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Regulation of neutrophil activation is critical for disease control. Neutrophil extracellular traps (NETs), which are web-like structures composed of DNA and neutrophil-derived proteins, are formed following pro-inflammatory signals; however, if this process is uncontrolled, NETs contribute to disease pathogenesis, exacerbating inflammation and host tissue damage1,2. Here we show that myeloid inhibitory C-type lectin-like (MICL), an inhibitory C-type lectin receptor, directly recognizes DNA in NETs; this interaction is vital to regulate neutrophil activation. Loss or inhibition of MICL functionality leads to uncontrolled NET formation through the ROS-PAD4 pathway and the development of an auto-inflammatory feedback loop. We show that in the context of rheumatoid arthritis, such dysregulation leads to exacerbated pathology in both mouse models and in human patients, where autoantibodies to MICL inhibit key functions of this receptor. Of note, we also detect similarly inhibitory anti-MICL autoantibodies in patients with other diseases linked to aberrant NET formation, including lupus and severe COVID-19. By contrast, dysregulation of NET release is protective during systemic infection with the fungal pathogen Aspergillus fumigatus. Together, we show that the recognition of NETs by MICL represents a fundamental autoregulatory pathway that controls neutrophil activity and NET formation.
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During the pandemic, there were a lot of lockdowns that brought changes to the population's daily routine, reducing social interactions, changing work and study methods, isolating the family at their home, which brought changes to family dynamics. These changes sparked the interest of nursing students in carrying out a research study. Starting from the question: What is the role of the dog in the family dynamics in times of pandemic? and the objective: identify the guardians' perceptions about the role of the dog in the family dynamics in a period of confinement, a qualitative, exploratory, and descriptive study was carried out, collecting data through a focus group with six guardians from different families. Bardin's protocol was used to analyze and process the data. Three categories emerged in this study, highlighting the benefits in terms of mental health, physical and psychological well-being of the family with the presence of the dog, its importance in strengthening family ties and the lessons learned from adopting the dogs. We conclude that, in nursing, it is necessary to highlight the presence of the dog in the family since it brings benefits to its dynamics.
Com o confinamento imposto pelo SARS-CoV-2, houve mudanças na dinâmica familiar. Para os estudantes de enfermagem este foi um assunto que gerou interesse em investigar. Partindo da questão: Qual o papel do cão na dinâmica familiar em tempo de pandemia? e do objetivo: identificar as perceções dos tutores sobre o papel do cão na dinâmica familiar num período de confinamento, enveredámos por um estudo qualitativo, descritivo, com recurso a focus group e amostra de seis membros de famílias diferentes. O tratamento e análise de dados seguiu o protocolo de Bardin. Identificámos que a existência de cão numa família influencia a sua dinâmica através dos benefícios obtidos quer a nível da saúde mental e bem-estar psicológico, quer a nível da saúde física. Igualmente, destacaram-se vantagens, apesar de algumas desvantagens. O vínculo afetivo entre cão e família, advém da reflexão sobre legislação portuguesa, proteção dos direitos dos animais, responsabilidades dos tutores e configuração familiar. Concluímos que na enfermagem, é necessário relevar a presença do cão na família uma vez que traz benefícios para a sua dinâmica. Esta torna-se uma visão inovadora quando pretendemos contribuir para a manutenção da saúde familiar focada nas necessidades de cada indivíduo, família e comunidade.
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COVID-19 , Cães , Animais , Humanos , COVID-19/epidemiologia , COVID-19/psicologia , Masculino , Feminino , Grupos Focais , Relações Familiares/psicologia , Saúde Mental , Vínculo Humano-Animal , Adulto , Família/psicologia , Pessoa de Meia-Idade , Quarentena/psicologiaRESUMO
OBJECTIVES: to evaluate the contribution of informal caregivers to the self-care of individuals with heart failure. METHODS: a cross-sectional study was conducted with 87 caregivers from March to October 2022 in the city of João Pessoa/PB. The caregivers' contribution was assessed using the Caregiver Contribution to Self-Care of Heart Failure Index instrument. Scores ≥ 70 points indicate adequate contribution. Data were analyzed using descriptive statistics and Spearman's correlation. RESULTS: the sample consisted of 81.6% female caregivers. Median scores obtained for the self-care contribution scales were: 63.3 for maintenance; 55.5 for management; and 66.6 for confidence. Caregivers never or rarely recommended monitoring body weight, regular physical exercise, extra use of diuretics, and fluid restriction. CONCLUSIONS: informal caregivers showed inadequate contribution in the areas of maintenance, management, and confidence in self-care of individuals with heart failure.
