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BACKGROUND: Advanced chronic obstructive pulmonary disease (COPD) often leads to hospitalisation and invasive aspergillosis (IA) is a serious complication. Aspergillus sensitisation may worsen symptoms in COPD. METHODS: We identified published papers between January 2000 and May 2019 with > 50 subjects and GOLD criteria for grade II, III or IV (FEV1/FVC < 70% and FEV1 < 80%) using standardised criteria in multiple countries, to re-estimate the prevalence of COPD. Hospitalised COPD patients develop IA in 1.3-3.9%, based on positive cultures of Aspergillus spp. and radiological findings. Given limited data on per-patient annual hospitalisation rates, we assumed a conservative 10.5% estimate. Annual IA mortality in COPD was estimated using the literature rates of 43-72%. A separate literature search assessed the impact of Aspergillus sensitisation on severity of COPD (by FEV1). RESULTS: We re-estimated the global prevalence of COPD GOLD stages II-IV at 552,300,599 people (7.39% of the population) with 339,206,893 (8.58%) in Asia, 85,278,783 (8.52%) in the Americas, 64,298,051 (5.37%) in Africa, 59,484,329 (7.77%) in Europe and 4,032,543 (10.86%) in Oceania. An estimated 57,991,563 (10.5%) people with COPD are admitted to hospital annually and of these 753,073 (1.3%) - 2,272,322 (3.9%) develop IA and 540,451-977,082 deaths are predicted annually. Aspergillus sensitisation prevalence in COPD was 13.6% (7.0-18.3%) and not related to lower predicted FEV1% (P > 0.05). CONCLUSIONS: The prevalence of COPD is much higher than previously estimated. Overall COPD mortality may be higher than estimated and IA probably contributes to many deaths. Improved rapid diagnosis of IA using culture and non-culture based techniques is required in COPD hospital admissions to reduce mortality.
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Aspergilose/complicações , Doença Pulmonar Obstrutiva Crônica/complicações , Saúde Global , Humanos , Doença Pulmonar Obstrutiva Crônica/epidemiologiaRESUMO
OBJECTIVES: Post-imaging mathematical prediction models (MPMs) provide guidance for the management of solid pulmonary nodules by providing a lung cancer risk score from demographic and radiologists-indicated imaging characteristics. We hypothesized calibrating the MPM risk score threshold to a local study cohort would result in improved performance over the original recommended MPM thresholds. We compared the pre- and post-calibration performance of four MPM models and determined if improvement in MPM prediction occurs as nodules are imaged longitudinally. MATERIALS AND METHODS: A common cohort of 317 individuals with computed tomography-detected, solid nodules (80 malignant, 237 benign) were used to evaluate the MPM performance. We created a web-based application for this study that allows others to easily calibrate thresholds and analyze the performance of MPMs on their local cohort. Thirty patients with repeated imaging were tested for improved performance longitudinally. RESULTS: Using calibrated thresholds, Mayo Clinic and Brock University (BU) MPMs performed the best (AUC = 0.63, 0.61) compared to the Veteran's Affairs (0.51) and Peking University (0.55). Only BU had consensus with the original MPM threshold; the other calibrated thresholds improved MPM accuracy. No significant improvements in accuracy were found longitudinally between time points. CONCLUSIONS: Calibration to a common cohort can select the best-performing MPM for your institution. Without calibration, BU has the most stable performance in solid nodules ≥ 8 mm but has only moderate potential to refine subjects into appropriate workup. Application of MPM is recommended only at initial evaluation as no increase in accuracy was achieved over time. KEY POINTS: ⢠Post-imaging lung cancer risk mathematical predication models (MPMs) perform poorly on local populations without calibration. ⢠An application is provided to facilitate calibration to new study cohorts: the Mayo Clinic model, the U.S. Department of Veteran's Affairs model, the Brock University model, and the Peking University model. ⢠No significant improvement in risk prediction occurred in nodules with repeated imaging sessions, indicating the potential value of risk prediction application is limited to the initial evaluation.
