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1.
Proc Natl Acad Sci U S A ; 117(6): 3053-3062, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31980526

RESUMO

Genome sequencing has established clinical utility for rare disease diagnosis. While increasing numbers of individuals have undergone elective genome sequencing, a comprehensive study surveying genome-wide disease-associated genes in adults with deep phenotyping has not been reported. Here we report the results of a 3-y precision medicine study with a goal to integrate whole-genome sequencing with deep phenotyping. A cohort of 1,190 adult participants (402 female [33.8%]; mean age, 54 y [range 20 to 89+]; 70.6% European) had whole-genome sequencing, and were deeply phenotyped using metabolomics, advanced imaging, and clinical laboratory tests in addition to family/medical history. Of 1,190 adults, 206 (17.3%) had at least 1 genetic variant with pathogenic (P) or likely pathogenic (LP) assessment that suggests a predisposition of genetic risk. A multidisciplinary clinical team reviewed all reportable findings for the assessment of genotype and phenotype associations, and 137 (11.5%) had genotype and phenotype associations. A high percentage of genotype and phenotype associations (>75%) was observed for dyslipidemia (n = 24), cardiomyopathy, arrhythmia, and other cardiac diseases (n = 42), and diabetes and endocrine diseases (n = 17). A lack of genotype and phenotype associations, a potential burden for patient care, was observed in 69 (5.8%) individuals with P/LP variants. Genomics and metabolomics associations identified 61 (5.1%) heterozygotes with phenotype manifestations affecting serum metabolite levels in amino acid, lipid and cofactor, and vitamin pathways. Our descriptive analysis provides results on the integration of whole-genome sequencing and deep phenotyping for clinical assessments in adults.


Assuntos
Diagnóstico por Imagem , Metabolômica , Medicina de Precisão/métodos , Sequenciamento Completo do Genoma , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Predisposição Genética para Doença/genética , Genótipo , Cardiopatias/genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Adulto Jovem
2.
Sci Rep ; 11(1): 5997, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33727616

RESUMO

3,4-Methylenedioxymethamphetamine (MDMA) is currently being evaluated by the Food and Drug Administration (FDA) for the treatment of post-traumatic stress disorder (PTSD). If MDMA is FDA-approved it will be important to understand what medications may pose a risk of drug-drug interactions. The goal of this study was to evaluate the risks due to MDMA ingestion alone or in combination with other common medications and drugs of abuse using the FDA drug safety surveillance data. To date, nearly one thousand reports of MDMA use have been reported to the FDA. The majority of these reports include covariates such as co-ingested substances and demographic parameters. Univariate and multivariate logistic regression was employed to uncover the contributing factors to the reported risk of death among MDMA users. Several drug classes (MDMA metabolites or analogs, anesthetics, muscle relaxants, amphetamines and stimulants, benzodiazepines, ethanol, opioids), four antidepressants (bupropion, sertraline, venlafaxine and citalopram) and olanzapine demonstrated increased odds ratios for the reported risk of death. Future drug-drug interaction clinical trials should evaluate if any of the other drug-drug interactions described in our results actually pose a risk of morbidity or mortality in controlled medical settings.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , N-Metil-3,4-Metilenodioxianfetamina/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Causas de Morte , Bases de Dados Factuais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/mortalidade , Pesquisas sobre Atenção à Saúde , Humanos , Mortalidade , Análise Multivariada , N-Metil-3,4-Metilenodioxianfetamina/uso terapêutico , Razão de Chances , Vigilância em Saúde Pública , Serotoninérgicos/efeitos adversos , Serotoninérgicos/uso terapêutico , Transtornos de Estresse Pós-Traumáticos/complicações , Transtornos de Estresse Pós-Traumáticos/epidemiologia , Transtornos de Estresse Pós-Traumáticos/mortalidade , Transtornos de Estresse Pós-Traumáticos/terapia , Estados Unidos/epidemiologia , United States Food and Drug Administration
3.
Sci Rep ; 11(1): 17324, 2021 08 30.
Artigo em Inglês | MEDLINE | ID: mdl-34462476

