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BACKGROUND: Nutritional impairment is associated with treatment toxicity and worse overall survival in patients with cancer. We aimed to (1) evaluate the association of nutritional impairment with psychological health and quality of life (QOL) and (2) examine which measures of nutrition had the strongest association with psychological health and QOL among older adults receiving cancer treatment with palliative intent. METHODS: This secondary analysis was performed on baseline data from a nationwide cluster randomized clinical trial (ClinicalTrials.gov identifier: NCT02107443; PI: Mohile). Adults age ≥70 with advanced cancer and ≥1 geriatric assessment (GA) impairment were enrolled from 2014 to 2017. In line with geriatric oncology standards, we defined nutritional impairment as Mini Nutritional Assessment Short Form (MNA-SF) ≤11, body mass index (BMI) <21 kg/m2, or >10% involuntary weight loss in the past 6 months. We conducted multivariable linear regressions to evaluate the association of nutritional impairment with each measure of psychological health and QOL: Geriatric Depression Scale (GDS-15, range 0-15), Generalized Anxiety Disorder-7 (GAD-7, range 0-21), NCCN Distress Thermometer (NCCN DT, range 0-10), and Functional Assessment of Cancer Therapy-General (FACT-G, range 0-108). Analyses were adjusted for patient demographics, clinical characteristics, and GA. RESULTS: Among 541 patients, the mean age was 77 (range 70-96) and 60% had nutritional impairment. Mean baseline scores: GDS-15 3.1 (SD 2.7), GAD-7 2.9 (SD 4.0), NCCN DT 2.9 (SD 2.7), and FACT-G 80 (SD 15). In the adjusted model, compared to those with no nutritional impairment, older adults with nutritional impairment had greater depression (ß = 0.79, 95% CI 0.36-1.23) and anxiety severity (ß = 0.86, 95% CI 0.19-1.53), and worse QOL (ß = -6.31, 95% CI -8.62 to -4.00). Of the measures of nutrition, MNA-SF ≤11 demonstrated the strongest associations with depression, anxiety, distress, and QOL. CONCLUSION: Nutritional impairment is associated with impaired psychological health and worse QOL. Clinicians should use the MNA-SF to screen older adults for nutritional impairment and offer tailored supportive interventions.
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Avaliação Geriátrica , Saúde Mental , Neoplasias , Estado Nutricional , Qualidade de Vida , Humanos , Idoso , Masculino , Feminino , Neoplasias/psicologia , Idoso de 80 Anos ou mais , Avaliação Nutricional , Desnutrição/psicologia , Cuidados Paliativos/psicologia , Depressão/epidemiologiaRESUMO
BACKGROUND: Americans consume diets that fall short of dietary recommendations, and the cost of healthier diets is often cited as a barrier to dietary change. We conducted a nonrandomized crossover trial with meals provided utilizing 2 diets: Dietary Approaches to Stop Hypertension (DASH) and whole food, plant-based (WFPB), and thus had intake data from baseline and both intervention diets. OBJECTIVES: Using actual diet records, describe food costs of baseline diets of individuals with type 2 diabetes (T2DM) as well as therapeutic DASH and WFPB diets. METHODS: Three-day food records were collected and analyzed for each 7-d diet phase: baseline, DASH, and WFPB. Nutrient content was analyzed using the Nutrient Data System for Research and cost was determined using Fillet, an application to manage menu pricing. Food costs were calculated for each diet as consumed and adjusted to a standardized 1800 kcal/d. Ingredient-only costs of food away from home (FAFH) were approximated and analyzed. Costs were analyzed using linear mixed-effect models as a function of diet. RESULTS: Fifteen subjects enrolled; 12 completed all dietary phases. The baseline, DASH, and WFPB diets, as consumed, cost $15.72/d (95% CI; $13.91, $17.53), $12.74/d ($11.23, $14.25), and $9.78/d ($7.97, $11.59), respectively. When adjusted to an 1800 kcal/d intake, the baseline, DASH, and WFPB diets cost $15.69/d ($13.87, $17.52), $14.92/d ($13.59, $16.26), and $11.96/d ($10.14, $13.78), respectively. When approximated ingredient-only costs of FAFH were analyzed, as consumed baseline [$11.01 ($9.53, $12.49)] and DASH diets [$11.81 ($10.44, $13.18)] had similar costs; WFPB diet [$8.83 ($7.35, $10.31)] cost the least. CONCLUSIONS: In this short-term study with meals provided, the food costs of plant-predominant diets offering substantial metabolic health benefits were less than or similar to baseline food costs of adults with insulin-treated T2DM. Longer-term data without meal provision are needed for more generalizable results. This trial was registered at clinicaltrials.gov as NCT04048642.
