RESUMO
BACKGROUND: With the COVID-19 pandemic came rapid uptake in virtual oncology care. During this, sociodemographic inequities in access to virtual visits (VVs) have become apparent. To better understand these issues, we conducted a qualitative study to describe the perceived usability and acceptability of VVs among Black adults diagnosed with cancer. METHODS: Adults who self-identified as Black and had a diagnosis of prostate, multiple myeloma, or head and neck cancer were recruited from 2 academic medical centers, and their community affiliates to participate in a semi-structured interview, regardless of prior VV experience. A patient and family advisory board was formed to inform all components of the study. Interviews were conducted between September 2, 2021 and February 23, 2022. Transcripts were organized topically, and themes and subthemes were determined through iterative and interpretive immersion/crystallization cycles. RESULTS: Of the 49 adults interviewed, 29 (59%) had participated in at least one VV. Three overarching themes were derived: (1) VVs felt comfortable and convenient in the right contexts; (2) the technology required for VVs with video presented new challenges, which were often resolved by an audio-only telephone call; and (3) participants reported preferring in-person visits, citing concerns regarding gaps in nonverbal communication, trusting providers, and distractions during VV. CONCLUSION: While VVs were reported to be acceptable in specific circumstances, Black adults reported preferring in-person care, in part due to a perceived lack of interpersonal connectedness. Nonetheless, retaining reimbursement for audio-only options for VVs is essential to ensure equitable access for those with less technology savvy and/or limited device/internet capabilities.
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COVID-19 , Pandemias , Adulto , Masculino , Humanos , Oncologia , Centros Médicos Acadêmicos , COVID-19/epidemiologia , InternetRESUMO
BACKGROUND: There is a lack of national guidance specifying how skin surgery, including Mohs micrographic surgery (MMS), should be conducted, leading to a degree of heterogeneity in the set-up of skin surgery services and how skin surgeries are performed. OBJECTIVES: To provide the first UK-wide cross-sectional study reporting real-world data on the set-up and waste management practices of skin surgery, including MMS. METHODS: A UK-wide service evaluation study was conducted between 1 March 2022 and 30 June 2022 using a standardized data collection pro forma. Twelve participating sites from England, Northern Ireland, Scotland and Wales provided data from 115 skin surgery lists involving 495 patients and 547 skin surgery procedures between 1 March 2022 and 30 June 2022. RESULTS: Mean total weight of nonsharps skin surgery waste was 0.52â kg per procedure (0.39â kg clinical waste, 0.05â kg general waste and 0.08â kg recycling waste). Data from a single site using disposable surgical instruments reported a mean of only 0.25â kg of sharps waste per procedure. The recycling rate ranged between 0% and 44% across the cohort with a mean recycling rate of 16%. CONCLUSIONS: We advocate that staff transition to the British Society of Dermatological Surgery 2022 sustainability guidance, which made wide-ranging recommendations to facilitate staff to transition to sustainable practices in skin surgery.
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Neoplasias Cutâneas , Gerenciamento de Resíduos , Humanos , Cirurgia de Mohs/métodos , Neoplasias Cutâneas/cirurgia , Estudos Transversais , Procedimentos Cirúrgicos Dermatológicos , EscóciaRESUMO
AIMS/HYPOTHESIS: We have previously shown that diabetes causes pericyte dysfunction, leading to loss of vascular integrity and vascular cognitive impairment and dementia (VCID). Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), used in managing type 2 diabetes mellitus, improve the cognitive function of diabetic individuals beyond glycaemic control, yet the mechanism is not fully understood. In the present study, we hypothesise that GLP-1 RAs improve VCID by preventing diabetes-induced pericyte dysfunction. METHODS: Mice with streptozotocin-induced diabetes and non-diabetic control mice received either saline (NaCl 154 mmol/l) or exendin-4, a GLP-1 RA, through an osmotic pump over 28 days. Vascular integrity was assessed by measuring cerebrovascular neovascularisation indices (vascular density, tortuosity and branching density). Cognitive function was evaluated with Barnes maze and Morris water maze. Human brain microvascular pericytes (HBMPCs), were grown in high glucose (25 mmol/l) and sodium palmitate (200 µmol/l) to mimic diabetic conditions. HBMPCs were treated with/without exendin-4 and assessed for nitrative and oxidative stress, and angiogenic and blood-brain barrier functions. RESULTS: Diabetic mice treated with exendin-4 showed a significant reduction in all cerebral pathological neovascularisation indices and an improved blood-brain barrier (p<0.05). The vascular protective effects were accompanied by significant improvement in the learning and memory functions of diabetic mice compared with control mice (p<0.05). Our results showed that HBMPCs expressed the GLP-1 receptor. Diabetes increased GLP-1 receptor expression and receptor nitration in HBMPCs. Stimulation of HBMPCs with exendin-4 under diabetic conditions decreased diabetes-induced vascular inflammation and oxidative stress, and restored pericyte function (p<0.05). CONCLUSIONS/INTERPRETATION: This study provides novel evidence that brain pericytes express the GLP-1 receptor, which is nitrated under diabetic conditions. GLP-1 receptor activation improves brain pericyte function resulting in restoration of vascular integrity and BBB functions in diabetes. Furthermore, the GLP-1 RA exendin-4 alleviates diabetes-induced cognitive impairment in mice. Restoration of pericyte function in diabetes represents a novel therapeutic target for diabetes-induced cerebrovascular microangiopathy and VCID.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Pericitos , Animais , Encéfalo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Exenatida/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Camundongos , Pericitos/metabolismoRESUMO
OBJECTIVE: Identify disease categories in which single-item global impression (GI) scales were included in product labeling of new drugs approved by the US Food and Drug Administration (FDA) in January 2009-December 2019 and review the characteristics of GIs included in product labeling of new FDA-approved drugs (January 2017-December 2019). METHODS: FDA Clinical Outcome Assessment (COA) Compendium was reviewed for drug labels that included GIs for drugs approved in 2009-2016. The indication, year of approval, ICD-10 code, and GI respondent were noted. A manual review of labels of FDA-approved drugs (2017-2019) was undertaken to identify GIs included in the labels. Corresponding drug approval packages were reviewed to identify details of any regulatory reviewer comments related to GIs. GI characteristics were noted from the drug label or the review documents, including the respondent, type of measure (static or dynamic), item wording, concept assessed, and response options. RESULTS: Product labeling containing GIs was most common in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs were included in 30/77 (39.0%) drug labels in the four disease categories. CONCLUSION: In the past 10 years, GIs have been included as endpoint measures in confirmatory clinical trials and have generated evidence of treatment benefit in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs frequently provide important insights into the patient experience. Before GIs are included in clinical trials to assess treatment benefit, it is important to ensure that they are valid, reliable, and responsive.
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Aprovação de Drogas , Rotulagem de Medicamentos/tendências , Medidas de Resultados Relatados pelo Paciente , Humanos , Estados UnidosRESUMO
OBJECTIVES: To compare US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labeling for evidence based on patient-reported outcomes (PROs) of new oncology treatments approved by both agencies. METHODS: Oncology drugs and indications approved between 2012 and 2016 by both the FDA and the EMA were identified. PRO-related language and analysis reported in US product labels and drug approval packages and EMA summaries of product characteristics were compared for each indication. RESULTS: In total, 49 oncology drugs were approved for a total of 64 indications. Of the 64 indications, 45 (70.3%) included PRO data in either regulatory submission. No FDA PRO labeling was identified. PRO language was included in the summary of product characteristics for 21 (46.7%) of 45 indications. European Organisation for Research and Treatment of Cancer and Functional Assessment of Cancer Therapy measures were used frequently in submissions. FDA's comments suggest that aspects of study design (eg, open labels) or the validity of PRO measures was the primary reason for the lack of labeling based on PRO endpoints. Both agencies identified missing PRO data as problematic for interpretation. CONCLUSIONS: During this time period, the FDA and the EMA used different evidentiary standards to assess PRO data from oncology studies, with the EMA more likely to accept data from open-label studies and broad concepts such as health-related quality of life. An understanding of the key differences between the agencies may guide sponsor PRO strategy when pursuing labeling. Patient-focused proximal concepts are more likely than distal concepts to receive positive reviews.
