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BACKGROUND: The linkage of primary care, hospital and other health registry data is a global goal, and a consent-based approach is often used. Understanding the attitudes of why participants take part is important, yet little is known about reasons for non-participation. The ATHENA COVID-19 feasibility study investigated: 1) health outcomes of people diagnosed with COVID-19 in Queensland, Australia through primary care health data linkage using consent, and 2) created a cohort of patients willing to be re-contacted in future to participate in clinical trials. This report describes the characteristics of participants declining to participate and reasons for non-consent. METHODS: Patients diagnosed with COVID-19 from January 1st, 2020, to December 31st, 2020, were invited to consent to having their primary healthcare data extracted from their GP into a Queensland Health database and linked to other data sets for ethically approved research. Patients were also asked to consent to future recontact for participation in clinical trials. Outcome measures were proportions of patients consenting to data extraction, permission to recontact, and reason for consent decline. RESULTS: Nine hundred and ninety-five participants were approached and 842(85%) reached a consent decision. 581(69%), 615(73%) and 629(75%) consented to data extraction, recontact, or both, respectively. Mean (range) age of consenters and non-consenters were 50.6(22-77) and 46.1(22-77) years, respectively. Adjusting for age, gender and remoteness, older participants were more likely to consent than younger (aOR 1.02, 95%CI 1.01 to 1.03). The least socio-economically disadvantaged were more likely to consent than the most disadvantaged (aOR 2.20, 95% 1.33 to 3.64). There was no difference in consent proportions regarding gender or living in more remote regions. The main reasons for non-consent were 'not interested in research' (37%), 'concerns about privacy' (15%), 'not registered with a GP' (8%) and 'too busy/no time' (7%). 'No reason' was given in 20%. CONCLUSION: Younger participants and the more socio-economically deprived are more likely to non-consent to primary care data linkage. Lack of patient interest in research, time required to participate and privacy concerns, were the most common reasons cited for non-consent. Future health care data linkage studies addressing these issues may prove helpful.
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COVID-19 , Humanos , Austrália , Bases de Dados Factuais , Instalações de Saúde , HospitaisRESUMO
BACKGROUND: Primary brain tumor (PBT) patients experience higher levels of distress and anxiety than other solid tumor patients, particularly at the time of clinical evaluation when uncertainty about disease status is high ("scanxiety"). There is promising evidence supporting use of virtual reality (VR) to target psychological symptoms in other solid tumor patients, though PBT patients have not been studied extensively in this context. The primary aim of this phase 2 clinical trial is to establish the feasibility of a remote VR-based relaxation intervention for a PBT population, with secondary aims designed to determine preliminary efficacy of improving distress and anxiety symptoms. METHODS: PBT patients (N = 120) with upcoming MRI scans and clinical appointments who meet eligibility will be recruited to participate in a single arm trial conducted remotely through the NIH. Following completion of baseline assessments, participants will complete a 5-min VR intervention via telehealth using a head-mounted immersive device while under supervision of the research team. Following the intervention, over the course of 1 month patients can use VR at their discretion with follow-up assessments done immediately post-VR intervention, as well as 1 week and 4 weeks later. Additionally, a qualitative phone interview will be conducted to assess patient satisfaction with the intervention. DISCUSSION: Use of immersive VR is an innovative interventional approach to target distress and scanxiety symptoms in PBT patients who are at high risk for experiencing these symptoms leading into their clinical appointments. Findings from this study may inform design of a future multicenter randomized VR trial for PBT patients and may aid in development of similar interventions for other oncology populations. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04301089), registered 9 March 2020.