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Neoplasias Pulmonares/diagnóstico por imagem , Modelos Teóricos , Nódulo Pulmonar Solitário/diagnóstico por imagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Pulmão/patologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico por imagem , Lesões Pré-Cancerosas/patologia , Nódulo Pulmonar Solitário/patologia , Tomografia Computadorizada por Raios X/métodosRESUMO
AIM: To establish a middle-range theory of organizational learning in hospitals. DESIGN: A realist review of the literature, conducted according to established standards for realist and meta-narrative evidence syntheses. Middle-range theory development was performed according to Smith and Liehr's recommendations. DATA SOURCES: Two comprehensive scientific databases and six discipline-focused databases spanning health care, life sciences, business, sociology, and psychology were searched from inception to 12 May 2016. REVIEW METHODS: Citations meeting the inclusion criteria were appraised using the Mixed Methods Appraisal Tool. Data extraction was guided by a focus on the contextual factors, mechanisms, and outcomes associated with organizational learning. RESULTS: The initial search yielded 2,332 citations, 147 of which were ultimately included in the review. The included citations were generally of high quality. Reviewed evidence indicates certain aspects of organizational context can be conducive to mechanisms of organizational learning, leading to a range of positive organizational outcomes. CONCLUSION: This review updates and expands on a previous review of the literature on organizational learning in hospitals, refines the concept of organizational learning in hospitals, and provides a middle-range theory of organizational learning in hospitals. IMPACT: This updated review provides a strong evidence base for future work on the topic of organizational learning in hospitals. The refined concept of organizational learning makes it possible to develop reliable, valid research instruments that better reflect of the full scope of organizational learning. Finally, the middle-range theory guides researchers and clinical leaders as they advance the science and practice of organizational learning.
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Hospitais , Aprendizagem , Cultura Organizacional , HumanosRESUMO
AIM: To provide a clear definition and description of organisational learning in hospitals. BACKGROUND: Organisational learning is a promising strategy nurse managers, and leaders can use to improve organisational performance. A clear definition and description of organisational learning is necessary to advance theory, research and practice in this field. METHODS: Walker & Avant's method was used to conduct a concept analysis of organisational learning in hospitals. Data sources included 147 empirical studies, 16 review articles, three dictionary entries and three book chapters. RESULTS: Organisational learning occurs when experiences are translated into positive changes in the organisation's collective knowledge, cognition and actions. Organisational context plays a key role in the learning process. Other manifestations of the concept are identified. CONCLUSIONS: This concept analysis provides a clear definition of organisational learning and a description of its defining attributes, antecedents, empirical referents and consequences. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse managers and leaders can improve patient and organisational outcomes by creating an environment conducive to translating experiences into organisational learning. Further research is needed to continue advancing the science of organisational learning in hospitals.
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Formação de Conceito , Aprendizagem , Cultura Organizacional , Humanos , LiderançaRESUMO
BACKGROUND: A specialist depression service (SDS) offering collaborative pharmacological and cognitive behaviour therapy treatment for persistent depressive disorder showed effectiveness against depression symptoms versus usual community based multidisciplinary care in a randomised controlled trial (RCT) in specialist mental health services in England. However, there is uncertainty concerning how specialist depression services effect such change. The current study aimed to evaluate the factors which may explain the greater effectiveness of SDS compared to Treatment as Usual (TAU) by exploring the experience of the RCT participants. METHODS: Qualitative audiotaped and transcribed semi-structured interviews were conducted 12-18 months after baseline with 21 service users (12 SDS, 9 TAU arms) drawn from all three sites. Inductive thematic analysis using a grounded approach contrasted the experiences of SDS with TAU participants. RESULTS: Four themes emerged in relation to service user experience: 1. Specific treatment components of the SDS: which included sub-themes of the management of medication change, explaining and developing treatment strategies, setting realistic expectations, and person-centred and holistic approach; 2. Individual qualities of SDS clinicians; 3. Collaborative team context in SDS: which included sub-themes of communication between healthcare professionals, and continuity of team members; 4. Accessibility to SDS: which included sub-themes of flexibility of locations, frequent consultation as reinforcement, gradual pace of treatment, and challenges of returning to usual care. CONCLUSIONS: The study uncovered important mechanisms and contextual factors in the SDS that service users experience as different from TAU, and which may explain the greater effectiveness of the SDS: the technical expertise of the healthcare professionals, personal qualities of clinicians, teamwork, gradual pace of care, accessibility and managing service transitions. Usual care in other specialist mental health services may share many of the features from the SDS. TRIAL REGISTRATION: "Trial of the Clinical and Cost Effectiveness of a Specialist Expert Mood Disorder Team for Refractory Unipolar Depressive Disorder" was registered in www.ClinicalTrials.gov ( NCT01047124 ) on 12-01-2010 and the ISRCTN registry was registered in www.isrctn.com ( ISRCTN10963342 ) on 25-11-2015 (retrospectively registered).