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Diabetes Mellitus Tipo 2 , Abordagens Dietéticas para Conter a Hipertensão , Hipertensão , Insulinas , Adulto , Humanos , Estudos Cross-Over , Dieta Baseada em Plantas , Dieta , RefeiçõesRESUMO
Maternal iron deficiency (ID) and environmental lead (Pb) exposure are co-occurring insults that both affect the neurodevelopment of offspring. Few studies have investigated how ID affects brain-region-specific Pb accumulations using human-relevant Pb concentrations. Furthermore, how these Pb exposures impact blood and brain Fe levels remains unclear. Importantly, we also wanted to determine whether the use of blood Pb levels as a surrogate for the brain Pb burden is affected by underlying iron status. We exposed virgin Swiss Webster female mice to one of six conditions differing by iron diet and Pb water concentration (0 ppm, 19 ppm, or 50 ppm lead acetate) and used Inductively Coupled Plasma Mass Spectrometry to measure the maternal and offspring circulating, stored, and brain Pb levels. We found that maternal ID rendered the offspring iron-deficient anemic and led to a region-specific depletion of brain Fe that was exacerbated by Pb in a dose-specific manner. The postnatal iron deficiency anemia also exacerbated cortical and hippocampal Pb accumulation. Interestingly, BPb levels only correlated with the brain Pb burden in ID pups but not in IN offspring. We conclude that ID significantly increases the brain Pb burden and that BPb levels alone are insufficient as a clinical surrogate to make extrapolations on the brain Pb burden.
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Doenças Fetais , Deficiências de Ferro , Animais , Feminino , Camundongos , Humanos , Ferro , Chumbo/toxicidade , Encéfalo , Dieta/efeitos adversosRESUMO
AIMS: There is limited research regarding insulin dosing changes following adoption of plant-based diets. We conducted a nonrandomized crossover trial utilizing two plant-based diets (Dietary Approaches to Stop Hypertension, or DASH, and Whole Food, Plant-Based, or WFPB) to assess acute changes in insulin requirements and associated markers among individuals with insulin-treated type 2 diabetes. METHODS: Participants (n = 15) enrolled in a 4-week trial with sequential, one-week phases: Baseline, DASH 1, WFPB, and DASH 2. Each diet was ad libitum and meals were provided. RESULTS: Compared to baseline, daily insulin usage was 24%, 39%, and 30% lower after DASH 1, WFPB, and DASH 2 weeks respectively (all p < 0.01). Insulin resistance (HOMA-IR) was 49% lower (p < 0.01) and the insulin sensitivity index was 38% higher (p < 0.01) at the end of the WFPB week before regressing toward baseline during DASH 2. Total, LDL, and HDL cholesterol, leptin, urinary glucose, and hsCRP decreased to a nadir at the end of the WFPB week before increasing during DASH 2. CONCLUSIONS: Adopting a DASH or WFPB diet can result in significant, rapid changes in insulin requirements, insulin sensitivity, and related markers among individuals with insulin-treated type 2 diabetes, with larger dietary changes producing larger benefits.
