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BACKGROUND: Trofinetide was approved for the treatment of Rett syndrome (RTT) in patients aged ≥2 years based on the results of the 12-week, randomized, phase 3 LAVENDER study. In LILAC, a 40-week, open-label extension study of LAVENDER, trofinetide continued to improve the symptoms of RTT, with a similar safety profile as LAVENDER. Here, we report long-term safety and efficacy results of LILAC-2, a 32-month, open-label extension study. METHODS: Females aged 5-22 years who completed LILAC were eligible to enter LILAC-2. Safety and tolerability were assessed with the incidence of adverse events (AEs). Efficacy was assessed with Rett Syndrome Behaviour Questionnaire (RSBQ) and Clinical Global Impression-Improvement (CGI-I) scores. Caregiver interviews explored the patient's experience with RTT and the efficacy of trofinetide during study participation. FINDINGS: In total, 77 participants were enrolled in LILAC-2. The most common AEs were diarrhea (53.2%), COVID-19 (27.3%), and vomiting (19.5%). The mean (standard error [SE]) change in RSBQ score from LAVENDER baseline to week 104 of LILAC-2 was -11.8 (2.45). The mean (SE) CGI-I score from LILAC baseline to week 12 of LILAC-2 was 3.1 (0.10). Most caregivers (96%; n = 24/25) were satisfied or very satisfied with the benefits of trofinetide. CONCLUSIONS: Long-term treatment with trofinetide continued to improve RTT symptoms, without new safety concerns. Caregivers reported satisfaction with trofinetide related to improvements that were meaningful for their child and themselves. FUNDING: The study was supported by Acadia Pharmaceuticals (San Diego, CA, USA). This study was registered at ClinicalTrials.gov: NCT04776746.
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WHAT IS THIS SUMMARY ABOUT?: This summary describes how researchers worked with people with multiple sclerosis (MS), neurologists and measurement experts to create an easy-to-use questionnaire to measure the physical function of people with MS. This questionnaire covers topics that are relevant and important to people with MS and their doctors.The ability to do what you want to do, when you want to do it, is one of the most important concerns for people with MS. This questionnaire could help doctors to record and manage how much MS affects people's lives.MS can bring a range of challenging symptoms such as 'brain fog', tiredness, and problems with movement and balance. Many of these symptoms can make day-to-day activities, like working, very difficult for people with MS. Doctors currently use examinations like the Expanded Disability Status Scale (EDSS) and the MS Functional Composite (MSFC), but these do not fully consider what is important to people living with MS. A questionnaire that specifically measures physical functioning of people with MS could help doctors and people with MS to better understand, communicate and manage the physical effects of MS. In this study, people with MS were asked to help create a questionnaire about physical function that reflects topics that are important to them. WHAT WERE THE RESULTS?: The PROMIS®nq physical function - Multiple Sclerosis 15a (the PROMIS® PF MS questionnaire) was successfully created with the help of people with MS. People with MS thought that the PROMIS® PF MS questionnaire covered issues important to their physical function. Scores were in line with results of other physical symptom measurement scales like the EDSS. WHAT DO THE RESULTS MEAN?: The PROMIS® PF MS questionnaire could be used to meaningfully record physical function among people with MS.
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INTRODUCTION: Multiple sclerosis (MS) is a disabling disease with unpredictable clinical manifestations. As clinical assessments may not fully capture the impact of MS on quality of life, they can be complemented by patient-reported outcome (PRO) measures to provide a more comprehensive picture of MS disease state and impact. The objectives of this study were to explore the experiences of people with relapsing-remitting MS, including symptoms and impacts on daily life, and to provide a conceptual model of MS outcomes. METHODS: A literature review of studies that evaluated the experiences of people with MS was completed and combined with semi-structured concept elicitation interviews conducted with 14 people with relapsing-remitting MS in the USA. RESULTS: The average age of the 14 participants was 43.9 (range 25-64) years, most were White (78.6%) and female (78.6%), and the mean duration since diagnosis was 6.6 (2-10) years. The most bothersome symptoms identified included fatigue (n = 9), cognitive dysfunction (n = 5), mobility/difficulty with walking (n = 3), and vision problems (n = 3). The most commonly reported impacts on daily life were balance problems/instability (n = 13), work life/productivity (n = 12), difficulty walking (n = 11), daily activities/household chores (n = 11), and leisure activities (n = 10). CONCLUSION: There was a high frequency of concepts associated with physical function, fatigue, and sensory-motor actions. A conceptual model was developed that captures the disease symptoms, impairments, and impacts identified in the interviews as well as known processes and symptoms identified in the literature search. This model underpins the appropriateness of PRO instruments, such as the PROMIS Fatigue (MS) 8a and PROMIS Physical Function (MS) 15a, which evaluate symptoms and impacts that matter most to people with MS.