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Depressão/terapia , Transtorno Depressivo Maior/terapia , Serviços de Saúde Mental/normas , Pesquisa Qualitativa , Especialização/normas , Adulto , Terapia Cognitivo-Comportamental/métodos , Terapia Cognitivo-Comportamental/normas , Depressão/diagnóstico , Depressão/psicologia , Transtorno Depressivo Maior/diagnóstico , Transtorno Depressivo Maior/psicologia , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The Pneumonia Etiology Research for Child Health (PERCH) study is the largest multicountry etiology study of pediatric pneumonia undertaken in the past 3 decades. The study enrolled 4232 hospitalized cases and 5325 controls over 2 years across 9 research sites in 7 countries in Africa and Asia. The volume and complexity of data collection in PERCH presented considerable logistical and technical challenges. The project chose an internet-based data entry system to allow real-time access to the data, enabling the project to monitor and clean incoming data and perform preliminary analyses throughout the study. To ensure high-quality data, the project developed comprehensive quality indicator, data query, and monitoring reports. Among the approximately 9000 cases and controls, analyzable laboratory results were available for ≥96% of core specimens collected. Selected approaches to data management in PERCH may be extended to the planning and organization of international studies of similar scope and complexity.
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Confiabilidade dos Dados , Coleta de Dados , Sistemas de Gerenciamento de Base de Dados , Pneumonia/diagnóstico , Pneumonia/etiologia , África , Ásia , Estudos de Casos e Controles , Criança , Técnicas de Laboratório Clínico , Humanos , Internacionalidade , Pneumonia Bacteriana/diagnóstico , Pneumonia Viral/diagnósticoRESUMO
Chikungunya virus (CHIKV) represents a reemerging global threat to human health. Recent outbreaks across Asia, Europe, Africa, and the Caribbean have prompted renewed scientific interest in this mosquito-borne alphavirus. There are currently no vaccines against CHIKV, and treatment has been limited to nonspecific antiviral agents, with suboptimal outcomes. Herein, we have identified ß-d-N4-hydroxycytidine (NHC) as a novel inhibitor of CHIKV. NHC behaves as a pyrimidine ribonucleoside and selectively inhibits CHIKV replication in cell culture.
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Antivirais/farmacologia , Vírus Chikungunya/efeitos dos fármacos , Citidina/análogos & derivados , Animais , Linhagem Celular , Citidina/farmacologia , Humanos , Replicação Viral/efeitos dos fármacosRESUMO
A library of 585 compounds built off a 7-azaindole core was evaluated for anti-HIV-1 activity, and ten hits emerged with submicromolar potency and therapeutic index >100. Of these, three were identified as non-nucleoside reverse transcriptase (RT) inhibitors and were assayed against relevant resistant mutants. Lead compound 8 inhibited RT with submicromolar potency (IC50=0.73µM) and also maintained some activity against the clinically important RT mutants K103N and Y181C (IC50=9.2, 3.5µM) in cell-free assays. Free energy perturbation guided lead optimization resulted in the development of a compound with a two-fold increase in potency against RT (IC50=0.36µM). These data highlight the discovery of a unique scaffold with the potential to move forward as next-generation anti-HIV-1 agents.
