RESUMO
BACKGROUND: Early treatment to prevent severe coronavirus disease 2019 (Covid-19) is an important component of the comprehensive response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. METHODS: In this phase 3, double-blind, randomized, placebo-controlled trial, we used a 2-by-3 factorial design to test the effectiveness of three repurposed drugs - metformin, ivermectin, and fluvoxamine - in preventing serious SARS-CoV-2 infection in nonhospitalized adults who had been enrolled within 3 days after a confirmed diagnosis of infection and less than 7 days after the onset of symptoms. The patients were between the ages of 30 and 85 years, and all had either overweight or obesity. The primary composite end point was hypoxemia (≤93% oxygen saturation on home oximetry), emergency department visit, hospitalization, or death. All analyses used controls who had undergone concurrent randomization and were adjusted for SARS-CoV-2 vaccination and receipt of other trial medications. RESULTS: A total of 1431 patients underwent randomization; of these patients, 1323 were included in the primary analysis. The median age of the patients was 46 years; 56% were female (6% of whom were pregnant), and 52% had been vaccinated. The adjusted odds ratio for a primary event was 0.84 (95% confidence interval [CI], 0.66 to 1.09; P = 0.19) with metformin, 1.05 (95% CI, 0.76 to 1.45; P = 0.78) with ivermectin, and 0.94 (95% CI, 0.66 to 1.36; P = 0.75) with fluvoxamine. In prespecified secondary analyses, the adjusted odds ratio for emergency department visit, hospitalization, or death was 0.58 (95% CI, 0.35 to 0.94) with metformin, 1.39 (95% CI, 0.72 to 2.69) with ivermectin, and 1.17 (95% CI, 0.57 to 2.40) with fluvoxamine. The adjusted odds ratio for hospitalization or death was 0.47 (95% CI, 0.20 to 1.11) with metformin, 0.73 (95% CI, 0.19 to 2.77) with ivermectin, and 1.11 (95% CI, 0.33 to 3.76) with fluvoxamine. CONCLUSIONS: None of the three medications that were evaluated prevented the occurrence of hypoxemia, an emergency department visit, hospitalization, or death associated with Covid-19. (Funded by the Parsemus Foundation and others; COVID-OUT ClinicalTrials.gov number, NCT04510194.).
Assuntos
Tratamento Farmacológico da COVID-19 , COVID-19 , Fluvoxamina , Ivermectina , Metformina , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/complicações , Vacinas contra COVID-19 , Método Duplo-Cego , Feminino , Fluvoxamina/uso terapêutico , Humanos , Hipóxia/etiologia , Ivermectina/uso terapêutico , Masculino , Metformina/uso terapêutico , Pessoa de Meia-Idade , Obesidade/complicações , Sobrepeso/complicações , Gravidez , Complicações Infecciosas na Gravidez/tratamento farmacológico , SARS-CoV-2RESUMO
BACKGROUND: Metformin has antiviral activity against RNA viruses including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The mechanism appears to be suppression of protein translation via targeting the host mechanistic target of rapamycin pathway. In the COVID-OUT randomized trial for outpatient coronavirus disease 2019 (COVID-19), metformin reduced the odds of hospitalizations/death through 28 days by 58%, of emergency department visits/hospitalizations/death through 14 days by 42%, and of long COVID through 10 months by 42%. METHODS: COVID-OUT was a 2 × 3 randomized, placebo-controlled, double-blind trial that assessed metformin, fluvoxamine, and ivermectin; 999 participants self-collected anterior nasal swabs on day 1 (n = 945), day 5 (n = 871), and day 10 (n = 775). Viral load was quantified using reverse-transcription quantitative polymerase chain reaction. RESULTS: The mean SARS-CoV-2 viral load was reduced 3.6-fold with metformin relative to placebo (-0.56 log10 copies/mL; 95% confidence interval [CI], -1.05 to -.06; P = .027). Those who received metformin were less likely to have a detectable viral load than placebo at day 5 or day 10 (odds ratio [OR], 0.72; 95% CI, .55 to .94). Viral rebound, defined as a higher viral load at day 10 than day 5, was less frequent with metformin (3.28%) than placebo (5.95%; OR, 0.68; 95% CI, .36 to 1.29). The metformin effect was consistent across subgroups and increased over time. Neither ivermectin nor fluvoxamine showed effect over placebo. CONCLUSIONS: In this randomized, placebo-controlled trial of outpatient treatment of SARS-CoV-2, metformin significantly reduced SARS-CoV-2 viral load, which may explain the clinical benefits in this trial. Metformin is pleiotropic with other actions that are relevant to COVID-19 pathophysiology. CLINICAL TRIALS REGISTRATION: NCT04510194.