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Diabetes Mellitus Tipo 2 , Abordagens Dietéticas para Conter a Hipertensão , Hipertensão , Resistência à Insulina , Humanos , Insulina/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta , Insulina Regular Humana , Dieta VegetarianaRESUMO
BACKGROUND: The correlates of coronavirus disease 2019 (COVID-19) illness severity following infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are incompletely understood. METHODS: We assessed peripheral blood gene expression in 53 adults with confirmed SARS-CoV-2 infection clinically adjudicated as having mild, moderate, or severe disease. Supervised principal components analysis was used to build a weighted gene expression risk score (WGERS) to discriminate between severe and nonsevere COVID-19. RESULTS: Gene expression patterns in participants with mild and moderate illness were similar, but significantly different from severe illness. When comparing severe versus nonsevere illness, we identified >4000 genes differentially expressed (false discovery rate < 0.05). Biological pathways increased in severe COVID-19 were associated with platelet activation and coagulation, and those significantly decreased with T-cell signaling and differentiation. A WGERS based on 18 genes distinguished severe illness in our training cohort (cross-validated receiver operating characteristic-area under the curve [ROC-AUC] = 0.98), and need for intensive care in an independent cohort (ROC-AUC = 0.85). Dichotomizing the WGERS yielded 100% sensitivity and 85% specificity for classifying severe illness in our training cohort, and 84% sensitivity and 74% specificity for defining the need for intensive care in the validation cohort. CONCLUSIONS: These data suggest that gene expression classifiers may provide clinical utility as predictors of COVID-19 illness severity.
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COVID-19 , Adulto , Humanos , COVID-19/genética , SARS-CoV-2/genética , Fatores de Risco , Gravidade do Paciente , Índice de Gravidade de Doença , Expressão Gênica , Estudos RetrospectivosRESUMO
Background: Risk stratification in long QT syndrome (LQTS) patients is important for optimizing patient care and informing clinical decision making. We developed a risk prediction algorithm with prediction of 5-year absolute risk of the first life-threatening arrhythmic event [defined as aborted cardiac arrest, sudden cardiac death, or appropriate implantable cardioverter defibrillator (ICD) shock] in LQTS patients, accounting for individual risk factors and their changes over time. Methods: Rochester-based LQTS Registry included the phenotypic cohort consisting of 1,509 LQTS patients with a QTc ≥ 470 ms, and the genotypic cohort including 1,288 patients with single LQT1, LQT2, or LQT3 mutation. We developed two separate risk prediction models which included pre-specified time-dependent covariates of beta-blocker use, syncope (never, syncope while off beta blockers, and syncope while on beta blockers), and sex by age < and ≥13 years, baseline QTc, and genotype (for the genotypic cohort only). Follow-up started from enrollment in the registry and was censored at patients' 50s birthday, date of death due to reasons other than sudden cardiac death, or last contact, whichever occurred first. The predictive models were externally validated in an independent cohort of 1,481 LQTS patients from Pavia, Italy. Results: In Rochester dataset, there were 77 endpoints in the phenotypic cohort during a median follow-up of 9.0 years, and 47 endpoints in the genotypic cohort during a median follow-up of 9.8 years. The time-dependent extension of Harrell's generalized C-statistics for the phenotypic model and genotypic model were 0.784 (95% CI: 0.740-0.827) and 0.785 (95% CI: 0.721-0.849), respectively, in the Rochester cohort. The C-statistics obtained from external validation in the Pavia cohort were 0.700 (95% CI: 0.610-0.790) and 0.711 (95% CI: 0.631-0.792) for the two models, respectively. Based on the above models, an online risk calculator estimating a 5-year risk of life-threatening arrhythmic events was developed. Conclusion: This study developed two risk prediction algorithms for phenotype and genotype positive LQTS patients separately. The estimated 5-year absolute risk can be used to quantify a LQTS patient's risk of developing life-threatening arrhythmic events and thus assisting in clinical decision making regarding prophylactic ICD therapy.
