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The KidGen Collaborative's Policy Implementation Workshop 2023 celebrated the 10th anniversary of Australia's first kidney genetics clinic in Brisbane. This event marked the establishment of a national network now comprising 19 kidney genetics clinics across Australia, all dedicated to providing equitable access to genomic testing for families affected by genetic kidney diseases. The workshop reflected on past progress and outlined future objectives for kidney genetics in Australia, recognising the collaborative efforts of clinical teams, researchers, and patients. Key insights from the workshop are documented in the proceedings.
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Enfermedades Renales , Humanos , Australia , Enfermedades Renales/genética , Pruebas Genéticas/tendenciasRESUMEN
BACKGROUND: Adult asthma is complex and incompletely understood. Plasma proteomics is an evolving technique that can both generate biomarkers and provide insights into disease mechanisms. We aimed to identify plasma proteomic signatures of adult asthma. METHODS: Protein abundance in plasma was measured in individuals from the Agricultural Lung Health Study (ALHS) (761 asthma, 1095 non-case) and the Atherosclerosis Risk in Communities study (470 asthma, 10,669 non-case) using the SOMAScan 5K array. Associations with asthma were estimated using covariate adjusted logistic regression and meta-analyzed using inverse-variance weighting. Additionally, in ALHS, we examined phenotypes based on both asthma and seroatopy (asthma with atopy (n = 207), asthma without atopy (n = 554), atopy without asthma (n = 147), compared to neither (n = 948)). RESULTS: Meta-analysis of 4860 proteins identified 115 significantly (FDR<0.05) associated with asthma. Multiple signaling pathways related to airway inflammation and pulmonary injury were enriched (FDR<0.05) among these proteins. A proteomic score generated using machine learning provided predictive value for asthma (AUC = 0.77, 95% CI = 0.75-0.79 in training set; AUC = 0.72, 95% CI = 0.69-0.75 in validation set). Twenty proteins are targeted by approved or investigational drugs for asthma or other conditions, suggesting potential drug repurposing. The combined asthma-atopy phenotype showed significant associations with 20 proteins, including five not identified in the overall asthma analysis. CONCLUSION: This first large-scale proteomics study identified over 100 plasma proteins associated with current asthma in adults. In addition to validating previous associations, we identified many novel proteins that could inform development of diagnostic biomarkers and therapeutic targets in asthma management.
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Asma , Hipersensibilidad Inmediata , Adulto , Humanos , Proteómica/métodos , Asma/metabolismo , Biomarcadores , Fenotipo , Proteínas Sanguíneas/genéticaRESUMEN
The analysis of contemporary genomic data typically operates on one-dimensional phenotypic measurements (e.g. standing height). Here we report on a data-driven, family-informed strategy to facial phenotyping that searches for biologically relevant traits and reduces multivariate 3D facial shape variability into amendable univariate measurements, while preserving its structurally complex nature. We performed a biometric identification of siblings in a sample of 424 children, defining 1,048 sib-shared facial traits. Subsequent quantification and analyses in an independent European cohort (n = 8,246) demonstrated significant heritability for a subset of traits (0.17-0.53) and highlighted 218 genome-wide significant loci (38 also study-wide) associated with facial variation shared by siblings. These loci showed preferential enrichment for active chromatin marks in cranial neural crest cells and embryonic craniofacial tissues and several regions harbor putative craniofacial genes, thereby enhancing our knowledge on the genetic architecture of normal-range facial variation.
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Identificación Biométrica , Cara/anatomía & histología , Genómica , Imagenología Tridimensional , Herencia Multifactorial/genética , Fenotipo , Hermanos , Adolescente , Niño , Preescolar , Anomalías Craneofaciales/genética , Conjuntos de Datos como Asunto , Europa (Continente)/etnología , Cara/anomalías , Cara/embriología , Femenino , Estudios de Asociación Genética , Humanos , Masculino , Población Blanca/genéticaRESUMEN
Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10-8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10-10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation.
