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OBJECTIVES: The objectives were to explore the clinical retention rate of an e-Device aimed at empowering chronic arthritis patients using certolizumab pegol (CZP) and to analyse beliefs about medication in the Danish population. METHOD: Patients treated with CZP were recruited from the Netherlands, Denmark, and Sweden through rheumatology clinics at initiation of, or switching to, the e-Device. Patients were adults (aged 18-85 years) diagnosed with rheumatoid arthritis, axial spondyloarthritis, or psoriatic arthritis. Patients administered three consecutive self-injections at home. Descriptive statistics regarding baseline characteristics, retention rates, and reasons for withdrawal were assessed, along with the Beliefs about Medicines Questionnaire. RESULTS: In total, 59 patients participated (Netherlands 25, Denmark 15, Sweden 19). Most subjects (71%) were women, with a mean ± sd age of 55 ± 16.2 years and mean disease duration 12 ± 8.8 years. Six patients (10%) started CZP de novo and the remaining patients switched device. The overall retention rate was 42% after 52 weeks, declining to 38% after 104 weeks. A sharp decline, 34%, was seen at week 8. Between weeks 32 and 112, only four patients (6.8%) withdrew from the study. The primary reason for withdrawal was the patient's request. Stratification by country showed significant differences for some outcomes. CONCLUSION: An initial large dropout was evident within the first 8 weeks, with almost no dropouts thereafter. The reasons for withdrawal were primarily patient requests. Thus, the injection experience must be tailored carefully when selecting patients for new autoinjector e-Devices to enhance retention rates and patient satisfaction.
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The advent of next generation sequencing has rapidly challenged the paediatric respiratory physician's understanding of lung microbiology and the role of the lung microbiome in host health and disease. In particular, the role of "microbial key players" in paediatric respiratory disease is yet to be fully explained. Accurate profiling of the lung microbiome in children is challenging since the ability to obtain lower airway samples coupled with processing "low-biomass specimens" are both technically difficult. Many studies provide conflicting results. Early microbiota-host relationships may be predictive of the development of chronic respiratory disease but attempts to correlate lower airway microbiota in premature infants and risk of developing bronchopulmonary dysplasia (BPD) have produced mixed results. There are differences in lung microbiota in asthma and cystic fibrosis (CF). The increased abundance of oral taxa in the lungs may (or may not) promote disease processes in asthma and CF. In CF, correlation between microbiota diversity and respiratory decline is commonly observed. When one considers other pathogens beyond the bacterial kingdom, the contribution and interplay of fungi and viruses within the lung microbiome further increase complexity. Similarly, the interaction between microbial communities in different body sites, such as the gut-lung axis, and the influence of environmental factors, including diet, make the co-existence of host and microbes ever more complicated. Future, multi-omics approaches may help uncover novel microbiome-based biomarkers and therapeutic targets in respiratory disease and explain how we can live in harmony with our microbial companions.
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OBJECTIVES: To examine the prevalence of sleep disturbances, quantified by the Pittsburgh Sleep Quality Index (PSQI), in patients with psoriatic arthritis (PsA), psoriasis (PsO) and healthy controls (HCs), explore associations between PSQI and clinical and patient-reported outcomes, and evaluate the effect of treatment on PSQI. METHOD: Patients were included from the Parker Institute's PsA patient cohort to evaluate the prevalence of sleep disturbances. Univariate and multivariate regression analyses were used to explore associations between sleep disturbance and outcome measures. Treatment effect in PsA patients was assessed with a mixed-effect model for repeated measures. RESULTS: In total, 109 PsA patients, 20 PsO patients, and 20 HCs were included. Sleep disturbances were reported by 66.1% of PsA patients, 45.0% of PsO patients, and 15.0% of HCs. Univariate regression analyses revealed statistically significant associations (p < 0.001) between PSQI and Disease Activity Score (DAS28CRP), tender points, visual analogue scale (VAS) patient global and pain, Psoriatic Arthritis Impact of Disease fatigue, Health Assessment Questionnaire (HAQ), and painDETECT score. Multivariate regression analysis demonstrated VAS patient global, VAS pain, and tender points as being independently associated with PSQI. The mixed-effect model revealed no effect of treatment. CONCLUSION: More PsA patients than PsO patients and HCs reported sleep disturbances. Sleep disturbances were associated with inflammatory and non-inflammatory measures possibly explaining the limited effect of treatment. This demonstrates the need for interdisciplinary approaches to improve the management of sleep disturbance in PsA.Trial registration: ClinicalTrials.gov (NCT02572700).