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Transcriptase Reversa do HIV/antagonistas & inibidores , HIV-1/enzimologia , Indóis/química , Inibidores da Transcriptase Reversa/química , Animais , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Avaliação Pré-Clínica de Medicamentos , Transcriptase Reversa do HIV/genética , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Humanos , Indóis/metabolismo , Indóis/farmacologia , Indóis/toxicidade , Simulação de Acoplamento Molecular , Mutagênese Sítio-Dirigida , Ligação Proteica , Estrutura Terciária de Proteína , Inibidores da Transcriptase Reversa/metabolismo , Inibidores da Transcriptase Reversa/farmacologia , Células VeroRESUMO
Medical imaging is a rapidly advancing field enabling the repeated, noninvasive assessment of physiological structure and function. These beneficial characteristics can supplement studies in swine by mirroring the clinical functions of detection, diagnosis, and monitoring in humans. In addition, swine may serve as a human surrogate, facilitating the development and comparison of new imaging protocols for translation to humans. This study presents methods for pulmonary imaging developed for monitoring pulmonary disease initiation and progression in a pig exposure model with computed tomography and magnetic resonance imaging. In particular, a focus was placed on systematic processes, including positioning, image acquisition, and structured reporting to monitor longitudinal change. The image-based monitoring procedure was applied to 6 Yucatan miniature pigs. A subset of animals (n= 3) were injected with crystalline silica into the apical bronchial tree to induce silicosis. The methodology provided longitudinal monitoring and evidence of progressive lung disease while simultaneously allowing for a cross-modality comparative study highlighting the practical application of medical image data collection in swine. The integration of multimodality imaging with structured reporting allows for cross comparison of modalities, refinement of CT and MRI protocols, and consistently monitors potential areas of interest for guided biopsy and/or necropsy.
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Pulmão/diagnóstico por imagem , Pulmão/patologia , Imageamento por Ressonância Magnética/métodos , Silicose/diagnóstico por imagem , Silicose/patologia , Tomografia Computadorizada por Raios X/métodos , Animais , Pesquisa Biomédica , Modelos Animais de Doenças , Feminino , Histocitoquímica , Suínos , Porco MiniaturaRESUMO
Introduction: There is evidence that providers often overprescribe opiates in the postoperative period. Despite an ever-growing geriatric population, there is little research detailing current opiate usage in older patients after trauma. This population presents a unique set of challenges for pain management and prescription drug dependence due to sensitivity, a narrow therapeutic window, and high rates of pre-existing polypharmacy.Objective: Assess the use of narcotics in geriatric trauma patients with various injury patterns to establish a reference point for future intervention for reduction in narcotic dependence.Methods: We created a database of trauma patients' age ≥65 years admitted to a single level 1 trauma center in the Southeastern United States during the 2019 calendar year. Information gathered included patient factors, injury patterns, operative intervention, pain medications prescribed during hospitalization and at discharge, total and average daily morphine milligram equivalents (MME) inpatient and outpatient, and requests/prescriptions for narcotics at follow-up.Results: In 2019, there were 475 patients aged ≥65 admitted to our level 1 trauma center for acute traumatic injuries. 219 of those patients required operative intervention. Average total inpatient MME for this cohort was 169.0 with average daily MME of 22.89. The average total prescribed MME upon discharge was 79.27. There were 29 patients documented to request narcotic prescription refill at time of clinic follow-up, 27 of whom were prescribed a narcotic medication at follow-up.Conclusion: This dataset establishes a reference point for opiate use in geriatric trauma patients to facilitate further research for mitigation of risk in this population.