RESUMO

Antibodies targeting the PD-1, PD-L1, and CTLA-4 immune checkpoint axis have been used in a variety of tumor types. They achieve anti-tumor activity through activating the patient's own immune system to target immune response evading cancer cells. However, this unique mechanism of action may cause immune-related adverse events, irAEs. One of these irAEs is myocarditis which is associated with an alarming mortality rate. In this study we presented clinical cases of myocarditis from safety trial datasets submitted to the U.S. Food and Drug Administration, FDA. Additionally, we analyzed over fourteen million FDA Adverse Event Reporting System, FAERS, submissions. The statistical analysis of the FAERS data provided evidence of significantly increased reporting of myocarditis in patients administered immune checkpoint inhibitors alone, in combination with another immune checkpoint inhibitor, the kinase inhibitor axitinib, or chemotherapy, for all cancer types, when compared to patients administered chemotherapy. All combination therapies led to further increased reporting odds ratios of myocarditis. We further analyzed the occurrence of myocarditis by stratifying the reports into sub-cohorts based on specific cancer types and treatment/control groups in major cancer immunotherapy efficacy trials and confirmed the observed trend for each cohort.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Imunoterapia/efeitos adversos , Miocardite/etiologia , Neoplasias/terapia , Sistemas de Notificação de Reações Adversas a Medicamentos , Antineoplásicos Imunológicos/uso terapêutico , Coleta de Dados , Humanos , Inibidores de Checkpoint Imunológico , Miocardite/complicações , Neoplasias/complicações , Razão de Chances , Estudos Retrospectivos , Estados Unidos , United States Food and Drug Administration
4.
Sci Rep ; 10(1): 19199, 2020 11 05.
Artigo em Inglês | MEDLINE | ID: mdl-33154498

RESUMO

Chloroquine (CQ) and hydroxychloroquine (HCQ) are on the World Health Organization's List of Essential Medications for treating non-resistant malaria, rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). In addition, both drugs are currently used off-label in hospitals worldwide and in numerous clinical trials for the treatment of SARS-CoV-2 infection. However, CQ and HCQ use has been associated with cardiac side effects, which is of concern due to the higher risk of COVID-19 complications in patients with heart related disorders, and increased mortality associated with COVID-19 cardiac complications. In this study we analyzed over thirteen million adverse event reports form the United States Food and Drug Administration Adverse Event Reporting System to confirm and quantify the association of cardiac side effects of CQ and HCQ. Additionally, we identified several confounding factors, including male sex, NSAID coadministration, advanced age, and prior diagnoses contributing to drug related cardiotoxicity. These findings may help guide therapeutic decision making and ethical trial design for COVID-19 treatment.


Assuntos
Cloroquina/efeitos adversos , Coração/efeitos dos fármacos , Hidroxicloroquina/efeitos adversos , Vigilância de Produtos Comercializados , Segurança , COVID-19 , Cloroquina/uso terapêutico , Estudos de Coortes , Infecções por Coronavirus/tratamento farmacológico , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/tratamento farmacológico
5.
Genome Med ; 12(1): 7, 2020 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-31924279

RESUMO

BACKGROUND: Modern medicine is rapidly moving towards a data-driven paradigm based on comprehensive multimodal health assessments. Integrated analysis of data from different modalities has the potential of uncovering novel biomarkers and disease signatures. METHODS: We collected 1385 data features from diverse modalities, including metabolome, microbiome, genetics, and advanced imaging, from 1253 individuals and from a longitudinal validation cohort of 1083 individuals. We utilized a combination of unsupervised machine learning methods to identify multimodal biomarker signatures of health and disease risk. RESULTS: Our method identified a set of cardiometabolic biomarkers that goes beyond standard clinical biomarkers. Stratification of individuals based on the signatures of these biomarkers identified distinct subsets of individuals with similar health statuses. Subset membership was a better predictor for diabetes than established clinical biomarkers such as glucose, insulin resistance, and body mass index. The novel biomarkers in the diabetes signature included 1-stearoyl-2-dihomo-linolenoyl-GPC and 1-(1-enyl-palmitoyl)-2-oleoyl-GPC. Another metabolite, cinnamoylglycine, was identified as a potential biomarker for both gut microbiome health and lean mass percentage. We identified potential early signatures for hypertension and a poor metabolic health outcome. Additionally, we found novel associations between a uremic toxin, p-cresol sulfate, and the abundance of the microbiome genera Intestinimonas and an unclassified genus in the Erysipelotrichaceae family. CONCLUSIONS: Our methodology and results demonstrate the potential of multimodal data integration, from the identification of novel biomarker signatures to a data-driven stratification of individuals into disease subtypes and stages-an essential step towards personalized, preventative health risk assessment.