Assuntos
Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Metformina , SARS-CoV-2 , Carga Viral , Humanos , Metformina/uso terapêutico , Metformina/farmacologia , Carga Viral/efeitos dos fármacos , Masculino , SARS-CoV-2/efeitos dos fármacos , Feminino , Pessoa de Meia-Idade , Método Duplo-Cego , Antivirais/uso terapêutico , Antivirais/farmacologia , Adulto , COVID-19/virologia , Ivermectina/uso terapêutico , Ivermectina/farmacologia , Fluvoxamina/uso terapêutico , Fluvoxamina/farmacologia , IdosoRESUMO
BACKGROUND: Current equations for estimated glomerular filtration rate (eGFR) that use serum creatinine or cystatin C incorporate age, sex, and race to estimate measured GFR. However, race in eGFR equations is a social and not a biologic construct. METHODS: We developed new eGFR equations without race using data from two development data sets: 10 studies (8254 participants, 31.5% Black) for serum creatinine and 13 studies (5352 participants, 39.7% Black) for both serum creatinine and cystatin C. In a validation data set of 12 studies (4050 participants, 14.3% Black), we compared the accuracy of new eGFR equations to measured GFR. We projected the prevalence of chronic kidney disease (CKD) and GFR stages in a sample of U.S. adults, using current and new equations. RESULTS: In the validation data set, the current creatinine equation that uses age, sex, and race overestimated measured GFR in Blacks (median, 3.7 ml per minute per 1.73 m2 of body-surface area; 95% confidence interval [CI], 1.8 to 5.4) and to a lesser degree in non-Blacks (median, 0.5 ml per minute per 1.73 m2; 95% CI, 0.0 to 0.9). When the adjustment for Black race was omitted from the current eGFR equation, measured GFR in Blacks was underestimated (median, 7.1 ml per minute per 1.73 m2; 95% CI, 5.9 to 8.8). A new equation using age and sex and omitting race underestimated measured GFR in Blacks (median, 3.6 ml per minute per 1.73 m2; 95% CI, 1.8 to 5.5) and overestimated measured GFR in non-Blacks (median, 3.9 ml per minute per 1.73 m2; 95% CI, 3.4 to 4.4). For all equations, 85% or more of the eGFRs for Blacks and non-Blacks were within 30% of measured GFR. New creatinine-cystatin C equations without race were more accurate than new creatinine equations, with smaller differences between race groups. As compared with the current creatinine equation, the new creatinine equations, but not the new creatinine-cystatin C equations, increased population estimates of CKD prevalence among Blacks and yielded similar or lower prevalence among non-Blacks. CONCLUSIONS: New eGFR equations that incorporate creatinine and cystatin C but omit race are more accurate and led to smaller differences between Black participants and non-Black participants than new equations without race with either creatinine or cystatin C alone. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).
Assuntos
Creatinina/sangue , Cistatina C/sangue , Taxa de Filtração Glomerular , Grupos Raciais , Insuficiência Renal Crônica/etnologia , Adulto , Idoso , Algoritmos , População Negra , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/epidemiologia , Insuficiência Renal Crônica/fisiopatologia , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Research suggests omega-3 polyunsaturated fatty acids (PUFAs) exert favorable effects on several biological processes involved in the development and progression of atherosclerotic cardiovascular disease (ASCVD). However, studies examining the relationship between omega-3 PUFAs and peripheral artery disease (PAD) are scarce. OBJECTIVES: We evaluated the associations between omega-3 PUFAs and incident PAD in a meta-analysis of the Multi-Ethnic Study of Atherosclerosis (MESA) and Atherosclerosis Risk in Communities (ARIC) study cohorts. METHODS: Omega-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were measured at baseline for all MESA (n = 6495) and Minnesota ARIC participants (n = 3612). Incident clinical PAD events (MESA n = 106; ARIC n = 149) identified primarily through ICD discharge codes were assessed through follow-up of each cohort. Associations between omega-3 PUFAs (EPA, DHA, and EPA+DHA) and incident PAD were modeled in MESA and ARIC as quartiles and continuously using Cox proportional hazards regression, respectively. A fixed-effects meta-analysis was conducted to evaluate associations in the 2 cohorts combined. RESULTS: In the fully adjusted model, in 10,107 participants, no significant associations were observed between EPA, DHA, or EPA+DHA, and incident PAD modeled as quartiles or continuously for either MESA or ARIC cohorts separately or in the meta-analysis after a follow-up of approximately 15 y. CONCLUSION: This study is consistent with previous literature indicating that the beneficial effects of omega-3 PUFAs on the markers of ASCVD may not translate to a clinically meaningful decrease in PAD risk.