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BACKGROUND: Women with congenital long QT syndrome (LQTS) experience increased cardiac event risk after the onset of adolescence, perhaps stemming from the known modulating effects of sex hormones on the cardiac potassium channels. OBJECTIVE: We hypothesized that the effect of sex hormones on cardiac ion channel function may modify electrocardiographic (ECG) parameters associated with the propensity for ventricular tachyarrhythmias during the menstrual cycle in women with LQTS. METHODS: We prospectively enrolled 65 women with congenital LQTS (type 1 LQTS [LQT1], n = 24 [36.9%]; type 2 LQTS [LQT2], n = 20 [30.8%]) and unaffected female relatives (n = 21 [32.3%]). Patients underwent three 7-day ECG recordings during their menstrual cycles. Simultaneous saliva testing of sex hormone levels was conducted on the first day of each 7-day ECG recording cycle. RESULTS: The mean age was 35 ± 8 years, without a significant difference among the groups. In women with LQT2, linear mixed effects models showed significant inverse correlations of the corrected QT interval with progesterone levels (P < .001) and with the progesterone to estradiol ratio (P < .001). Inverse relationships of the R-R interval with estradiol levels (P = .003) and of the T-wave duration with testosterone levels (P = .014) were also observed in women with LQT2. In contrast, no significant associations were observed between ECG parameters and sex hormone levels in women with LQT1 or unaffected relatives. CONCLUSION: This is the first study to prospectively assess correlations between repolarization dynamics and sex hormone levels during the menstrual cycle in women with congenital LQTS. Our findings show genotype-specific unique corrected QT dynamics during the menstrual cycle that may affect the propensity for ventricular tachyarrhythmia in women with LQTS, particularly women with LQT2.
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Síndrome do QT Longo , Síndrome de Romano-Ward , Taquicardia Ventricular , Adolescente , Adulto , Eletrocardiografia , Estradiol , Feminino , Humanos , Ciclo Menstrual , ProgesteronaRESUMO
INTRODUCTION: Cardiac resynchronization therapy (CRT) improves outcomes in sinus rhythm, but the data in atrial fibrillation (AF) is limited. Atrio-ventricular junctional ablation (AVJA) has been proposed as a remedy. The objective was to test if AVJA results in LV end-systolic volume (ESV) reduction ≥ 15% from baseline to 6 months. METHODS: The trial was a prospective multicenter randomized trial in 26 patients with permanent AF who were randomized 1:1 to CRT-D with or without AVJA. RESULTS: LVESV improved similarly by at least 15% in 5/10 (50%) in the CRT-D-only arm and in 6/12 (50%) in the AVJA + CRT-D arm (OR = 1.00 [0.14, 7.21], p = 1.00). In the CRT-D-only arm, the median 6-month improvement in LVEF was 9.2%, not different from the AVJA + CRT-D arm, 8.2%. When both groups were combined, a significant increase in LVEF was observed (25.4% at baseline vs 36.2% at 6 months, p = 0.002). NYHA class from baseline to 6 months for all patients combined improved 1 class in 15 of 24 (62.5%), whereas 9 remained in the same class and 0 degraded to a worse class. CONCLUSION: In patients with permanent AF, reduced LVEF, and broad QRS who were eligible for CRT, there was insufficient evidence that AVJA improved echocardiographic or clinical outcomes; the results should be interpreted in light of a smaller than planned sample size. CRT, however, seemed to be effective in the combined study cohort overall, suggesting that CRT can be reasonably deployed in patients with AF. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02946853.