Assuntos
Genômica/métodos , Síndrome Metabólica/genética , Metabolômica/métodos , Aprendizado de Máquina não Supervisionado , Adulto , Biomarcadores/metabolismo , Genoma Humano , Humanos , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/metabolismo , Metaboloma , Microbiota
6.
Sci Rep ; 9(1): 2282, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30783195

RESUMO

Proton pump inhibitors, PPIs, are widely prescribed and sold globally. Although initially intended for time-limited treatment of acute disorders, such as gastric ulcers and esophagitis, PPIs are now commonly used for prolonged durations and are considered safe for over the counter access. Recent studies have raised concern over associations between PPI use and acute kidney injury, chronic kidney disease, end-stage renal disease, and electrolyte abnormalities. The growing concern over potentially serious adverse drug reactions warrants an evaluation of post marketing surveillance data. In this study of over ten million FDA Adverse Event Reporting System records, we provided evidence of kidney injury and electrolyte imbalances in an alarming number of patients taking PPIs. Additionally, we assessed differences between specific PPIs and observed significant electrolyte and renal abnormalities for each individual drug with varying magnitudes.


Assuntos
Injúria Renal Aguda , Nefrolitíase , Inibidores da Bomba de Prótons/efeitos adversos , Equilíbrio Hidroeletrolítico/efeitos dos fármacos , Injúria Renal Aguda/induzido quimicamente , Injúria Renal Aguda/epidemiologia , Injúria Renal Aguda/metabolismo , Feminino , Humanos , Masculino , Nefrolitíase/induzido quimicamente , Nefrolitíase/epidemiologia , Nefrolitíase/metabolismo , Vigilância de Produtos Comercializados , Inibidores da Bomba de Prótons/uso terapêutico
7.
PLoS One ; 13(4): e0195521, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29668764

RESUMO

Currently approved monoamine modulating antidepressant and anxiolytic pharmaceutics fail in over one third of patients due to delayed and variable therapeutic effect, adverse reactions preceding the therapeutic action, and adherence issues. Even with adequate adherence to the regimen and tolerability, one third of the patients do not respond to any class of antidepressants. There is a strong correlation between treatment resistant depression and increase in inflammatory cytokines in plasma and cerebrospinal fluid. Furthermore, epidemiological studies suggest that depression and anxiety are commonly comorbid with pain and inflammation. While a link between pain, inflammation and depression has been suggested it remains unclear which anti-inflammatory treatment may be beneficial to patients with depression and anxiety due to pain. Here, we analyzed 430,783 FDA adverse effect reports of patients treated for pain to identify potential antidepressant and anxiolytic effects of various anti-inflammatory medications. Patients treated for depression or patients taking any known antidepressants were excluded. The odds ratio analysis of 139,072 NSAID reports revealed that ketoprofen was associated with decreased reports of depression by a factor of 2.32 (OR 0.43 and 95% Confidence Interval [0.31, 0.59]) and decreased reports of anxiety by a factor of 2.86 (OR 0.35 [0.22, 0.56]), diclofenac with decreased depression reports by a factor of 2.22 (OR 0.45 [0.40, 0.49]) and anxiety by a factor of 2.13 (OR 0.47 [0.41, 0.54]), while naproxen decreased depression reports by a factor of 1.92 (OR 0.52 [0.49, 0.57]) and anxiety by a factor of 1.23 (OR 0.81 [0.75, 0.88]). Other NSAIDs did not exhibit any noticeable antidepressant and/or anxiolytic effect.