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Población Negra/genética , Cara/anatomía & histología , Estudio de Asociación del Genoma Completo/métodos , Sitios de Carácter Cuantitativo , Población Blanca/genética , Adolescente , Niño , Preescolar , Estudios de Cohortes , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Polimorfismo de Nucleótido Simple , Tanzanía , Adulto JovenRESUMEN
Recent studies have called into question the idea that facial masculinity is a condition-dependent male ornament that indicates immunocompetence in humans. We add to this growing body of research by calculating an objective measure of facial masculinity/femininity using 3D images in a large sample (n = 1,233) of people of European ancestry. We show that facial masculinity is positively correlated with adult height in both males and females. However, facial masculinity scales with growth similarly in males and females, suggesting that facial masculinity is not exclusively a male ornament, as male ornaments are typically more sensitive to growth in males compared with females. Additionally, we measured immunocompetence via heterozygosity at the major histocompatibility complex (MHC), a widely-used genetic marker of immunity. We show that, while height is positively correlated with MHC heterozygosity, facial masculinity is not. Thus, facial masculinity does not reflect immunocompetence measured by MHC heterozygosity in humans. Overall, we find no support for the idea that facial masculinity is a condition-dependent male ornament that has evolved to indicate immunocompetence.
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Cara/fisiología , Complejo Mayor de Histocompatibilidad/fisiología , Adolescente , Adulto , Belleza , Conducta de Elección/fisiología , Femenino , Heterocigoto , Humanos , Inmunocompetencia/fisiología , Masculino , Masculinidad , Fenómenos Fisiológicos/fisiología , Caracteres Sexuales , Conducta Sexual/fisiología , Adulto JovenRESUMEN
Defensins are an extensive family of host defense peptides found ubiquitously across plant and animal species. In addition to protecting against infection by pathogenic microorganisms, some defensins are selectively cytotoxic toward tumor cells. As such, defensins have attracted interest as potential antimicrobial and anticancer therapeutics. The mechanism of defensin action against microbes and tumor cells appears to be conserved and involves the targeting and disruption of cellular membranes. This has been best defined for plant defensins, which upon binding specific phospholipids, such as phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidic acid, form defensin-lipid oligomeric complexes that destabilize membranes, leading to cell lysis. In this study, to further define the anticancer and therapeutic properties of plant defensins, we have characterized a novel plant defensin, Nicotiana occidentalis defensin 173 (NoD173), from N. occidentalis. NoD173 at low micromolar concentrations selectively killed a panel of tumor cell lines over normal primary cells. To improve the anticancer activity of NoD173, we explored increasing cationicity by mutation, with NoD173 with the substitution of Q22 with lysine [NoD173(Q22K)], increasing the antitumor cell activity by 2-fold. NoD173 and the NoD173(Q22K) mutant exhibited only low levels of hemolytic activity, and both maintained activity against tumor cells in serum. The ability of NoD173 to inhibit solid tumor growth in vivo was tested in a mouse B16-F1 model, whereby injection of NoD173 into established subcutaneous tumors significantly inhibited tumor growth. Finally, we showed that NoD173 specifically targets PIP2 and determined by X-ray crystallography that a high-resolution structure of NoD173, which forms a conserved family-defining cysteine-stabilized-αß motif with a dimeric lipid-binding conformation, configured into an arch-shaped oligomer of 4 dimers. These data provide insights into the mechanism of how defensins target membranes to kill tumor cells and provide proof of concept that defensins are able to inhibit tumor growth in vivo.-Lay, F. T., Ryan, G. F., Caria, S., Phan, T. K., Veneer, P. K., White, J. A., Kvansakul, M., Hulett M. D. Structural and functional characterization of the membrane-permeabilizing activity of Nicotiana occidentalis defensin NoD173 and protein engineering to enhance oncolysis.