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Fibrilação Atrial , Terapia de Ressincronização Cardíaca , Insuficiência Cardíaca , Fibrilação Atrial/diagnóstico por imagem , Fibrilação Atrial/cirurgia , Terapia de Ressincronização Cardíaca/métodos , Insuficiência Cardíaca/terapia , Humanos , Projetos Piloto , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND AND PURPOSE: Genome-wide association studies (GWAS) of late hematuria following prostate cancer radiotherapy identified single nucleotide polymorphisms (SNPs) near AGT, encoding angiotensinogen. We tested the hypothesis that patients taking angiotensin converting enzyme inhibitors (ACEi) have a reduced risk of late hematuria. We additionally tested genetically-defined hypertension. MATERIALS AND METHODS: Prostate cancer patients undergoing potentially-curative radiotherapy were enrolled onto two multi-center observational studies, URWCI (N = 256) and REQUITE (N = 1,437). Patients were assessed pre-radiotherapy and followed prospectively for development of toxicity for up to four years. The cumulative probability of hematuria was estimated by the Kaplan-Meier method. Multivariable grouped relative risk models assessed the effect of ACEi on time to hematuria adjusting for clinical factors and stratified by enrollment site. A polygenic risk score (PRS) for blood pressure was tested for association with hematuria in REQUITE and our Radiogenomics Consortium GWAS. RESULTS: Patients taking ACEi during radiotherapy had a reduced risk of hematuria (HR 0.51, 95%CI 0.28 to 0.94, p = 0.030) after adjusting for prior transurethral prostate and/or bladder resection, heart disease, pelvic node radiotherapy, and bladder volume receiving 70 Gy, which are associated with hematuria. A blood pressure PRS was associated with hypertension (odds ratio per standard deviation 1.38, 95%CI 1.31 to 1.46, n = 5,288, p < 0.001) but not hematuria (HR per standard deviation 0.96, 95%CI 0.87 to 1.06, n = 5,126, p = 0.41). CONCLUSIONS: Our study is the first to show a radioprotective effect of ACEi on bladder in an international, multi-site study of patients receiving pelvic radiotherapy. Mechanistic studies are needed to understand how targeting the angiotensin pathway protects the bladder.
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Inibidores da Enzima Conversora de Angiotensina , Neoplasias da Próstata , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Estudo de Associação Genômica Ampla , Humanos , Masculino , Próstata , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/genética , Neoplasias da Próstata/radioterapia , Bexiga UrináriaRESUMO
BACKGROUND: Respiratory syncytial virus (RSV) causes acute respiratory illness (ARI) and triggers exacerbations of cardiopulmonary disease. Estimates of incidence in hospitalized adults range widely, with few data on incidence in adults with comorbidities that increase the risk of severity. We conducted a prospective, population-based, surveillance study to estimate incidence of RSV hospitalization among adults overall and those with specific comorbidities. METHODS: Hospitalized adults aged ≥18 years residing in the surveillance area with ≥2 ARI symptoms or exacerbation of underlying cardiopulmonary disease were screened during the 2017-2018, 2018-2019, and 2019-2020 RSV seasons in 3 hospitals in Rochester, New York and New York City. Respiratory specimens were tested for RSV using polymerase chain reaction assays. RSV incidence per 100 000 was adjusted by market share. RESULTS: Active and passive surveillance identified 1099 adults hospitalized with RSV. Annual incidence during 3 seasons ranged from 44.2 to 58.9/100 000. Age-group-specific incidence ranged from 7.7 to 11.9/100 000, 33.5 to 57.5/100 000, and 136.9 to 255.6/100 000 in patients ages 18-49, 50-64, and ≥65 years, respectively. Incidence rates in patients with chronic obstructive pulmonary disease, coronary artery disease, and congestive heart failure were 3-13, 4-7, and 4-33 times, respectively, the incidence in patients without these conditions. CONCLUSIONS: We found a high burden of RSV hospitalization in this large prospective study. Notable was the high incidence among older patients and those with cardiac conditions. These data confirm the need for effective vaccines to prevent RSV infection in older and vulnerable adults.