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Antineoplásicos/normas , Aprovação de Drogas , Rotulagem de Medicamentos/normas , Medidas de Resultados Relatados pelo Paciente , United States Food and Drug Administration/normas , Rotulagem de Medicamentos/legislação & jurisprudência , Europa (Continente)/epidemiologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Estados Unidos/epidemiologia , United States Food and Drug Administration/legislação & jurisprudênciaRESUMO
The intersection of genome-wide association analyses with physiological and functional data indicates that variants regulating islet gene transcription influence type 2 diabetes (T2D) predisposition and glucose homeostasis. However, the specific genes through which these regulatory variants act remain poorly characterized. We generated expression quantitative trait locus (eQTL) data in 118 human islet samples using RNA-sequencing and high-density genotyping. We identified fourteen loci at which cis-exon-eQTL signals overlapped active islet chromatin signatures and were coincident with established T2D and/or glycemic trait associations. At some, these data provide an experimental link between GWAS signals and biological candidates, such as DGKB and ADCY5. At others, the cis-signals implicate genes with no prior connection to islet biology, including WARS and ZMIZ1. At the ZMIZ1 locus, we show that perturbation of ZMIZ1 expression in human islets and beta-cells influences exocytosis and insulin secretion, highlighting a novel role for ZMIZ1 in the maintenance of glucose homeostasis. Together, these findings provide a significant advance in the mechanistic insights of T2D and glycemic trait association loci.
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Diabetes Mellitus Tipo 2/genética , Predisposição Genética para Doença , Insulina/genética , Fatores de Transcrição/genética , Diabetes Mellitus Tipo 2/patologia , Éxons , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Glucose/metabolismo , Humanos , Insulina/metabolismo , Secreção de Insulina , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Locos de Características Quantitativas/genética , Transdução de Sinais , Fatores de Transcrição/biossínteseRESUMO
Significant resources have been invested in sequencing studies to investigate the role of rare variants in complex disease etiology. However, the diagnostic interpretation of individual rare variants remains a major challenge, and may require accurate variant functional classification and the collection of large numbers of variant carriers. Utilizing sequence data from 458 individuals with hypertriglyceridemia and 333 controls with normal plasma triglyceride levels, we investigated these issues using GCKR, encoding glucokinase regulatory protein. Eighteen rare non-synonymous GCKR variants identified in these 791 individuals were comprehensively characterized by a range of biochemical and cell biological assays, including a novel high-throughput-screening-based approach capable of measuring all variant proteins simultaneously. Functionally deleterious variants were collectively associated with hypertriglyceridemia, but a range of in silico prediction algorithms showed little consistency between algorithms and poor agreement with functional data. We extended our study by obtaining sequence data on family members; however, functional variants did not co-segregate with triglyceride levels. Therefore, despite evidence for their collective functional and clinical relevance, our results emphasize the low predictive value of rare GCKR variants in individuals and the complex heritability of lipid traits.
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Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Hiperlipoproteinemia Tipo IV/genética , Polimorfismo de Nucleotídeo Único , Triglicerídeos/sangue , Proteínas Adaptadoras de Transdução de Sinal/química , Algoritmos , Animais , Células COS , Estudos de Casos e Controles , Chlorocebus aethiops , Variação Genética , Células HeLa , Humanos , Hiperlipoproteinemia Tipo IV/sangue , Camundongos , Modelos Moleculares , Estrutura Terciária de Proteína , Análise de Sequência de DNARESUMO
Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI ≤ 0.01). There was no correlation between CSG and RAI (r(2) = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r(2) = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity.
