RESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary joint efficacy analysis of the Anthracyclines in Early Breast Cancer (ABC) trials reported in 2017 failed to demonstrate nonanthracycline adjuvant therapy was noninferior to anthracycline-based regimens in high-risk, early breast cancer. Full analyses of the studies had proceeded when the prespecified futility boundary was crossed at a planned futility analysis for the ability to demonstrate noninferiority of a nonanthracycline regimen with continued follow-up. These results were presented with 3.3 years of median follow-up. This manuscript reports results of the final analyses of the study efficacy end points conducted with 6.9 years of median follow-up. Long-term analysis of invasive disease-free survival (IDFS), the primary end point of the ABC trials, remains consistent with the original results, as noninferiority of the nonanthracycline regimens could not be declared on the basis of the original criteria. The secondary end point of recurrence-free interval, which excluded deaths not due to breast cancer as events, favored anthracycline-based regimens, and tests for heterogeneity were significant for hormone receptor status (P = .02) favoring anthracycline regimens for the hormone receptor-negative cohorts. There was no difference in overall survival, and review of the type of IDFS events in the groups suggested reductions in cancer recurrences achieved with anthracycline regimens were offset by late leukemias and deaths unrelated to breast cancer.
Assuntos
Neoplasias da Mama , Taxoides , Humanos , Feminino , Taxoides/uso terapêutico , Seguimentos , Neoplasias da Mama/tratamento farmacológico , Antraciclinas , Hormônios , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Recipient responses to primary graft dysfunction (PGD) after lung transplantation may have important implications to the fate of the allograft. We therefore evaluated longitudinal differences in peripheral blood gene expression in subjects with PGD. RNA expression was measured throughout the first transplant year in 106 subjects enrolled in the Clinical Trials in Organ Transplantation-03 study using a panel of 100 hypothesis-driven genes. PGD was defined as grade 3 in the first 72 posttransplant hours. Eighteen genes were differentially expressed over the first year based on PGD development, with significant representation from innate and adaptive immunity genes, with most differences identified very early after transplant. Sixteen genes were overexpressed in the blood of patients with PGD compared to those without PGD within 7 days of allograft reperfusion, with most transcripts encoding innate immune/inflammasome-related proteins, including genes previously associated with PGD. Thirteen genes were underexpressed in patients with PGD compared to those without PGD within 7 days of transplant, highlighted by T cell and adaptive immune regulation genes. Differences in gene expression present within 2 h of reperfusion and persist for days after transplant. Future investigation will focus on the long-term implications of these gene expression differences on the outcome of the allograft.
Assuntos
Biomarcadores/metabolismo , Perfilação da Expressão Gênica , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/diagnóstico , Aloenxertos , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/etiologia , Estudos Prospectivos , Fatores de RiscoRESUMO
Primary graft dysfunction (PGD) is a principal cause of early morbidity and mortality after lung transplantation, but its pathogenic mechanisms are not fully clarified. To date, studies using standard clinical assays have not linked microbial factors to PGD. We previously used comprehensive metagenomic methods to characterize viruses in lung allografts >1 mo after transplant and found that levels of Anellovirus, mainly torque teno viruses (TTVs), were significantly higher than in nontransplanted healthy controls. We used quantitative polymerase chain reaction to analyze TTV and shotgun metagenomics to characterize full viral communities in acellular bronchoalveolar lavage from donor organs and postreperfusion allografts in PGD and non-PGD lung transplant recipient pairs. Unexpectedly, TTV DNA levels were elevated 100-fold in donor lungs compared with healthy adults (p = 0.0026). Although absolute TTV levels did not differ by PGD status, PGD cases showed a smaller increase in TTV levels from before to after transplant than did control recipients (p = 0.041). Metagenomic sequencing revealed mainly TTV and bacteriophages of respiratory tract bacteria, but no viral taxa distinguished PGD cases from controls. These findings suggest that conditions associated with brain death promote TTV replication and that greater immune activation or tissue injury associated with PGD may restrict TTV abundance in the lung.