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Infecções por Vírus Respiratório Sincicial , Vírus Sincicial Respiratório Humano , Adolescente , Adulto , Idoso , Criança , Hospitalização , Humanos , Incidência , Lactente , Cidade de Nova Iorque , Estudos Prospectivos , Infecções por Vírus Respiratório Sincicial/epidemiologiaRESUMO
AIMS: Risk stratification of patients with long QT syndrome (LQTS) represents a difficult task. In 2018, we proposed a granular estimate of the baseline 5-year risk of life-threatening arrhythmias (LAE) for patients with LQTS, based on the genotype (long QT syndrome Type 1, long QT syndrome Type 2, and long QT syndrome Type 3) and the duration of the QTc interval. We sought to externally validate a novel risk score model (1-2-3-LQTS-Risk model) in a geographically diverse cohort from the USA and to evaluate its performance and assess potential clinical implication of this novel model. METHODS AND RESULTS: The prognostic model (1-2-3-LQTS-Risk model) was derived using data from a prospective, single-centre longitudinal cohort study published in 2018 (discovery cohort) and was validated using an independent cohort of 1689 patients enrolled in the International LQTS Registry (Rochester NY, USA). The validation study revealed a C-index of 0.69 [95% confidence interval (CI): 0.61-0.77] in the validation cohort, when compared with C-index of 0.79 (95% CI: 0.70-0.88) in the discovery cohort. Adopting a 5-year risk ≥5%, as suggested by the ROC curve analysis as the most balanced threshold for implantable cardioverter-defibrillator (ICD) implantation, would result in a number needed to treat (NNT) of nine (NNT = 9; 95% CI: 6.3-13.6). CONCLUSION: The 1-2-3-LQTS-Risk model, the first validated 5-year risk score model for patients with LQTS, can be used to aid clinicians to identify patients at the highest risk of LAE who could benefit most from an ICD implant and avoid unnecessary implants.
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Síndrome do QT Longo , Arritmias Cardíacas , Morte Súbita Cardíaca , Eletrocardiografia , Humanos , Síndrome do QT Longo/diagnóstico , Síndrome do QT Longo/genética , Síndrome do QT Longo/terapia , Estudos Longitudinais , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: The effectiveness of implantable cardioverter-defibrillators (ICDs) on reducing mortality has not been well studied in patients with long QT syndrome (LQTS). OBJECTIVES: This study aimed to assess the survival benefits of ICDs in the overall LQTS population and in subgroups defined by ICD indications. METHODS: This study included 3,035 patients (597 with ICD) from the Rochester LQTS Registry with a QTc ≥470 milliseconds or confirmed LQTS mutation. Using multivariable Cox proportional hazards models, the risk of all-cause mortality, all-cause mortality before age 50 years, and sudden cardiac death (SCD) were estimated as functions of time-dependent ICD therapy. Indication subgroups examined included patients with: 1) nonfatal cardiac arrest; 2) syncope while on beta-blockers; and 3) a QTc ≥500 milliseconds and syncope while off beta-blockers. RESULTS: During the 118,837 person-years of follow-up, 389 patients died (137 before age 50 years, and 116 experienced SCD). In the entire population, patients with ICDs had a lower risk of death (HR: 0.54; 95% CI: 0.34-0.86), death before age 50 years (HR: 0.29; 95% CI: 0.14-0.61), and SCD (HR: 0.22; 95% CI: 0.09-0.55) than patients without ICDs did. Patients with ICDs also had a lower risk of mortality among the 3 indication subgroups (HR: 0.14; 95% CI: 0.06-0.34; HR: 0.27; 95% CI: 0.10-0.72; and HR: 0.42; 95% CI: 0.19-0.96, respectively). CONCLUSIONS: ICD therapy was associated with a lower risk of all-cause mortality, all-cause mortality before age 50 years, and SCD in the LQTS population, as wells as with a lower risk of all-cause mortality in indication subgroups. This study provides evidence supporting ICD implantation in patients with high-risk LQTS.
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Antagonistas Adrenérgicos beta/uso terapêutico , Morte Súbita Cardíaca/epidemiologia , Desfibriladores Implantáveis/tendências , Síndrome do QT Longo/mortalidade , Síndrome do QT Longo/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Seguimentos , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mortalidade/tendências , Estudos Prospectivos , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: The correlates of COVID-19 illness severity following infection with SARS-Coronavirus 2 (SARS-CoV-2) are incompletely understood. METHODS: We assessed peripheral blood gene expression in 53 adults with confirmed SARS-CoV-2-infection clinically adjudicated as having mild, moderate or severe disease. Supervised principal components analysis was used to build a weighted gene expression risk score (WGERS) to discriminate between severe and non-severe COVID. RESULTS: Gene expression patterns in participants with mild and moderate illness were similar, but significantly different from severe illness. When comparing severe versus non-severe illness, we identified >4000 genes differentially expressed (FDR<0.05). Biological pathways increased in severe COVID-19 were associated with platelet activation and coagulation, and those significantly decreased with T cell signaling and differentiation. A WGERS based on 18 genes distinguished severe illness in our training cohort (cross-validated ROC-AUC=0.98), and need for intensive care in an independent cohort (ROC-AUC=0.85). Dichotomizing the WGERS yielded 100% sensitivity and 85% specificity for classifying severe illness in our training cohort, and 84% sensitivity and 74% specificity for defining the need for intensive care in the validation cohort. CONCLUSION: These data suggest that gene expression classifiers may provide clinical utility as predictors of COVID-19 illness severity.