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Diabetes Mellitus/genética , Glucoquinase/genética , Mutação de Sentido Incorreto , Fenótipo , Idade de Início , Peso ao Nascer , Criança , Pré-Escolar , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/enzimologia , Diabetes Mellitus/patologia , Ensaios Enzimáticos , Estabilidade Enzimática , Feminino , Genótipo , Glucoquinase/metabolismo , Homozigoto , Temperatura Alta , Humanos , Lactente , Recém-Nascido , Cinética , Masculino , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Índice de Gravidade de DoençaRESUMO
Epigenetic modifications such as DNA methylation play a key role in gene regulation and disease susceptibility. However, little is known about the genome-wide frequency, localization, and function of methylation variation and how it is regulated by genetic and environmental factors. We utilized the Multiple Tissue Human Expression Resource (MuTHER) and generated Illumina 450K adipose methylome data from 648 twins. We found that individual CpGs had low variance and that variability was suppressed in promoters. We noted that DNA methylation variation was highly heritable (h(2)median = 0.34) and that shared environmental effects correlated with metabolic phenotype-associated CpGs. Analysis of methylation quantitative-trait loci (metQTL) revealed that 28% of CpGs were associated with nearby SNPs, and when overlapping them with adipose expression quantitative-trait loci (eQTL) from the same individuals, we found that 6% of the loci played a role in regulating both gene expression and DNA methylation. These associations were bidirectional, but there were pronounced negative associations for promoter CpGs. Integration of metQTL with adipose reference epigenomes and disease associations revealed significant enrichment of metQTL overlapping metabolic-trait or disease loci in enhancers (the strongest effects were for high-density lipoprotein cholesterol and body mass index [BMI]). We followed up with the BMI SNP rs713586, a cg01884057 metQTL that overlaps an enhancer upstream of ADCY3, and used bisulphite sequencing to refine this region. Our results showed widespread population invariability yet sequence dependence on adipose DNA methylation but that incorporating maps of regulatory elements aid in linking CpG variation to gene regulation and disease risk in a tissue-dependent manner.
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Tecido Adiposo , Metilação de DNA , Polimorfismo de Nucleotídeo Único , Sequências Reguladoras de Ácido Nucleico , Índice de Massa Corporal , Mapeamento Cromossômico , Epigenômica , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Genoma Humano , Humanos , Hibridização Genética , Análise de Sequência com Séries de Oligonucleotídeos , Fenótipo , Locos de Características Quantitativas , Análise de Sequência de DNA , Sulfitos/metabolismo , Gêmeos/genéticaRESUMO
Hepatic glucose phosphorylation by GK (glucokinase) is regulated by GKRP (GK regulatory protein). GKRP forms a cytosolic complex with GK followed by nuclear import and storage, leading to inhibition of GK activity. This process is initiated by low glucose, but reversed nutritionally by high glucose and fructose or pharmacologically by GKAs (GK activators) and GKRPIs (GKRP inhibitors). To study the regulation of this process by glucose, fructose-phosphate esters and a GKA, we measured the TF (tryptophan fluorescence) of human WT (wild-type) and GKRP-P446L (a mutation associated with high serum triacylglycerol) in the presence of non-fluorescent GK with its tryptophan residues mutated. Titration of GKRP-WT by GK resulted in a sigmoidal increase in TF, suggesting co-operative PPIs (protein-protein interactions) perhaps due to the hysteretic nature of GK. The affinity of GK for GKRP was decreased and binding co-operativity increased by glucose, fructose 1-phosphate and GKA, reflecting disruption of the GK-GKRP complex. Similar studies with GKRP-P446L showed significantly different results compared with GKRP-WT, suggesting impairment of complex formation and nuclear storage. The results of the present TF-based biophysical analysis of PPIs between GK and GKRP suggest that hepatic glucose metabolism is regulated by a metabolite-sensitive drug-responsive co-operative molecular switch, involving complex formation between these two allosterically regulated proteins.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Glucoquinase/metabolismo , Modelos Moleculares , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/genética , Regulação Alostérica , Substituição de Aminoácidos , Frutosefosfatos/metabolismo , Glucoquinase/química , Glucoquinase/genética , Glucose/metabolismo , Humanos , Ligantes , Proteínas Mutantes/química , Proteínas Mutantes/metabolismo , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Redobramento de Proteína , Estabilidade Proteica , Transporte Proteico , Desdobramento de Proteína , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Espectrometria de Fluorescência , Triptofano/químicaRESUMO