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BACKGROUND: With the COVID-19 pandemic came rapid uptake in virtual oncology care. During this, sociodemographic inequities in access to virtual visits (VVs) have become apparent. To better understand these issues, we conducted a qualitative study to describe the perceived usability and acceptability of VVs among Black adults diagnosed with cancer. METHODS: Adults who self-identified as Black and had a diagnosis of prostate, multiple myeloma, or head and neck cancer were recruited from 2 academic medical centers, and their community affiliates to participate in a semi-structured interview, regardless of prior VV experience. A patient and family advisory board was formed to inform all components of the study. Interviews were conducted between September 2, 2021 and February 23, 2022. Transcripts were organized topically, and themes and subthemes were determined through iterative and interpretive immersion/crystallization cycles. RESULTS: Of the 49 adults interviewed, 29 (59%) had participated in at least one VV. Three overarching themes were derived: (1) VVs felt comfortable and convenient in the right contexts; (2) the technology required for VVs with video presented new challenges, which were often resolved by an audio-only telephone call; and (3) participants reported preferring in-person visits, citing concerns regarding gaps in nonverbal communication, trusting providers, and distractions during VV. CONCLUSION: While VVs were reported to be acceptable in specific circumstances, Black adults reported preferring in-person care, in part due to a perceived lack of interpersonal connectedness. Nonetheless, retaining reimbursement for audio-only options for VVs is essential to ensure equitable access for those with less technology savvy and/or limited device/internet capabilities.
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COVID-19 , Pandemias , Adulto , Masculino , Humanos , Oncologia , Centros Médicos Acadêmicos , COVID-19/epidemiologia , InternetRESUMO
BACKGROUND: There is a lack of national guidance specifying how skin surgery, including Mohs micrographic surgery (MMS), should be conducted, leading to a degree of heterogeneity in the set-up of skin surgery services and how skin surgeries are performed. OBJECTIVES: To provide the first UK-wide cross-sectional study reporting real-world data on the set-up and waste management practices of skin surgery, including MMS. METHODS: A UK-wide service evaluation study was conducted between 1 March 2022 and 30 June 2022 using a standardized data collection pro forma. Twelve participating sites from England, Northern Ireland, Scotland and Wales provided data from 115 skin surgery lists involving 495 patients and 547 skin surgery procedures between 1 March 2022 and 30 June 2022. RESULTS: Mean total weight of nonsharps skin surgery waste was 0.52â kg per procedure (0.39â kg clinical waste, 0.05â kg general waste and 0.08â kg recycling waste). Data from a single site using disposable surgical instruments reported a mean of only 0.25â kg of sharps waste per procedure. The recycling rate ranged between 0% and 44% across the cohort with a mean recycling rate of 16%. CONCLUSIONS: We advocate that staff transition to the British Society of Dermatological Surgery 2022 sustainability guidance, which made wide-ranging recommendations to facilitate staff to transition to sustainable practices in skin surgery.
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Neoplasias Cutâneas , Gerenciamento de Resíduos , Humanos , Cirurgia de Mohs/métodos , Neoplasias Cutâneas/cirurgia , Estudos Transversais , Procedimentos Cirúrgicos Dermatológicos , EscóciaRESUMO
In 2019, the first cases of SARS-CoV-2 were detected in Wuhan, China, and by early 2020 the first cases were identified in the United States. SARS-CoV-2 infections increased in the US causing many states to implement stay-at-home orders and additional safety precautions to mitigate potential outbreaks. As policies changed throughout the pandemic and restrictions lifted, there was an increase in demand for COVID-19 testing which was costly, difficult to obtain, or had long turn-around times. Some academic institutions, including Boston University (BU), created an on-campus COVID-19 screening protocol as part of a plan for the safe return of students, faculty, and staff to campus with the option for in-person classes. At BU, we put together an automated high-throughput clinical testing laboratory with the capacity to run 45,000 individual tests weekly by Fall of 2020, with a purpose-built clinical testing laboratory, a multiplexed reverse transcription PCR (RT-qPCR) test, robotic instrumentation, and trained staff. There were many challenges including supply chain issues for personal protective equipment and testing materials in addition to equipment that were in high demand. The BU Clinical Testing Laboratory (CTL) was operational at the start of Fall 2020 and performed over 1 million SARS-CoV-2 PCR tests during the 2020-2021 academic year.