Assuntos
Ansiolíticos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Diclofenaco/uso terapêutico , Cetoprofeno/uso terapêutico , Naproxeno/uso terapêutico , Anti-Inflamatórios não Esteroides/farmacologia , Antidepressivos/uso terapêutico , Ansiedade/tratamento farmacológico , Estudos de Coortes , Depressão/tratamento farmacológico , Humanos , Dor/tratamento farmacológico
8.
EBioMedicine ; 28: 316-323, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29398597

RESUMO

BACKGROUND: Acetaminophen (paracetamol) is one of the most common medications used for management of pain in the world. There is lack of consensus about the mechanism of action, and concern about the possibility of adverse effects on reproductive health. METHODS: We first established the metabolome profile that characterizes use of acetaminophen, and we subsequently trained and tested a model that identified metabolomic differences across samples from 455 individuals with and without acetaminophen use. We validated the findings in a European ancestry adult twin cohort of 1880 individuals (TwinsUK), and in a study of 1235 individuals of African American and Hispanic ancestry. We used genomics to elucidate the mechanisms targeted by acetaminophen. FINDINGS: We identified a distinctive pattern of depletion of sulfated sex hormones with use of acetaminophen across all populations. We used a Mendelian randomization approach to characterize the role of Sulfotransferase Family 2A Member 1 (SULT2A1) as the site of the interaction. Although CYP3A7-CYP3A51P variants also modified levels of some sulfated sex hormones, only acetaminophen use phenocopied the effect of genetic variants of SULT2A1. Overall, acetaminophen use, age, gender and SULT2A1 and CYP3A7-CYP3A51P genetic variants are key determinants of variation in levels of sulfated sex hormones in blood. The effect of taking acetaminophen on sulfated sex hormones was roughly equivalent to the effect of 35years of aging. INTERPRETATION: These findings raise concerns of the impact of acetaminophen use on hormonal homeostasis. In addition, it modifies views on the mechanism of action of acetaminophen in pain management as sulfated sex hormones can function as neurosteroids and modify nociceptive thresholds.


Assuntos
Acetaminofen/efeitos adversos , Hormônios Esteroides Gonadais/metabolismo , Sulfatos/metabolismo , Adulto , Mapeamento Cromossômico , Estudos de Coortes , Análise Discriminante , Feminino , Humanos , Análise dos Mínimos Quadrados , Masculino , Análise da Randomização Mendeliana , Metaboloma , Reprodutibilidade dos Testes , Estudos em Gêmeos como Assunto
9.
Sci Rep ; 7(1): 1450, 2017 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-28469132

RESUMO

Current therapeutic approaches to depression fail for millions of patients due to lag in clinical response and non-adherence. Here we provide new support for the antidepressant effect of an anesthetic drug, ketamine, by Inverse-Frequency Analysis of eight million reports from the FDA Adverse Effect Reporting System. The results of the examination of population scale data revealed that patients who received ketamine had significantly lower frequency of reports of depression than patients who took any other combination of drugs for pain. The analysis also revealed that patients who took ketamine had significantly lower frequency of reports of pain and opioid induced side effects, implying ketamine's potential to act as a beneficial adjunct agent in pain management pharmacotherapy. Further, the Inverse-Frequency Analysis methodology provides robust statistical support for the antidepressant action of other currently approved therapeutics including diclofenac and minocycline.


Assuntos
Analgésicos/uso terapêutico , Antidepressivos/uso terapêutico , Mineração de Dados/estatística & dados numéricos , Depressão/tratamento farmacológico , Armazenamento e Recuperação da Informação/estatística & dados numéricos , Ketamina/uso terapêutico , Dor/tratamento farmacológico , Sistemas de Notificação de Reações Adversas a Medicamentos , Antibacterianos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Depressão/fisiopatologia , Diclofenaco/uso terapêutico , Reposicionamento de Medicamentos , Humanos , Minociclina/uso terapêutico , Dor/fisiopatologia , Estados Unidos , United States Food and Drug Administration
10.
Sci Rep ; 7(1): 17268, 2017 12 05.
Artigo em Inglês | MEDLINE | ID: mdl-29208902

RESUMO

A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper.

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