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Sustitución de Aminoácidos , Antineoplásicos Fitogénicos , Defensinas , Neoplasias , Nicotiana , Proteínas de Plantas , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Permeabilidad de la Membrana Celular/efectos de los fármacos , Defensinas/química , Defensinas/genética , Defensinas/farmacología , Células HeLa , Células Endoteliales de la Vena Umbilical Humana , Humanos , Mutación Missense , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Células PC-3 , Proteínas de Plantas/química , Proteínas de Plantas/genética , Proteínas de Plantas/farmacología , Multimerización de Proteína , Estructura Cuaternaria de Proteína , Relación Estructura-Actividad , Nicotiana/química , Nicotiana/genética , Células U937RESUMEN
BACKGROUND: Prostate cancer development involves various mechanisms, which are poorly understood but pointing to epithelial mesenchymal transition (EMT) as the key mechanism in progression to metastatic disease. ABI1, a member of WAVE complex and actin cytoskeleton regulator and adaptor protein, acts as tumor suppressor in prostate cancer but the role of ABI1 in EMT is not clear. METHODS: To investigate the molecular mechanism by which loss of ABI1 contributes to tumor progression, we disrupted the ABI1 gene in the benign prostate epithelial RWPE-1 cell line and determined its phenotype. Levels of ABI1 expression in prostate organoid tumor cell lines was evaluated by Western blotting and RNA sequencing. ABI1 expression and its association with prostate tumor grade was evaluated in a TMA cohort of 505 patients and metastatic cell lines. RESULTS: Low ABI1 expression is associated with biochemical recurrence, metastasis and death (p = 0.038). Moreover, ABI1 expression was significantly decreased in Gleason pattern 5 vs. pattern 4 (p = 0.0025) and 3 (p = 0.0012), indicating an association between low ABI1 expression and highly invasive prostate tumors. Disruption of ABI1 gene in RWPE-1 cell line resulted in gain of an invasive phenotype, which was characterized by a loss of cell-cell adhesion markers and increased migratory ability of RWPE-1 spheroids. Through RNA sequencing and protein expression analysis, we discovered that ABI1 loss leads to activation of non-canonical WNT signaling and EMT pathways, which are rescued by re-expression of ABI1. Furthermore, an increase in STAT3 phosphorylation upon ABI1 inactivation and the evidence of a high-affinity interaction between the FYN SH2 domain and ABI1 pY421 support a model in which ABI1 acts as a gatekeeper of non-canonical WNT-EMT pathway activation downstream of the FZD2 receptor. CONCLUSIONS: ABI1 controls prostate tumor progression and epithelial plasticity through regulation of EMT-WNT pathway. Here we discovered that ABI1 inhibits EMT through suppressing FYN-STAT3 activation downstream from non-canonical WNT signaling thus providing a novel mechanism of prostate tumor suppression.
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Proteínas Adaptadoras Transductoras de Señales/deficiencia , Proteínas Adaptadoras Transductoras de Señales/genética , Carcinogénesis/genética , Proteínas del Citoesqueleto/deficiencia , Proteínas del Citoesqueleto/genética , Transición Epitelial-Mesenquimal/genética , Técnicas de Inactivación de Genes , Neoplasias de la Próstata/patología , Vía de Señalización Wnt/genética , Cadherinas/metabolismo , Adhesión Celular/genética , Línea Celular Tumoral , Movimiento Celular/genética , Receptores Frizzled/metabolismo , Humanos , Masculino , Clasificación del Tumor , Fenotipo , Recurrencia , Factor de Transcripción STAT3/metabolismo , Regulación hacia Arriba/genética , beta Catenina/metabolismoRESUMEN
Virtual in silico structure-guided modeling, followed by in vitro biochemical screening of a subset of commercially purchasable compound collection resulted in the identification of several human tropomyosin receptor kinase A (hTrkA) inhibitors that bind the orthosteric ATP site and exhibit binding preference for the inactive kinase conformation. The type 2 binding mode with the DFG-out and αC-helix out hTrkA kinase domain conformation was confirmed from X-ray crystallographic solution of a representative inhibitor analog, 1b. Additional hTrkA and hTrkB (selectivity) assays in recombinant cells, neurite outgrowth inhibition using rat PC12 cells, early ADME profiling, and preliminary pharmacokinetic evaluation in rodents guided the lead inhibitor progression in the discovery screening funnel.