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Artrite Psoriásica , Psoríase , Humanos , Artrite Psoriásica/complicações , Artrite Psoriásica/epidemiologia , Artrite Psoriásica/diagnóstico , Dor , Prevalência , Psoríase/complicações , Psoríase/epidemiologia , SonoRESUMO
The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.
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Epigênese Genética/genética , Epigenômica , Genoma Humano/genética , Sequência de Bases , Linhagem da Célula/genética , Células Cultivadas , Cromatina/química , Cromatina/genética , Cromatina/metabolismo , Cromossomos Humanos/química , Cromossomos Humanos/genética , Cromossomos Humanos/metabolismo , DNA/química , DNA/genética , DNA/metabolismo , Metilação de DNA , Conjuntos de Dados como Assunto , Elementos Facilitadores Genéticos/genética , Variação Genética/genética , Estudo de Associação Genômica Ampla , Histonas/metabolismo , Humanos , Especificidade de Órgãos/genética , RNA/genética , Valores de ReferênciaRESUMO
AIM: To explore, which differential diagnoses to consider in individuals with elevated troponins without acute myocardial infarction (AMI), and the mortality for those individuals. METHODS: Retrospective, register-based study on a representative sample of the Danish population with the following inclusion criteria: High-sensitive troponin I (hs-TnI) â25 ng/L, age â18 years, and exclusion of AMI. RESULTS: 3067 individuals without AMI but increased hs-TnI were included. Most frequent discharge diagnoses: Pneumonia (12.8%), Aortic valve disorder (11.3%), Medical observation (10.9%) and Heart failure (8.9%). The 30-days and one-year mortality was 15.8% and 32.0%, respectively. CONCLUSIONS: A selected number of alternative diagnoses must be considered in individuals with increased hs-TnI. Due to high mortality it is crucial to carefully evaluate these individuals despite the absence of AMI.
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Insuficiência Cardíaca , Infarto do Miocárdio , Adolescente , Biomarcadores , Humanos , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/epidemiologia , Estudos Retrospectivos , Troponina IRESUMO
Objective: The aim of this study was to investigate whether incident proteinuria in patients with systemic lupus erythematosus (SLE) was preceded by changes in blood lymphocytes and neutrophil counts and/or neutrophil-lymphocyte ratio (NLR).Method: SLE patients with no proteinuria before or at the time of classification were included. Longitudinal data on SLE manifestations, vital status, and SLE-associated medications were collected during clinical visits and chart review. Laboratory data were collected through a nationwide database. Lymphopenia, severe lymphopenia, and neutropenia were defined as values below 0.8 × 109, 0.5 × 109, and 2.0 × 109 cells/L, respectively. High NLR was defined as values above the median. Proteinuria was defined by at least two measurements of elevated urine protein excretion (> 0.5 g/day). Hazard ratios (HRs) were calculated by Cox modelling using time-dependent continuous and binary covariates based on multiple laboratory measurements adjusted for use of immunosuppressants.Results: In total, 260 SLE patients were available for the analysis, of whom 30 (12%) developed incident proteinuria following the diagnosis of SLE. Median follow-up time was 73.5 months. Lymphocyte and neutrophil counts, but not NLR, were associated with incident proteinuria. HRs for incident proteinuria were 2.71 for lymphopenia [95% confidence interval (CI) 1.20-6.11], 4.73 for severe lymphopenia (95% CI 1.93-11.59), and 2.54 for neutropenia (95% CI 1.14-5.65).Conclusion: Lymphopenia and neutropenia predicted the risk of first-time proteinuria independently of immunosuppressants.