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Cuidadores , Insuficiência Cardíaca , Autocuidado , Humanos , Insuficiência Cardíaca/terapia , Insuficiência Cardíaca/psicologia , Feminino , Autocuidado/métodos , Autocuidado/estatística & dados numéricos , Estudos Transversais , Cuidadores/psicologia , Cuidadores/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Idoso , Inquéritos e Questionários , Adulto , BrasilRESUMO
Introduction: Benzodiazepines are frequently prescribed and misused therefore urine drug screening (UDS) is performed in many patient populations. Most current benzodiazepine immunoassays have poor sensitivity, particularly for detecting the metabolites of newer benzodiazepines such as lorazepam in urine. Objectives: We aimed to verify the clinical performance of the new qualitative Roche Benzodiazepines II (BNZ2) immunoassay, as well as compare its performance to the Roche Benzodiazepines Plus (BENZ) assay in two patient populations: UDS in the emergency department (ED) and compliance monitoring. Methods: An initial verification study was performed, selecting for samples containing clonazepam and lorazepam metabolites. Performance of the BNZ2 and BENZ assays was compared to liquid chromatography-tandem mass spectrometry (LC-MS/MS) as the reference method. Sensitivity, specificity, false positive rate (FPR) and false negative rate (FNR) were determined. Results: We verified the performance claims in the initial verification and demonstrated similar precision, with coefficient of variations (CVs) of 12.8% and 7.7% for negative and positive controls, respectively. Furthermore, we observed higher clinical sensitivity and lower FNR with the BNZ2 assay in both the ED and compliance monitoring populations due to improved cross-reactivity for lorazepam and clonazepam metabolites. Despite these improvements, the BNZ2 assay was unable to detect 27% of specimens positive by LC-MS/MS, including specimens from patients using benzodiazepines without prescription. Discussion: Due to its improved performance and rapid turnaround time, the BNZ2 assay should be implemented for UDS in the ED. However, the assay should not replace LC-MS/MS testing for compliance monitoring, as unsuspected benzodiazepine use may go undetected.
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The objective of this review is to expose the main genetic changes and genetic polymorphisms that may or may not be associated with greater susceptibility to reduced survival of dental implants and, consequently, to their loss. Case-control studies that fully portrayed the specific types of genetic polymorphisms that may be associated with dental implant failure were included by searching in the PubMed, Scopus, and Web of Science databases from 2010 to 2023. The following descriptors and their combinations in English were used to search for articles: "dental implants," "bone genes," "genetics," "polymorphism genetics," "genetic risk factor," and "interleukin." The initial search resulted in 107 results (PubMed n = 47, Scopus n = 14, and Web of Science n = 46). After a manual search, reviewing each article's title and abstract, and excluding duplicates, systematic reviews, and literature reviews, 30 articles were selected. After reading these 30 articles in full, 18 studies that did not describe the specific genetic polymorphism in relation to dental implant survival were excluded. Therefore, 12 articles were included in this review. The genetic polymorphisms of interleukin (IL)-1A, IL-1B, IL-4, IL-6, IL-10, IL-1 receptor antagonist, tumor necrosis factor-α, receptor activator of nuclear factor kappa B legend, and cluster of differentiation 14 were analyzed in the included studies. In seven of the studies, a statistically significant correlation between genetic polymorphisms and dental implant failure was observed. Of the polymorphisms studied, IL-1A (-899), IL-1B (+3954), and IL-4 (+33) showed a greater association with dental implant loss.