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Receptor trkA/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Humanos , Modelos Moleculares , Estructura Molecular , Proyección Neuronal/efectos de los fármacos , Células PC12 , Ratas , Receptor trkA/metabolismo , Relación Estructura-ActividadRESUMEN
OBJECTIVES: To assess national trends in selected prescription opioid risk mitigation practices and associations with prescriber type, state-specific opioid overdose severity, and required pain education. METHODS: Analysis of the national SCOPE of Pain registrants' baseline self-report of five safer opioid prescribing practices over three years (March 2013-Februrary 2016). RESULTS: Of 6,889 registrants for SCOPE of Pain, 70-94% reported performing each of five opioid risk mitigation practices for "most or all" patients, with 49% doing so for all five practices. Only 28% performed all five practices for "all" patients prescribed opioids. There were few differences among three yearly cohorts. Advanced practice nurses reported performing practices for "all" patients more often than physicians or physician assistants. Clinicians from states with high opioid overdose rates reported significantly higher implementation of most practices, compared with clinicians from states with low rates. CONCLUSIONS: Prescribers report low levels of employing five opioid risk mitigation practices for all patients prescribed opioids before attending a safer opioid prescribing training. POLICY IMPLICATIONS: Safer opioid prescribing education should transition from knowledge acquisition toward universal implementation of opioid risk mitigation practices.
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Analgésicos Opioides/uso terapéutico , Conocimientos, Actitudes y Práctica en Salud , Pautas de la Práctica en Medicina/estadística & datos numéricos , Adulto , Prescripciones de Medicamentos/estadística & datos numéricos , Femenino , Personal de Salud/estadística & datos numéricos , Humanos , MasculinoRESUMEN
Homologous recombination (HR) is a template-driven repair pathway that mends DNA double-stranded breaks (DSBs), and thus helps to maintain genome stability. The RAD51 recombinase facilitates DNA joint formation during HR, but to accomplish this task, RAD51 must be loaded onto the single-stranded DNA. DSS1, a candidate gene for split hand/split foot syndrome, provides the ability to recognize RPA-coated ssDNA to the tumor suppressor BRCA2, which is complexed with RAD51. Together BRCA2-DSS1 displace RPA and load RAD51 onto the ssDNA. In addition, the BRCA2 interacting protein BCCIP normally colocalizes with chromatin bound BRCA2, and upon DSB induction, RAD51 colocalizes with BRCA2-BCCIP foci. Down-regulation of BCCIP reduces DSB repair and disrupts BRCA2 and RAD51 foci formation. While BCCIP is known to interact with BRCA2, the relationship between BCCIP and RAD51 is not known. In this study, we investigated the biochemical role of the ß-isoform of BCCIP in relation to the RAD51 recombinase. We demonstrate that BCCIPß binds DNA and physically and functionally interacts with RAD51 to stimulate its homologous DNA pairing activity. Notably, this stimulatory effect is not the result of RAD51 nucleoprotein filament stabilization; rather, we demonstrate that BCCIPß induces a conformational change within the RAD51 filament that promotes release of ADP to help maintain an active presynaptic filament. Our findings reveal a functional role for BCCIPß as a RAD51 accessory factor in HR.
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Adenosina Difosfato/metabolismo , Emparejamiento Base , Proteínas de Unión al Calcio/metabolismo , Proteínas de Ciclo Celular/metabolismo , Recombinación Homóloga , Proteínas Nucleares/metabolismo , Recombinasa Rad51/metabolismo , Adenosina Trifosfato/metabolismo , Proteínas de Unión al Calcio/química , Proteínas de Ciclo Celular/química , Reparación del ADN , Humanos , Hidrólisis , Proteínas Nucleares/química , Unión Proteica , Conformación Proteica , Isoformas de Proteínas , Multimerización de ProteínaRESUMEN
In the past decade, NOD.Cg- Prkdcscid Il2rgtm1Wjl/SzJ (NSG, NOD scid gamma) mice have become a model of choice in several areas of biomedical research; however, comprehensive data on their spontaneous age-related pathology are not currently available in the literature. The prevalence of spontaneous morbidity affecting aged NSG female breeders enrolled in a parasitology study was documented with classification of neoplastic and non-neoplastic (inflammatory, metabolic, degenerative) lesions. Malignant mammary neoplasms were most commonly diagnosed, often accompanied by pulmonary metastases, while a low frequency of lymphoma and histiocytic sarcoma was documented. The major inflammatory conditions were suppurative pleuropneumonia and bronchopneumonia with abscess formation, from which Pasteurella pneumotropica was commonly isolated, followed by otitis media. Both inflammatory and degenerative lesions of the genital tract were identified, along with neoplasms such as endometrial yolk sac carcinomas and granulosa cell tumors. Novel conditions identified included renal tubular degeneration and necrosis associated with 2 concurrent types of intranuclear inclusions, focal or multifocal hyperostosis of the skull, and neuroendocrine tumors of the mesometrium. The majority of degenerative lesions that affected the genital tract, endocrine, and skeletal systems did not represent the actual underlying cause of death but rather were considered incidental findings. This study indicates that both inflammatory and neoplastic conditions contribute to morbidity and mortality in experimentally manipulated aged female NSG mice.