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COVID-19 , SARS-CoV-2 , COVID-19/diagnóstico , Teste para COVID-19 , Humanos , Pandemias/prevenção & controle , Reação em Cadeia da Polimerase em Tempo Real/métodos , Estados UnidosRESUMO
AIMS/HYPOTHESIS: We have previously shown that diabetes causes pericyte dysfunction, leading to loss of vascular integrity and vascular cognitive impairment and dementia (VCID). Glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1 RAs), used in managing type 2 diabetes mellitus, improve the cognitive function of diabetic individuals beyond glycaemic control, yet the mechanism is not fully understood. In the present study, we hypothesise that GLP-1 RAs improve VCID by preventing diabetes-induced pericyte dysfunction. METHODS: Mice with streptozotocin-induced diabetes and non-diabetic control mice received either saline (NaCl 154 mmol/l) or exendin-4, a GLP-1 RA, through an osmotic pump over 28 days. Vascular integrity was assessed by measuring cerebrovascular neovascularisation indices (vascular density, tortuosity and branching density). Cognitive function was evaluated with Barnes maze and Morris water maze. Human brain microvascular pericytes (HBMPCs), were grown in high glucose (25 mmol/l) and sodium palmitate (200 µmol/l) to mimic diabetic conditions. HBMPCs were treated with/without exendin-4 and assessed for nitrative and oxidative stress, and angiogenic and blood-brain barrier functions. RESULTS: Diabetic mice treated with exendin-4 showed a significant reduction in all cerebral pathological neovascularisation indices and an improved blood-brain barrier (p<0.05). The vascular protective effects were accompanied by significant improvement in the learning and memory functions of diabetic mice compared with control mice (p<0.05). Our results showed that HBMPCs expressed the GLP-1 receptor. Diabetes increased GLP-1 receptor expression and receptor nitration in HBMPCs. Stimulation of HBMPCs with exendin-4 under diabetic conditions decreased diabetes-induced vascular inflammation and oxidative stress, and restored pericyte function (p<0.05). CONCLUSIONS/INTERPRETATION: This study provides novel evidence that brain pericytes express the GLP-1 receptor, which is nitrated under diabetic conditions. GLP-1 receptor activation improves brain pericyte function resulting in restoration of vascular integrity and BBB functions in diabetes. Furthermore, the GLP-1 RA exendin-4 alleviates diabetes-induced cognitive impairment in mice. Restoration of pericyte function in diabetes represents a novel therapeutic target for diabetes-induced cerebrovascular microangiopathy and VCID.
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Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Receptor do Peptídeo Semelhante ao Glucagon 1 , Pericitos , Animais , Encéfalo/metabolismo , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Exenatida/uso terapêutico , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Receptor do Peptídeo Semelhante ao Glucagon 1/metabolismo , Humanos , Camundongos , Pericitos/metabolismoRESUMO
BACKGROUND: A valid, sensitive patient-reported outcome (PRO) measure of physical function (PF) for people with multiple sclerosis (MS) would have substantial value in routine care and clinical research. We now describe development of the PROMISnq Short Form v2.0 PF - Multiple Sclerosis 15a [PROMISnq PF(MS)15a] for assessing PF in relapsing and progressive MS. Also, the validity, reliability, and responsiveness of the PROMISnq PF(MS)15a is evaluated, minimal important difference (MID) thresholds for score change estimated and a score interpretation guide developed. METHODS: A mixed-methods sequential design was employed. Relevant PF concepts were elicited through semi-structured interviews with people with relapsing MS, and then mapped to the PROMIS PF item bank. Measurement experts integrated results from interviews with people with MS and input from a panel of neurologists to generate a draft short form. Relevance and comprehensiveness of the draft short form were assessed in cognitive debriefing interviews with people with relapsing or progressive MS. Subsequently, item reduction and evaluation of psychometric properties were performed in two observational studies: a cross-sectional study in the US (n = 296), and a 96-week longitudinal study in the UK MS Register cohort (n = 558). The main outcomes and measures are estimates of: known-groups validity, convergent validity, reliability, responsiveness; MID for worsening. RESULTS: Factor analyses supported the unidimensionality of the newly derived 15-item short form. Cronbach's alpha (≥ 0.97) and intraclass correlation coefficient (≥ 0.97) of test-retest scores (5-27 days) indicated strong reliability. Convergent validity was demonstrated by moderate-to-strong correlations with scores on related PRO measures. Scores discriminated among patient groups classified by levels of physical health and other criteria. Score changes of 2.3-2.7 points are proposed as MID criteria for minimal worsening in PF. CONCLUSION: PROMISnq PF(MS)15a demonstrated reliability, validity and sensitivity to change. Input from patients and clinicians ensured the content is comprehensive and relevant for people with MS.