Metabolic Syndrome (MetS) is highly prevalent and has considerable public health impact, but its underlying genetic factors remain elusive. To identify gene networks involved in MetS, we conducted whole-genome expression and genotype profiling on abdominal (ABD) and gluteal (GLU) adipose tissue, and whole blood (WB), from 29 MetS cases and 44 controls. Co-expression network analysis for each tissue independently identified nine, six, and zero MetS-associated modules of coexpressed genes in ABD, GLU, and WB, respectively. Of 8,992 probesets expressed in ABD or GLU, 685 (7.6%) were expressed in ABD and 51 (0.6%) in GLU only. Differential eigengene network analysis of 8,256 shared probesets detected 22 shared modules with high preservation across adipose depots (D(ABD-GLU)â=â0.89), seven of which were associated with MetS (FDR P<0.01). The strongest associated module, significantly enriched for immune response-related processes, contained 94/620 (15%) genes with inter-depot differences. In an independent cohort of 145/141 twins with ABD and WB longitudinal expression data, median variability in ABD due to familiality was greater for MetS-associated versus un-associated modules (ABD: 0.48 versus 0.18, Pâ=â0.08; GLU: 0.54 versus 0.20, Pâ=â7.8×10(-4)). Cis-eQTL analysis of probesets associated with MetS (FDR P<0.01) and/or inter-depot differences (FDR P<0.01) provided evidence for 32 eQTLs. Corresponding eSNPs were tested for association with MetS-related phenotypes in two GWAS of >100,000 individuals; rs10282458, affecting expression of RARRES2 (encoding chemerin), was associated with body mass index (BMI) (Pâ=â6.0×10(-4)); and rs2395185, affecting inter-depot differences of HLA-DRB1 expression, was associated with high-density lipoprotein (Pâ=â8.7×10(-4)) and BMI-adjusted waist-to-hip ratio (Pâ=â2.4×10(-4)). Since many genes and their interactions influence complex traits such as MetS, integrated analysis of genotypes and coexpression networks across multiple tissues relevant to clinical traits is an efficient strategy to identify novel associations.
Assuntos
Tecido Adiposo/metabolismo , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Síndrome Metabólica/genética , Índice de Massa Corporal , Quimiocinas/genética , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Cadeias HLA-DRB1/genética , Humanos , Peptídeos e Proteínas de Sinalização Intercelular , Síndrome Metabólica/patologia , Especificidade de Órgãos , Fenótipo , Locos de Características QuantitativasRESUMO
Small RNAs are functional molecules that modulate mRNA transcripts and have been implicated in the aetiology of several common diseases. However, little is known about the extent of their variability within the human population. Here, we characterise the extent, causes, and effects of naturally occurring variation in expression and sequence of small RNAs from adipose tissue in relation to genotype, gene expression, and metabolic traits in the MuTHER reference cohort. We profiled the expression of 15 to 30 base pair RNA molecules in subcutaneous adipose tissue from 131 individuals using high-throughput sequencing, and quantified levels of 591 microRNAs and small nucleolar RNAs. We identified three genetic variants and three RNA editing events. Highly expressed small RNAs are more conserved within mammals than average, as are those with highly variable expression. We identified 14 genetic loci significantly associated with nearby small RNA expression levels, seven of which also regulate an mRNA transcript level in the same region. In addition, these loci are enriched for variants significant in genome-wide association studies for body mass index. Contrary to expectation, we found no evidence for negative correlation between expression level of a microRNA and its target mRNAs. Trunk fat mass, body mass index, and fasting insulin were associated with more than twenty small RNA expression levels each, while fasting glucose had no significant associations. This study highlights the similar genetic complexity and shared genetic control of small RNA and mRNA transcripts, and gives a quantitative picture of small RNA expression variation in the human population.