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Envejecimiento/patología , Modelos Animales de Enfermedad , Ratones Endogámicos NOD/fisiología , Ratones SCID/fisiología , Animales , Femenino , Estudios Longitudinales , RatonesRESUMEN
BACKGROUND: Due to the high prevalence of prescription opioid misuse, the US Food and Drug Administration (FDA) mandated a Risk Evaluation and Mitigation Strategy (REMS) requiring manufacturers of extended-release/long-acting (ER/LA) opioids to fund continuing education based on an FDA curricular Blueprint. This paper describes the Safe and Competent Opioid Prescribing Education (SCOPE of Pain) train-the-trainer program and its impact on (1) disseminating the SCOPE of Pain curriculum and (2) knowledge, confidence, attitudes, and performance of the participants of trainer-led compared with expert-led meetings. METHODS: SCOPE of Pain is a 3-hour ER/LA opioid REMS education. In addition to expert-led live statewide meetings, a 2-hour train-the-trainer (TTT) workshop was developed to increase dissemination nationally. The trainers were expected to conduct SCOPE of Pain meetings at their institutions. Participants of both the trainer-led and expert-led SCOPE of Pain programs were surveyed immediately post and 2 months post meetings to assess improvements in knowledge, confidence, attitudes, and self-reported safe opioid prescribing practices. RESULTS: During 9 months (May 2013 to February 2014), 89 trainers were trained during 9 TTT workshops in 9 states. Over 24 months (May 2013 to April 2015), 33% of the trainers conducted at least 1 SCOPE of Pain training, with a total of 79 meetings that educated 1419 participants. The average number of meetings of those who conducted at least 1 meeting was 2.8 (range: 1-19). The participants of the trainer-led programs were significantly more likely to be practicing in rural settings than those who participated in the expert-led meetings (39% vs. 26%, P < .001). At 2 months post training, there were no significant differences in improvements in participant knowledge, confidence, attitudes, and performance between expert-led and trainer-led meetings. CONCLUSIONS: The SCOPE of Pain TTT program holds promise as an effective dissemination strategy to increase guideline-based safe opioid prescribing knowledge, confidence, attitudes, and self-reported practices.
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Educación Médica Continua , Conocimientos, Actitudes y Práctica en Salud , Formación del Profesorado/métodos , Enfermería de Práctica Avanzada/educación , Analgésicos Opioides/uso terapéutico , Educación , Humanos , Dolor/tratamiento farmacológico , Asistentes Médicos/educación , Médicos , Evaluación de Programas y Proyectos de SaludRESUMEN
BACKGROUND: In 2012, the US Food and Drug Administration (FDA) responded to the opioid crisis with a Risk Evaluation and Mitigation Strategy, requiring manufacturers of extended-release/long-acting opioids to fund continuing medical education based on the "FDA Blueprint for Prescriber Education." Topics in the Blueprint are "Assessing Patients for Treatment," "Initiating Therapy, Modifying Dosing, and Discontinuing Use," "Managing Therapy," "Counseling Patients and Caregivers about Safe Use," "General Drug Information," and "Specific Drug Information." Based on the FDA Blueprint, Boston University School of Medicine's "Safe and Competent Opioid Prescribing Education" (SCOPE of Pain) offers live trainings for physicians and other prescribers. During trainings, participants submit written questions about the curriculum and/or their clinical experiences. METHODS: The objective was to compare themes that arose from questions asked by SCOPE of Pain participants with content of the FDA Blueprint in order to evaluate how well the Blueprint answers prescribers' concerns. The authors conducted qualitative analyses of all 1309 questions submitted by participants in 29 trainings across 16 states from May 2013 to May 2015, using conventional content analysis to code the questions. Themes that emerged from participants' questions were then compared with the Blueprint. RESULTS: Most themes fell into the topic categories of the Blueprint. Five main themes diverged: Participants sought information on (1) safe alternatives to opioids, (2) overcoming barriers to safe opioid prescribing, (3) government regulations of opioid prescribing, (4) the role of marijuana in opioid prescribing, and (5) maintaining a positive provider-patient relationship while prescribing opioids. CONCLUSIONS: In addition to learning the mechanics of safe opioid prescribing, providers want to understand government regulations and effective patient communication skills. Aware of the limitations of opioids in managing chronic pain, providers seek advice on alternatives therapies. Future updates to the FDA Blueprint and other educational guidelines on opioid prescribing should address providers' additional questions.