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Esclerose Múltipla , Estudos Transversais , Humanos , Estudos Longitudinais , Esclerose Múltipla/diagnóstico , Medidas de Resultados Relatados pelo Paciente , Psicometria/métodos , Reprodutibilidade dos Testes , Inquéritos e QuestionáriosRESUMO
OBJECTIVE: Identify disease categories in which single-item global impression (GI) scales were included in product labeling of new drugs approved by the US Food and Drug Administration (FDA) in January 2009-December 2019 and review the characteristics of GIs included in product labeling of new FDA-approved drugs (January 2017-December 2019). METHODS: FDA Clinical Outcome Assessment (COA) Compendium was reviewed for drug labels that included GIs for drugs approved in 2009-2016. The indication, year of approval, ICD-10 code, and GI respondent were noted. A manual review of labels of FDA-approved drugs (2017-2019) was undertaken to identify GIs included in the labels. Corresponding drug approval packages were reviewed to identify details of any regulatory reviewer comments related to GIs. GI characteristics were noted from the drug label or the review documents, including the respondent, type of measure (static or dynamic), item wording, concept assessed, and response options. RESULTS: Product labeling containing GIs was most common in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs were included in 30/77 (39.0%) drug labels in the four disease categories. CONCLUSION: In the past 10 years, GIs have been included as endpoint measures in confirmatory clinical trials and have generated evidence of treatment benefit in diseases related to the skin, nervous system, behavioral disorders, and the musculoskeletal system. GIs frequently provide important insights into the patient experience. Before GIs are included in clinical trials to assess treatment benefit, it is important to ensure that they are valid, reliable, and responsive.
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Aprovação de Drogas , Rotulagem de Medicamentos/tendências , Medidas de Resultados Relatados pelo Paciente , Humanos , Estados UnidosRESUMO
BACKGROUND: The purpose of this study was to investigate the relationship between sleep problems, gastrointestinal symptoms, social functioning, autism traits, and social support on quality of life (QoL) in 107 adults with autism spectrum disorder (ASD). METHOD: Questionnaires included the Autism Spectrum Quotient-10 (Adult), Multidimensional Scale of Perceived Social Support, Social Functioning Questionnaire, Pittsburgh Sleep Quality Index, Gastrointestinal Symptom Inventory, and World Health Organization Quality of Life-BREF. RESULTS: GI symptoms were a common comorbidity with 86 % of participants presenting with them. Sleep problems were also frequent issues with 89 % of participants being classified as poor sleepers. Greater sleep problems were correlated with poorer QoL in the physical health and environment domains. Specifically, the sleep problem of daytime dysfunction was correlated with poorer QoL in physical health. Daytime dysfunction and sleep duration were correlated with poorer QoL in the environment domain. Better social support was correlated with greater QoL in the psychological, social and environment domains. Poorer social functioning was correlated with poorer QoL in each of the four domains. CONCLUSION: This research indicated that GI symptoms and sleep problems are common comorbid conditions in the adult ASD population. This paper expanded upon the existing literature by highlighting unexplored factors influencing QoL in adults with ASD.
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Transtorno do Espectro Autista , Qualidade de Vida , Adulto , Transtorno do Espectro Autista/epidemiologia , Humanos , Sono , Interação Social , Problemas Sociais , Apoio Social , Inquéritos e QuestionáriosRESUMO
BACKGROUND: It has been suggested that dietary polyunsaturated fatty acids (PUFA) are partitioned into oxidation pathways to a greater extent than dietary saturated fatty acids (SFA). Whilst this has been demonstrated in animal models, evidence in humans is lacking. The potential divergence in the metabolic fate of these dietary fatty acids (FA) may explain some of the reported differences in ectopic fat deposition with SFA and PUFA enriched diets. AIMS: To compare whole-body oxidation of dietary palmitate and linoleate after consumption of a single test meal. METHODS: In a randomized, crossover design 24 healthy volunteers (12 males and 12 females, matched for age and BMI) underwent two study days separated by 2-week washout period. During each study day participants consumed a standardized test meal which contained [U13C]palmitate or [U13C]linoleate. Blood and breath samples were collected over the 6 h postprandial period and the 13C enrichment in breath CO2 samples and plasma lipid fractions was determined. RESULTS: Appearance of 13C in expired CO2 was significantly (p < 0.05) increased after consumption of the meal containing [U13C]linoleate compared to the meal containing [U13C]palmitate. The recovery of tracer was 8.9 ± 1.2% [U13C]linoleate vs. 5.6 ± 0.4% [U13C]palmitate (p < 0.05). The incorporation of 13C from [U13C]palmitate was greater in plasma triacylglycerol and non-esterified fatty acids than [U13C]linoleate, whereas the incorporation of 13C from [U13C]linoleate was greater than [U13C]palmitate in plasma phospholipids. Although 13CO2 was significantly (p < 0.05) higher in females compared to males after consumption of [U13C]palmitate, there was no difference in 13CO2 between sexes after consumption of [U13C]linoleate. CONCLUSIONS: We demonstrate that whole-body oxidation of dietary linoleate is comparatively higher than that of dietary palmitate in humans following consumption of a single mixed-test meal. We found indications of sexual dimorphism for dietary palmitate but not dietary linoleate. STUDY REGISTRATION: http://www.clinicaltrials.org/ ID number NCT03587753.