Assuntos
Variação Genética , MicroRNAs , RNA Mensageiro/genética , RNA Nucleolar Pequeno , Pequeno RNA não Traduzido/genética , Gordura Subcutânea , Animais , Glicemia , Distribuição da Gordura Corporal , Índice de Massa Corporal , Jejum , Feminino , Regulação da Expressão Gênica , Estudo de Associação Genômica Ampla , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Insulina/sangue , MicroRNAs/genética , MicroRNAs/metabolismo , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , RNA Mensageiro/metabolismo , RNA Nucleolar Pequeno/genética , RNA Nucleolar Pequeno/metabolismo , Pequeno RNA não Traduzido/metabolismo , Gordura Subcutânea/metabolismoRESUMO
While there have been studies exploring regulatory variation in one or more tissues, the complexity of tissue-specificity in multiple primary tissues is not yet well understood. We explore in depth the role of cis-regulatory variation in three human tissues: lymphoblastoid cell lines (LCL), skin, and fat. The samples (156 LCL, 160 skin, 166 fat) were derived simultaneously from a subset of well-phenotyped healthy female twins of the MuTHER resource. We discover an abundance of cis-eQTLs in each tissue similar to previous estimates (858 or 4.7% of genes). In addition, we apply factor analysis (FA) to remove effects of latent variables, thus more than doubling the number of our discoveries (1,822 eQTL genes). The unique study design (Matched Co-Twin Analysis--MCTA) permits immediate replication of eQTLs using co-twins (93%-98%) and validation of the considerable gain in eQTL discovery after FA correction. We highlight the challenges of comparing eQTLs between tissues. After verifying previous significance threshold-based estimates of tissue-specificity, we show their limitations given their dependency on statistical power. We propose that continuous estimates of the proportion of tissue-shared signals and direct comparison of the magnitude of effect on the fold change in expression are essential properties that jointly provide a biologically realistic view of tissue-specificity. Under this framework we demonstrate that 30% of eQTLs are shared among the three tissues studied, while another 29% appear exclusively tissue-specific. However, even among the shared eQTLs, a substantial proportion (10%-20%) have significant differences in the magnitude of fold change between genotypic classes across tissues. Our results underline the need to account for the complexity of eQTL tissue-specificity in an effort to assess consequences of such variants for complex traits.
Assuntos
Tecido Adiposo/metabolismo , Genes Reguladores/genética , Locos de Características Quantitativas/genética , Pele/metabolismo , Linhagem Celular , Células Cultivadas , Interpretação Estatística de Dados , Feminino , Perfilação da Expressão Gênica , Genótipo , Humanos , Especificidade de Órgãos/genética , Fenótipo , GêmeosRESUMO
We have performed a metabolite quantitative trait locus (mQTL) study of the (1)H nuclear magnetic resonance spectroscopy ((1)H NMR) metabolome in humans, building on recent targeted knowledge of genetic drivers of metabolic regulation. Urine and plasma samples were collected from two cohorts of individuals of European descent, with one cohort comprised of female twins donating samples longitudinally. Sample metabolite concentrations were quantified by (1)H NMR and tested for association with genome-wide single-nucleotide polymorphisms (SNPs). Four metabolites' concentrations exhibited significant, replicable association with SNP variation (8.6×10(-11)
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Estudo de Associação Genômica Ampla , Redes e Vias Metabólicas/genética , Metaboloma/genética , Locos de Características Quantitativas/genética , Seleção Genética , Acetiltransferases/genética , Acetiltransferases/metabolismo , Dimetilaminas/sangue , Dimetilaminas/metabolismo , Feminino , Haplótipos , Humanos , Isobutiratos/metabolismo , Isobutiratos/urina , Espectroscopia de Ressonância Magnética , Metilaminas/metabolismo , Metilaminas/urina , Polimorfismo de Nucleotídeo ÚnicoRESUMO
INTRODUCTION: Multiple sclerosis (MS) is a disabling disease with unpredictable clinical manifestations. As clinical assessments may not fully capture the impact of MS on quality of life, they can be complemented by patient-reported outcome (PRO) measures to provide a more comprehensive picture of MS disease state and impact. The objectives of this study were to explore the experiences of people with relapsing-remitting MS, including symptoms and impacts on daily life, and to provide a conceptual model of MS outcomes. METHODS: A literature review of studies that evaluated the experiences of people with MS was completed and combined with semi-structured concept elicitation interviews conducted with 14 people with relapsing-remitting MS in the USA. RESULTS: The average age of the 14 participants was 43.9 (range 25-64) years, most were White (78.6%) and female (78.6%), and the mean duration since diagnosis was 6.6 (2-10) years. The most bothersome symptoms identified included fatigue (n = 9), cognitive dysfunction (n = 5), mobility/difficulty with walking (n = 3), and vision problems (n = 3). The most commonly reported impacts on daily life were balance problems/instability (n = 13), work life/productivity (n = 12), difficulty walking (n = 11), daily activities/household chores (n = 11), and leisure activities (n = 10). CONCLUSION: There was a high frequency of concepts associated with physical function, fatigue, and sensory-motor actions. A conceptual model was developed that captures the disease symptoms, impairments, and impacts identified in the interviews as well as known processes and symptoms identified in the literature search. This model underpins the appropriateness of PRO instruments, such as the PROMIS Fatigue (MS) 8a and PROMIS Physical Function (MS) 15a, which evaluate symptoms and impacts that matter most to people with MS.