Assuntos
Rejeição de Enxerto/etiologia , Transplante de Pulmão/efeitos adversos , Metagenômica , Disfunção Primária do Enxerto/etiologia , Sistema Respiratório/virologia , Doadores de Tecidos , Torque teno virus/genética , Adulto , Idoso , Estudos de Casos e Controles , DNA Viral/genética , Feminino , Seguimentos , Genoma Viral , Sobrevivência de Enxerto , Humanos , Masculino , Pessoa de Meia-Idade , Assistência Perioperatória , Disfunção Primária do Enxerto/patologia , Prognóstico , Estudos Prospectivos , Fatores de RiscoRESUMO
Lungs stored ahead of transplant surgery experience ischemia. Pulmonary ischemia differs from ischemia in the systemic organs in that stop of blood flow in the lung leads to loss of shear alone because the lung parenchyma does not rely on blood flow for its cellular oxygen requirements. Our earlier studies on the ischemia-induced mechanosignaling cascade showed that the pulmonary endothelium responds to stop of flow by production of reactive oxygen species (ROS). We hypothesized that ROS produced in this way led to induction of proinflammatory mediators. In this study, we used lungs or cells subjected to various periods of storage and evaluated the induction of several proinflammatory mediators. Isolated murine, porcine and human lungs in situ showed increased expression of cellular adhesion molecules; the damage-associated molecular pattern protein high-mobility group box 1 and the corresponding pattern recognition receptor, called the receptor for advanced glycation end products; and induction stabilization and translocation of hypoxia-inducible factor 1α and its downstream effector VEGFA, all of which are participants in inflammation. We concluded that signaling with lung preservation drives expression of inflammatory mediators that potentially predispose the donor lung to an inflammatory response after transplant.
Assuntos
Sobrevivência de Enxerto , Inflamação/epidemiologia , Isquemia/fisiopatologia , Transplante de Pulmão , Pulmão/fisiopatologia , Preservação de Órgãos/métodos , Doadores de Tecidos , Animais , Rejeição de Enxerto/prevenção & controle , Humanos , Incidência , Mediadores da Inflamação/metabolismo , Peroxidação de Lipídeos , Camundongos , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisAssuntos
Rejeição de Enxerto/etiologia , Transplante de Pulmão/efeitos adversos , Complicações Pós-Operatórias , Disfunção Primária do Enxerto/etiologia , Rejeição de Enxerto/epidemiologia , Sobrevivência de Enxerto , Humanos , Incidência , Philadelphia/epidemiologia , Disfunção Primária do Enxerto/epidemiologia , Prognóstico , Fatores de Risco , Inquéritos e QuestionáriosRESUMO
The authors previously identified plasma plasminogen activator inhibitor-1 (PAI-1) level as a quantitative lung injury biomarker in primary graft dysfunction (PGD). They hypothesized that plasma levels of PAI-1 used as a quantitative trait could facilitate discovery of genetic loci important in PGD pathogenesis. A two-stage cohort study was performed. In stage 1, they tested associations of loci with PAI-1 plasma level using linear modeling. Genotyping was performed using the Illumina CVD Bead Chip v2. Loci meeting a p < 5 × 10(-4) cutoff were carried forward and tested in stage 2 for association with PGD. Two hundred ninety-seven enrollees were evaluated in stage 1. Six loci, associated with PAI-1, were carried forward to stage 2 and evaluated in 728 patients. rs3168046 (Toll interacting protein [TOLLIP]) was significantly associated with PGD (p = 0.006). The increased risk of PGD for carrying at least one copy of this variant was 11.7% (95% confidence interval 4.9-18.5%). The false-positive rate for individuals with this genotype who did not have PGD was 6.1%. Variants in the TOLLIP gene are associated with higher circulating PAI-1 plasma levels and validate for association with clinical PGD. A protein quantitative trait analysis for PGD risk prioritizes genetic variations in TOLLIP and supports a role for Toll-like receptors in PGD pathogenesis.