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BACKGROUND: Non-syndromic orofacial cleft (NSOC) is a complex phenotype, involving multiple genetic and environmental factors. Association studies exploring the genetic susceptibility to this prevalent oral malformation show variability of results in different populations. Using a candidate gene approach, we aimed to verify the role of four single-nucleotide polymorphisms (SNPs) in the susceptibility to NSOC in Portuguese patients. METHODS: A total of 254 non-consanguineous individuals of Portuguese were recruited, including 120 patients with NSOC and 134 controls. About 92% of these patients had non-syndromic cleft lip with or without cleft palate (NSCL/P) and 8% had only non-syndromic cleft palate (NSCP). SNPs in the MTHFR (rs1801133), IRF6 (rs642961), PAX7 (rs742071) and TP63 (rs9332461) genes were studied, using a real-time approach with TaqMan probes. Allelic, genotypic, dominant, recessive and over-dominant models were explored using a chi-squared test. Adjusted p-value was calculated for multiple comparisons using the Benjamini-Hochberg false discovery rate (FDR). RESULTS: All SNPs were in Hardy-Weinberg equilibrium. For MTHFR, IRF6, and PAX7 SNPs, no statistically significant difference was highlighted for any of the evaluated models. For TP63 SNP, data fitted an over-dominant model, with a protective effect for heterozygotes (OR 1.897; CI 95% [1.144-3.147]; p < .016, when comparing controls vs. cases), but significance was lost when applying adjusted p-value for multiple comparisons (4 × 5 tests). CONCLUSION: In this Portuguese population, there was no evidence of an association between the evaluated SNPs and NSOC. For TP63 SNP, the possibility of a protective effect of heterozygotes should be further investigated.
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Background: Tuberculosis (TB) and depression are highly comorbid and linked to higher rates of death and disability. Several evidence-based treatments for depression have been successfully implemented in low- and middle-income countries, but more knowledge is needed on how to bring these innovations to scale within complex 'real world' public health systems. Objective: To explore whether the principles of social network analysis could be used to enhance receptivity to integrating depression treatment into primary care for individuals with and without TB in Brazil. Methods: We used existing scales to identify settings and providers with high receptivity and connectivity within the primary care network. We trained and supervised existing staff in three primary care sites to deliver a brief evidence-based intervention over one year, coupled with active dissemination activities. Afterwards, we reassessed receptivity among individuals involved, and not involved, in the pilot. Results: Highly significant changes were observed in mental health literacy, attitudes towards evidence-based practices, work self-efficacy, and implementation leadership supporting our hypothesis. Limited social connections between primary care clinics precluded the examination of the hypothesis that targeting settings with high connectivity could capitalize on the information flow between and transcend the decentralized structure of the network, but leveraging the centralized nature of the TB program to integrate mental health services emerged as a promising alternative. Conclusions: The findings of this study strongly suggest that social networks may be leveraged to change individual providers' attitudes, thereby contributing to the enhanced dissemination of evidence-based interventions.
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The globalization in plant material trading has caused the emergence of invasive pests in many ecosystems, such as the alder pathogen Phytophthora ×alni in European riparian forests. Due to the ecological importance of alder to the functioning of rivers and the increasing incidence of P. ×alni-induced alder decline, effective and accessible decision tools are required to help managers and stakeholders control the disease. This study proposes a Bayesian belief network methodology to integrate diverse information on the factors affecting the survival and infection ability of P. ×alni in riparian habitats to help predict and manage disease incidence. The resulting Alder Decline Network (ADnet) management tool integrates information about alder decline from scientific literature, expert knowledge and empirical data. Expert knowledge was gathered through elicitation techniques that included 19 experts from 12 institutions and 8 countries. An original dataset was created covering 1189 European locations, from which P. ×alni occurrence was modeled based on bioclimatic variables. ADnet uncertainty was evaluated through its sensitivity to changes in states and three scenario analyses. The ADnet tool indicated that mild temperatures and high precipitation are key factors favoring pathogen survival. Flood timing, water velocity, and soil type have the strongest influence on disease incidence. ADnet can support ecosystem management decisions and knowledge transfer to address P. ×alni-induced alder decline at local or regional levels across Europe. Management actions such as avoiding the planting of potentially infected trees or removing man-made structures that increase the flooding period in disease-affected sites could decrease the incidence of alder disease in riparian forests and limit its spread. The coverage of the ADnet tool can be expanded by updating data on the pathogen's occurrence, particularly from its distributional limits. Research on the role of genetic variability in alder susceptibility and pathogen virulence may also help improve future ADnet versions.