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Actitud del Personal de Salud , Enfermeras Practicantes/psicología , Asistentes Médicos/psicología , Médicos/psicología , Analgésicos Opioides/uso terapéutico , Educación Médica , Humanos , Enfermeras Practicantes/educación , Asistentes Médicos/educaciónRESUMEN
INTRODUCTION: ED crowding is associated with increased mortality, poor staff and patient experience, an increased inpatient length of stay and poor compliance with the four-hour emergency access standard.1 Where crowding is caused by exit block, the focus needs to be on whole system patient management, reducing the temporal mismatch between admissions and discharges since at times of peak demand hospitals may become gridlocked until patients are discharged.In an attempt to tackle exit block, the Scottish Government Unscheduled Care Team have implemented the Daily Dynamic Discharge (DDD) approach, which aims to increase the number of inpatient discharges by 12 pm, thus enabling more timeous flow through the ED. METHODS: A series of meetings were held between the Unscheduled Care Team and the clinical and managerial staff of Dumfries and Galloway Royal Infirmary over a two-week period to train staff on implementing the elements of the Daily Dynamic Discharge approach. These included holding a daily whiteboard meeting with input from the multidisciplinary team, early determination of an Estimated Date of Discharge (EDD) for each patient, and conducting 'golden hour' ward rounds whereby the highest acuity patients were seen first followed by those who were expected to be discharged that day, thus increasing the number of discharges by 12 pm. RESULTS: Over a twelve-week period the average number of weekly discharges increased from 26.5 to 30.2, i.e., an average increase of 3.7 discharges per week. Average length of stay dropped from 6.8 days to 6.2 days, a saving of 0.6 days.The median discharge time was 32 min earlier once DDD had been implemented. Previously, a third (33%) of patients were discharged before 4 pm; after implementation, this rose to 44%. DISCUSSION: Emergency Department activity, and particularly crowding, is the barometer for the rest of the hospital, and the only way to guarantee that patients who require admission, get into the right bed, and in a timely way, is to ensure that the downstream wards discharge sufficient numbers early in the day to accommodate admissions from the ED.The DDD approach has been shown to be effective in increasing the number of discharges by 12 pm, smoothing the admission/discharge profile, and is now being adopted in other hospitals throughout Scotland. REFERENCE: Richardson DB. Increase in patient mortality at 10 days associated with emergency department overcrowding. Med J Aust2006;184(5):213-216.