Assuntos
Aterosclerose , Ácidos Graxos Ômega-3 , Doença Arterial Periférica , Humanos , Ácido Eicosapentaenoico/farmacologia , Ácidos Docosa-Hexaenoicos/farmacologia , Aterosclerose/prevenção & controleRESUMO
Though the microbiome's impact on immune system homeostasis is well documented, the effect of circulating T cells on the gut microbiome remains unexamined. We analyzed data from 50 healthy volunteers in a pilot trial of aspirin, using immunophenotyping and 16S rRNA sequencing to evaluate the effect of baseline T cells on microbiome changes over 6 weeks. We employed an unsupervised sparse canonical correlation analysis (sCCA) and used multivariable linear regression models to evaluate the association between selected T cell subsets and selected bacterial genera after adjusting for covariates. In the cross-sectional analysis, percentages of naïve CD4+ T cells were positively associated with a relative abundance of Intestinimonas, and the percentage of activated CD8+ T cells was inversely associated with Cellulosibacter. In the longitudinal analysis, the baseline percentages of naïve CD4+ T cells and activated CD4+ T cells were inversely associated with a 6-week change in the relative abundance of Clostridium_XlVb and Anaerovorax, respectively. The baseline percentage of terminal effector CD4+ T cells was positively associated with the change in Flavonifractor. Notably, the microbiome taxa associated with T cell subsets exclusively belonged to the Bacillota phylum. These findings can guide future experimental studies focusing on the role of T cells in impacting gut microbiome homeostasis.
Assuntos
Microbioma Gastrointestinal , Voluntários Saudáveis , RNA Ribossômico 16S , Humanos , Projetos Piloto , Masculino , Feminino , Adulto , RNA Ribossômico 16S/genética , Linfócitos T CD4-Positivos/imunologia , Pessoa de Meia-Idade , Estudos Transversais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T/imunologia , Linfócitos T CD8-Positivos/imunologia , Bactérias/classificação , Bactérias/genéticaRESUMO
BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination has decreasing protection from acquiring any infection with emergence of new variants; however, vaccination continues to protect against progression to severe coronavirus disease 2019 (COVID-19). The impact of vaccination status on symptoms over time is less clear. METHODS: Within a randomized trial on early outpatient COVID-19 therapy testing metformin, ivermectin, and/or fluvoxamine, participants recorded symptoms daily for 14 days. Participants were given a paper symptom diary allowing them to circle the severity of 14 symptoms as none (0), mild (1), moderate (2), or severe (3). This is a secondary analysis of clinical trial data on symptom severity over time using generalized estimating equations comparing those unvaccinated, SARS-CoV-2 vaccinated with primary vaccine series only, or vaccine-boosted. RESULTS: The parent clinical trial prospectively enrolled 1323 participants, of whom 1062 (80%) prospectively recorded some daily symptom data. Of these, 480 (45%) were unvaccinated, 530 (50%) were vaccinated with primary series only, and 52 (5%) vaccine-boosted. Overall symptom severity was least for the vaccine-boosted group and most severe for unvaccinated at baseline and over the 14 days (P < .001). Individual symptoms were least severe in the vaccine-boosted group including cough, chills, fever, nausea, fatigue, myalgia, headache, and diarrhea, as well as smell and taste abnormalities. Results were consistent over Delta and Omicron variant time periods. CONCLUSIONS: SARS-CoV-2 vaccine-boosted participants had the least severe symptoms during COVID-19, which abated the quickest over time. Clinical Trial Registration. NCT04510194.
Assuntos
COVID-19 , SARS-CoV-2 , Humanos , COVID-19/prevenção & controle , Vacinas contra COVID-19 , VacinaçãoRESUMO
BACKGROUND: Higher serum urate levels are associated with an increased risk of diabetic kidney disease. Lowering of the serum urate level with allopurinol may slow the decrease in the glomerular filtration rate (GFR) in persons with type 1 diabetes and early-to-moderate diabetic kidney disease. METHODS: In a double-blind trial, we randomly assigned participants with type 1 diabetes, a serum urate level of at least 4.5 mg per deciliter, an estimated GFR of 40.0 to 99.9 ml per minute per 1.73 m2 of body-surface area, and evidence of diabetic kidney disease to receive allopurinol or placebo. The primary outcome was the baseline-adjusted GFR, as measured with iohexol, after 3 years plus a 2-month washout period. Secondary outcomes included the decrease in the iohexol-based GFR per year and the urinary albumin excretion rate after washout. Safety was also assessed. RESULTS: A total of 267 patients were assigned to receive allopurinol and 263 to receive placebo. The mean age was 51.1 years, the mean duration of diabetes 34.6 years, and the mean glycated hemoglobin level 8.2%. The mean baseline iohexol-based GFR was 68.7 ml per minute per 1.73 m2 in the allopurinol group and 67.3 ml per minute per 1.73 m2 in the placebo group. During the intervention period, the mean serum urate level decreased from 6.1 to 3.9 mg per deciliter with allopurinol and remained at 6.1 mg per deciliter with placebo. After washout, the between-group difference in the mean iohexol-based GFR was 0.001 ml per minute per 1.73 m2 (95% confidence interval [CI], -1.9 to 1.9; P = 0.99). The mean decrease in the iohexol-based GFR was -3.0 ml per minute per 1.73 m2 per year with allopurinol and -2.5 ml per minute per 1.73 m2 per year with placebo (between-group difference, -0.6 ml per minute per 1.73 m2 per year; 95% CI, -1.5 to 0.4). The mean urinary albumin excretion rate after washout was 40% (95% CI, 0 to 80) higher with allopurinol than with placebo. The frequency of serious adverse events was similar in the two groups. CONCLUSIONS: We found no evidence of clinically meaningful benefits of serum urate reduction with allopurinol on kidney outcomes among patients with type 1 diabetes and early-to-moderate diabetic kidney disease. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; PERL ClinicalTrials.gov number, NCT02017171.).