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Lúpus Eritematoso Sistêmico/complicações , Linfopenia/complicações , Neutropenia/complicações , Proteinúria/etiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Imunossupressores/uso terapêutico , Interferon-alfa/fisiologia , Estudos Longitudinais , Nefrite Lúpica/etiologia , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Adulto JovemRESUMO
Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.
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Cromatina/química , Cromatina/genética , Período de Replicação do DNA , DNA/biossíntese , Animais , Compartimento Celular , Cromatina/metabolismo , Montagem e Desmontagem da Cromatina , DNA/genética , Genoma/genética , Heterocromatina/química , Heterocromatina/genética , Heterocromatina/metabolismo , Humanos , Camundongos , Especificidade de Órgãos , Fatores de TempoRESUMO
The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining â¼8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is â¼95% similar with that derived from human TF footprints. However, only â¼20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity.
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Sequência Conservada/genética , Evolução Molecular , Mamíferos/genética , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Animais , Pegada de DNA , Regulação da Expressão Gênica no Desenvolvimento/genética , Redes Reguladoras de Genes/genética , Humanos , CamundongosRESUMO
The number of lifelong learning institutes serving older adults in the U.S. has increased in the last few decades. To date, these institutes have functioned primarily in traditional, in-person classroom, and seminar formats; however, technology-enhanced methods may help provide greater access to high-quality lifelong learning experiences. This research note reports the results of a cross-institutional survey of Osher Lifelong Learning Network participants. The survey participants' high levels of computer utilization and experience with modern distance education capabilities opens the possibility that Technology-Based Instruction (TBI) can augment or supplement in-person lifelong learning experiences. Specifically, TBI may be effective in expanding access for older adults who have mobility or other health limitations, as well as those who live far from the location of any such program. Example approaches are suggested for developing blended, hybrid in-person, and online lifelong learning environments, which may offer enriching intellectual engagement and meaningful socialization.
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Instrução por Computador , Tecnologia Educacional , Geriatria , Aprendizagem Baseada em Problemas , Desenvolvimento de Programas , Idoso , Idoso de 80 Anos ou mais , Educação Continuada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estados UnidosRESUMO
OBJECTIVE: Proximal muscle weakness is common in patients with systemic sclerosis (SSc). Dynamic muscle endurance, muscle strength in the lower extremities, and active range of motion (AROM) in the upper extremities are less studied. We investigated functional muscle endurance, strength, and AROM, and explored differences depending on skin and/or lung involvement in SSc patients. METHOD: The study divided 205 patients with limited/diffuse cutaneous systemic sclerosis (lcSSc/dcSSc) into no-mild and moderate-end-stage lung involvement, the latter based on the Medsger disease severity score. Dynamic muscle endurance in shoulder and hip flexion was assessed by the Functional Index-2, lower extremity muscle strength by the Timed-Stands Test (TST), and shoulder-arm AROM by the Functional Shoulder Assessment (FSA). RESULTS: Shoulder and hip flexion muscle endurance were reduced in relation to reference values median (IQR) [53% (27-100%) and 40% (23-90%), respectively, p < 0.001]. Patients with moderate-end-stage lung involvement had less endurance in shoulder [39% (21-71%) and hip flexion 35% (20-70%)] than patients with no-mild lung involvement [57% (33-99%) and 48% (28-100%), p < 0.05]. All patients, regardless of subtype/grouping, needed longer to complete the TST [21 s (17-27 s)] compared to reference values [17 s (15-18 s), p < 0.001], and patients with moderate-end-stage lung involvement had worse TST score than patients with no-mild lung involvement, [25 s (18-30 s) vs 19 s (16-25 s), p < 0.001]. The FSA sum scores were lower compared with reference values (p < 0.01). DcSSc patients had a lower FSA-sum score [53 (48-57)] than lcSSc patients [57 (52-60), p < 0.01]. CONCLUSION: SSc patients have markedly reduced muscle endurance in the upper and lower extremities, reduced muscle strength in the lower extremities, and impaired AROM in the shoulders and arms. Patients with moderate-end-stage lung involvement had more impaired muscle endurance and strength but no differences were found between lcSSc and dcSSc patients. Not only muscle strength, but also dynamic muscle endurance should be measured in SSc patients.