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Aglomeración , Alta del Paciente/tendencias , Protocolos Clínicos , Servicio de Urgencia en Hospital/organización & administración , Capacidad de Camas en Hospitales/estadística & datos numéricos , Humanos , Tiempo de Internación/tendencias , Alta del Paciente/normas , Desarrollo de Programa/métodos , Escocia , Factores de TiempoRESUMEN
OBJECTIVE: Due to the high prevalence of prescription opioid misuse, the US Food and Drug Administration (FDA) mandated a Risk Evaluation and Mitigation Strategy (REMS) requiring manufacturers of extended-release/long-acting (ER/LA) opioid analgesics to fund continuing education based on a FDA Blueprint. This article describes the Safe and Competent Opioid Prescribing Education (SCOPE of Pain) program, an ER/LA opioid analgesic REMS program, and its impact on clinician knowledge, confidence, attitudes, and self-reported clinical practice. METHOD: Participants of the 3-h SCOPE of Pain training completed pre-, immediate post- and 2-month post-assessments. SUBJECTS: The primary target group (n = 2,850), and a subset (n = 476) who completed a 2-month post-assessment, consisted of clinicians licensed to prescribe ER/LA opioid analgesics, who care for patients with chronic pain and who completed the 3-h training between February 28, 2013 and June 13, 2014. RESULTS: Immediately post-program, there was a significant increase in correct responses to knowledge questions (60% to 84%, P ≤ 0.02) and 87% of participants planned to make practice changes. At 2-months post-program, there continued to be a significant increase in correct responses to knowledge questions (60% to 69%, P ≤ 0.03) and 67% reported increased confidence in applying safe opioid prescribing care and 86% reported implementing practice changes. There was also an improvement in alignment of desired attitudes toward safe opioid prescribing. CONCLUSIONS: The SCOPE of Pain program improved knowledge, attitudes, confidence, and self-reported clinical practice in safe opioid prescribing. This national REMS program holds potential to improve the safe use of opioids for the treatment of chronic pain.
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Analgésicos Opioides/uso terapéutico , Trastornos Relacionados con Opioides/tratamiento farmacológico , Pautas de la Práctica en Medicina/legislación & jurisprudencia , Dolor Crónico/tratamiento farmacológico , Prescripciones de Medicamentos , Educación Médica Continua , Humanos , Trastornos Relacionados con Opioides/epidemiología , Medición de Riesgo , Estados Unidos , United States Food and Drug Administration/legislación & jurisprudenciaRESUMEN
Heparanase is a ß-d-endoglucuronidase that cleaves heparan sulphate, a key component of the ECM and basement membrane. The remodelling of the ECM by heparanase has been proposed to regulate both normal physiological and pathological processes, including wound healing, inflammation, tumour angiogenesis and cell migration. Heparanase is also known to exhibit non-enzymatic functions by regulating cell adhesion, cell signalling and differentiation. In this study, constitutive heparanase-deficient (Hpse(-/-) ) mice were generated on a C57BL/6 background using the Cre/loxP recombination system, with a complete lack of heparanase mRNA, protein and activity. Although heparanase has been implicated in embryogenesis and development, Hpse(-/-) mice are anatomically normal and fertile. Interestingly, consistent with the suggested function of heparanase in cell migration, the trafficking of dendritic cells from the skin to the draining lymph nodes was markedly reduced in Hpse(-/-) mice. Furthermore, the ability of Hpse(-/-) mice to generate an allergic inflammatory response in the airways, a process that requires dendritic cell migration, was also impaired. These findings establish an important role for heparanase in immunity and identify the enzyme as a potential target for regulation of an immune response.
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Movimiento Celular/inmunología , Células Dendríticas/inmunología , Glucuronidasa/inmunología , Neumonía/inmunología , Animales , Western Blotting , Movimiento Celular/genética , Células Cultivadas , Células Dendríticas/metabolismo , Femenino , Citometría de Flujo , Expresión Génica/genética , Expresión Génica/inmunología , Glucuronidasa/deficiencia , Glucuronidasa/genética , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Fluorescente , Neumonía/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Piel/inmunología , Piel/metabolismoRESUMEN
Background: Alcohol use disorder (AUD) has a profound public health impact. However, understanding of the molecular mechanisms underlying the development and progression of AUD remain limited. Here, we interrogate AUD-associated DNA methylation (DNAm) changes within and across addiction-relevant brain regions: the nucleus accumbens (NAc) and dorsolateral prefrontal cortex (DLPFC). Methods: Illumina HumanMethylation EPIC array data from 119 decedents of European ancestry (61 cases, 58 controls) were analyzed using robust linear regression, with adjustment for technical and biological variables. Associations were characterized using integrative analyses of public gene regulatory data and published genetic and epigenetic studies. We additionally tested for brain region-shared and -specific associations using mixed effects modeling and assessed implications of these results using public gene expression data. Results: At a false discovery rate ≤ 0.05, we identified 53 CpGs significantly associated with AUD status for NAc and 31 CpGs for DLPFC. In a meta-analysis across the regions, we identified an additional 21 CpGs associated with AUD, for a total of 105 unique AUD-associated CpGs (120 genes). AUD-associated CpGs were enriched in histone marks that tag active promoters and our strongest signals were specific to a single brain region. Of the 120 genes, 23 overlapped with previous genetic associations for substance use behaviors; all others represent novel associations. Conclusions: Our findings identify AUD-associated methylation signals, the majority of which are specific within NAc or DLPFC. Some signals may constitute predisposing genetic and epigenetic variation, though more work is needed to further disentangle the neurobiological gene regulatory differences associated with AUD.