Assuntos
Alopurinol/uso terapêutico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/prevenção & controle , Inibidores Enzimáticos/uso terapêutico , Taxa de Filtração Glomerular/efeitos dos fármacos , Ácido Úrico/sangue , Xantina Oxidase/antagonistas & inibidores , Adulto , Idoso , Alopurinol/efeitos adversos , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/fisiopatologia , Método Duplo-Cego , Inibidores Enzimáticos/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Sistema Renina-Angiotensina , Falha de TratamentoRESUMO
PURPOSE: Inflammation is associated with diabetic retinopathy development and progression, and previous studies have demonstrated that omega-3 polyunsaturated fatty acids have anti-inflammatory properties. Therefore, the goal of this study was to determine if omega-3 polyunsaturated fatty acids, docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), are associated with decreased risk and severity of retinopathy in individuals with type 2 diabetes. METHODS: In a combined population of 1,356 individuals with type 2 diabetes from the Multi-Ethnic Study of Atherosclerosis and Genetics of Latino Diabetic Retinopathy cohorts, odds ratios using logistic regression were determined to assess the association between polyunsaturated fatty acids and retinopathy. RESULTS: In 1,356 participants with type 2 diabetes, individuals in the fourth quartile of DHA were 17% less likely to have retinopathy compared with the first quartile ( P = 0.009, CI: 0.72-0.95). Secondary analysis revealed 38% lower severity of retinopathy in individuals in the fourth quartile compared with the first quartile of DHA ( P = 0.006; CI: 0.44-0.87) and EPA + DHA ( P = 0.004; CI: 0.44-0.85). No significant associations were observed between EPA and retinopathy. CONCLUSION: DHA is inversely associated with the presence and severity of diabetic retinopathy. Increased intake of dietary sources of DHA may provide some protection against retinopathy in individuals with type 2 diabetes and warrants more research as a preventative option.
Assuntos
Diabetes Mellitus Tipo 2 , Retinopatia Diabética , Ácidos Graxos Ômega-3 , Humanos , Diabetes Mellitus Tipo 2/complicações , Retinopatia Diabética/diagnóstico , Ácido Eicosapentaenoico , Ácidos Docosa-Hexaenoicos , Ácidos Graxos InsaturadosRESUMO
PURPOSE: To examine the association between omega-3 polyunsaturated fatty acids, docosahexaenoic acid, and eicosapentaenoic acid and age-related macular degeneration (AMD) in the Multi-Ethnic Study of Atherosclerosis cohort. METHODS: Multi-Ethnic Study of Atherosclerosis is a multicenter, prospective cohort study designed to identify risk factors for cardiovascular disease in four ethnic groups. Six thousand eight hundred and fourteen participants of White, African American, Hispanic/Latino, and Chinese descent, aged 45-84 years, were recruited, with those found to have cardiovascular disease excluded. Our study population included all Multi-Ethnic Study of Atherosclerosis participants with baseline polyunsaturated fatty acid measurements and retinal photography at Examination 5 (n = 3,772). Fundus photographs were assessed for AMD using a standard grading protocol. Relative risk regression (log link) determined associations between polyunsaturated fatty acid levels and AMD. RESULTS: There was a significant association between increasing docosahexaenoic acid levels and increasing docosahexaenoic acid + eicosapentaenoic acid levels with reduced risk for early AMD (n = 214 participants with early AMD, of which n = 99 (46.3%) are non-White). Eicosapentaenoic acid levels alone were not significantly associated with AMD. CONCLUSION: Our analysis suggests increasing levels of docosahexaenoic acid are associated with reduced risk for early AMD in a multiethnic cohort. This represents the first racially diverse study demonstrating an association between omega-3 polyunsaturated fatty acids and AMD risk.