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Gorduras na Dieta/farmacologia , Ácido Linoleico/farmacologia , Refeições/fisiologia , Oxirredução/efeitos dos fármacos , Palmitatos/farmacologia , Adolescente , Adulto , Idoso , Testes Respiratórios , Dióxido de Carbono/análise , Estudos Cross-Over , Feminino , Voluntários Saudáveis , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Adulto JovemRESUMO
AIMS: Diabetes-induced retinal vascular cell death aggravates diabetic retinopathy (DR) to the proliferative stage and blindness. Pericytes play a crucial role in retinal capillaries survival, stability, and angiogenesis. Ephrin-B2 is a tyrosine kinase that regulates pericytes/endothelial cells communication during angiogenesis; yet, its role in DR is still unclear. We hypothesize that diabetes increases Ephrin-B2 signaling in pericytes, which contributes to inflammation and retinal vascular cell death. METHODS: Selective inhibition of the Ephrin-B2 expression in the retinal pericytes was achieved using an intraocular injection of adeno-associated virus (AAV) with a specific pericyte promotor. Vascular death was determined by retinal trypsin digest. Pathological angiogenesis was assessed using the oxygen-induced retinopathy model in pericyte-Ephrin-B2 knockout mice, wild type, and wild type injected with AAV. Angiogenic properties, inflammatory, and apoptotic markers were measured in human retinal pericytes (HRP) grown under diabetic conditions. KEY FINDING: Diabetes significantly increased the expression of Ephrin-B2, inflammatory, and apoptotic markers in the diabetic retinas and HRP. These effects were prevented by silencing Ephrin-B2 in HRP. Moreover, Ephrin-B2 silencing in retinal pericytes decreased pathological angiogenesis and acellular capillaries formation in diabetic retinas. SIGNIFICANCE: Increased Ephrin-B2 expression in the pericytes contributed to diabetes-induced retinal inflammation and vascular death. These results identify pericytes-Ephrin-B2 as a therapeutic target for DR.
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Apoptose , Retinopatia Diabética/metabolismo , Efrina-B2/metabolismo , Pericitos/metabolismo , Neovascularização Retiniana/metabolismo , Vasos Retinianos/metabolismo , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/etiologia , Retinopatia Diabética/genética , Retinopatia Diabética/patologia , Efrina-B2/deficiência , Efrina-B2/genética , Humanos , Mediadores da Inflamação/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pericitos/patologia , Ratos Wistar , Neovascularização Retiniana/etiologia , Neovascularização Retiniana/genética , Neovascularização Retiniana/patologia , Vasos Retinianos/patologia , Transdução de Sinais , EstreptozocinaRESUMO
IMPORTANCE: The number of patients presenting to emergency departments (EDs) for psychiatric care continues to increase. Psychiatrists often make a conservative recommendation to admit patients because robust outpatient services for close follow-up are lacking. OBJECTIVE: To assess whether the availability of a 45-day behavioral health-virtual patient navigation program decreases hospitalization among patients presenting to the ED with a behavioral health crisis or need. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical trial enrolled 637 patients who presented to 6 EDs spanning urban and suburban locations within a large integrated health care system in North Carolina from June 12, 2017, through February 14, 2018; patients were followed up for up to 45 days. Eligible patients were aged 18 years or older, with a behavioral health crisis and a completed telepsychiatric ED consultation. The availability of the behavioral health-virtual patient navigation intervention was randomly allocated to specific days (Monday through Friday from 7 am to 7 pm) so that, in a 2-week block, there were 5 intervention days and 5 usual care days; 323 patients presented on days when the program was offered, and 314 presented on usual care days. Data analysis was performed from March 7 through June 13, 2018, using an intention-to-treat approach. INTERVENTIONS: The behavioral health-virtual patient navigation program included video contact with a patient while in the ED and telephonic outreach 24 to 72 hours after discharge and then at least weekly for up to 45 days. MAIN OUTCOMES AND MEASURES: The primary outcome was the conversion of an ED encounter to hospital admission. Secondary outcomes included 45-day follow-up encounters with a self-harm diagnosis and postdischarge acute care use. RESULTS: Among 637 participants, 358 (56.2%) were men, and the mean (SD) age was 39.7 (16.6) years. The conversion rates were 55.1% (178 of 323) in the intervention group vs 63.1% (198 of 314) in the usual care group (odds ratio, 0.74; 95% CI, 0.54-1.02; P = .06). The percentage of patient encounters with follow-up encounters having a self-harm diagnosis was significantly lower in the intervention group compared with the usual care group (36.8% [119 of 323] vs 45.5% [143 of 314]; P = .03). CONCLUSIONS AND RELEVANCE: Although the primary result did not reach statistical significance, there is a strong signal of potential positive benefit in an area that lacks evidence, suggesting that there should be additional investment and inquiry into virtual behavioral health programs. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03204643.