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Neoplasias Encefálicas , Terapia de Exposição à Realidade Virtual , Humanos , Terapia de Exposição à Realidade Virtual/métodos , Estudos de Viabilidade , Ansiedade/etiologia , Ansiedade/terapia , Transtornos de Ansiedade , Neoplasias Encefálicas/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Ensaios Clínicos Fase II como AssuntoRESUMO
PURPOSE: Cancer patients experience distress and anxiety when undergoing imaging studies to monitor disease status, yet these symptoms are not always appropriately identified or well-managed. This interim analysis of a phase 2 clinical trial explored feasibility and acceptability of a virtual reality relaxation (VR) intervention for primary brain tumor (PBT) patients at the time of clinical evaluation. METHODS: English speaking, adult PBT patients with previous reports of distress and upcoming neuroimaging were recruited between March of 2021 and March 2022. A brief VR session was done within 2 weeks prior to neuroimaging with patient-reported outcomes (PROs) collected before and immediately post-intervention. Self-directed VR use over the next 1 month was encouraged with additional PROs assessments at 1 and 4 weeks. Feasibility metrics included enrollment, eligibility, attrition, and device-related adverse effects with satisfaction measured with qualitative phone interviews. RESULTS: Fifty-five patients were approached via email, 40 (73%) responded and 20 (50%) enrolled (9 declines, 11 screen fails). 65% of participants were ≤ 50 years, 50% were male, 90% were White/non-Hispanic, 85% had good KPS (≥ 90), and most were on active treatment. All patients completed the VR intervention, PROs questionnaires, weekly check-ins, and qualitative interview. Most (90%) reported frequent VR use and high satisfaction and only 7 mild AEs were recorded (headache, dizziness, nausea, neck pain). CONCLUSION: This interim analysis supports feasibility and acceptability of a novel VR intervention to target psychological symptoms for PBT patients. Trial enrollment will continue to assess for intervention efficacy. TRIAL REGISTRATION: NCT04301089 registered on 3/9/2020.
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Neoplasias Encefálicas , Terapia de Exposição à Realidade Virtual , Adulto , Humanos , Masculino , Feminino , Estudos de Viabilidade , Ansiedade/etiologia , Ansiedade/terapia , Neoplasias Encefálicas/complicações , Neoplasias Encefálicas/terapiaRESUMO
OBJECTIVE: Accurately assigning phenotype information to individual patients via computational phenotyping using Electronic Health Records (EHRs) has been seen as the first step towards enabling EHRs for precision medicine research. Chart review labels annotated by clinical experts, also known as "gold standard" labels, are essential for the development and validation of computational phenotyping algorithms. However, given the complexity of EHR systems, the process of chart review is both labor intensive and time consuming. We propose a fully automated algorithm, referred to as pGUESS, to rank EHR notes according to their relevance to a given phenotype. By identifying the most relevant notes, pGUESS can greatly improve the efficiency and accuracy of chart reviews. METHOD: pGUESS uses prior guided semantic similarity to measure the informativeness of a clinical note to a given phenotype. We first select candidate clinical concepts from a pool of comprehensive medical concepts using public knowledge sources and then derive the semantic embedding vector (SEV) for a reference article (SEVref) and each note (SEVnote). The algorithm scores the relevance of a note as the cosine similarity between SEVnote and SEVref. RESULTS: The algorithm was validated against four sets of 200 notes that were manually annotated by clinical experts to assess their informativeness to one of three disease phenotypes. pGUESS algorithm substantially outperforms existing unsupervised approaches for classifying the relevance status with respect to both accuracy and scalability across phenotypes. Averaging over the three phenotypes, the rank correlation between the algorithm ranking and gold standard label was 0.64 for pGUESS, but only 0.47 and 0.35 for the next two best performing algorithms. pGUESS is also much more computationally scalable compared to existing algorithms. CONCLUSION: pGUESS algorithm can substantially reduce the burden of chart review and holds potential in improving the efficiency and accuracy of human annotation.