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Músculo Esquelético/fisiopatologia , Escleroderma Sistêmico/fisiopatologia , Adulto , Idoso , Estudos de Coortes , Estudos Transversais , Feminino , Articulação do Quadril/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Força Muscular , Resistência Física , Amplitude de Movimento Articular , Articulação do Ombro/fisiopatologiaRESUMO
To understand the consequences of underwater noise exposure for cetaceans, there is a need for assessments of behavioural responses over increased spatial and temporal scales. Bottom-moored acoustic recorders and satellite tags provide such long-term and large spatial coverage of behaviour compared to short-duration acoustic-recording tags. However, these tools result in a decreased resolution of data from which an animal response can be inferred, and no direct recording of the sound received at the animal. This study discusses the consequence of the decreased resolution of data from satellite tags and fixed acoustic recorders on the acoustic dose estimated by propagation modelling and presents a method for estimating the range of sound levels that animals observed with these methods have received. This problem is illustrated using experimental results obtained during controlled exposures of northern bottlenose whales (Hyperoodon ampullatus) exposed to naval sonar, carried out near Jan Mayen, Norway. It is shown that variability and uncertainties in the sound field, resulting from limited sampling of the acoustic environment, as well as decreased resolution in animal locations, can lead to quantifiable uncertainties in the estimated acoustic dose associated with the behavioural response (in this case avoidance and cessation of foraging).
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Acústica/instrumentação , Ecolocação , Comunicações Via Satélite/instrumentação , Baleias/fisiologia , Animais , Comunicações Via Satélite/normasRESUMO
The age-friendliness of universities and colleges is a growing area of research and practice. This study focuses on lifelong learning institutes at universities and colleges who provide courses and experiences for older adults but do not award academic or work-related credentials. The Osher Lifelong Learning Institute (OLLI) network in the U.S. is used as an exemplary case of institutes that aim to increase the age-friendliness of their supporting institutions, whilst also aiming for greater diversity among their learners. This study draws upon literature regarding OLLIs and Age-Friendly Universities (AFUs) and national demographic surveys of OLLI student members in 2014 and 2016 (n= 5,500). The study highlights the 2016 demographic characteristics of OLLI learners, notes changes since 2014, and makes comparisons to national trends. Furthermore, this study investigates the barriers to participation identified by older learners participating in OLLIs, considered in light of studies that have addressed such obstacles for underrepresented groups.
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Envelhecimento , Estudantes , Universidades/organização & administração , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Participação da Comunidade , Feminino , Humanos , Relação entre Gerações , Conhecimento , Aprendizagem , Masculino , Pessoa de Meia-Idade , Grupos Minoritários , Aposentadoria , Fatores Sexuais , Fatores Socioeconômicos , Estados UnidosRESUMO
Immune abnormalities have been described in some individuals with autism spectrum disorders (ASDs) as well as their family members. However, few studies have directly investigated the role of prenatal cytokine and chemokine profiles on neurodevelopmental outcomes in humans. In the current study, we characterized mid-gestational serum profiles of 22 cytokines and chemokines in mothers of children with ASD (N=415), developmental delay (DD) without ASD (N=188), and general population (GP) controls (N=428) using a bead-based multiplex technology. The ASD group was further divided into those with intellectual disabilities (developmental/cognitive and adaptive composite score<70) (ASD+ID, N=184) and those without (composite score⩾70) (ASD-noID, N=201). Levels of cytokines and chemokines were compared between groups using multivariate logistic regression analyses, adjusting for maternal age, ethnicity, birth country and weight, as well as infant gender, birth year and birth month. Mothers of children with ASD+ID had significantly elevated mid-gestational levels of numerous cytokines and chemokines, such as granulocyte macrophage colony-stimulating factor, interferon-γ, interleukin-1α (IL-1α) and IL-6, compared with mothers of children with either ASD-noID, those with DD, or GP controls. Conversely, mothers of children with either ASD-noID or with DD had significantly lower levels of the chemokines IL-8 and monocyte chemotactic protein-1 compared with mothers of GP controls. This observed immunologic distinction between mothers of children with ASD+ID from mothers of children with ASD-noID or DD suggests that the intellectual disability associated with ASD might be etiologically distinct from DD without ASD. These findings contribute to the ongoing efforts toward identification of early biological markers specific to subphenotypes of ASD.