Assuntos
Biomarcadores/análise , Variação Genética/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/diagnóstico , Locos de Características Quantitativas , Adulto , Feminino , Seguimentos , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Inibidor 1 de Ativador de Plasminogênio/sangue , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/etiologia , Prognóstico , Estudos ProspectivosRESUMO
Primary graft dysfunction (PGD) is a major cause of early mortality after lung transplant. We aimed to define objective estimates of PGD risk based on readily available clinical variables, using a prospective study of 11 centers in the Lung Transplant Outcomes Group (LTOG). Derivation included 1255 subjects from 2002 to 2010; with separate validation in 382 subjects accrued from 2011 to 2012. We used logistic regression to identify predictors of grade 3 PGD at 48/72 h, and decision curve methods to assess impact on clinical decisions. 211/1255 subjects in the derivation and 56/382 subjects in the validation developed PGD. We developed three prediction models, where low-risk recipients had a normal BMI (18.5-25 kg/m(2) ), chronic obstructive pulmonary disease/cystic fibrosis, and absent or mild pulmonary hypertension (mPAP<40 mmHg). All others were considered higher-risk. Low-risk recipients had a predicted PGD risk of 4-7%, and high-risk a predicted PGD risk of 15-18%. Adding a donor-smoking lung to a higher-risk recipient significantly increased PGD risk, although risk did not change in low-risk recipients. Validation demonstrated that probability estimates were generally accurate and that models worked best at baseline PGD incidences between 5% and 25%. We conclude that valid estimates of PGD risk can be produced using readily available clinical variables.
Assuntos
Transplante de Pulmão , Disfunção Primária do Enxerto , Adulto , Feminino , Humanos , Masculino , Fatores de RiscoRESUMO
Few studies have examined the lung virome in health and disease. Outcomes of lung transplantation are known to be influenced by several recognized respiratory viruses, but global understanding of the virome of the transplanted lung is incomplete. To define the DNA virome within the respiratory tract following lung transplantation we carried out metagenomic analysis of allograft bronchoalveolar lavage (BAL), and compared with healthy and HIV+ subjects. Viral concentrates were purified from BAL and analyzed by shotgun DNA sequencing. All of the BAL samples contained reads mapping to anelloviruses, with high proportions in lung transplant samples. Anellovirus populations in transplant recipients were complex, with multiple concurrent variants. Quantitative polymerase chain reaction quantification revealed that anellovirus sequences were 56-fold more abundant in BAL from lung transplant recipients compared with healthy controls or HIV+ subjects (p < 0.0001). Anellovirus sequences were also more abundant in upper respiratory tract specimens from lung transplant recipients than controls (p = 0.006). Comparison to metagenomic data on bacterial populations showed that high anellovirus loads correlated with dysbiotic bacterial communities in allograft BAL (p = 0.008). Thus the respiratory tracts of lung transplant recipients contain high levels and complex populations of anelloviruses, warranting studies of anellovirus lung infection and transplant outcome.
Assuntos
Anelloviridae/genética , Líquido da Lavagem Broncoalveolar/química , Transplante de Pulmão , Metagenômica , Sistema Respiratório/virologia , Anelloviridae/isolamento & purificação , Estudos de Casos e Controles , Biologia Computacional , DNA Viral/genética , Seguimentos , Rejeição de Enxerto/genética , Rejeição de Enxerto/virologia , Sobrevivência de Enxerto , Humanos , Complicações Pós-Operatórias , Prognóstico , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , TransplantadosRESUMO
Inherent recipient factors, including pretransplant diagnosis, obesity and elevated pulmonary pressures, are established primary graft dysfunction (PGD) risks. We evaluated the relationship between preoperative lung injury biomarkers and PGD to gain further mechanistic insight in recipients. We performed a prospective cohort study of recipients in the Lung Transplant Outcomes Group enrolled between 2002 and 2010. Our primary outcome was Grade 3 PGD on Day 2 or 3. We measured preoperative plasma levels of five biomarkers (CC-16, sRAGE, ICAM-1, IL-8 and Protein C) that were previously associated with PGD when measured at the postoperative time point. We used multivariable logistic regression to adjust for potential confounders. Of 714 subjects, 130 (18%) developed PGD. Median CC-16 levels were elevated in subjects with PGD (10.1 vs. 6.0, p<0.001). CC-16 was associated with PGD in nonidiopathic pulmonary fibrosis (non-IPF) subjects (OR for highest quartile of CC-16: 2.87, 95% CI: 1.37, 6.00, p=0.005) but not in subjects with IPF (OR 1.38, 95% CI: 0.43, 4.45, p=0.59). After adjustment, preoperative CC-16 levels remained associated with PGD (OR: 3.03, 95% CI: 1.26, 7.30, p=0.013) in non-IPF subjects. Our study suggests the importance of preexisting airway epithelial injury in PGD. Markers of airway epithelial injury may be helpful in pretransplant risk stratification in specific recipients.
