5 HA (Ad4-H5-Vtn) administered as an oral capsule or via tonsillar swab or nasal spray.METHODSViral shedding from the nose, mouth, and rectum was measured by PCR and culturing. H5-specific IgG and IgA antibodies were measured by bead array binding assays. Serum antibodies were measured by a pseudovirus entry inhibition, microneutralization, and HA inhibition assays.RESULTSAd4-H5-Vtn DNA was shed from most upper respiratory tract-immunized (URT-immunized) volunteers for 2 to 4 weeks, but cultured from only 60% of participants, with a median duration of 1 day. Ad4-H5-Vtn vaccination induced increases in H5-specific CD4+ and CD8+ T cells in the peripheral blood as well as increases in IgG and IgA in nasal, cervical, and rectal secretions. URT immunizations induced high levels of serum neutralizing antibodies (NAbs) against H5 that remained stable out to week 26. The duration of viral shedding correlated with the magnitude of the NAb response at week 26. Adverse events (AEs) were mild, and peak NAb titers were associated with overall AE frequency and duration. Serum NAb titers could be boosted to very high levels 2 to 5 years after Ad4-H5-Vtn vaccination with recombinant H5 or inactivated split H5N1 vaccine.CONCLUSIONReplicating Ad4 delivered to the URT caused prolonged exposure to antigen, drove durable systemic and mucosal immunity, and proved to be a promising platform for the induction of immunity against viral surface glycoprotein targets.TRIAL REGISTRATIONClinicalTrials.gov NCT01443936 and NCT01806909.FUNDINGIntramural and Extramural Research Programs of the NIAID, NIH (U19 AI109946) and the Centers of Excellence for Influenza Research and Surveillance (CEIRS), NIAID, NIH (contract HHSN272201400008C).


Assuntos
Adenovírus Humanos/genética , Vetores Genéticos , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/imunologia , Adenovírus Humanos/imunologia , Adenovírus Humanos/fisiologia , Administração Oral , Adolescente , Adulto , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , Antígenos Virais/genética , Feminino , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Imunidade Celular , Imunidade Humoral , Imunidade nas Mucosas , Virus da Influenza A Subtipo H5N1/genética , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/genética , Influenza Humana/imunologia , Influenza Humana/prevenção & controle , Masculino , Sprays Nasais , Tonsila Palatina , Replicação Viral , Eliminação de Partículas Virais , Adulto Jovem
14.
Pediatr Crit Care Med ; 10(4): e43-5, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19584634

RESUMO

OBJECTIVE: Case reports of two patients with unusually late initial presentation of chronic granulomatous disease with fulminant Aspergillus pneumonia. DATA SOURCES AND EXTRACTION: Medical notes; retrospective study. STUDY SELECTION: Identical pattern of clinical presentation in two patients referred for support with extracorporeal membrane oxygenation (ECMO). Our Institutional Review Board waived the need for consent. DATA SYNTHESIS: Two school-aged boys presented with features of, and were initially treated, for community-acquired pneumonia. However, the disease course was rapidly progressive to fulminant respiratory failure and because both failed conventional intensive care management, they were referred to ECMO support. Although both died of evolving multiorgan failure, ECMO support allowed open lung biopsy leading to diagnosis of invasive Aspergillus pneumonia and chronic granulomatous disease. CONCLUSIONS: Failure of adequate therapy for acute community-acquired pneumonia and rapid progression to respiratory failure should lead to the possibility of fungal etiology. Congenital immunodeficiency may present for the first time late in life, so acute invasive pulmonary aspergillosis in the absence of known risk factors should lead to consideration of chronic granulomatous disease regardless of patient age.