RESUMEN
BACKGROUND: Smoking impacts DNA methylation, but data are lacking on smoking-related differential methylation by sex or dietary intake, recent smoking cessation (<1 year), persistence of differential methylation from in utero smoking exposure, and effects of environmental tobacco smoke (ETS). METHODS: We meta-analysed data from up to 15,014 adults across 5 cohorts with DNA methylation measured in blood using Illumina's EPIC array for current smoking (2560 exposed), quit < 1 year (500 exposed), in utero (286 exposed), and ETS exposure (676 exposed). We also evaluated the interaction of current smoking with sex or diet (fibre, folate, and vitamin C). FINDINGS: Using false discovery rate (FDR < 0.05), 65,857 CpGs were differentially methylated in relation to current smoking, 4025 with recent quitting, 594 with in utero exposure, and 6 with ETS. Most current smoking CpGs attenuated within a year of quitting. CpGs related to in utero exposure in adults were enriched for those previously observed in newborns. Differential methylation by current smoking at 4-71 CpGs may be modified by sex or dietary intake. Nearly half (35-50%) of differentially methylated CpGs on the 450 K array were associated with blood gene expression. Current smoking and in utero smoking CpGs implicated 3049 and 1067 druggable targets, including chemotherapy drugs. INTERPRETATION: Many smoking-related methylation sites were identified with Illumina's EPIC array. Most signals revert to levels observed in never smokers within a year of cessation. Many in utero smoking CpGs persist into adulthood. Smoking-related druggable targets may provide insights into cancer treatment response and shared mechanisms across smoking-related diseases. FUNDING: Intramural Research Program of the National Institutes of Health, Norwegian Ministry of Health and Care Services and the Ministry of Education and Research, Chief Scientist Office of the Scottish Government Health Directorates and the Scottish Funding Council, Medical Research Council UK and the Wellcome Trust.
Asunto(s)
Cese del Hábito de Fumar , Contaminación por Humo de Tabaco , Adulto , Humanos , Recién Nacido , Metilación de ADN , Epigénesis Genética , Fumar/efectos adversos , Fumar/genética , Fumar Tabaco , Islas de CpGRESUMEN
Background: There is growing demand for developmental and behavioral pediatric services including autism evaluation and care management. Clinician trainings have been found to result in an increase of knowledge and attitudes. This study utilizes Normalization Process theory (NPT) to evaluate a clinician training program and its effects on practice. Methods: The year-long virtual training program about autism screening and care management included didactic portions and case presentations. Focus groups and interviews were conducted with primary care clinicians (n = 10) from community health centers (n = 6) across an urban area five months post-training. Transcripts were deductively coded using NPT to uncover barriers to implementation of autism screening and care, benefits of the training program, and areas for future training. Results: Participants were motivated by the benefits of expanding and improving support for autistic patients but noted this effort requires effective collaboration within a complex network of care providers including clinicians, insurance agencies, and therapy providers. Although there were support that participants could provide to families there were still barriers including availability of behavior therapy and insufficient staffing. Overall, participants positively viewed the training and reported implementing new strategies into practice. Conclusion: Despite the small sample size, application of NPT allowed for assessment of both training delivery and implementation of strategies, and identification of recommendations for future training and practice sustainability. Follow-up focus groups explored participants' practice five months post-program. Variations in participants' baseline experience and context at follow-up to enable application of skills should be considered when using NPT to evaluate clinician trainings.