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Algoritmos , Semântica , Registros Eletrônicos de Saúde , Humanos , Processamento de Linguagem Natural , Fenótipo , Medicina de PrecisãoRESUMO
OBJECTIVE: Optimal prescriptions practices of opioids in the post-cesarean period remain controversial. The primary aim of this initiative was to minimize unused prescription narcotic medication, with a goal of ≤4 leftover pills of 5-mg oxycodone at postoperative day (POD) 14 without affecting pain or satisfaction measures. STUDY DESIGN: This was a prospective longitudinal quality improvement (QI) initiative starting in 2017 utilizing the DMAIC methodology. The measurement phase consisted of validated surveys over 3 months, along with chart review to determine current institutional prescription practices and predictors of outpatient opioid use. Resulting recommendations were adopted, and 1 year later, all patients undergoing cesarean were surveyed for 3 months to determine the effectiveness of the intervention. The study was approved by the Department's QI Committee. RESULTS: The response rate was 48%, with 50 of 101 patients completing surveys pre-intervention and 52 of 111 post-intervention. Pre-intervention, surplus medication was predicted (p <0.05) only by the quantity of the opioid prescription. In addition, patients who required ≤37.5 morphine milligram equivalents (MMEs) during the inpatient postoperative stay did not require outpatient narcotic prescriptions. Thereafter, a strategy of matching inpatient use to outpatient prescription 1:1 in a linear regression model (p <0.001, R 2 0.55) optimally matched patient needs up to 200 MME. In the post-intervention survey, mean (SD) prescription decreased from 17.6 (13.7) MME to 8.4 (8.3) MME (p <0.01); 39% compared with 16% of women were discharged without a prescription (p <0.01); and amongst all patients 82.7% compared with 59.6% (p <0.01) had ≤4 pills remaining without differences in patient satisfaction or pain perception. CONCLUSION: This initiative highlights a practical approach to QI utilizing industry techniques in health care. This approach resulted in significant reductions in over-prescription and unused medication, without impacting pain or satisfaction scores. KEY POINTS: · 20% of patients may manage pain at home without opioids.. · In-hospital opioid use is reflective of outpatient need.. · Customize prescriptions to reduce leftover narcotics..
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Analgésicos Opioides , Dor Pós-Operatória , Analgésicos Opioides/uso terapêutico , Feminino , Humanos , Entorpecentes/uso terapêutico , Dor Pós-Operatória/tratamento farmacológico , Padrões de Prática Médica , Gravidez , Prescrições , Estudos Prospectivos , Melhoria de QualidadeRESUMO
The development of noble-metal-free catalysts capable of electrochemically converting carbon dioxide (CO2) selectively into value-added compounds remains one of the central challenges in catalysis research. Here, we present a systematic study of Fe(II) complexes of the functionalized ligands bpyRPY2Me (bpyPY2Me = 6-(1,1-bis(pyridin-2-yl)ethyl)-2,2'-bipyridine) in the pursuit of water-stable molecular Fe complexes that are selective for the catalytic formation of CO from CO2. Taking advantage of the inherently high degree of tunability of this ligand manifold, we followed a bioinspired approach by installing protic functional groups of varying acidities (-H, -OH, -OMe, -NHEt, and -NEt2) into the ligand framework to systematically modify the second coordination sphere of the Fe center. This family of [(bpyRPY2Me)FeII] complexes was characterized using single-crystal X-ray analysis, 1H NMR spectroscopy, and mass spectrometry. Comparative catalytic evaluation of this set of compounds via voltammetry and electrolysis experiments identified [(bpyNHEtPY2Me)Fe]2+ in particular as an efficient, iron-based, non-heme CO2 electroreduction catalyst that displays significant selectivity for the conversion of CO2 to CO in acetonitrile solution with 11 M H2O. We propose that the NH group acts as a local proton source for cleaving the C-O bond in CO2 to form CO. Interestingly, the complex with the most acidic functional group in the second coordination sphere, [(bpyOHPY2Me)Fe]2+, favors formation of H2 over CO. Our results correlate the selectivity of water versus carbon dioxide reduction to the acidity of the second coordination sphere functional group and emphasize the continued untapped potential that synthetic molecular chemistry offers in the pursuit of next-generation CO2 reduction electrocatalysts.