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Many premature babies who are born with neonatal respiratory distress syndrome (RDS) go on to develop Bronchopulmonary Dysplasia (BPD) and later Post-Prematurity Respiratory Disease (PRD) at one year corrected age, characterized by persistent or recurrent lower respiratory tract symptoms frequently related to inflammation and viral infection. Transcriptomic profiles were generated from sorted peripheral blood CD8+ T cells of preterm and full-term infants enrolled with consent in the NHLBI Prematurity and Respiratory Outcomes Program (PROP) at the University of Rochester and the University at Buffalo. We identified outcome-related gene expression patterns following standard methods to identify markers for oxygen utilization and BPD as outcomes in extremely premature infants. We further identified predictor gene sets for BPD based on transcriptomic data adjusted for gestational age at birth (GAB). RNA-Seq analysis was completed for CD8+ T cells from 145 subjects. Among the subjects with highest risk for BPD (born at <29 weeks gestational age (GA); n=72), 501 genes were associated with oxygen utilization. In the same set of subjects, 571 genes were differentially expressed in subjects with a diagnosis of BPD and 105 genes were different in BPD subjects as defined by physiologic challenge. A set of 92 genes could predict BPD with a moderately high degree of accuracy. We consistently observed dysregulation of TGFB, NRF2, HIPPO, and CD40-associated pathways in BPD. Using gene expression data from both premature and full-term subjects (n=116), we identified a 28 gene set that predicted the PRD status with a moderately high level of accuracy, which also were involved in TGFB signaling. Transcriptomic data from sort-purified peripheral blood CD8+ T cells from 145 preterm and full-term infants identified sets of molecular markers of inflammation associated with independent development of BPD in extremely premature infants at high risk for the disease and of PRD among the preterm and full-term subjects.
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Displasia Broncopulmonar/sangue , Displasia Broncopulmonar/genética , Linfócitos T CD8-Positivos/imunologia , Nascimento Prematuro/sangue , Nascimento Prematuro/genética , Síndrome do Desconforto Respiratório do Recém-Nascido/sangue , Síndrome do Desconforto Respiratório do Recém-Nascido/genética , Transcriptoma/genética , Biomarcadores/sangue , Feminino , Idade Gestacional , Humanos , Lactente Extremamente Prematuro/sangue , Recém-Nascido , Ativação Linfocitária , Masculino , Gravidez , Prognóstico , RNA-SeqRESUMO
BACKGROUND: A total of 10%-20% of patients develop long-term toxicity following radiotherapy for prostate cancer. Identification of common genetic variants associated with susceptibility to radiotoxicity might improve risk prediction and inform functional mechanistic studies. METHODS: We conducted an individual patient data meta-analysis of six genome-wide association studies (n = 3871) in men of European ancestry who underwent radiotherapy for prostate cancer. Radiotoxicities (increased urinary frequency, decreased urinary stream, hematuria, rectal bleeding) were graded prospectively. We used grouped relative risk models to test associations with approximately 6 million genotyped or imputed variants (time to first grade 2 or higher toxicity event). Variants with two-sided Pmeta less than 5 × 10-8 were considered statistically significant. Bayesian false discovery probability provided an additional measure of confidence. Statistically significant variants were evaluated in three Japanese cohorts (n = 962). All statistical tests were two-sided. RESULTS: Meta-analysis of the European ancestry cohorts identified three genomic signals: single nucleotide polymorphism rs17055178 with rectal bleeding (Pmeta = 6.2 × 10-10), rs10969913 with decreased urinary stream (Pmeta = 2.9 × 10-10), and rs11122573 with hematuria (Pmeta = 1.8 × 10-8). Fine-scale mapping of these three regions was used to identify another independent signal (rs147121532) associated with hematuria (Pconditional = 4.7 × 10-6). Credible causal variants at these four signals lie in gene-regulatory regions, some modulating expression of nearby genes. Previously identified variants showed consistent associations (rs17599026 with increased urinary frequency, rs7720298 with decreased urinary stream, rs1801516 with overall toxicity) in new cohorts. rs10969913 and rs17599026 had similar effects in the photon-treated Japanese cohorts. CONCLUSIONS: This study increases the understanding of the architecture of common genetic variants affecting radiotoxicity, points to novel radio-pathogenic mechanisms, and develops risk models for testing in clinical studies. Further multinational radiogenomics studies in larger cohorts are worthwhile.