Assuntos
Biomarcadores/sangue , Pneumopatias/cirurgia , Transplante de Pulmão/efeitos adversos , Disfunção Primária do Enxerto/diagnóstico , Uteroglobina/sangue , Adulto , Idoso , Feminino , Seguimentos , Humanos , Pneumopatias/sangue , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios , Disfunção Primária do Enxerto/sangue , Disfunção Primária do Enxerto/etiologia , Prognóstico , Estudos ProspectivosRESUMO
BACKGROUND: Trichomonas vaginalis is the most prevalent nonviral sexually transmitted infection in the United States, affecting 3.1% of women of reproductive age. Infection is associated with HIV acquisition and pelvic inflammatory disease. In the United States, Centers for Disease Control and Prevention guidelines recommend testing all women with vaginal discharge for T. vaginalis, but except for HIV-infected women, there are no national guidelines for screening asymptomatic persons. The objective of this analysis is to assess testing and screening practices for T. vaginalis among symptomatic and asymptomatic women in the sexually transmitted disease (STD) clinic setting. METHODS: We analyzed data on demographics, clinical presentation, and laboratory testing for all women visiting a clinician in 2010 to 2011 at any of 15 STD clinics participating in the STD Surveillance Network. Prevalence of laboratory-confirmed T. vaginalis infection was calculated among symptomatic women tested and among asymptomatic women screened. RESULTS: A total of 59,176 women visited STD clinicians: 39,979 were considered symptomatic and 19,197 were considered asymptomatic for T. vaginalis infection, whereas 211 were HIV-infected. Diagnostic practices varied by jurisdiction: 4.0% to 96.1% of women were tested or screened for T. vaginalis using any laboratory test. Among 17,952 symptomatic women tested, prevalence was 26.2%. Among 3909 asymptomatic women screened, prevalence was 6.5%. Among 92 HIV-infected women tested/screened, prevalence was 29.3%. CONCLUSIONS: Trichomoniasis is common among STD clinic patients. In this analysis, most STD clinics tested symptomatic women seeking care, in accordance with national guidelines. All HIV-infected women should be screened annually. Additional evidence and national guidance are needed regarding potential benefits of T. vaginalis screening in other asymptomatic women.
Assuntos
Infecções por HIV/epidemiologia , Doença Inflamatória Pélvica/epidemiologia , Infecções Sexualmente Transmissíveis/epidemiologia , Vaginite por Trichomonas/epidemiologia , Trichomonas vaginalis/isolamento & purificação , Adolescente , Adulto , Antiprotozoários/uso terapêutico , Feminino , Infecções por HIV/diagnóstico , Humanos , Pessoa de Meia-Idade , Nitroimidazóis/uso terapêutico , Doença Inflamatória Pélvica/diagnóstico , Fatores de Risco , Infecções Sexualmente Transmissíveis/diagnóstico , Vaginite por Trichomonas/diagnóstico , Estados Unidos/epidemiologiaRESUMO
Methane was the most abundant hydrocarbon released during the 2010 Deepwater Horizon oil spill in the Gulf of Mexico. Beyond relevancy to this anthropogenic event, this methane release simulates a rapid and relatively short-term natural release from hydrates into deep water. Based on methane and oxygen distributions measured at 207 stations throughout the affected region, we find that within ~120 days from the onset of release ~3.0 × 10(10) to 3.9 × 10(10) moles of oxygen were respired, primarily by methanotrophs, and left behind a residual microbial community containing methanotrophic bacteria. We suggest that a vigorous deepwater bacterial bloom respired nearly all the released methane within this time, and that by analogy, large-scale releases of methane from hydrate in the deep ocean are likely to be met by a similarly rapid methanotrophic response.