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OBJECTIVES: Allostatic load (AL) represents cumulative biological "wear and tear" that results from chronic stress exposure over time, ultimately increasing risk for chronic disease. A consensus is lacking regarding the best operationalization of AL, particularly for younger, less studied populations. The purpose of this study was to test multiple hypothesized factor structures for AL to determine the best measurement approach for adolescents. METHODS: We analyzed biologic data for 1900 adolescents aged 12-18 from four waves (2003-2010) of the National Health and Nutrition Examination Survey. AL indicator variables included cardiovascular (systolic BP, creatinine), metabolic (HDL, LDL, triglycerides, insulin, fasting glucose, HA1C, body mass index [BMI], waist circumference), and immune (albumin, CRP, WBC, EBV) biomarkers. Structural equation modeling was used to test the fit of five hypothesized AL factor structures. RESULTS: The data best supported a unidimensional factor structure, where the AL construct directly influenced each of the indicator variables. All but two of the indicators (HDL and albumin) had positive factor loadings, thus, as AL increases the values for those indicators also increase. The best indicators for AL were those measuring metabolic dysregulation, with BMI and waist circumference having the highest factor loadings (0.95 and 0.982, respectively). CONCLUSIONS: BMI and waist circumference may be some of the earliest clinical signs of elevated AL that manifest among adolescents. Future research should aim to include neuroendocrine biomarkers in their AL measures to have a more robust estimation of AL in younger populations.
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Alostase/fisiologia , Antropometria/métodos , Análise Química do Sangue/métodos , Adolescente , Determinação da Pressão Arterial/métodos , Criança , Feminino , Testes Hematológicos , Humanos , Masculino , Modelos BiológicosRESUMO
OBJECTIVE: Patients with comorbid cancer and dementia have poorer outcomes than those without dementia. We observe oncology teams managing patients with dementia and memory loss and explore these patients' needs and experiences of outpatient cancer services. METHODS: A single site investigation of case study design to examine practices in four clinics using multi-methods of data collection: retrospective note review, observation, interviews, and recorded consultations. A framework analytic approach identifies themes within and across cases. RESULTS: Thirty-three clinical encounters with patients with memory loss were observed. Ten consultations were audio-recorded and 16 individuals interviewed (n = 6 patients-carer dyads, n = 1 lone patient, and n = 5 staff). Medical records were reviewed for 338 cases. Cancer referrals did not document memory health, so clinicians rely on patient/carer disclosure to identify patients with memory problems. In practice, the problem often remains hidden. Treating teams who do become aware of memory difficulties are unsure how to support patients, but marked memory loss can limit treatment options and preclude radical intent. Carers are key facilitators of successful cancer consultations and management. Their support needs are largely unrecognized. CONCLUSIONS: Training that educates cancer teams on how to identify and support individuals with memory problems before and during treatment and recognize the carer role may facilitate complex cancer care and help reduce inequalities of outcomes.
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Antineoplásicos/uso terapêutico , Cuidadores/psicologia , Demência/diagnóstico , Neoplasias/tratamento farmacológico , Demência/epidemiologia , Feminino , Humanos , Masculino , Memória , Neoplasias/epidemiologia , Neoplasias/psicologia , Estudos RetrospectivosRESUMO
The article reflects on the ways in which a person-centred approach was used to ensure that people with dementia were given an opportunity to participate in research. The authors discuss three key issues-the importance of including people with dementia in research, informed consent and the possibility of accidental disclosure of diagnosis. The study was an in-depth examination of the ways in which the cancer team manages patients with memory problems and patients with dementia, and the experiences of these patients and their families in accessing outpatient cancer treatment and care in Wales. The study findings will be reported elsewhere. This article aims to add to the small body of existing knowledge within the literature that describes the experiences of researchers in actively involving people with dementia in research.