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Alnus , Teorema de Bayes , Doenças das Plantas/microbiologia , Doenças das Plantas/estatística & dados numéricos , Phytophthora , Ecossistema , Europa (Continente)/epidemiologia , Florestas , Conservação dos Recursos NaturaisRESUMO
As patient exposure to ionizing radiation from medical imaging and its risks are continuing issues, this study aimed to evaluate DNA damage and repair markers after myocardial perfusion single-photon emission computed tomography (MPS). Thirty-two patients undergoing Tc-99m sestamibi MPS were studied. Peripheral blood was collected before radiotracer injection at rest and 60-90 min after injection. The comet assay (single-cell gel electrophoresis) was performed with peripheral blood cells to detect DNA strand breaks. Three descriptors were evaluated: the percentage of DNA in the comet tail, tail length, and tail moment (the product of DNA tail percentage and tail length). Quantitative PCR (qPCR) was performed to evaluate the expression of five genes related to signaling pathways in response to DNA damage and repair (ATM, ATR, BRCA1, CDKN1A, and XPC). Mann-Whitney's test was employed for statistical analysis; p < 0.05 was considered significant. Mean Tc-99m sestamibi dose was 15.1 mCi. After radiotracer injection, comparing post-exposure to pre-exposure samples of each of the 32 patients, no statistically significant differences of the DNA percentage in the tail, tail length or tail moment were found. qPCR revealed increased expression of BRCA1 and XPC, without any significant difference regarding the other genes. No significant increase in DNA strand breaks was detected after a single radiotracer injection for MPS. There was activation of only two repair genes, which may indicate that, in the current patient sample, the effects of ionizing radiation on the DNA were not large enough to trigger intense repair responses, suggesting the absence of significant DNA damage.
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Dano ao DNA , Reparo do DNA , Tomografia Computadorizada de Emissão de Fóton Único , Humanos , Feminino , Masculino , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Reparo do DNA/genética , Pessoa de Meia-Idade , Idoso , Tecnécio Tc 99m Sestamibi , Imagem de Perfusão do Miocárdio/métodos , Proteína BRCA1/genética , Ensaio CometaRESUMO
Direct scanning of silicone impressions is a valid technique. However, studies in implant-supported rehabilitations are lacking. This in vitro study aims to compare the trueness of impressions obtained with two types of silicone and their corresponding stone casts, using two laboratory scanners in a full-arch implant rehabilitation. A master cast with six dental implants was scanned with a 12-megapixel scanner to obtain a digital master cast. Ten implant impressions were made using two silicones (Zhermack and Coltene) with the open-tray technique. The impressions and stone casts were scanned by two extraoral scanners (Identica T500, Medit; and S600 ARTI, Zirkonzhan). Trueness was assessed by comparing linear and angular distances in digital casts with the master cast. A p < 0.05 significance level was considered. The results showed that for the linear measurements, 72% were higher than the master cast measurements, and no consistent pattern was observed in the angular measurements. The greatest deviations were detected between the most posterior implants, with mean values ranging between 173 and 314 µm. No significant differences were found between scanners. However, differences were observed in the distances between silicones (46.7%) and between impressions and stone casts (73.3%). This work demonstrates that the direct scanning of silicone impressions yields results comparable to those obtained from scanning gypsum casts in full-arch implant-supported rehabilitation.