Assuntos
Aterosclerose , Ácidos Graxos Ômega-3 , Degeneração Macular , Ácidos Docosa-Hexaenoicos , Ácido Eicosapentaenoico , Etnicidade , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/epidemiologia , Estudos Prospectivos , Fatores de RiscoRESUMO
BACKGROUND: Establishment and improvement of glomerular filtration rate estimating equations requires accurate and precise laboratory measurement procedures (MPs) for filtration markers. The Advanced Research and Diagnostic Laboratory (ARDL) at the University of Minnesota, which has served as the central laboratory for the Chronic Kidney Disease Epidemiology Collaboration since 2009, has implemented several quality assurance measures to monitor the accuracy and stability of filtration marker assays over time. METHODS: To assess longitudinal stability for filtration marker assays, a 40-sample calibration panel was created using pooled serum, divided into multiple frozen aliquots stored at -80 °C. ARDL monitored 4 markers-creatinine, cystatin C, beta-2-microglobulin (B2M) and beta-trace protein-measuring 15 calibration panel aliquots from 2009 to 2019. Initial target values were established using the mean of the first 3 measurements performed in 2009-10, and differences from target were monitored over time. New MPs for cystatin C and B2M were added in 2012, with target values established using the first measurement. RESULTS: The mean percentage difference from mean target values across time was <2% for all original MPs (-0.59% for creatinine; -0.94% for cystatin C; -0.82% for B2M; 1.24% for beta-trace protein). CONCLUSIONS: Close monitoring of filtration marker trends with a calibration panel at ARDL demonstrates remarkable long-term stability of the MPs. Routine use of a calibration panel for both research studies and clinical care is recommended for filtration markers where longitudinal monitoring is important to detect analytical biases, which can mask or confound true clinical trends in patients.
Assuntos
Taxa de Filtração Glomerular , Falência Renal Crônica/fisiopatologia , Biomarcadores/metabolismo , Creatinina/sangue , Cistatina C/sangue , Feminino , Humanos , Oxirredutases Intramoleculares/sangue , Falência Renal Crônica/metabolismo , Lipocalinas/sangue , Masculino , Pessoa de Meia-Idade , Microglobulina beta-2/sangueRESUMO
RATIONALE AND OBJECTIVE: Glomerular filtration rate (GFR) estimation based on creatinine and cystatin C (eGFRcr-cys) is more accurate than estimated GFR (eGFR) based on creatinine or cystatin C alone (eGFRcr or eGFRcys, respectively), but the inclusion of creatinine in eGFRcr-cys requires specification of a person's race. ß2-Microglobulin (B2M) and ß-trace protein (BTP) are alternative filtration markers that appear to be less influenced by race than creatinine is. STUDY DESIGN: Study of diagnostic test accuracy. SETTING AND PARTICIPANTS: Development in a pooled population of 7 studies with 5,017 participants with and without chronic kidney disease. External validation in a pooled population of 7 other studies with 2,245 participants. TESTS COMPARED: Panel eGFR using B2M and BTP in addition to cystatin C (3-marker panel) or creatinine and cystatin C (4-marker panel) with and without age and sex or race. OUTCOMES: GFR measured as the urinary clearance of iothalamate, plasma clearance of iohexol, or plasma clearance of [51Cr]EDTA. RESULTS: Mean measured GFRs were 58.1 and 83.2 mL/min/1.73 m2, and the proportions of Black participants were 38.6% and 24.0%, in the development and validation populations, respectively. In development, addition of age and sex improved the performance of all equations compared with equations without age and sex, but addition of race did not further improve the performance. In validation, the 4-marker panels were more accurate than the 3-marker panels (P < 0.001). The 3-marker panel without race was more accurate than eGFRcys (percentage of estimates greater than 30% different from measured GFR [1 - P30] of 15.6% vs 17.4%; P = 0.01), and the 4-marker panel without race was as accurate as eGFRcr-cys (1 - P30 of 8.6% vs 9.4%; P = 0.2). Results were generally consistent across subgroups. LIMITATIONS: No representation of participants with severe comorbid illness and from geographic areas outside of North America and Europe. CONCLUSIONS: The 4-marker panel eGFR is as accurate as eGFRcr-cys without requiring specification of race. A more accurate race-free eGFR could be an important advance.