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Demência , Enfermagem de Cuidados Paliativos na Terminalidade da Vida/organização & administração , Competência Mental , Pesquisa em Enfermagem/organização & administração , Enfermagem Oncológica/organização & administração , Seleção de Pacientes , Assistência Centrada no Paciente/organização & administração , Idoso , Feminino , Humanos , Consentimento Livre e Esclarecido , Masculino , Pesquisa Qualitativa , Projetos de Pesquisa , País de GalesRESUMO
OBJECTIVE: To describe cumulative radiation exposure in a large single-center cohort of children with congenital heart disease (CHD) and identify risk factors for greater exposure. STUDY DESIGN: A detailed medical radiation exposure history was collected retrospectively for patients aged <18 years who underwent surgery for CHD between January 1, 2001, and July 22, 2009. Cumulative per patient exposure was quantified as the effective dose in millisieverts (mSv) and annualized (mSv/year). RESULTS: A total of 4132 patients were subjected to 134,715 radiation examinations at a median follow-up of 4.3 years (range, 0-8.6 years). Exposure clustered around the time of surgery. The median exposure was 14 radiologic tests (the majority of which were plain film radiographs) at an effective dose of 0.96 mSv (the majority of which was from cardiac catheterization), although this distribution had a very wide range. Almost three-quarters (73.7%) were exposed to <3 mSv/year, and 5.3% were exposed to >20 mSv/year. Neonates, children with genetic syndromes, and children requiring surgery for cardiomyopathy, pulmonary valve, single ventricle, or tricuspid valve diseases were more likely to have higher exposure levels, and those requiring surgery for aortic arch anomalies or atrioventricular septal defects were more likely to have lower levels. CONCLUSION: Children with CHD requiring surgery are exposed to numerous medical forms of ionizing radiation. Although the majority of patients receive <3 mSv/year, there are identifiable risk factors for higher exposure levels. This may have important health implications as these patients age.
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Cardiopatias Congênitas/diagnóstico por imagem , Cardiopatias Congênitas/cirurgia , Cardiopatias/congênito , Cardiopatias/diagnóstico por imagem , Cardiopatias/cirurgia , Doses de Radiação , Adolescente , Criança , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Radiografia , Estudos Retrospectivos , Fatores de RiscoRESUMO
The ubiquity of vanadium oxo complexes in the V+ and IV+ oxidation states has contributed to a comprehensive understanding of their electronic structure and reactivity. However, despite being predicted to be stable by ligand-field theory, the isolation and characterization of a well-defined terminal mononuclear vanadium(III) oxo complex has remained elusive. We present the synthesis and characterization of a unique terminal mononuclear vanadium(III) oxo species supported by the pentadentate polypyridyl ligand 2,6-bis[1,1-bis(2-pyridyl)ethyl]pyridine (PY5Me2). Exposure of [V(II)(NCCH3)(PY5Me2)](2+) (1) to either dioxygen or selected O-atom-transfer reagents yields [V(IV)(O)(PY5Me2)](2+) (2). The metal-centered one-electron reduction of this vanadium(IV) oxo complex furnishes a stable, diamagnetic [V(III)(O)(PY5Me2)](+) (3) species. The vanadium(III) oxo species is unreactive toward H- and O-atom transfer but readily reacts with protons to form a putative vanadium hydroxo complex. Computational results predict that further one-electron reduction of the vanadium(III) oxo species will result in ligand-based reduction, even though pyridine is generally considered to be a poor π-accepting ligand. These results have implications for future efforts toward low-valent vanadyl chemistry, particularly with regard to the isolation and study of formal vanadium(II) oxo species.