Assuntos
Bactérias/metabolismo , Poluição Ambiental , Metano/metabolismo , Oxigênio/análise , Petróleo , Água do Mar/microbiologia , Oceano Atlântico , Bactérias/classificação , Bactérias/crescimento & desenvolvimento , Biodegradação Ambiental , Hidrocarbonetos/análise , Metano/análise , Dados de Sequência Molecular , Oxirredução , Consumo de Oxigênio , Filogenia , Água do Mar/químicaRESUMO
A recent shortage of erythromycin ointment has resulted in the use of alternative agents for newborn ocular infection prophylaxis in the United States. We report a series of 26 newborns in whom a characteristic periocular ulcerative dermatitis developed after gentamicin ointment administration at 2 Philadelphia hospitals.
Assuntos
Antibacterianos/efeitos adversos , Antibioticoprofilaxia/efeitos adversos , Doenças Palpebrais/induzido quimicamente , Dermatoses Faciais/induzido quimicamente , Gentamicinas/efeitos adversos , Administração Tópica , Toxidermias/etiologia , Feminino , Humanos , Recém-Nascido , Masculino , Pomadas , PhiladelphiaRESUMO
In artificial drains similar to those used in banana culture on St. Lucia, Helisoma duryi, the rams-horn snail, controlled Biomphalaria glabrata, intermediate host of schistosomiasis on that island. Time required for elimination of B. glabrata depended on environmental temperature and numbers of H. duryi initially introduced in the drains. Best fit to the data was given by the equation for the logistic curve rather than by an equation for unlimited growth. Multiple regression analyses of natality and mortality rates of both species of snails indicated that populations of B. glabrata were regulated by temperature rather than by density-dependent means while numbers of H. duryi were strongly influenced by numbers of rams-horn snails already present in the drains. Fitting of snail shell growth to von Bertalanffy equations showed that H. duryi shell diameter was uninfluenced by environmental temperatures or presence of B. glabrata while growth of the intermediate host was strongly affected both by temperature and numbers of H. duryi.
Assuntos
Biomphalaria/parasitologia , Crescimento Demográfico , Caramujos/parasitologia , Animais , Coeficiente de Natalidade , Ecologia , Mortalidade , Chuva , Esquistossomose/parasitologia , Temperatura , Índias OcidentaisRESUMO
An area-wide mollusciciding campaign in Cul de Sac valley, St. Lucia reduced incidence of Schistosoma mansoni from 22% to 4.3% between 1970 and 1975. Following this, a two-year focal surveillance-mollusciciding programme was introduced. Sites of potential transmission of S. mansoni were identified and routinely searched for Biomphalaria glabrata. If found, the site was treated with clonitralide 25% emulsifiable concentrate. Two chemotherapy campaigns supplemented the snail control programme. As a result of the combined measures, incidence of the infection dropped from 4.3% to 1.0% and from 2.2% to 0.6% in areas originally of high and low transmission respectively. The cost of protecting the 7,000 population was US $20,362: of these costs, labour absorbed 68%, transport 24%, equipment 4% and molluscicide 4%. The cost per person per year protected was US $1.45 which compares favourably with the $3.24 of the previous scheme. Although effective and relatively cheap, this programme was still dependent on a high standard of supervision for maximum benefit.