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Analgésicos Opioides , Ferimentos e Lesões , Humanos , Idoso , Masculino , Feminino , Analgésicos Opioides/uso terapêutico , Ferimentos e Lesões/terapia , Ferimentos e Lesões/cirurgia , Idoso de 80 Anos ou mais , Centros de Traumatologia , Dor Pós-Operatória/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Estudos Retrospectivos , Manejo da Dor/métodos , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Sudeste dos Estados UnidosRESUMO
BACKGROUND/AIMS: Radiofrequency treatment of the gastroesophageal junction using the Stretta procedure for treating gastroesophageal reflux disease (GERD) is observed to improve the symptoms and proton pump inhibitor (PPI) dependence and reduce the need for anti-reflux operations. As one of the largest studies in Europe, we evaluated the clinical outcomes of Stretta in patients with medically refractory GERD. METHODS: A tertiary UK center evaluated all patients with refractory GERD who underwent Stretta between 2014 and 2022. Patients and primary care professionals were contacted to obtain information regarding the initiation of PPI and reintervention after Stretta. RESULTS: Of the 195 patients (median age, 55 years; 116 women [59.5%]) who underwent Stretta, PPI-free period (PFP) data were available for 144 (73.8%) patients. Overall, 66 patients (45.8%) did not receive PPI after a median follow-up of 55 months. Six patients (3.1%) underwent further interventions. The median PFP after Stretta was 41 months. There was a significant negative correlation between PFP and age (p=0.007), with no differences between sexes (p=0.96). Patients younger than 55 years of age had a longer PFP than their older counterparts (p=0.005). Younger males had a significantly longer PFP than older males (p=0.021). However, this was not observed in the female cohort (p=0.09) or between the younger men and women (p=0.66). CONCLUSION: Our findings suggest that Stretta is a safe and feasible option for treating refractory GERD, especially in younger patients. It prevents further anti-reflux interventions in most patients and increases the lead-time to surgery in patients with refractory GERD.
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Posterior rectus sheath hernias are rare hernias that can be difficult to diagnose due to unreliable physical exam characteristics and subtle radiological findings. We present an interesting case of an elderly female found to have a posterior rectus sheath hernia during a diagnostic laparoscopy for chronic abdominal pain. CT evaluation revealed possible appendicitis and laxity of the abdominal wall of the right lower quadrant. Intraoperatively, a 4 cm hernia defect in the right lateral abdominal wall was appreciated. Appendectomy and herniorrhaphy with mesh repair were performed. Postoperative review of CT imaging and intraoperative photographs determined that this hernia defect is a posterior rectus sheath hernia likely caused by trocar placement from previous laparoscopic surgery. This report contributes to the limited body of the literature for this rare type of hernia. Posterior rectus sheath hernias should be considered in differential diagnoses for patients presenting with chronic abdominal pain without clear etiology.
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Parede Abdominal , Hérnia Ventral , Laparoscopia , Idoso , Feminino , Humanos , Dor Abdominal/diagnóstico , Dor Abdominal/etiologia , Dor Abdominal/cirurgia , Parede Abdominal/cirurgia , Fáscia , Hérnia Ventral/complicações , Hérnia Ventral/diagnóstico , Hérnia Ventral/cirurgia , Herniorrafia/métodos , Laparoscopia/métodos , Telas Cirúrgicas/efeitos adversosRESUMO
Low-intensity psychological interventions that target cognitive risk factors for depressive relapse may improve access to relapse prevention programs and thereby reduce subsequent risk. This study provides the first evaluation of an autobiographical memory-based intervention for relapse prevention, to establish whether memory-training programs that are efficacious for acute depression may also aid those currently in remission. We also provide the longest follow-up to-date of the effects of autobiographical memory training on autobiographical memory processes themselves. This pre-registered randomized-controlled proof-of-concept trial (N = 74) compared an autobiographical Memory Flexibility (MemFlex) intervention to Psychoeducation about cognitive-behavioral mechanisms which maintain depression. Both interventions were primarily self-guided, and delivered via paper workbooks completed over four weeks. The key cognitive outcome was ability to retrieve and alternate between specific and general autobiographical memories. Co-primary clinical outcomes were time until depressive relapse and depression-free days in the twelve-months following intervention. Results indicated a small-moderate effect size (d = 0.35) in favor of MemFlex for the cognitive outcome. A small Hazard Ratio (1.08) was observed for time until depressive relapse, along with a negligible effect size for depression-free days (d = 0.11). Although MemFlex produced long-term improvement in memory retrieval skills, there was little support for MemFlex as a relapse prevention program for depression.