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Transtorno Autístico/etiologia , Quimiocinas/efeitos adversos , Citocinas/efeitos adversos , Adulto , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/etiologia , Transtorno Autístico/complicações , Estudos de Casos e Controles , Quimiocinas/sangue , Criança , Desenvolvimento Infantil , Transtornos Globais do Desenvolvimento Infantil/epidemiologia , Transtornos Globais do Desenvolvimento Infantil/etiologia , Pré-Escolar , Citocinas/sangue , Deficiências do Desenvolvimento/complicações , Feminino , Humanos , Lactente , Deficiência Intelectual/etiologia , Masculino , Mães , Gravidez , Efeitos Tardios da Exposição Pré-Natal/patologiaRESUMO
DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify â¼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect â¼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.
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Cromatina/genética , Cromatina/metabolismo , DNA/genética , Enciclopédias como Assunto , Genoma Humano/genética , Anotação de Sequência Molecular , Sequências Reguladoras de Ácido Nucleico/genética , Pegada de DNA , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Desoxirribonuclease I/metabolismo , Evolução Molecular , Genômica , Humanos , Taxa de Mutação , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo , Sítio de Iniciação de Transcrição , Transcrição GênicaRESUMO
Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis-regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein-DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency.
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Pegada de DNA , DNA/genética , Enciclopédias como Assunto , Genoma Humano/genética , Anotação de Sequência Molecular , Sequências Reguladoras de Ácido Nucleico/genética , Fatores de Transcrição/metabolismo , Metilação de DNA , Proteínas de Ligação a DNA/metabolismo , Desoxirribonuclease I/metabolismo , Impressão Genômica , Genômica , Humanos , Polimorfismo de Nucleotídeo Único/genética , Sítio de Iniciação de TranscriçãoRESUMO
BACKGROUND: Tattooed persons examined with magnetic resonance imaging (MRI) can develop burning sensation suggested in the literature to be thermal burn from the procedure. MRI-induced thermal effect and magnetic behavior of known tattoo pigments were examined ex vivo. MATERIALS AND METHODS: Magnetic resonance imaging effects on 3 commonly used commercial ink stock products marketed for cosmetic tattooing was studied. A main study tested 22 formulations based on 11 pigment raw materials, for example, one line of 11 called pastes and another called dispersions. Samples were spread in petri dishes and tested with a 0.97 T neodymium solid magnet to observe visual magnetic behavior. Before MRI, the surface temperature of the ink was measured using an infrared probe. Samples were placed in a clinical 3T scanner. Two scans were performed, that is, one in the isocenter and one 30 cm away from the center. After scanning, the surface temperature was measured again. Chemical analysis of samples was performed by mass spectroscopy. RESULTS: Mean temperature increase measured in the isocenter ranged between 0.14 and 0.26°C (P < .01) and in the off-center position from -0.16 to 0.21°C (P < .01). Such low increase of temperature is clinically irrelevant. Chemical analysis showed high concentrations of iron, but also nickel and chrome were found as contaminants. High concentration of iron was not associated with any increase of temperature or any physical draw or move of ink. CONCLUSION: The study could not confirm any clinically relevant temperature increase of tattoo pigments after MRI.