Assuntos
Biomphalaria , Moluscocidas , Controle de Pragas/métodos , Esquistossomose/prevenção & controle , Animais , Biomphalaria/parasitologia , Humanos , Controle de Pragas/economia , Schistosoma mansoni , Esquistossomose/transmissão , Índias OcidentaisRESUMO
Tests of a slow-release molluscicide containing 50% copper sulfate were under-taken in laboratory and field situations in St. Lucia. In laboratory trials, a granule form of the molluscicide produced 100% mortality of Biomphalaria glabrata down to 4 mg/liter active ingredient (a.i), while the pellet form produced 100% mortality down to 8 mg/liter a.i. In field trials, a dose of 100 mg/liter a.i. in granule form caused mortality of B. glabrata in banana drains but had no effect on B. glabrata populations in a marsh habitat. In both habitats, the dose of 100 mg/liter produced mortality of other molluscan fauna which caused changes in the molluscan diversity indices. This failure in field trials may have been due to dilution of copper levels caused by flooding and also by uptake of copper by mud and algae.
Assuntos
Cobre , Moluscocidas , Animais , Biomphalaria , Eucariotos , População , Sulfatos , Fatores de Tempo , Índias OcidentaisRESUMO
The size and number of colonies of Biomphalaria glabrata were reduced after four years of a surveillance/treatment snail control programme using an emulsifiable concentrate of niclosamide (25% active ingredient). Surveys among the human population showed that the incidence of new Schistosoma mansoni infections in 0-10 year-old children fell from 22% to 4.3%, while in a comparison area the incidence remained at 20%. With reduced transmission over four years, the prevalence of infection in a cohort of children examined in 1971 and 1975 fell from 34% to 23%. The fall in prevalence and intensity of infection led to a reduction of 66% in the index of potential contamination, which was reflected in a reduced rate of infection among sentinel snails and representative samples of B. glabrata collected during surveillance searches.The overall annual cost of the programme was US $3.24 per capita.
Assuntos
Biomphalaria/parasitologia , Moluscocidas , Schistosoma mansoni , Esquistossomose/transmissão , Animais , Estudos de Avaliação como Assunto , Niclosamida , Esquistossomose/prevenção & controle , Índias OcidentaisRESUMO
Individual households in five settlements were provided with piped water in a pilot scheme to investigate the effect on transmission of S. mansoni in St Lucia. Nearby comparison settlements, in the same valley, were provided with water through a public standpipe system. The incidence of S. mansoni infection among children decreased in the experimental area, leading to lower prevalence rates and lower intensity of infection in all age groups. Over the study period, indices of infection increased in the comparison settlements, but by the end of the period development was making those settlements less suitable for comparison purposes and some reduction in transmission was occurring.The changes in human infection rates were reflected in the results of studies with sentinel snails. In the experimental area, infection rates gradually fell owing to reduced water contact and consequently less contamination of the river and its banks, and possibly to the gradual reduction in contamination potential of the community with reduced prevalence and intensity of infection. It is suggested that a piped water supply be considered as a method of schistosomiasis control, but that the cost should not be debited only to the control of this disease since a clean water supply has other medical and social benefits.
Assuntos
Esquistossomose/prevenção & controle , Abastecimento de Água , Adolescente , Adulto , Criança , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade , Schistosoma mansoni , Esquistossomose/transmissão , Índias OcidentaisRESUMO
Chemotherapy of all persons infected with Schistosoma mansoni was begun in Marquis Valley, St. Lucia, in March 1974. From January 1972 to the start of chemotherapy, the infection rate in field Biomphalaria glabrata collected in the valley was 1.09% (117/10,736) and the rate in sentinel B. glabrata was 1.48% (56/3,790). From March 1974 through December 1975, no infections were detected in either field snails (11,742 collected) or sentinel snails (3,230 exposed). The accumulated date suggest that, because of differences in topography and average annual rainfall, S. mansoni transmission occurs in this valley during the rainy season, whereas in other St. Lucian valleys under study it occurs during the dry season.