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Terapia Comportamental/métodos , Serviço Hospitalar de Emergência , Transtornos Mentais/terapia , Admissão do Paciente/estatística & dados numéricos , Telemedicina/organização & administração , Adulto , Medicina do Comportamento/métodos , Feminino , Humanos , Masculino , Transtornos Mentais/psicologia , Pessoa de Meia-Idade , North Carolina , Autogestão/educação , Resultado do Tratamento , Adulto JovemRESUMO
Patient-reported outcome measures (PROMs) provide an important complement to physician-assessed clinical outcome measures in dermatologic diseases such as atopic dermatitis (AD) and chronic hand eczema (CHE). AD and CHE are chronic and relapsing inflammatory skin conditions that often co-occur. While both diseases result in various signs and symptoms that are burdensome and can negatively affect patients' lives, there may be distinct differences in the signs, symptoms, burden, and health-related quality of life (HRQOL) impact of these diseases. The objective of this study was to identify and evaluate PROMs used in studies of AD and CHE. The aim was to explore the assessment of key symptoms and impacts, and identify any gaps in the measures in use. A structured review of the PubMed database was conducted to identify PROMs used or developed for use in AD or CHE. The Dermatology Life Quality Index (DLQI), the Pruritus/Itch Numeric Rating Scale (NRS), the Patient-Oriented Eczema Measure (POEM), and the Quality of Life in Hand Eczema Questionnaire (QOLHEQ) were identified and reviewed in detail. With these measures, the AD and CHE symptoms and impacts most commonly evaluated in the literature include dermatology-related HRQOL in the domains of symptoms and feelings, daily activities, leisure, work and school, personal relationships, and adverse effects; pruritus; sleep disturbance; AD-specific symptoms (dryness, itching, flaking, cracking, bleeding, and weeping/oozing); and CHE-specific symptoms (pain, itch, fissuring, redness, bleeding, and dryness). A review of regulatory labels of drugs approved for AD by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) found that, among the four measures reviewed, the Pruritus NRS was included in the FDA and EMA labels for dupilumab, the DLQI was included in the EMA labels for dupilumab and tacrolimus, and the POEM was included in the EMA label for dupilumab. Key symptoms of AD (e.g. itching, flaking, cracking) and CHE (e.g. pain, itching, fissuring) are increasingly being assessed with PROMs; however, primary endpoints in clinical trials are often based on clinician-reported outcome measures. As therapeutic strategies in dermatology are targeted at specific dermatologic symptoms and diseases affecting specific sites (e.g. CHE), future research should explore patients' experiences with these symptoms and sites and the changes with treatment that are most meaningful to them.
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Doença Crônica , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/fisiopatologia , Eczema/tratamento farmacológico , Eczema/fisiopatologia , Mãos/fisiopatologia , Medidas de Resultados Relatados pelo Paciente , Adulto , HumanosRESUMO
BACKGROUND: This study aimed to develop and provide a psychometric and feasibility pilot evaluation of the Heart Failure (HF) Symptom Tracker (HFaST), a new patient-reported tool designed to facilitate communication between patients and health care providers (HCPs) in routine clinical care. The HFaST enables patients to identify worsening HF symptoms, with a long-term goal of preventing hospitalizations or emergency room visits. METHODS: The HFaST was developed drawing on evidence from the literature, qualitatively with cognitive interviews (12 patient/caregiver and 8 HCPs), and evaluated quantitatively (psychometric, feasibility assessment). The HFaST was administered for 7 consecutive days to 100 individuals diagnosed with HF during a multisite, non-interventional US pilot study. Health care providers then completed a survey assessing the feasibility and importance of the HFaST in clinical practice. Qualitative development included a literature review and cognitive interviews with patients, caregivers, and HCPs. The psychometric properties of the HFaST were evaluated using classical test theory methods. Descriptive statistics provided insight into HCPs' perceptions of the feasibility of using the HFaST in clinical practice. RESULTS: A preliminary set of 40 items was developed for the symptom tracker and iteratively reduced to 10 items based on the qualitative phase. Test-retest reliability (weighted kappa 0.71-0.97), discriminating validity, and construct validity of the HFaST were acceptable. HCPs rated the HFaST as a good (70%) or excellent (30%) means of tracking HF symptoms. Six HFaST items were ultimately retained, covering concepts of fatigue, shortness of breath (3 items), swelling, and rapid weight gain. CONCLUSIONS: The 6-item HFaST is an easy-to-use tool designed to raise patients' awareness of HF symptoms and facilitate communication with HCPs. Future research should evaluate HFaST implementation in clinical practice and effectiveness as an intervention to potentially prevent hospitalizations and emergency room visits.