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Queimaduras/etiologia , Tinta , Imageamento por Ressonância Magnética/efeitos adversos , Tatuagem/efeitos adversos , Corantes/química , Compostos Férricos/química , Temperatura Alta , Humanos , Magnetismo , Metais/química , Projetos Piloto , Fatores de RiscoRESUMO
WHAT IS KNOWN AND OBJECTIVE: Some public scepticism exists about generics in terms of whether brand and generic drugs produce identical outcomes. This study explores whether adverse event (AE) reporting patterns are similar between brand and generic drugs, using authorized generics (AGs) as a control for possible generic drug perception biases. METHODS: Events reported to the FDA Adverse Event Reporting System from the years 2004-2015 were analysed. Drugs were classified as brand, AG or generic based on drug and manufacturer names. Reports were included if amlodipine, losartan, metoprolol extended release (ER) or simvastatin were listed as primary or secondary suspect drugs. Disproportionality analyses using the reporting odds ratio (ROR) assessed the relative rate of reporting labelled AEs compared to reporting these AEs with all other drugs. The Breslow-Day test compared RORs across brand, AG and generic. Interrupted time series analysis evaluated the impact of generic entry on reporting trends. RESULTS AND DISCUSSION: Generics accounted for significant percentages of total U.S. reports, but AGs accounted for smaller percentages of reports, including for amlodipine (14.26%), losartan (1.48%), metoprolol ER (0.35%) and simvastatin (0.70%). Whereas the RORs were significantly different for multiple brand vs generic comparisons, the AG vs generic comparisons yielded fewer statistically significant findings. Namely, only the ROR for AG differed from generic for amlodipine with peripheral oedema (P < .01). WHAT IS NEW AND CONCLUSION: Inconsistent reporting patterns were observed more between brand and generic compared with AG and generic. Use of AGs as a control for perception biases against generics is useful, but this approach can be limited by small AG report numbers. Requiring the manufacturer name to be printed on the prescription bottle or packaging could improve the accuracy of assignment for products being reported.
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Fármacos Cardiovasculares/efeitos adversos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Medicamentos Genéricos/efeitos adversos , Sistemas de Notificação de Reações Adversas a Medicamentos , Fármacos Cardiovasculares/administração & dosagem , Medicamentos Genéricos/administração & dosagem , Humanos , Análise de Séries Temporais Interrompida , Estados Unidos , United States Food and Drug AdministrationRESUMO
BACKGROUND: Cixutumumab is a fully human IgG1 monoclonal antibody to the insulin-like growth factor type I receptor that can potentially reverse resistance and enhance the efficacy of chemotherapy. METHODS: Bevacizumab-eligible patients with stage IV or recurrent non-squamous, non-small-cell lung cancer and good performance status were randomized to receive standard doses of paclitaxel, carboplatin, and bevacizumab to a maximum of six cycles followed by bevacizumab maintenance (CPB) until progression (arm A) or CPB plus cixutumumab 6 mg/kg i.v. weekly (arm B). RESULTS: Of 175 patients randomized, 153 were eligible and treated (78 in arm A; 75 in arm B). The median progression-free survival was 5.8 months (95% CI 5.4-7.1) in arm A versus 7 months (95% CI 5.7-7.6) in arm B (P = 0.33); hazard ratio 0.92 (95% CI 0.65-1.31). Objective response was 46.2% versus 58.7% in arm A versus arm B (P = 0.15). The median overall survival was 16.2 months in arm A versus 16.1 months in arm B (P = 0.95). Grade 3/4 neutropenia and febrile neutropenia, thrombocytopenia, fatigue, and hyperglycemia were increased with cixutumumab. CONCLUSIONS: The addition of cixutumumab to CPB increased toxicity without improving efficacy and is not recommended for further development in non-small-cell lung cancer. Both treatment groups had longer OS than historical controls which may be attributed to several factors, and emphasizes the value of a comparator arm in phase II trials. CLINICALTRIALS.GOV IDENTIFIER: NCT00955305.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma/tratamento farmacológico , Adenocarcinoma de Pulmão , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Bevacizumab/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Intervalo Livre de Doença , Esquema de Medicação , Feminino , Humanos , Masculino , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Taxa de SobrevidaRESUMO