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Transtorno Depressivo Maior , Memória Episódica , Depressão/terapia , Transtorno Depressivo Maior/terapia , Humanos , Aprendizagem , RecidivaRESUMO
BACKGROUND: African Americans (AA) have higher rejection rates and poorer graft outcomes compared to non-AAs. Induction therapy is yet unproven in this high risk population. METHODS: This retrospective study compared the efficacy of induction therapy [IL-2 receptor antibodies (IL2RA) or thymoglobulin] vs. no induction. RESULTS: One hundred and seventy-five AA patients were included in this analysis. Patients were well matched for demographic and immunologic characteristics in the non-induction and IL2RA induction groups; the Thymoglobulin induction group had significantly higher risk patients. Significantly fewer episodes of acute rejection occurred at one yr in patients treated with thymoglobulin and IL2RA vs. no induction (18% vs. 47%, p = 0.003, 26% vs. 47%, p = 0.02). Three yr graft survival was significantly improved in the IL2RA group compared to the non-induction group (85% vs. 68%, p = 0.032). Despite the thymoglobulin group being at high risk, they had similar graft survival rates compared to both the IL2RA group (76% vs. 85%, p = 0.18) and the non-induction group (76% vs. 68%, p = 0.48). Multivariate analysis demonstrated that induction therapy (combining IL2RA and thymoglobulin) independently reduced the risk of both acute rejection and graft loss. CONCLUSION: The use and type of induction therapy in AA patients significantly reduces acute rejection rates and may improve long-term graft outcomes in AA patients.
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Anticorpos Monoclonais/uso terapêutico , Negro ou Afro-Americano , Rejeição de Enxerto/etnologia , Imunossupressores/uso terapêutico , Nefropatias/cirurgia , Transplante de Rim/etnologia , Adulto , Anticorpos Monoclonais Humanizados , Soro Antilinfocitário , Basiliximab , Estudos de Coortes , Daclizumabe , Feminino , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto , Humanos , Imunoglobulina G/uso terapêutico , Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Nefropatias/etnologia , Nefropatias/imunologia , Masculino , Pessoa de Meia-Idade , Proteínas Recombinantes de Fusão/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Greater diversity in the experience of negative and positive emotions - emodiversity - is associated with better mental health outcomes in the general population (Quoidbach et al. 2014). However, conceptual accounts of depression suggest this might differ in clinical depression. In this study, the diversity of negative and positive emotion experiences as remembered by a recurrently depressed sample and a never-depressed control group were compared. METHODS: Emodiversity was assessed using a life structure card sort task which allowed for the assessment of memory for emotional experience over the life course. Depressed (n=34) and non-depressed (n=34) participants completed the card sort task, from which emodiversity metrics were calculated for negative and positive emotion experience. RESULTS: Depressed individuals showed recollections of enhanced emodiversity across negative emotion but reduced emodiversity across positive emotion, relative to never-depressed individuals. LIMITATIONS: This study involved a relatively small sample size. DISCUSSION: This study indicates that greater diversity of negative emotion experience, which has been interpreted as a protective factor against depressed mood in community samples (Quoidbach et al., 2014), instead characterises the remembered experience of recurrent clinical depression. The finding that positive emodiversity is adaptive in depression suggests that therapeutic outcomes may be improved by facilitating exposure to a diverse range of positive emotions. These findings indicate that the relationship between emotion diversity and mental health is more complex than hitherto assumed.