Assuntos
Negro ou Afro-Americano , Creatinina/metabolismo , Cistatina C/metabolismo , Taxa de Filtração Glomerular , Oxirredutases Intramoleculares/metabolismo , Lipocalinas/metabolismo , Insuficiência Renal Crônica/diagnóstico , População Branca , Microglobulina beta-2/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , População Negra , Estudos de Casos e Controles , Radioisótopos de Cromo , Ácido Edético , Feminino , Humanos , Iohexol , Ácido Iotalâmico , Masculino , Pessoa de Meia-Idade , Insuficiência Renal Crônica/etnologia , Insuficiência Renal Crônica/metabolismo , Reprodutibilidade dos Testes , Índice de Gravidade de Doença , Adulto JovemRESUMO
BACKGROUND: Current literature examining the prospective relation of circulating omega-3 (n-3) and omega-6 (n-6) PUFAs and atrial fibrillation (AF) is limited to predominantly white populations. OBJECTIVES: We investigated the association of circulating n-3 and n-6 PUFAs with incident AF in participants from the Multi-Ethnic Study of Atherosclerosis. METHODS: A total of 6229 participants (mean age = 62 y; 53% female; 39% white, 27% black, 22% Hispanic, and 12% Chinese) who were free of baseline AF and with plasma phospholipid PUFAs measured at baseline using GC were prospectively followed for the development of AF. Incident AF was ascertained using International Classification of Diseases-9 codes from hospital discharge records and Medicare claims data with follow-up through 2014. Multivariable Cox proportional hazards regression analysis was performed to determine the risk of incident AF. RESULTS: During a median follow-up of 12.9 y, 813 (13%) participants developed AF. Each higher SD increment in arachidonic acid (AA; 20:4n-6) concentrations was associated with an 11% decreased risk of incident AF (HR: 0.89; 95% CI: 0.82, 0.96). Similarly, higher overall n-6 PUFA concentrations were also associated with a reduced AF risk (HR per SD increment: 0.93; 95% CI: 0.87, 1.00). Although no significant overall associations were observed for any individual n-3 PUFAs, higher circulating concentrations of DHA (22:6n-3) and EPA (20:5n-3) were associated with a decreased AF risk in blacks and Hispanics (DHA only) but not whites or Chinese Americans. CONCLUSIONS: In a multiethnic cohort of individuals free of baseline cardiovascular disease, higher plasma concentrations of n-6 PUFAs, particularly AA, were associated with a reduced risk of incident AF. Important differences in AF risk were also noted across race/ethnicity for the n-3 PUFAs DHA and EPA.
Assuntos
Fibrilação Atrial , Ácidos Graxos Ômega-3 , Ácidos Graxos Ômega-6/sangue , Aterosclerose , Fibrilação Atrial/etnologia , Etnicidade , Ácidos Graxos Ômega-3/sangue , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
RATIONALE & OBJECTIVE: Glomerular filtration rate (GFR) estimation based on creatinine or cystatin C level is currently the standard method for assessing GFR in epidemiologic research and clinical trials despite several important and well-known limitations. Plasma iohexol clearance has been proposed as an inexpensive method for measuring GFR that could replace estimated GFR in many research projects. However, lack of standardization for iohexol assays and the use of different protocols such as single- and multiple-sample methods could potentially hamper comparisons across studies. We compared iohexol assays and GFR measurement protocols in 3 population-based European cohorts. STUDY DESIGN: Cross-sectional investigation. SETTING & PARTICIPANTS: Participants in the Age, Gene/Environment Susceptibility-Kidney Study (AGES-Kidney; n=805), the Berlin Initiative Study (BIS, n=570), and the Renal Iohexol Clearance Survey Follow-up Study (RENIS-FU; n=1,324). TESTS COMPARED: High-performance liquid chromatography analyses of iohexol. Plasma iohexol clearance calculated using single- versus multiple-sample protocols. OUTCOMES: Measures of agreement between methods. RESULTS: Frozen samples from the 3 studies were obtained and iohexol concentrations were remeasured in the laboratory at the University Hospital of North Norway. Lin's concordance correlation coefficient ρ was>0.96 and Cb (accuracy) was>0.99 for remeasured versus original serum iohexol concentrations in all 3 cohorts, and Passing-Bablok regression did not find differences between measurements, except for a slope of 1.025 (95% CI, 1.006-1.046) for the log-transformed AGES-Kidney measurements. The multiple-sample iohexol clearance measurements in AGES-Kidney and BIS were compared with single-sample GFRs derived from the same iohexol measurements. Mean bias for multiple-sample relative to single-sample GFRs in AGES-Kidney and BIS were-0.25 and-0.15mL/min, and 99% and 97% of absolute differences were within 10% of the multiple-sample result, respectively. LIMITATIONS: Lack of comparison with an independent gold-standard method. CONCLUSIONS: Agreement between the iohexol assays and clearance protocols in the 3 investigated cohorts was substantial. Our findings indicate that plasma iohexol clearance measurements can be compared across these studies.