RESUMO
WHAT IS THIS SUMMARY ABOUT?: This summary describes how researchers worked with people with multiple sclerosis (MS), neurologists and measurement experts to create an easy-to-use questionnaire to measure the physical function of people with MS. This questionnaire covers topics that are relevant and important to people with MS and their doctors.The ability to do what you want to do, when you want to do it, is one of the most important concerns for people with MS. This questionnaire could help doctors to record and manage how much MS affects people's lives.MS can bring a range of challenging symptoms such as 'brain fog', tiredness, and problems with movement and balance. Many of these symptoms can make day-to-day activities, like working, very difficult for people with MS. Doctors currently use examinations like the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC), but these do not fully consider what is important to people living with MS. A questionnaire that specifically measures physical functioning of people with MS could help doctors and people with MS to better understand, communicate and manage the physical effects of MS. In this study, people with MS were asked to help create a questionnaire about physical function that reflects topics that are important to them. WHAT WERE THE RESULTS?: The PROMIS®nq physical function - Multiple Sclerosis 15a (the PROMIS® PF MS questionnaire) was successfully created with the help of people with MS. People with MS thought that the PROMIS® PF MS questionnaire covered issues important to their physical function. Scores were in line with results of other physical symptom measurement scales like the EDSS. WHAT DO THE RESULTS MEAN?: The PROMIS® PF MS questionnaire could be used to meaningfully record physical function among people with MS.
RESUMO
BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome (RTT) in patients aged ≥2 years based on the results of the 12-week, randomized, phase 3 LAVENDER study. In LILAC, a 40-week, open-label extension study of LAVENDER, trofinetide continued to improve the symptoms of RTT, with a similar safety profile as LAVENDER. Here, we report long-term safety and efficacy results of LILAC-2, a 32-month, open-label extension study. METHODS: Females aged 5-22 years who completed LILAC were eligible to enter LILAC-2. Safety and tolerability were assessed with the incidence of adverse events (AEs). Efficacy was assessed with Rett Syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression-Improvement (CGI-I) scores. Caregiver interviews explored the patient's experience with RTT and the efficacy of trofinetide during study participation. FINDINGS: In total, 77 participants were enrolled in LILAC-2. The most common AEs were diarrhea (53.2%), COVID-19 (27.3%), and vomiting (19.5%). The mean (standard error [SE]) change in RSBQ score from LAVENDER baseline to week 104 of LILAC-2 was -11.8 (2.45). The mean (SE) CGI-I score from LILAC baseline to week 12 of LILAC-2 was 3.1 (0.10). Most caregivers (96%; n = 24/25) were satisfied or very satisfied with the benefits of trofinetide. CONCLUSIONS: Long-term treatment with trofinetide continued to improve RTT symptoms, without new safety concerns. Caregivers reported satisfaction with trofinetide related to improvements that were meaningful for their child and themselves. FUNDING: The study was supported by Acadia Pharmaceuticals (San Diego, CA, USA). This study was registered at ClinicalTrials.gov: NCT04776746.
RESUMO
Which proxy-reported outcome measures have been developed for use with children aged 6 years and younger to assess asthma symptoms, asthma control, and asthma-specific health-related quality of life, and do these questionnaires' measurement properties support their use as end-points in clinical trials? A two-phase literature search was conducted: 1) studies describing relevant questionnaires were identified, and the questionnaires were assessed against predefined criteria; 2) studies providing information on the measurement properties of questionnaires meeting the predefined inclusion criteria were identified. Literature sources included PubMed and EMBASE databases, scientific conference proceedings, a clinical trial registry, and a quality of life instrument database. The initial search of literature databases and conference abstracts identified 631 records. 20 paediatric asthma proxy-reported outcome instruments were identified; seven met the inclusion criteria: Childhood Asthma Control Test, Control de Asma en Niños Questionnaire, Pediatric Asthma Caregiver Diary, Pediatric Asthma Control Tool, PedsQL 3.0 Short-Form 22 Asthma Module, PedsQL Asthma Symptoms Scale, and Test for Respiratory and Asthma Control in Kids. Three proxy-reported outcome instruments were considered suitable for use as end-points in paediatric asthma clinical trials; the Pediatric Asthma Caregiver Diary possesses the strongest measurement properties of the three.