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BACKGROUND: Recently there has been a growing interest in the potential for host transcriptomic analysis to augment the diagnosis of infectious diseases. METHODS: We compared nasal and blood samples for evaluation of the host transcriptomic response in children with acute respiratory syncytial virus (RSV) infection, symptomatic non-RSV respiratory virus infection, asymptomatic rhinovirus infection, and virus-negative asymptomatic controls. We used nested leave-one-pair-out cross-validation and supervised principal components analysis to define small sets of genes whose expression patterns accurately classified subjects. We validated gene classification scores using an external data set. RESULTS: Despite lower quality of nasal RNA, the number of genes detected by microarray in each sample type was equivalent. Nasal gene expression signal derived mainly from epithelial cells but also included a variable leukocyte contribution. The number of genes with increased expression in virus-infected children was comparable in nasal and blood samples, while nasal samples also had decreased expression of many genes associated with ciliary function and assembly. Nasal gene expression signatures were as good or better for discriminating between symptomatic, asymptomatic, and uninfected children. CONCLSUSIONS: Our results support the use of nasal samples to augment pathogen-based tests to diagnose viral respiratory infection.
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Mucosa Nasal/virologia , Infecções por Vírus Respiratório Sincicial/diagnóstico , Infecções Respiratórias/diagnóstico , Transcriptoma , Adolescente , Infecções Assintomáticas , Estudos de Casos e Controles , Criança , Pré-Escolar , Feminino , Perfilação da Expressão Gênica , Humanos , Lactente , Masculino , Mucosa Nasal/patologia , Infecções por Picornaviridae/sangue , Infecções por Picornaviridae/diagnóstico , Infecções por Picornaviridae/virologia , Infecções por Vírus Respiratório Sincicial/sangue , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano , Infecções Respiratórias/sangue , Infecções Respiratórias/virologia , RhinovirusRESUMO
The inverse relationship between gestational age at birth and postviral respiratory morbidity suggests that infants born preterm (PT) may miss a critical developmental window of T cell maturation. Despite a continued increase in younger PT survivors with respiratory complications, we have limited understanding of normal human fetal T cell maturation, how ex utero development in premature infants may interrupt normal T cell development, and whether T cell development has an effect on infant outcomes. In our longitudinal cohort of 157 infants born between 23 and 42 weeks of gestation, we identified differences in T cells present at birth that were dependent on gestational age and differences in postnatal T cell development that predicted respiratory outcome at 1 year of age. We show that naive CD4+ T cells shift from a CD31-TNF-α+ bias in mid gestation to a CD31+IL-8+ predominance by term gestation. Former PT infants discharged with CD31+IL8+CD4+ T cells below a range similar to that of full-term born infants were at an over 3.5-fold higher risk for respiratory complications after NICU discharge. This study is the first to our knowledge to identify a pattern of normal functional T cell development in later gestation and to associate abnormal T cell development with health outcomes in infants.