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BACKGROUND/OBJECTIVE: Nocturia's impact on sleep causes significant burden for patients. This study aimed to develop a novel patient-reported outcome (PRO) measure, the Nocturia Sleep Quality Scale (NSQS), for the assessment of the impact of nocturia (defined as ≥2 nocturnal voids/night) on sleep. METHODS: Sleep-related concepts were identified through a targeted literature review, after which in-depth concept elicitation interviews with patients with a clinical diagnosis of nocturia were conducted. Draft items were generated to address concepts identified as important, meaningful, and relevant. Items were further refined through three iterative sets of cognitive debriefing interviews to optimize instructions, question wording, and response options. Two sleep research experts also provided input. RESULTS: The literature review and data from 18 concept elicitation interviews provided the basis for a comprehensive set of concepts. Constant comparative analysis was used to identify themes and support item development. The draft questionnaire consisted of 14 items with item-specific response scales. Wording and scaling of the items was optimized based on feedback from the 22 cognitive debriefing interviews and expert input. The results confirmed the completeness and relevance of the NSQS, providing support for the content validity and ability of items to reflect patient perception of nocturia-related sleep impacts. CONCLUSIONS: The 6-item NSQS assesses the impact of nocturia on sleep by evaluating nighttime awakenings, sleep quantity, and sleep quality. The NSQS is self-administered and is intended to assess change in nocturia's impact on sleep after treatment in a standardized manner. Psychometric evaluation is under way to describe key measurement properties.
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Noctúria/psicologia , Medidas de Resultados Relatados pelo Paciente , Transtornos do Sono-Vigília/psicologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Noctúria/complicações , Pesquisa Qualitativa , Qualidade de Vida , Transtornos do Sono-Vigília/etiologiaRESUMO
There is a pressing need for objective, quantifiable outcome measures in intervention trials for children with autism spectrum disorder (ASD). The current study investigated the use of eye tracking as a biomarker of treatment response in the context of a pilot randomized clinical trial of treatment for young children with ASD. Participants included 28 children with ASD, aged 18-48 months, who were randomized to one of two conditions: Pivotal Response Intervention for Social Motivation (PRISM) or community treatment as usual (TAU). Eye-tracking and behavioral assessment of developmental functioning were administered at Time 1 (prior to randomization) and at Time 2 (after 6 months of intervention). Two well-established eye-tracking paradigms were used to measure social attention: social preference and face scanning. As a context for understanding relationships between social attention and developmental ability, we first examined how scanning patterns at Time 1 were associated with concurrent developmental functioning and compared to those of 23 age-matched typically developing (TD) children. Changes in scanning patterns from Time 1 to Time 2 were then compared between PRISM and TAU groups and associated with behavioral change over time. Results showed that the social preference paradigm differentiated children with ASD from TD children. In addition, attention during face scanning was associated with language and adaptive communication skills at Time 1 and change in language skills from Time 1 to Time 2. These findings highlight the importance of examining targeted biomarkers that measure unique aspects of child functioning and that are well-matched to proposed mechanisms of change. Autism Research 2019, 12: 779-793. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Biomarkers have the potential to provide important information about how and why early interventions effect positive change for young children with ASD. The current study suggests that eye-tracking measures of social attention can be used to track change in specific areas of development, such as language, and points to the need for targeted eye-tracking paradigms designed to measure specific behavioral changes. Such biomarkers could inform the development of optimal, individualized, and adaptive interventions for young children with ASD.