Assuntos
Asma/diagnóstico , Avaliação de Sintomas/métodos , Asma/terapia , Cuidadores , Criança , Pré-Escolar , Ensaios Clínicos como Assunto , Humanos , Pais , Procurador , Psicometria/métodos , Qualidade de Vida , Reprodutibilidade dos Testes , Projetos de Pesquisa , Inquéritos e Questionários , Resultado do TratamentoRESUMO
¹H Nuclear Magnetic Resonance spectroscopy (¹H NMR) is increasingly used to measure metabolite concentrations in sets of biological samples for top-down systems biology and molecular epidemiology. For such purposes, knowledge of the sources of human variation in metabolite concentrations is valuable, but currently sparse. We conducted and analysed a study to create such a resource. In our unique design, identical and non-identical twin pairs donated plasma and urine samples longitudinally. We acquired ¹H NMR spectra on the samples, and statistically decomposed variation in metabolite concentration into familial (genetic and common-environmental), individual-environmental, and longitudinally unstable components. We estimate that stable variation, comprising familial and individual-environmental factors, accounts on average for 60% (plasma) and 47% (urine) of biological variation in ¹H NMR-detectable metabolite concentrations. Clinically predictive metabolic variation is likely nested within this stable component, so our results have implications for the effective design of biomarker-discovery studies. We provide a power-calculation method which reveals that sample sizes of a few thousand should offer sufficient statistical precision to detect ¹H NMR-based biomarkers quantifying predisposition to disease.
Assuntos
Biomarcadores , Interação Gene-Ambiente , Metaboloma/genética , Ressonância Magnética Nuclear Biomolecular/métodos , Biologia de Sistemas/métodos , População Branca/genética , Idoso , Algoritmos , Biomarcadores/sangue , Biomarcadores/urina , Bases de Dados Genéticas , Feminino , Variação Genética , Humanos , Pessoa de Meia-Idade , Modelos Estatísticos , Projetos de Pesquisa , Tamanho da Amostra , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genéticaRESUMO
BACKGROUND: The objective of this literature review was to determine whether crowding in the home is associated with an increased risk of severe respiratory syncytial virus (RSV) disease in children younger than 5 years. METHODS: A computerized literature search of PubMed and EMBASE was conducted on residential crowding as a risk factor for laboratory-confirmed RSV illness in children younger than 5 years. Study populations were stratified by high-risk populations, defined by prematurity, chronic lung disease of prematurity, hemodynamically significant congenital heart disease, or specific at-risk ethnicity (i.e. Alaska Native, Inuit), and mixed-risk populations, including general populations of mostly healthy children. The search was conducted for articles published from January 1, 1985, to October 8, 2009, and was limited to studies reported in English. To avoid indexing bias in the computerized databases, the search included terms for multivariate analysis and risk factors to identify studies in which residential crowding was evaluated but was not significant. Methodological quality of included studies was assessed using a Cochrane risk of bias tool. RESULTS: The search identified 20 relevant studies that were conducted in geographically diverse locations. Among studies of patients in high-risk populations, 7 of 9 found a statistically significant association with a crowding variable; in studies in mixed-risk populations, 9 of 11 found a significant association with a crowding variable. In studies of high-risk children, residential crowding significantly increased the odds of laboratory-confirmed RSV hospitalization (i.e. odds ratio ranged from 1.45 to 2.85). In studies of mixed-risk populations, the adjusted odds ratios ranged from 1.23 to 9.1. The findings on the effect of residential crowding on outpatient RSV lower respiratory tract infection were inconsistent. CONCLUSIONS: Residential crowding was associated with an increased risk of laboratory-confirmed RSV hospitalization among high-risk infants and young children. This association was consistent despite differences in definitions of residential crowding, populations, or geographic locations.