Assuntos
Envelhecimento/sangue , Meios de Contraste/metabolismo , Taxa de Filtração Glomerular/fisiologia , Iohexol/metabolismo , Taxa de Depuração Metabólica/fisiologia , Vigilância da População , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Estudos de Coortes , Estudos Transversais , Feminino , Seguimentos , Interação Gene-Ambiente , Alemanha/epidemiologia , Humanos , Islândia/epidemiologia , Testes de Função Renal/métodos , Masculino , Pessoa de Meia-Idade , Noruega/epidemiologiaRESUMO
Objective- Lp(a) [lipoprotein(a)] is a well-described risk factor for atherosclerosis, but Lp(a)-associated risk may vary by race/ethnicity. We aimed to determine whether race/ethnicity modifies Lp(a)-related risk of carotid atherosclerotic plaque outcomes among black, white, Chinese, and Hispanic individuals. Approach and Results- Carotid plaque presence and score were assessed by ultrasonography at baseline (n=5155) and following a median 9.4 year period (n=3380) in MESA (Multi-Ethnic Study of Atherosclerosis) participants. Lp(a) concentrations were measured by immunoassay and examined as a continuous and categorical variable using clinically-based cutoffs, 30 and 50 mg/dL. Lp(a) was related to greater risk of prevalent carotid plaque at baseline in whites alone (all P<0.001): per log unit (relative risk, 1.05); Lp(a)≥30 mg/dL (relative risk, 1.16); and Lp(a)≥50 mg/dL (relative risk, 1.20). Lp(a) levels over 50 mg/dL were associated with a higher plaque score at baseline in whites (all P<0.001) and Hispanics ( P=0.04). In prospective analyses, whites with Lp(a) ≥50 mg/dL were found to have greater risk of plaque progression (relative risk, 1.12; P=0.03) and higher plaque scores (all P<0.001) over the 9.4-year follow-up. Race-based differences between whites and black participants were significant for cross-sectional associations and for carotid plaque score following the 9.4 year study period. Conclusions- Race was found to be a modifying variable in Lp(a)-related risk of carotid plaque, and Lp(a) levels may have greater influence on plaque burden in whites than in black individuals. Borderline results in Hispanics suggest that elevated Lp(a) may increase the risk of carotid plaque, but follow-up studies are needed.
Assuntos
Doenças das Artérias Carótidas/etnologia , Lipoproteína(a)/sangue , Placa Aterosclerótica/etnologia , Grupos Raciais , Idoso , Idoso de 80 Anos ou mais , Antropometria , Asiático , População Negra , Doenças das Artérias Carótidas/sangue , Comorbidade , Estudos Transversais , Diabetes Mellitus/etnologia , Feminino , Seguimentos , Hispânico ou Latino , Humanos , Hipertensão/etnologia , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Placa Aterosclerótica/sangue , Prevalência , Risco , Fumar/etnologia , Fatores Socioeconômicos , População BrancaRESUMO
Importance: Biotinylated antibodies and analogues, with their strong binding to streptavidin, are used in many clinical laboratory tests. Excess biotin in blood due to supplemental biotin ingestion may affect biotin-streptavidin binding, leading to potential clinical misinterpretation. However, the degree of interference remains undefined in healthy adults. Objective: To assess performance of specific biotinylated immunoassays after 7 days of ingesting 10 mg/d of biotin, a dose common in over-the-counter supplements for healthy adults. Design, Setting, and Participants: Nonrandomized crossover trial involving 6 healthy adults who were treated at an academic medical center research laboratory. Exposure: Administration of 10 mg/d of biotin supplementation for 7 days. Main Outcomes and Measures: Analyte concentrations were compared with baseline (day 0) measures on the seventh day of biotin treatment and 7 days after treatment had stopped (day 14). The 11 analytes included 9 hormones (ie, thyroid-stimulating hormone, total thyroxine, total triiodothyronine, free thyroxine, free triiodothyronine, parathyroid hormone, prolactin, N-terminal pro-brain natriuretic peptide, 25-hydroxyvitamin D) and 2 nonhormones (prostate-specific antigen and ferritin). A total of 37 immunoassays for the 11 analytes were evaluated on 4 diagnostic systems, including 23 assays that incorporated biotin and streptavidin components and 14 assays that did not include biotin and streptavidin components and served as negative controls. Results: Among the 2 women and 4 men (mean age, 38 years [range, 31-45 years]) who took 10 mg/d of biotin for 7 days, biotin ingestion-associated interference was found in 9 of the 23 (39%) biotinylated assays compared with none of the 14 nonbiotinylated assays (P = .007). Results from 5 of 8 biotinylated (63%) competitive immunoassays tested falsely high and results from 4 out of 15 (27%) biotinylated sandwich immunoassays tested falsely low. Conclusions and Relevance: In this preliminary study of 6 healthy adult participants and 11 hormone and nonhormone analytes measured by 37 immunoassays, ingesting 10 mg/d of biotin for 1 week was associated with potentially clinically important assay interference in some but not all biotinylated assays studied. These findings should be considered for patients taking biotin supplements before ordering blood tests or when interpreting results. Trial Registration: clinicaltrials.gov Identifier: NCT03034707.