Assuntos
Atenção/fisiologia , Transtorno do Espectro Autista/fisiopatologia , Transtorno do Espectro Autista/terapia , Terapia Comportamental/métodos , Intervenção Educacional Precoce/métodos , Movimentos Oculares/fisiologia , Biomarcadores , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Motivação , Projetos Piloto , Comportamento Social , Resultado do TratamentoRESUMO
The symptoms of autism spectrum disorder are conceptualized to alter the quality of parent-children interactions, exposure to social learning exchanges, and ultimately the course of child development. There is evidence that modifying the procedures of Pivotal Response Treatment (PRT) to explicitly target social motivation enhances child engagement and parent-child synchrony in moment-by-moment exchanges. However, it is unclear if these within session improvements ultimately yield favorable developmental outcomes over time. The current investigation presents feasibility, utility, and preliminary efficacy data of a pilot randomized clinical trial (RCT) of a Pivotal Response Intervention for Social Motivation (PRISM) model. Data on participant factors, treatment protocol acceptability, and outcome variance and effect size are highly favorable and support the pursuit of a future, large scale RCT.
Assuntos
Transtorno Autístico/psicologia , Transtorno Autístico/terapia , Motivação , Relações Pais-Filho , Transtorno Autístico/diagnóstico , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Pais/psicologia , Projetos Piloto , Resultado do TratamentoRESUMO
OBJECTIVES: To compare US Food and Drug Administration (FDA) and European Medicines Agency (EMA) labeling for evidence based on patient-reported outcomes (PROs) of new oncology treatments approved by both agencies. METHODS: Oncology drugs and indications approved between 2012 and 2016 by both the FDA and the EMA were identified. PRO-related language and analysis reported in US product labels and drug approval packages and EMA summaries of product characteristics were compared for each indication. RESULTS: In total, 49 oncology drugs were approved for a total of 64 indications. Of the 64 indications, 45 (70.3%) included PRO data in either regulatory submission. No FDA PRO labeling was identified. PRO language was included in the summary of product characteristics for 21 (46.7%) of 45 indications. European Organisation for Research and Treatment of Cancer and Functional Assessment of Cancer Therapy measures were used frequently in submissions. FDA's comments suggest that aspects of study design (eg, open labels) or the validity of PRO measures was the primary reason for the lack of labeling based on PRO endpoints. Both agencies identified missing PRO data as problematic for interpretation. CONCLUSIONS: During this time period, the FDA and the EMA used different evidentiary standards to assess PRO data from oncology studies, with the EMA more likely to accept data from open-label studies and broad concepts such as health-related quality of life. An understanding of the key differences between the agencies may guide sponsor PRO strategy when pursuing labeling. Patient-focused proximal concepts are more likely than distal concepts to receive positive reviews.
Assuntos
Antineoplásicos/normas , Aprovação de Drogas , Rotulagem de Medicamentos/normas , Medidas de Resultados Relatados pelo Paciente , United States Food and Drug Administration/normas , Rotulagem de Medicamentos/legislação & jurisprudência , Europa (Continente)/epidemiologia , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto/normas , Estados Unidos/epidemiologia , United States Food and Drug Administration/legislação & jurisprudênciaRESUMO
We have previously shown that diabetes causes dysfunctional cerebral neovascularization that increases the risk for cerebrovascular disorders such as stroke and cognitive impairment. Pericytes (PCs) play a pivotal role in the angiogenic process through their interaction with the endothelial cells (EC). Yet, the role of PCs in dysfunctional cerebral neovascularization in diabetes is unclear. In the present study, we tested the hypothesis that the increased proangiogenic Ephrin-B2 signaling in PCs contributes to the dysfunctional cerebral neovascularization in diabetes. Type-II diabetes was induced by a combination of high fat diet and low dose streptozotocin injection in male Wistar rats. Selective in vivo Ephrin-B2 silencing in brain PCs was achieved using the stereotactic injection of adeno-associated virus (AAV) with NG2-promoter that expresses Ephrin-B2 shRNA. Neovascularization was assessed using vascular fluorescent dye stain. Novel object recognition (NOR) test was used to determine cognitive functions. Human brain microvascular pericytes HBMVPCs were grown in high glucose 25 mM and palmitate 200 uM (HG/Pal) to mimic diabetic conditions. Scratch migration and tube formation assays were conducted to evaluate PC/EC interaction and angiogenic functions in PC/EC co-culture. Diabetes increased the expression of Ephrin-B2 in the cerebrovasculature and pericytes. Concomitant increases in cerebral neovascularization parameters including vascular density, tortuosity and branching density in diabetic rats were accompanied by deterioration of cognitive function. Inhibition of Ephrin-B2 expression in PCs significantly restored cerebral vascularization and improved cognitive functions. HG/Pal increased PC/EC angiogenic properties in co-culture. Silencing Ephrin-B2 in PCs significantly reduced PC migration and PC/EC co-culture angiogenic properties. This study emphasizes the significant contribution of PCs to the pathological neovascularization in diabetes. Our findings introduce Ephrin-B2 signaling as a promising therapeutic target to improve cerebrovascular integrity in diabetes.