Assuntos
Doença Granulomatosa Crônica/diagnóstico , Pneumonia/diagnóstico , Aspergilose Pulmonar/diagnóstico , Adolescente , Criança , Infecções Comunitárias Adquiridas/diagnóstico , Diagnóstico Diferencial , Evolução Fatal , Doença Granulomatosa Crônica/complicações , Humanos , Masculino , Pneumonia/complicações , Pneumonia/microbiologia , Pneumonia/terapia , Aspergilose Pulmonar/complicações , Aspergilose Pulmonar/terapia , Estudos Retrospectivos
15.
Sci Immunol ; 4(34)2019 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-31004012

RESUMO

Induction of an antibody response capable of recognizing highly diverse strains is a major obstacle to the development of vaccines for viruses such as HIV and influenza. Here, we report the dynamics of B cell expansion and evolution at the single-cell level after vaccination with a replication-competent adenovirus type 4 recombinant virus expressing influenza H5 hemagglutinin. Fluorescent H1 or H5 probes were used to quantitate and isolate peripheral blood B cells and their antigen receptors. We observed increases in H5-specific antibody somatic hypermutation and potency for several months beyond the period of active viral replication that was not detectable at the serum level. Individual broad and potent antibodies could be isolated, including one stem-specific antibody that is part of a new multidonor class. These results demonstrate prolonged evolution of the B cell response for months after vaccination and should be considered in efforts to evaluate or boost vaccine-induced immunity.


Assuntos
Adenoviridae/genética , Linfócitos B/imunologia , Virus da Influenza A Subtipo H5N1/imunologia , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Adenoviridae/imunologia , Administração Oral , Adolescente , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/genética , Anticorpos Antivirais/imunologia , Feminino , Vetores Genéticos/genética , Vetores Genéticos/imunologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Glicoproteínas de Hemaglutininação de Vírus da Influenza/imunologia , Humanos , Imunogenicidade da Vacina , Virus da Influenza A Subtipo H5N1/genética , Vacinas contra Influenza/administração & dosagem , Vacinas contra Influenza/efeitos adversos , Vacinas contra Influenza/genética , Influenza Humana/imunologia , Influenza Humana/virologia , Masculino , Pessoa de Meia-Idade , Hipermutação Somática de Imunoglobulina/imunologia , Vacinas Sintéticas/administração & dosagem , Vacinas Sintéticas/efeitos adversos , Vacinas Sintéticas/genética , Vacinas Sintéticas/imunologia , Replicação Viral/imunologia , Adulto Jovem
17.
PLoS One ; 13(11): e0207103, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30408086

RESUMO

This paper documents the first U-Pb zircon ages for Ashfall Fossil Beds (Nebraska, USA), a terrestrial Konservat-Lagerstätte mass-death assemblage that is arguably the most diverse of its type and age. The Ashfall tephra was correlated with ignimbrites from the Bruneau-Jarbidge volcanic field (12.7-10.5 Ma) in southwest Idaho based on geochemical analysis. The methods and geochemical data supporting the original age assessment of the ash bed, however, were never published, and there has been a persistent misconception that dateable heavy minerals (e.g., zircon) are absent. Notwithstanding, we recovered abundant zircons from Ashfall Fossil Beds, and from an ash bed ~6 km to the southeast at Grove Lake, Nebraska, and analyzed them through LA-ICP-MS. Our new zircon U-Pb age of 11.86 ± 0.13 Ma substantiates correlation of the Ashfall Fossil Beds deposit to tuffs originating from the Bruneau-Jarbidge caldera (~12.7-10.5 Ma). Our U-Pb zircon age of 6.42 ± 0.06 Ma for the Grove Lake ash bed coincides with supervolcanic activity in the Heise volcanic field (6.6-4.3 Ma) in eastern Idaho. These new dates improve age constraints of strata comprising the Ogallala Group and the important paleontological site. Moreover, we find that detrital and airfall zircons are unevenly distributed in the stratified ash beds we describe herein and presumably in similar deposits worldwide. Therefore, a higher-resolution sampling scheme is necessary in such cases.