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To address the challenges posed by biofilm presence and achieve a substantial reduction in bacterial load within root canals during endodontic treatment, various irrigants, including nanoparticle suspensions, have been recommended. Berberine (BBR), a natural alkaloid derived from various plants, has demonstrated potential applications in dentistry treatments due to its prominent antimicrobial, anti-inflammatory, and antioxidant properties. This study aimed to produce and characterize a novel polymeric nanoparticle of poly (lactic-co-glycolic acid) (PLGA) loaded with berberine and evaluate its antimicrobial activity against relevant endodontic pathogens, Enterococcus faecalis, and Candida albicans. Additionally, its cytocompatibility using gingival fibroblasts was assessed. The polymeric nanoparticle was prepared by the nanoprecipitation method. Physicochemical characterization revealed spheric nanoparticles around 140 nm with ca, -6 mV of surface charge, which was unaffected by the presence of BBR. The alkaloid was successfully incorporated at an encapsulation efficiency of 77% and the designed nanoparticles were stable upon 20 weeks of storage at 4 °C and 25 °C. Free BBR reduced planktonic growth at ≥125 µg/mL. Upon incorporation into PLGA nanoparticles, 20 µg/mL of [BBR]-loaded nanoparticles lead to a significant reduction, after 1 h of contact, of both planktonic bacteria and yeast. Sessile cells within biofilms were also considered. At 30 and 40 µg/mL, [BBR]-loaded PLGA nanoparticles reduced the viability of the sessile endodontic bacteria, upon 24 h of exposure. The cytotoxicity of BBR-loaded nanoparticles to oral fibroblasts was negligible. The novel berberine-loaded polymeric nanoparticles hold potential as a promising supplementary approach in the treatment of endodontic infections.
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A systematic review with meta-analysis following Joanna Briggs Institute recommendations. It aimed to determine the effectiveness of mindfulness for the management of anxiety symptoms in the nursing staff and stress as a secondary outcome. The databases searched were MEDLINE, Embase, LILACS, CINAHL, Web of Science, Scopus and Psycinfo. Search was conducted in October 2022. Independent reviewers used standardized methods to research, track, and code the included studies. Data meta-analysis was performed using random effects models. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was used as an approach to assess the quality and certainty of evidence in research studies. The review examined the effectiveness of mindfulness on nursing staff in 13 studies. The meta-analysis revealed a statistically significant decrease in anxiety and stress after treatment, with an average reduction of 0.36 in anxiety and 0.48 in stress. The results emphasizes the possibility of mindfulness being an effective intervention to the management of anxiety and stress in nursing staff. However, the studies analyzed presented limitations in the design and sampling in the development of the intervention, which impact the conclusive statements about the effectiveness of mindfulness and the generalization of the results. The implications to the nursing field involve adopting evidence-based research and practices to improve the well-being and quality of life of nursing professionals, as well as strengthening the evidence base surrounding mindfulness interventions in nursing practice. This may lead to changes in healthcare policies, care practices, and recognition of the importance of nurses' well-being for effective healthcare delivery.
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Ansiedade , Atenção Plena , Recursos Humanos de Enfermagem , Humanos , Ansiedade/psicologia , Ansiedade/terapia , Recursos Humanos de Enfermagem/psicologia , Estresse Psicológico/psicologia , Estresse Psicológico/terapiaRESUMO
OBJECTIVES: to assess risk factors for excess fluid volume in hemodialysis patients. METHODS: a retrospective case-control study was conducted. A total of 392 patients (196 cases and 196 controls) from two hemodialysis centers were included. Sociodemographic data and 23 risk factors for excess fluid volume were assessed using a data collection form. Data were analyzed using a multivariate logistic regression model. RESULTS: the insufficient knowledge (OR=2.06), excessive fluid intake (OR=2.33), inadequate fluid removal during hemodialysis (OR=2.62) and excessive sodium intake (OR=1.91) risk factors may increase the chance of occurrence of excess fluid volume in hemodialysis patients by approximately two times. Education level (OR=0.95) and age (OR=0.97) are protective factors for excessive fluid volume. CONCLUSIONS: knowing these risk factors may help nurses with accurate and rapid diagnostic inference of the risk of excessive fluid volume.
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Diálise Renal , Humanos , Diálise Renal/métodos , Feminino , Masculino , Pessoa de Meia-Idade , Estudos de Casos e Controles , Estudos Retrospectivos , Fatores de Risco , Idoso , Adulto , Modelos LogísticosRESUMO
OBJECTIVE: to evaluate the association between different forms of childhood trauma and postpartum depression in Brazilian puerperal women. METHOD: this cross-sectional survey included 253 puerperal women who were evaluated using the Edinburgh Postnatal Depression Scale and the Childhood Trauma Questionnaire. Multivariate logistic regression analyses were performed to verify the association of different types of trauma and the co-occurrence of forms of abuse and neglect with postpartum depression. RESULTS: postpartum depression was identified in 93 women (36.8%; 95% Confidence Interval: 30.8-42.7). All forms of childhood trauma assessed (emotional abuse, emotional neglect, physical abuse, physical neglect and sexual abuse) were independently associated with postpartum depression after adjusting for confounding variables. Emotional abuse remained associated with postpartum depression when the co-occurrence of all forms of childhood trauma was analyzed. CONCLUSION: the results suggest an association between the different forms of childhood trauma and postpartum depression. In this sense, childhood trauma is an indicator for Nursing professionals to screen for risk factors of postpartum depression during obstetric_follow-up.