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Compostos Organometálicos/química , Oxigênio/química , Vanádio/química , Modelos Moleculares , Estrutura Molecular , Compostos Organometálicos/síntese química , Teoria QuânticaRESUMO
Social determinants of health (SDOH) impact cancer-related health outcomes, including survival, but their impact on symptoms is less understood among the primary brain tumor (PBT) population. We conducted a systematic review to examine the relationships between SDOH and neurocognitive and mood-related symptoms among the PBT population. PubMed, EMBASE, and CINAHL were searched using PROGRESS criteria (place of residence, race/ethnicity, occupation, gender/sex, religion, education, socioeconomic status, and social capital) on March 8th, 2022. Two individuals screened and assessed study quality using the NHLBI Assessment Tool for Observational Cohort and Cross-sectional Studies. Of 3006 abstracts identified, 150 full-text articles were assessed, and 48 were included for a total sample of 28 454 study participants. Twenty-two studies examined 1 SDOH; none examined all 8. Four studies measured place of residence, 2 race/ethnicity, 13 occupation, 42 gender, 1 religion, 18 education, 4 socioeconomic status, and 15 social capital. Fifteen studies assessed neurocognitive and 37 mood-related symptoms. While higher education was associated with less neurocognitive symptoms, and among individuals with meningioma sustained unemployment after surgery was associated with depressive symptoms, results were otherwise disparate among SDOH and symptoms. Most studies were descriptive or exploratory, lacking comprehensive inclusion of SDOH. Standardizing SDOH collection, reducing bias, and recruiting diverse samples are recommended in future interventions.
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The proliferation of technology has accelerated exponentially over the past 50 years. Contemporarily, researchers have explored the influences technology use is having on individuals and relationships. Theoretical frameworks such as the couple, family, and technology (CFT) Framework have been applied to individuals and couples in committed relationships to better understand the implications of technology adoption and use within this relational subsystem. Research examining technology's impact on couple relationships recognizes the potential for technology use to be either helpful or unhelpful to the relationship but fails to fully examine the helpful aspects of technology use. This study addresses this gap with the creation of a theory grounded in data from N = 45 couples (n = 90 individuals) in committed relationships. Results indicate couples' technology use can augment emotional connection and unity within the relationship as couples manage the influence of technology in a way that is relationally helpful.
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Relações Interpessoais , Cônjuges , Humanos , Feminino , Adulto , Masculino , Cônjuges/psicologia , Terapia de Casal/métodos , Pessoa de Meia-IdadeRESUMO
PURPOSE: Research has demonstrated that solid tumor patients experience high levels of psychological distress at the time of diagnosis. While distress has been associated with many adverse clinical outcomes, little is known about how this symptom may influence the disease trajectory for cancer patients, affecting outcomes such as progression, recurrence, and survival. The purpose of this systematic review was to explore the literature linking distress with survival in solid tumor patients, which may guide future work exploring clinical outcomes as a function of distress. METHODS: A systematic search of PubMed, Embase, and Web of Science was performed using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines with predefined eligibility criteria. Thirteen studies met the inclusion criteria and were selected for review. RESULTS: Findings from this review demonstrated a weak-to-moderate relationship between cancer patients' experience of distress and overall survival, with most included studies (11/13) finding at least one predictive analysis to be significant when controlling for confounders. However, significant heterogeneity in the literature, particularly with study sample characteristics and varying methodologies, made direct comparisons across studies challenging. CONCLUSION: Findings from this review suggest that psychological distress may have an impact on disease-related outcomes, including (but not limited to) survival. Future work should consider performing disease-specific analyses controlling for key prognostic factors to better understand the nuanced relationship between distress and clinical outcomes, which may allow further understanding of the biological underpinnings of this relationship and enable the development of targeted interventions for improving distress.
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Neoplasias , Angústia Psicológica , HumanosRESUMO
This article describes a pilot test of a community engaged, culturally relevant, arts-based intervention. The purpose was to increase children's personal protective buffering resources. Protective buffering resources help children cope with stressful stimuli, reduce activation of their systemic stress response, mitigate allostatic load, and promote optimal health. The "Learning a Healthy Rhythm" intervention included a stress management component and an ongoing Afro-Latino percussion program for 18 children ages 9-11. The stress management component included educational content about stress, self-assessment of stress symptoms, and stress management techniques. A mixed-method intervention evaluation design was used. Qualitative data, quantitative data, and biometrics including hair cortisol were collected. Six intervention parameters were evaluated: effectiveness, fidelity, feasibility, acceptability, necessity, and safety. Positive results were obtained for all parameters. Reduction in physiological and subjective measures of stress was evident. This stress management intervention was well-received and supported by participants.