Common fragile sites have long been identified by cytogeneticists as chromosomal regions prone to breakage upon replication stress. They are increasingly recognized to be preferential targets for oncogene-induced DNA damage in pre-neoplastic lesions and hotspots for chromosomal rearrangements in various cancers. Common fragile site instability was attributed to the fact that they contain sequences prone to form secondary structures that may impair replication fork movement, possibly leading to fork collapse resulting in DNA breaks. Here we show, in contrast to this view, that the fragility of FRA3B--the most active common fragile site in human lymphocytes--does not rely on fork slowing or stalling but on a paucity of initiation events. Indeed, in lymphoblastoid cells, but not in fibroblasts, initiation events are excluded from a FRA3B core extending approximately 700 kilobases, which forces forks coming from flanking regions to cover long distances in order to complete replication. We also show that origins of the flanking regions fire in mid-S phase, leaving the site incompletely replicated upon fork slowing. Notably, FRA3B instability is specific to cells showing this particular initiation pattern. The fact that both origin setting and replication timing are highly plastic in mammalian cells explains the tissue specificity of common fragile site instability we observed. Thus, we propose that common fragile sites correspond to the latest initiation-poor regions to complete replication in a given cell type. For historical reasons, common fragile sites have been essentially mapped in lymphocytes. Therefore, common fragile site contribution to chromosomal rearrangements in tumours should be reassessed after mapping fragile sites in the cell type from which each tumour originates.
Assuntos
Hidrolases Anidrido Ácido/genética , Sítios Frágeis do Cromossomo/genética , Fragilidade Cromossômica/fisiologia , Replicação do DNA/fisiologia , Proteínas de Neoplasias/genética , Origem de Replicação/genética , Linhagem Celular , Quebra Cromossômica , Fragilidade Cromossômica/genética , Replicação do DNA/genética , Fibroblastos , Genes Supressores de Tumor , Loci Gênicos/genética , Humanos , Linfócitos/metabolismo , Modelos Biológicos , Especificidade de ÓrgãosRESUMO
BACKGROUND: In sudden, unexpected, non-traumatic death in young individuals, structural abnormalities of the heart are frequently identified at autopsy. However, the findings may be unspecific and cause of death may remain unclear. A significant proportion of these cases are most likely caused by inherited cardiac diseases, and the cases are categorized as sudden cardiac death (SCD). The purpose of this study was to explore the added diagnostic value of genetic testing by next-generation sequencing (NGS) of a broad gene panel, as a supplement to the traditional forensic investigation in cases with non-diagnostic structural abnormalities of the heart. METHODS AND RESULTS: We screened 72 suspected SCD cases (<50 years) using the HaloPlex Target Enrichment System (Agilent) and NGS (Illumina MiSeq) for 100 genes previously associated with inherited cardiomyopathies and channelopathies. Fifty-two cases had non-diagnostic structural cardiac abnormalities and 20 cases, diagnosed with a cardiomyopathy post-mortem (ARVC = 14, HCM = 6), served as comparators. Fifteen (29%) of the deceased individuals with non-diagnostic findings had variants with likely functional effects based on conservation, computational prediction, allele-frequency and supportive literature. The corresponding frequency in deceased individuals with cardiomyopathies was 35% (p = 0.8). CONCLUSION: The broad genetic screening revealed variants with likely functional effects at similar high rates, i.e. in 29 and 35% of the suspected SCD cases with non-diagnostic and diagnostic cardiac abnormalities, respectively. Although the interpretation of broad NGS screening is challenging, it can support the forensic investigation and help the cardiologist's decision to offer counselling and clinical evaluation to relatives of young SCD victims.