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Depressão Pós-Parto , Humanos , Feminino , Depressão Pós-Parto/epidemiologia , Estudos Transversais , Brasil/epidemiologia , Adulto , Adulto Jovem , AdolescenteRESUMO
INTRODUCTION: Child health actions in Brazil have their primary focus on early childhood. A new epidemiological profile is emerging for children after the first one thousand days: an increase in non-communicable chronic diseases. This research aimed to analyze the attributes of Primary Health Care comparatively among different age groups, using three years of age as the cutoff point. METHODS: The study design was cross-sectional and conducted in three Primary Health Care Units and three Ambulatory Medical Assistance facilities in the Western Region of São Paulo. The PCA Tool Brazil was used as the assessment instrument. RESULTS: A total of 311 interviews were conducted with caregivers of children aged 0 to 12 years; 153 children were under three years old, and 158 were three years or older. The attributes that showed statistically significant differences between age groups (< 3 years and > 3 years) were affiliation (4.9 × 3.8), longitudinality (5.7 × 5.2), information system (7.4 × 6.3), and services provided (5.4 × 4.5). Through linear regression analysis, it was observed that there was a trend for better overall and essential scores in the evaluations of the group of children under three years old who attended Primary Health Care Units. CONCLUSION: The comparative analysis of Primary Health Care attributes among pediatric age groups revealed a trend towards higher scores, according to caregivers' perceptions, for children under three years old. This study suggests the need for the implementation of programs that can better address the healthcare needs of children beyond early childhood.
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Cuidadores , Atenção Primária à Saúde , Humanos , Criança , Pré-Escolar , Estudos Transversais , Brasil/epidemiologia , Projetos de PesquisaRESUMO
Accurate imaging is key for the diagnosis and treatment of esophageal and gastroesophageal junction cancers . Current imaging modalities, such as computed tomography (CT) and 18F-FDG (2-deoxy-2-[18F]fluoro-D-glucose) positron emission tomography (PET)/CT, have limitations in accurately staging these cancers. MRI shows promise for T staging and residual disease assessment. Novel PET tracers, like FAPI, FLT, and hypoxia markers, offer potential improvements in diagnostic accuracy. 18F-FDG PET/MRI combines metabolic and anatomic information, enhancing disease evaluation. Radiomics and artificial intelligence hold promise for early detection, treatment planning, and response assessment. Theranostic nanoparticles and personalized medicine approaches offer new avenues for cancer therapy.
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Neoplasias Esofágicas , Junção Esofagogástrica , Humanos , Neoplasias Esofágicas/diagnóstico por imagem , Neoplasias Esofágicas/diagnóstico , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Junção Esofagogástrica/diagnóstico por imagem , Junção Esofagogástrica/patologia , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Estadiamento de Neoplasias , Imageamento por Ressonância Magnética/métodos , Neoplasias Gástricas/diagnóstico por imagem , Neoplasias Gástricas/diagnóstico , Neoplasias Gástricas/patologiaRESUMO
Rectal cancer management has evolved over the past decade with the emergence of total neoadjuvant therapy (TNT). For select patients who achieve a clinical complete response following TNT, organ preservation by means of the watch-and-wait (WW) strategy is an increasingly adopted alternative that preserves rectal function and quality of life without compromising oncologic outcomes. Recently, published 5-year results from the OPRA trial demonstrated that organ preservation can be achieved in approximately half of patients managed with the WW strategy, with most local regrowth events occurring within two years. Considering the potential for local regrowth, the implementation of the WW strategy mandates rigorous clinical and radiographic surveillance. Magnetic resonance imaging (MRI) serves as the conventional imaging modality for local staging and surveillance of rectal cancer given its excellent soft-tissue resolution. This review will discuss the current evidence for the WW strategy and the role of restaging rectal MRI in determining patient eligibility for this strategy. Restaging rectal MRI acquisition parameters and treatment response assessment, including important factors to assess, pitfalls, and classification systems, will be discussed in the context of the WW strategy.