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Depressão , Transtorno Depressivo Maior , Emoções , Humanos , Saúde Mental , Rememoração MentalRESUMO
Neurofibromatosis type 1 (NF1) is a rare, autosomal dominant disease with variable clinical presentations. Large animal models are useful to help dissect molecular mechanisms, determine relevant biomarkers, and develop effective therapeutics. Here, we studied a NF1 minipig model (NF1+/ex42del) for the first 12 months of life to evaluate phenotype development, track disease progression, and provide a comparison to human subjects. Through systematic evaluation, we have shown that compared to littermate controls, the NF1 model develops phenotypic characteristics of human NF1: [1] café-au-lait macules, [2] axillary/inguinal freckling, [3] shortened stature, [4] tibial bone curvature, and [5] neurofibroma. At 4 months, full body computed tomography imaging detected significantly smaller long bones in NF1+/ex42del minipigs compared to controls, indicative of shorter stature. We found quantitative evidence of tibial bowing in a subpopulation of NF1 minipigs. By 8 months, an NF1+/ex42del boar developed a large diffuse shoulder neurofibroma, visualized on magnetic resonance imaging, which subsequently grew in size and depth as the animal aged up to 20 months. The NF1+/ex42del minipig model progressively demonstrates signature attributes that parallel clinical manifestations seen in humans and provides a viable tool for future translational NF1 research.
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Modelos Animais de Doenças , Neurofibromatose 1/diagnóstico por imagem , Neurofibromatose 1/patologia , Fenótipo , Animais , Progressão da Doença , Humanos , Imageamento por Ressonância Magnética , Neurofibroma/diagnóstico por imagem , Neurofibroma/patologia , Suínos , Porco Miniatura , Tíbia/diagnóstico por imagem , Tíbia/patologia , Fatores de Tempo , Tomografia Computadorizada por Raios X , Pesquisa Translacional BiomédicaRESUMO
Successful navigation within the autobiographical memory store is integral to daily cognition. Impairment in the flexibility of memory retrieval can thereby have a detrimental impact on mental health. This randomised controlled phase II exploratory trial (Nâ¯=â¯60) evaluated the potential of a novel intervention drawn from basic science - an autobiographical Memory Flexibility (MemFlex) training programme - which sought to ameliorate memory difficulties and improve symptoms of Major Depressive Disorder. MemFlex was compared to Psychoeducation (an evidence-based low-intensity intervention) to determine the likely range of effects on a primary cognitive target of memory flexibility at post-intervention, and co-primary clinical targets of self-reported depressive symptoms and diagnostic status at three-month follow-up. These effect sizes could subsequently be used to estimate sample size for a fully-powered trial. Results demonstrated small-moderate, though as expected statistically non-significant, effect sizes in favour of MemFlex for memory flexibility (dâ¯=â¯0.34, pâ¯=â¯.20), and loss of diagnosis (ORâ¯=â¯0.65, pâ¯=â¯.48), along with the secondary outcome of depression-free days (dâ¯=â¯0.36, pâ¯=â¯.18). A smaller effect size was observed for between-group difference in self-reported depressive symptoms (dâ¯=â¯0.24, pâ¯=â¯.35). Effect sizes in favour of MemFlex in this early-stage trial suggest that fully-powered evaluation of MemFlex may be warranted as an avenue to improving low-intensity treatment of depression. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier NCT02371291.
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Transtorno Depressivo Maior/psicologia , Transtorno Depressivo Maior/terapia , Aprendizagem , Transtornos da Memória/psicologia , Transtornos da Memória/terapia , Memória Episódica , Adulto , Transtorno Depressivo Maior/complicações , Feminino , Humanos , Masculino , Transtornos da Memória/complicações , Método Simples-Cego , Resultado do Tratamento , Adulto JovemRESUMO
INTRODUCTION: Major depressive disorder (MDD) is a chronic condition. Although current treatment approaches are effective in reducing acute depressive symptoms, rates of relapse are high. Chronic and inflexible retrieval of autobiographical memories, and in particular a bias towards negative and overgeneral memories, is a reliable predictor of relapse. This randomised controlled single-blind trial will determine whether a therapist-guided self-help intervention to ameliorate autobiographical memory biases using Memory Flexibility training (MemFlex) will increase the experience of depression-free days, relative to a psychoeducation control condition, in the 12 months following intervention. METHODS AND ANALYSIS: Individuals (aged 18 and above) with a diagnosis of recurrent MDD will be recruited when remitted from a major depressive episode. Participants will be randomly allocated to complete 4 weeks of a workbook providing either MemFlex training, or psychoeducation on factors that increase risk of relapse. Assessment of diagnostic status, self-report depressive symptoms, depression-free days and cognitive risk factors for depression will be completed post-intervention, and at 6 and 12 months follow-up. The cognitive target of MemFlex will be change in memory flexibility on the Autobiographical Memory Test- Alternating Instructions. The primary clinical endpoints will be the number of depression-free days in the 12 months following workbook completion, and time to depressive relapse. ETHICS AND DISSEMINATION: Ethics approval has been granted by the NHS National Research Ethics Committee (East of England, 11/H0305/1). Results from this study will provide a point-estimate of the effect of MemFlex on depressive relapse, which will be used to inform a fully powered trial evaluating the potential of MemFlex as an effective, low-cost and low-intensity option for reducing relapse of MDD. TRIAL REGISTRATION NUMBER: NCT02614326.