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Adaptação Psicológica , Humanos , Criança , Hispânico ou Latino , Hidrocortisona , AprendizagemRESUMO
Background: Primary brain tumor (PBT) patients experience higher levels of distress and anxiety than other solid tumor patients, particularly at the time of clinical evaluation when uncertainty about disease status is high ("scanxiety"). There is promising evidence supporting use of virtual reality (VR) to target psychological symptoms in other solid tumor patients, though PBT patients have not been studied extensively in this context. The primary aim of this phase 2 clinical trial is to establish the feasibility of a remote VR-based relaxation intervention for a PBT population, with secondary aims designed to determine preliminary efficacy of improving distress and anxiety symptoms. Methods: PBT patients (N=120) with upcoming MRI scans and clinical appointments who meet eligibility will be recruited to participate in a single arm trial conducted remotely through the NIH. Following completion of baseline assessments, participants will complete a 5-minute VR intervention via telehealth using a head-mounted immersive device while under supervision of the research team. Following the intervention, over the course of 1 month patients can use VR at their discretion with follow-up assessments done immediately post-VR intervention, as well as 1 week and 4 weeks later. Additionally, a qualitative phone interview will be conducted to assess patient satisfaction with the intervention. Discussion: Use of immersive VR is an innovative interventional approach to target distress and scanxiety symptoms in PBT patients who are at high risk for experiencing these symptoms leading into their clinical appointments. Findings from this study may inform design of a future multicenter randomized VR trial for PBT patients and may aid in development of similar interventions for other oncology populations. Trial Registration: clinicaltrials.gov (NCT04301089), registered 9 March 2020.
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Background: Precision health approaches to managing symptom burden in primary brain tumor (PBT) patients are imperative to improving patient outcomes and quality of life, but require tackling the complexity and heterogeneity of the symptom experience. Network Analysis (NA) can identify complex symptom co-severity patterns, and unsupervised clustering can unbiasedly stratify patients into clinically relevant subgroups based on symptom patterns. We combined these approaches in a novel study seeking to understand PBT patients' clinical and demographic determinants of symptom burden. Methods: MDASI-BT symptom severity data from a two-institutional cohort of 1128 PBT patients were analyzed. Gaussian Graphical Model networks were constructed for the all-patient cohort and subgroups identified by unsupervised clustering based on co-severity patterns. Network characteristics were analyzed and compared using permutation-based statistical tests. Results: NA of the all-patient cohort revealed 4 core dimensions that drive the overall symptom burden of PBT patients: Cognitive, physical, focal neurologic, and affective. Fatigue/drowsiness was identified as pivotal to the symptom experience based on the network characteristics. Unsupervised clustering discovered 4 patient subgroups: PC1 (n = 683), PC2 (n = 244), PC3 (n = 92), and PC4 (n = 109). Moderately accurate networks could be constructed for PC1 and PC2. The PC1 patients had the highest interference scores among the subgroups and their network resembled the all-patient network. The PC2 patients were older and their symptom burden was driven by cognitive symptoms. Conclusions: In the future, the proposed framework might be able to prioritize symptoms for targeting individual patients, informing more personalized symptom management.