Assuntos
Biotina/farmacologia , Erros de Diagnóstico , Interações Medicamentosas , Imunoensaio , Adulto , Artefatos , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico/sangue , Hormônio Paratireóideo/sangue , Fragmentos de Peptídeos/sangue , Prolactina/sangue , Antígeno Prostático Específico/sangue , Testes de Função Tireóidea , Hormônios Tireóideos/sangue , Vitamina D/análogos & derivados , Vitamina D/sangueRESUMO
BACKGROUND: ß-Trace protein (BTP) and ß2-microglobulin (B2M) are novel glomerular filtration markers that have stronger associations with adverse outcomes than creatinine. Comparisons of BTP and B2M to creatinine and cystatin C are limited by the absence of rigorously developed glomerular filtration rate (GFR) estimating equations for the novel markers. STUDY DESIGN: Study of diagnostic test accuracy. SETTING & PARTICIPANTS: Pooled database of 3 populations with chronic kidney disease (CKD) with mean measured GFR of 48 mL/min/1.73 m2 (N=3,551; MDRD [Modification of Diet in Renal Disease] Study, AASK [African American Study of Kidney Disease and Hypertension], and CRIC [Chronic Renal Insufficiency Cohort] Study). INDEX TESTS: GFR estimated using creatinine, cystatin C, BTP, or B2M level. REFERENCE TEST: GFR measured as the urinary clearance of iothalamate. RESULTS: For BTP and B2M, coefficients for age, sex, and race were smaller than for creatinine and were similar or smaller than for cystatin C. For B2M, coefficients for sex, age, and race were smaller than for creatinine and were similar (age and race) or smaller (sex) than for cystatin C. The final equations with BTP (BTP, age, and sex) or B2M (B2M alone) were less accurate than either the CKD-EPI (CKD Epidemiology Collaboration) creatinine or cystatin C equations. The combined BTP-B2M equation (BTP and B2M alone) had similar accuracy to the CKD-EPI creatinine or cystatin C equation. The average of the BTP-B2M equation and the CKD-EPI creatinine-cystatin C equation was not more accurate than the CKD-EPI creatinine-cystatin C equation. LIMITATIONS: No external validation population, study population was restricted to CKD, few participants older than 65 years, or nonblack nonwhite race. CONCLUSIONS: BTP and B2M are less influenced by age, sex, and race than creatinine and less influenced by race than cystatin C, but provide less accurate GFR estimates than the CKD-EPI creatinine and cystatin C equations. The CKD-EPI BTP and B2M equation provides a methodological advance for their study as filtration markers and in their associations with risk and adverse outcomes, but further study is required before clinical use.
Assuntos
Taxa de Filtração Glomerular , Oxirredutases Intramoleculares/sangue , Lipocalinas/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/fisiopatologia , Adulto , Idoso , Biomarcadores/sangue , Estudos de Coortes , Creatinina/sangue , Cistatina C/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Microglobulina beta-2/sangueRESUMO
Efficient recruitment of eligible participants is a significant challenge for clinical research studies. This challenge was exacerbated during the COVID-19 pandemic when in-person recruitment was not an option. In 2020, the University of Minnesota was tasked, as part of the National Cancer Institute's Serological Sciences Network for COVID-19 (SeroNet), to recruit participants for a longitudinal serosurveillance clinical research study with a goal of characterizing the COVID-19 vaccine-elicited immune response among immunocompromised individuals, which necessitated reliance on non-traditional strategies for participant recruitment. To meet our enrollment target of 300 transplant patients, 300 cancer patients, 100 persons living with HIV, and 200 immunocompetent individuals, we utilized targeted electronic health record (EHR)-based recruitment in addition to traditional recruitment tools, which was an effective combination of recruitment strategies. A significant advantage of patient portal messaging or other digital recruitment strategies such as email communication is timing. We reached 85 % (769 out of 900) of our enrollment target within one year with a 14.3 % response rate to invitations to participate in our study. This achievement is perhaps more salient given the COVID-19 pandemic-related constraints within which we were operating. We demonstrated that the EHR can be leveraged to quickly identify potentially eligible study participants either via EHR communication or mail. We also illustrate how the online portal MyChart can be used to efficiently send targeted recruitment messages.