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Terapia Cognitivo-Comportamental/métodos , Transtorno Depressivo Maior/terapia , Memória Episódica , Educação de Pacientes como Assunto , Análise Custo-Benefício , Inglaterra , Humanos , Modelos Logísticos , Recidiva , Projetos de Pesquisa , Autorrelato , Método Simples-CegoRESUMO
Loss of the NF1 tumor suppressor gene causes the autosomal dominant condition, neurofibromatosis type 1 (NF1). Children and adults with NF1 suffer from pathologies including benign and malignant tumors to cognitive deficits, seizures, growth abnormalities, and peripheral neuropathies. NF1 encodes neurofibromin, a Ras-GTPase activating protein, and NF1 mutations result in hyperactivated Ras signaling in patients. Existing NF1 mutant mice mimic individual aspects of NF1, but none comprehensively models the disease. We describe a potentially novel Yucatan miniswine model bearing a heterozygotic mutation in NF1 (exon 42 deletion) orthologous to a mutation found in NF1 patients. NF1+/ex42del miniswine phenocopy the wide range of manifestations seen in NF1 patients, including café au lait spots, neurofibromas, axillary freckling, and neurological defects in learning and memory. Molecular analyses verified reduced neurofibromin expression in swine NF1+/ex42del fibroblasts, as well as hyperactivation of Ras, as measured by increased expression of its downstream effectors, phosphorylated ERK1/2, SIAH, and the checkpoint regulators p53 and p21. Consistent with altered pain signaling in NF1, dysregulation of calcium and sodium channels was observed in dorsal root ganglia expressing mutant NF1. Thus, these NF1+/ex42del miniswine recapitulate the disease and provide a unique, much-needed tool to advance the study and treatment of NF1.
Assuntos
Modelos Animais de Doenças , Neurofibromatose 1 , Neurofibromina 1/metabolismo , Suínos , Animais , Manchas Café com Leite , Éxons/genética , Fibroblastos/metabolismo , Proteínas Ativadoras de GTPase/genética , Gânglios Espinais/metabolismo , Deleção de Genes , Regulação da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Canais Iônicos , Aprendizagem , Masculino , Memória , Mutação , Neurofibroma , Neurofibromatose 1/genética , Neurofibromatose 1/patologia , Neurofibromina 1/genética , Neurofibromina 1/fisiologia , Transdução de SinaisRESUMO
BACKGROUND: Modified nucleoside and nucleotide analogs are now the cornerstone of antiviral and anticancer chemotherapies. However, these compounds are not active on their own and need, after entering the cell, to be metabolized to their active 5'-triphosphate form. METHOD: Limitations of these metabolic processes led to development of nucleoside/nucleotide prodrugs in which nucleosides are masked with different groups that can be intracellularly cleaved either chemically or enzymatically. RESULTS: Several prodrug approaches have been successfully developed in order to increase the efficacy, bioavailability, penetration in target organ, and selectivity of nucleoside/nucleotide analogs. CONCLUSION: The concept of nucleoside/nucleotide prodrug is now a well-established approach that led to the approval of numerous drugs for the treatment of HIV, HBV, HCV, HSV and cancer.