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Imageamento por Ressonância Magnética , Terapia Neoadjuvante , Neoplasias Retais , Conduta Expectante , Humanos , Neoplasias Retais/diagnóstico por imagem , Neoplasias Retais/terapia , Neoplasias Retais/patologia , Terapia Neoadjuvante/métodos , Imageamento por Ressonância Magnética/métodos , Conduta Expectante/métodos , Estadiamento de Neoplasias , Resultado do TratamentoRESUMO
BACKGROUND: Many fentanyl immunoassays are limited in their ability to detect norfentanyl. Urine specimens collected from individuals who have been exposed to fentanyl frequently have detectable concentrations of norfentanyl (≥2â ng/mL) but low concentrations of fentanyl (<2â ng/mL) by LC-MS/MS. The Lin-Zhi Fentanyl II Immunoassay (Lin-Zhi) claims 100% cross-reactivity with norfentanyl and therefore may detect exposure missed by other assays. METHODS: In addition to verifying the manufacturer's analytical sensitivity claims, we selected 92 urine specimens with low-positive Lin-Zhi results (1-99 absorbance units, lowest 10%) for analysis by the Immunalysis Health Equity Impact Assessment and ARK II fentanyl methods. The accuracy of the 3 immunoassays was compared to LC-MS/MS as the reference method. RESULTS: Spiking studies using purified fentanyl and norfentanyl and a set of 100 consecutive specimens confirmed the manufacturer's claims of limit of detection for fentanyl (3.8â ng/mL) and norfentanyl (5.0â ng/mL). However, the 92 low-positive patient specimens demonstrated concentrations of norfentanyl and fentanyl below 2.0â ng/mL by LC-MS/MS, with 47 (51%) having only norfentanyl detected. When comparing Lin-Zhi to the Immunalysis and ARK II immunoassays, only 27 (29%) of the 92 specimens were concordant. Fifty-two (57%) of the specimens were positive by LC-MS/MS and Lin-Zhi but false negative by one or both other immunoassays. Seven specimens (8%) were positive by Lin-Zhi but negative by the other immunoassays and had undetectable concentrations (<2â ng/mL) of fentanyl and norfentanyl by LC-MS/MS. CONCLUSIONS: The clinical sensitivity of the Lin-Zhi exceeds the manufacturer's claims, providing results comparable to LC-MS/MS methods.
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BACKGROUND: Untranslated regions (UTRs) are important mediators of post-transcriptional regulation. The length of UTRs and the composition of regulatory elements within them are known to vary substantially across genes, but little is known about the reasons for this variation in humans. Here, we set out to determine whether this variation, specifically in 5'UTRs, correlates with gene dosage sensitivity. RESULTS: We investigate 5'UTR length, the number of alternative transcription start sites, the potential for alternative splicing, the number and type of upstream open reading frames (uORFs) and the propensity of 5'UTRs to form secondary structures. We explore how these elements vary by gene tolerance to loss-of-function (LoF; using the LOEUF metric), and in genes where changes in dosage are known to cause disease. We show that LOEUF correlates with 5'UTR length and complexity. Genes that are most intolerant to LoF have longer 5'UTRs, greater TSS diversity, and more upstream regulatory elements than their LoF tolerant counterparts. We show that these differences are evident in disease gene-sets, but not in recessive developmental disorder genes where LoF of a single allele is tolerated. CONCLUSIONS: Our results confirm the importance of post-transcriptional regulation through 5'UTRs in tight regulation of mRNA and protein levels, particularly for genes where changes in dosage are deleterious and lead to disease. Finally, to support gene-based investigation we release a web-based browser tool, VuTR, that supports exploration of the composition of individual 5'UTRs and the impact of genetic variation within them.