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Background: Hypersomnolence is a common and disruptive side effect of cranial radiotherapy and is associated with fatigue and disturbances in mood and cognition in primary brain tumor (PBT) patients. The biological underpinnings of this effect are not understood. Our laboratory has previously found that the presence of a single nucleotide polymorphism (rs934945, G-E mutation) in the PERIOD2 (PER2) clock gene was associated with a decreased likelihood of fatigue in PBT patients. Here, we aim to understand the effects of PER2 polymorphism on radiation susceptibility within a murine model of cranial-irradiation-induced hypersomnolence (C-RIH). Methods: Male and female transgenic mice were generated using CRISPR-Cas9, replacing the endogenous mouse PER2:CRY1 binding domain with its human isoform with (hE1244 KI) or without the SNP rs934945 (hG1244 KI). Activity and sleep were monitored continuously 10 days before and after cranial irradiation (whole brain, 15Gy, single fraction). Behavioral assessments measuring anxiety, depression, and working memory were used to assess mood and cognitive changes 2 months postradiation. Results: During their active phase, hE1244 knock-ins (KIs) had less radiation-induced suppression of activity relative to hG1244 KIs and female hE1244 KIs saw a reduction of hypersomnolence over 10 days. hE1244 KIs displayed less anxiety behavior and were more ambulatory within all behavioral tests. Conclusions: The PER2 rs934945 polymorphism had long-lasting behavioral effects associated with radiation toxicity, particularly in sleep in females and the activity of all animals. Our findings shed light on biological mechanisms underlying C-RIH.
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Background: Recognising the importance of clinical outcomes assessments (COAs), the Response Assessment in Neuro-Oncology-Patient Reported Outcome (RANO-PRO) Working Group recommended inclusion of core symptoms and functions in clinical care or research for malignant glioma patients. This study evaluated the association of the recommended symptoms (pain, perceived cognition, seizures, aphasia, symptomatic adverse events) and functions (weakness, walking, work, usual activities) with disease progression in these patients. Methods: In this retrospective cohort study, patients with malignant glioma were included from the US National Cancer Institute Neuro-Oncology Branch Natural History Study (NOB-NHS) which follows primary central nervous system tumour patients aged 18 years and older throughout their disease trajectory. The M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT), EQ-5D-3L, Karnofsky Performance Status (KPS), and Neurologic Function scores (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons at first assessment and over time to a second assessment. Radiographic disease progression was determined on the interpretation of the imaging study by a radiologist and neuro-oncologist using standard criteria as part of clinical trial participation or routine standard of care. The priority constructs were evaluated to provide initial evidence of their relevance, relationship to disease status over time, and sensitivity to change in a diverse group of patients with malignant glioma. Findings: Seven hundred and sixty-five patients had enrolled into the NOB-NHS between September 1, 2016 and January 31, 2020. Three hundred and thirty-six patients had a diagnosis of a malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, and gliosarcoma) and were included in the current study. The sample was 64% male (n = 215), 36% female (n = 121), median age of 52 years (IQR = 18.75), 82% White (n = 276), and 65% had tumour recurrence (n = 219). One hundred and fifty-four (46%) had radiographic disease progression. Difficulty remembering, fatigue, and weakness were worse in the group whose imaging was interpreted as radiographic disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (1.1 < difference < 1.8). Patients with disease progression were four times more likely to have a poor KPS (≤80) and worse NFS. Among patients with disease progression at a second assessment (n = 112), all symptoms, except seizures, worsened between first assessment and disease progression and up to 22% of patients (n = 25) reported worsening mobility, self-care, and usual activity; 46% (n = 51) and 35% (n = 30) had worsened KPS and NFS, respectively. On average, 4 symptoms or functions (SD = 3) were reported as moderate-to-severe and 30% (n = 33) and 23% (n = 26) had a change to moderate-to-severe fatigue and walking, respectively, at time of disease progression. Over 7% of patients with worsening (n = 7 of 100) reported every symptom and function as having changed the most severely including seizures with fatigue and activity reported as the top symptom and function, respectively. Interpretation: The identified core symptoms and functions worsened at the time of progression, supporting the relevance and sensitivity of the priority constructs identified by the RANO-PRO Working Group for clinical care and clinical trials for malignant glioma patients. Funding: The Natural History Study is supported by Intramural Project 1ZIABC011786-03.