Assuntos
Erupções Vulcânicas/história , História Antiga , Idaho , Chumbo/análise , Nebraska , Paleontologia , Datação Radiométrica , Silicatos/análise , Solo/química , Urânio/análise , Erupções Vulcânicas/análise , Zircônio/análise
18.
EBioMedicine ; 27: 61-70, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29269041

RESUMO

Zika virus (ZIKV) poses a serious public health threat due to its association with birth defects in developing fetuses and Guillain-Barré Syndrome in adults. We are developing a ZIKV vaccine based on virus-like particles (VLPs) generated in transiently transfected HEK293 cells. The genetic construct consists of the prM and envelope structural protein genes of ZIKV placed downstream from a heterologous signal sequence. To better understand the humoral responses and correlates of protection (CoP) induced by the VLP vaccine, we evaluated VLP immunogenicity with and without alum in immune-competent mice (C57Bl/6 x Balb/c) and observed efficient induction of neutralizing antibody as well as a dose-sparing effect of alum. To assess the efficacy of the immune sera, we performed passive transfer experiments in AG129 mice. Mice that received the immune sera prior to ZIKV infection demonstrated significantly reduced viral replication as measured by viral RNA levels in the blood and remained healthy, whereas control mice succumbed to infection. The results underscore the protective effect of the antibody responses elicited by this ZIKV VLP vaccine candidate. These studies will help define optimal vaccine formulations, contribute to translational efforts in developing a vaccine for clinical development, and assist in the definition of immunologic CoP.


Assuntos
Soros Imunes/imunologia , Imunização Passiva , Vacinas de Partículas Semelhantes a Vírus/imunologia , Vacinas Virais/imunologia , Infecção por Zika virus/imunologia , Infecção por Zika virus/prevenção & controle , Zika virus/imunologia , Animais , Anticorpos Neutralizantes/imunologia , Peso Corporal , Humanos , Camundongos , RNA Viral/sangue , Especificidade da Espécie , Análise de Sobrevida , Infecção por Zika virus/virologia
19.
Eur J Cardiothorac Surg ; 51(4): 709-714, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28329112

RESUMO

Objectives: With the scarcity of organs, a durable, reliable ventricular assist device (VAD) is required. The Berlin Heart EXCOR ® (BH) remains the most established VAD in the paediatric population. Implantable continuous flow (CF) VADs have been introduced to the paediatric field with encouraging early results. In this study, we compared the results of a newly introduced CF VAD (HeartWare VAD [HVAD] ® ) to results in a matched group of BH recipients. Methods: The study included patients aged <16 years who received mechanical left VAD (LVAD) support between December 2005 and January 2016. The preimplant characteristics and postimplant outcomes of patients who received the HVAD were compared with those of a matched group who received the BH. Patients with congenital heart disease were excluded. Results: Thirty patients were included in the study: 13 had received the HVAD and were matched with 17 patients who had received the BH LVAD. The only difference in preimplant characteristics was the need for higher inotropic support in the BH group. There was no difference in the need for right ventricular (RV) support (58.8% for BH vs 53.8% for HVAD, P = 1.00) or in the incidence of cerebrovascular accidents (12.5% vs 7.7%, respectively, P = 1.00), though the BH group showed prolonged mechanical ventilation (31.3% vs 0%, P = 0.047). There were no deaths while on VAD support in either group. Patients with the HVAD showed a bimodal distribution for the primary end point (transplant/explant): All HVAD recipients who also required early RV support reached this end point within 30 days of receiving the implant. Conclusions: Our early experience with the CF intracorporeal LVAD system (HVAD) indicates outcomes comparable to those with the well-established pulsatile flow paracorporeal LVAD (BH). The theoretical durability of the CF device, which might also allow for the possibility of hospital discharge and better quality of life, is yet to be proven.


Assuntos
Insuficiência Cardíaca/cirurgia , Coração Auxiliar , Adolescente , Criança , Pré-Escolar , Feminino , Seguimentos , Transplante de Coração , Coração Auxiliar/efeitos adversos , Humanos , Masculino , Desenho de Prótese , Falha de Prótese , Fluxo Pulsátil , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Resultado do Tratamento
20.
J Surg Case Rep ; 2016(11)2016 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-27887018

RESUMO

Focal periphyseal oedema (FOPE) is a rare MRI finding associated with pain in adolescent patients with very few reported cases. We present a case of FOPE in a 13-year-old girl and the only follow-up imaging available for an isolated presentation of this condition.This article describes a clinical course that correlates well with the imaging obtained. This article describes a clinical course that correlates well with the imaging obtained.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA