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Adoptive cell therapy (ACT), particularly chimeric antigen receptor (CAR)-T cell therapy, has emerged as a promising approach for targeting and treating rare oncological conditions. The orphan medicinal product designation by the European Union (EU) plays a crucial role in promoting development of medicines for rare conditions according to the EU Orphan Regulation.This regulatory landscape analysis examines the evolution, regulatory challenges, and clinical outcomes of genetically engineered ACT, with a focus on CAR-T cell therapies, based on the European Medicines Agency's Committee for Orphan Medicinal Products review of applications evaluated for orphan designation and maintenance of the status over a 10-year period. In total, 30 of 36 applications were granted an orphan status, and 14 subsequently applied for maintenance of the status at time of marketing authorisation or extension of indication. Most of the products were autologous cell therapies using a lentiviral vector and were developed for the treatment of rare haematological B-cell malignancies. The findings revealed that 80% (29/36) of the submissions for orphan designation were supported by preliminary clinical data showing a potential efficacy of the candidate products and an added clinical benefit over currently authorised medicines for the proposed orphan condition. Notably, in 89% (32/36) of the cases significant benefit of the new products was accepted based on a clinically relevant advantage over existing therapies. Twelve of fourteen submissions reviewed for maintenance of the status at time of marketing authorisation or extension of indication demonstrated significant benefit of the products over existing satisfactory methods of treatment within the approved therapeutic indications, but one of the applications was withdrawn during the regulatory evaluation.This article summarises the key findings related to the use of engineered ACT, primarily CAR-T cell therapies, in targeting and treating rare cancers in the EU. It emphasises the importance of use of clinical data in supporting medical plausibility and significant benefit at the stage of orphan designation and highlights the high success rate for these products in obtaining initial orphan designations and subsequent maintaining the status at the time of marketing authorisation or extension of indication.
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Imunoterapia Adotiva , Produção de Droga sem Interesse Comercial , Doenças Raras , Humanos , Doenças Raras/terapia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/uso terapêutico , União Europeia , Neoplasias/terapia , Terapia Baseada em Transplante de Células e Tecidos/métodosRESUMO
In 2000, the European Union (EU) introduced the orphan pharmaceutical legislation to incentivize the development of medicinal products for rare diseases. The Committee for Orphan Medicinal Products (COMP), the European Medicines Agency committee responsible for evaluation of applications for orphan designation (OD), received an increasing flow of applications in the field of gene therapies over the last years. Here, the COMP has conducted a descriptive analysis of applications regarding gene therapies in non-oncological rare diseases, with respect to (a) targeted conditions and their rarity, (b) characteristics of the gene therapy products proposed for OD, with a focus on the type of vector used, and (c) regulatory aspects pertaining to the type of sponsor and development, by examining the use of available frameworks offered in the EU such as protocol assistance and PRIME. It was noted that gene therapies are being developed by sponsors from different backgrounds. Most conditions being targeted are monogenic, the most common being lysosomal disorders, and with a very low prevalence. Generally, adeno-associated viral vectors were being used to deliver the transgene. Finally, sponsors are not frequently using the incentives that may support the development and the reasons for this are unclear.
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Produção de Droga sem Interesse Comercial , Doenças Raras , Humanos , Doenças Raras/genética , Doenças Raras/terapia , União Europeia , Terapia Genética , RNA , Aprovação de DrogasRESUMO
BACKGROUND: This study aimed to explore predictors associated with intermediate (six months) and post-intervention (24 months) increases in daily steps among people with prediabetes or type 2 diabetes participating in a two-year pedometer intervention. METHODS: A secondary analysis was conducted based on data from people with prediabetes or type 2 diabetes from two intervention arms of the randomised controlled trial Sophia Step Study. Daily steps were measured with an ActiGraph GT1M accelerometer. Participants were divided into two groups based on their response to the intervention: Group 1) ≥ 500 increase in daily steps or Group 2) a decrease or < 500 increase in daily steps. Data from baseline and from six- and 24-month follow-ups were used for analysis. The response groups were used as outcomes in a multiple logistic regression together with baseline predictors including self-efficacy, social support, health-related variables, intervention group, demographics and steps at baseline. Predictors were included in the regression if they had a p-value < 0.2 from bivariate analyses. RESULTS: In total, 83 participants were included. The mean ± SD age was 65.2 ± 6.8 years and 33% were female. At six months, a lower number of steps at baseline was a significant predictor for increasing ≥ 500 steps per day (OR = 0.82, 95% CI 0.69-0.98). At 24 months, women had 79% lower odds of increasing ≥ 500 steps per day (OR = 0.21, 95% CI 0.05-0.88), compared to men. For every year of increase in age, the odds of increasing ≥ 500 steps per day decreased by 13% (OR = 0.87, 95% CI 0.78-0.97). Also, for every step increase in baseline self-efficacy, measured with the Self-Efficacy for Exercise Scale, the odds of increasing ≥ 500 steps per day increased by 14% (OR = 1.14, 95% CI 1.02-1.27). CONCLUSIONS: In the Sophia Step Study pedometer intervention, participants with a lower number of steps at baseline, male gender, lower age or higher baseline self-efficacy were more likely to respond to the intervention with a step increase above 500 steps per day. More knowledge is needed about factors that influence response to pedometer interventions. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02374788.
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Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Caminhada , Humanos , Diabetes Mellitus Tipo 2/terapia , Masculino , Feminino , Estado Pré-Diabético/terapia , Idoso , Pessoa de Meia-Idade , Caminhada/estatística & dados numéricos , Autoeficácia , AcelerometriaRESUMO
OBJECTIVE: The aim of the study was to evaluate transanal irrigation (TAI) as a treatment for low anterior resection syndrome (LARS). BACKGROUND: LARS is a bowel disorder that is common after sphincter preserving rectal cancer surgery. Despite symptomatic medical treatment of LARS many patients still experience bowel symptoms that may have a negative impact on quality of life (QoL). TAI is a treatment strategy, of which the clinical experience is promising but scientific evidence is limited. MATERIALS AND METHODS: A multicenter randomized trial comparing TAI (intervention) with conservative treatment (control) was performed. Inclusion criteria were major LARS, age above 18 years, low anterior resection with anastomosis and a defunctioning stoma as primary surgery, >6 months since stoma reversal, anastomosis without signs of leakage or stricture, and no signs of recurrence at 1-year follow-up. The primary endpoint was differences in bowel function at 12-month follow-up measured by LARS score, Cleveland Clinic Florida Fecal Incontinence Score, and 4 study-specific questions. The secondary outcome was QoL. RESULTS: A total of 45 patients were included, 22 in the TAI group and 23 in the control group. Follow-up was available for 16 and 22 patients, respectively. At 12 months, patients in the TAI group reported significantly lower LARS scores (22.9 vs 32.4; P =0.002) and Cleveland Clinic Florida Fecal Incontinence Score (6.4 vs 9.2; P =0.050). In addition, patients in the TAI group also scored significantly higher QoL [8 of 16 European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) QoL aspects] compared with the control group. CONCLUSIONS: The results confirm our clinical experience that TAI reduces symptoms included in LARS and improves QoL.
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Incontinência Fecal , Neoplasias Retais , Humanos , Adolescente , Neoplasias Retais/cirurgia , Qualidade de Vida , Síndrome de Ressecção Anterior Baixa , Complicações Pós-Operatórias , Tratamento ConservadorRESUMO
OBJECTIVE: To be regularly physically active is of major importance for the health of people with metabolic risk factors. Many of these persons are insufficiently active and in need of support. This study aimed to explore barriers and facilitators perceived by health care professionals' within Swedish primary care in their work to support persons with metabolic risk factors to increase their physical activity. DESIGN: A qualitative design with focus group discussions was used. The data were analysed using qualitative content analysis with a manifest, inductive approach. SETTING: Primary health care in five Swedish healthcare regions. SUBJECTS: Nine physiotherapists, ten physicians and five nurses participated in six digital focus group discussions including two to six participants. RESULTS: Barriers and facilitators to supporting persons with metabolic risk factors to increase their physical activity were found within four generic categories, where the barriers and facilitators related to each generic category: 'Patient readiness for change', 'Supporting the process of change', 'The professional role', and 'The organisation of primary care'. CONCLUSION: The findings suggests that barriers and facilitators for supporting patients with metabolic risk factors can be found at several levels within primary care, from individual patient and the health care professionals to the organisational level. In the primary care setting, this should be highlighted when implementing support to increase physical activity in people with metabolic risk factors.KEY POINTSHealth care professionals within primary care are in a position to support people with metabolic risk factors to increase their physical activity.Barriers and facilitators to support the patients should be addressed at several levels within primary care.The study highlights factors on multiple levels such as professional responsibility, organisational prioritisation and resources, and the challenge to motivate behaviour change.
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Exercício Físico , Pessoal de Saúde , Humanos , Pesquisa Qualitativa , Fatores de Risco , Atenção Primária à SaúdeRESUMO
BACKGROUND: Changes in Swedish university students' lifestyle behaviors during the COVID-19 pandemic are unknown. This study aimed to assess physical activity, sitting time, meal frequency and risk substance use (alcohol, tobacco, and illicit use of drugs) in Swedish university students before and during the first six months of the COVID-19 pandemic, for all and stratified by age and sex. METHODS: Data were obtained from the Sustainable University Life cohort study in which web-based surveys were sent to university students repeatedly for one year. Baseline assessment (before the pandemic) was between August 2019-March 2020, follow-up 1 (FU1) between March-June 2020, and follow-up 2 (FU2) between June-September 2020. Participants reported weekly minutes of physical activity, daily sitting hours, meal frequency by weekly intake of different meals, and motivation for eating irregularly, if so. Also, harmful use of alcohol, tobacco and illicit drugs was assessed. Population means and differences with 95% confidence intervals (95% CI) in lifestyle behaviors between time points were calculated with Generalized Estimating Equations. RESULTS: 1877 students (73% women, mean age 26.5 years) answered the baseline survey. Weekly exercise decreased by -5.7 min (95% CI: -10.0, -1.5) and -7.7 min (95% CI: -12.6, -2.8) between baseline and FU1 and FU2, respectively. Weekly daily activities increased by 5.6 min (95% CI: 0.3, 11.7) and 14.2 min (95% CI: 7.9, 20.5) between baseline and FU1 and FU2. Daily sitting time decreased by -1.4 h (95% CI: -1.7, -1.2) between baseline and FU2. Breakfast intake increased by 0.2 days per week (95% CI: 0.1, 0.3) between baseline and FU2. Lunch intake decreased by -0.2 days per week (95% CI: -0.2, -0.1) between baseline and FU1 and by -0.2 days per week (95% CI: -0.3, -0.0) between baseline and FU2. Dinner intake decreased by -0.1 days per week (95% CI: -0.2, -0.0) between baseline and both FU1 and FU2. Only minor differences in risk substance use were observed. Similar changes were observed in analyses stratified by age and sex. CONCLUSIONS: Lifestyle behaviors in Swedish university students slightly improved during the first six months of the COVID-19 pandemic compared to before. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04465435 . 10/07/2020.
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COVID-19 , Pandemias , Adulto , COVID-19/epidemiologia , Estudos de Coortes , Comportamento Alimentar , Feminino , Humanos , Estilo de Vida , Masculino , Estudantes , Suécia/epidemiologia , UniversidadesRESUMO
BACKGROUND: This aimed to evaluate the effects of self-monitoring of daily steps with or without counselling support on HbA1c, other cardiometabolic risk factors and objectively measured physical activity (PA) during a 2-year intervention in a population with prediabetes or type 2 diabetes. METHODS: The Sophia Step Study was a three-armed parallel randomised controlled trial. Participants with prediabetes or type 2 diabetes were recruited in a primary care setting. Allocation (1:1:1) was made to a multi-component intervention (self-monitoring of steps with counselling support), a single-component intervention (self-monitoring of steps without counselling support) or standard care. Data were collected for primary outcome HbA1c at baseline and month 6, 12, 18 and 24. Physical activity was assessed as an intermediate outcome by accelerometer (ActiGraph GT1M) for 1 week at baseline and the 6-, 12-, 18- and 24-month follow-up visits. The intervention effects were evaluated by a robust linear mixed model. RESULTS: In total, 188 subjects (64, 59, 65 in each group) were included. The mean (SD) age was 64 (7.7) years, BMI was 30.0 (4.4) kg/m2 and HbA1c was 50 (11) mmol/mol, 21% had prediabetes and 40% were female. The dropout rate was 11% at 24 months. Effect size (CI) for the primary outcome (HbA1c) ranged from -1.3 (-4.8 to 2.2) to 1.1 (-2.4 to 4.6) mmol/mol for the multi-component vs control group and from 0.3 (-3.3 to 3.9) to 3.1 (-0.5 to 6.7) mmol/mol for the single-component vs control group. Effect size (CI) for moderate-to-vigorous physical activity ranged from 8.0 (0.4 to 15.7) to 11.1 (3.3 to 19.0) min/day for the multi-component vs control group and from 7.6 (-0.4 to 15.6) to 9.4 (1.4 to 17.4) min/day for the single-component group vs control group. CONCLUSION: This 2-year intervention, including self-monitoring of steps with or without counselling, prevented a decrease in PA but did not provide evidence for improved metabolic control and cardiometabolic risk factors in a population with prediabetes or type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02374788 . Registered 2 March 2015-Retrospectively registered.
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Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Aconselhamento , Diabetes Mellitus Tipo 2/prevenção & controle , Exercício Físico , Feminino , Humanos , Pessoa de Meia-Idade , Estado Pré-Diabético/terapia , Atenção Primária à SaúdeRESUMO
BACKGROUND: Sedentary behaviour has been closely linked to metabolic and cardiovascular health and is therefore of importance in disease prevention. A user-friendly tool for assessment of sitting time is thus needed. Previous studies concluded that the present tools used to assess a number of sedentary behaviours are more likely to overestimate sitting than single-item questions which often underestimate sitting time, and that categorical answering options are recommended. In line with this, the single-item question with categorical answering options, SED-GIH, was developed. The aim of this study was to investigate the criterion validity of the SED-GIH question using activPAL3 micro as the criterion measure. The second aim was to evaluate the test-retest reliability of the SED-GIH questionnaire. METHOD: In the validity section of this study, 284 middle-aged adults answered a web questionnaire, which included SED-GIH, wore activPAL and filled in a diary log for one week. Spearman's rho assessed the relationship between the SED-GIH answers and the daily average sitting time as monitored by the activPAL (activPAL-SIT), a Weighted Kappa assessed the agreement, ANOVA assessed differences in activPAL-SIT between the SED-GIH answer categories, and a Chi2 compared the proportions of hazardous sitters between the different SED-GIH answer categories. In the reliability section, 95 elderly participants answered the SED-GIH question twice, with a mean interval of 5.2 days. The reliability was assessed with ICC and a weighted Kappa. RESULTS: The SED-GIH question correlated moderately with activPAL-SIT (rho = 0.31), with a poor agreement (weighted Kappa 0.12). In total, 40.8% underestimated and 22.2% overestimated their sitting time. The ANOVA showed significant differences in activPAL-SIT between the different SED-GIH answer categories (p < 0.001). The Chi2 showed a significant difference in proportion of individuals sitting more than 10 h per day within each SED-GIH answer category. ICC for the test-retest reliability of SED-GIH was excellent with ICC = 0.86, and the weighted Kappa showed an agreement of 0.77. CONCLUSIONS: The unanchored single item SED-GIH question showed excellent reliability but poor validity in the investigated populations. Validity and reliability of SED-GIH is in line with other questionnaires that are commonly used when assessing sitting time.
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Postura Sentada , Inquéritos e Questionários , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Comportamento Sedentário , TempoRESUMO
Inherited Retinal Dystrophies (IRD) are diverse rare diseases that affect the retina and lead to visual impairment or blindness. Research in this field is ongoing, with over 60 EU orphan medicinal products designated in this therapeutic area by the Committee for Orphan Medicinal Products (COMP) at the European Medicines Agency (EMA). Up to now, COMP has used traditional disease terms, like retinitis pigmentosa, for orphan designation regardless of the product's mechanism of action. The COMP reviewed the designation approach for IRDs taking into account all previous Orphan Designations (OD) experience in IRDs, the most relevant up to date scientific literature and input from patients and clinical experts. Following the review, the COMP decided that there should be three options available for orphan designation concerning the condition: i) an amended set of OD groups for therapies that might be used in a broad spectrum of conditions, ii) a gene-specific designation for targeted therapies, and iii) an occasional term for products that do not fit in the above two categories. The change in the approach to orphan designation in IRDs caters for different scenarios to allow an optimum approach for future OD applications including the option of a gene-specific designation. By applying this new approach, the COMP increases the regulatory clarity, efficiency, and predictability for sponsors, aligns EU regulatory tools with the latest scientific and medical developments in the field of IRDs, and ensures that all potentially treatable patients will be included in the scope of an OD.
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BACKGROUND: This study aimed to identify distinct profiles of physical activity (PA) patterns among individuals with prediabetes or type 2 diabetes participating in a two-year PA trial and to investigate predictors of the profiles. METHODS: Data (n = 168, collected 2013-2020) from the cohort of a randomized trial aimed at increasing PA in individuals with prediabetes and type 2 diabetes were used. PA and sedentary behaviours were assessed by waist-worn ActiGraph GT1M accelerometers at baseline and at 6, 12, 18 and 24 months. Fifteen PA and sedentary variables were entered into a latent class mixed model for multivariate longitudinal outcomes. Multinominal regression analysis modelled profile membership based on baseline activity level, age, gender, BMI, disease status and group randomisation. RESULTS: Two profiles of PA patterns were identified: "Increased activity" (n = 37, 22%) included participants increasing time in PA and decreasing sedentary time. "No change in activity" (n = 131, 78%) included participants with no or minor changes. "Increased activity" were younger (p = 0.003) and more active at baseline (p = 0.011), compared to "No change in activity". No other predictor was associated with profile membership. CONCLUSIONS: A majority of participants maintained PA and sedentary patterns over two years despite being part of a PA intervention. Individuals improving PA patterns were younger and more active at baseline.
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Diabetes Mellitus Tipo 2 , Estado Pré-Diabético , Diabetes Mellitus Tipo 2/epidemiologia , Exercício Físico , Feminino , Humanos , Análise de Classes Latentes , Estudos Longitudinais , Masculino , Estado Pré-Diabético/epidemiologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Comportamento SedentárioRESUMO
OBJECTIVE: To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels. METHODS AND RESULTS: In Npc1(-/-) mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1(-/-) mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. TGs were reduced in Npc1(-/-) mouse serum and hepatocytes. In Npc1(-/-) hepatocytes, the incorporation of [3H]oleic acid and [3H]acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [3H]carbons into cholesterol was increased. Inhibition of cholesterol synthesis normalized TG synthesis, content, and secretion in Npc1(-/-) hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest P=8.7 x 10(-4) for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals. CONCLUSIONS: This study provides evidence of the following: (1) in mice, loss of NPC1 function reduces hepatocyte TG content and secretion by increasing the metabolic flux of carbons into cholesterol synthesis; and (2) common variation in NPC1 contributes to serum TG levels in humans.
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Proteínas de Transporte/genética , Colesterol/biossíntese , Hepatócitos/metabolismo , Fígado/metabolismo , Glicoproteínas de Membrana/genética , Doença de Niemann-Pick Tipo C/genética , Polimorfismo de Nucleotídeo Único , Proteínas/genética , Triglicerídeos/sangue , Ácido Acético/metabolismo , Idoso , Animais , Estudos de Coortes , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Proteína C1 de Niemann-Pick , Doença de Niemann-Pick Tipo C/metabolismo , Ácido Oleico/metabolismo , Fenótipo , Proteínas/metabolismo , Fatores de TempoRESUMO
Twenty years of orphan regulation in Europe have now elapsed, with almost 2,400 orphan designated medicinal products and more than 190 orphan products authorised in the EU. Alongside the evolution in understanding of rare diseases, considerable regulatory knowledge has also been accumulated regarding the level of evidence that would support inclusion of products into the framework. This article reviews publications and regulatory documents pertaining to orphan medicinal product designation in the EU and discusses the general expectations in submitted applications as reflected in the current regulatory practise. Important elements to recommend granting a European orphan designation are the key considerations of orphan condition, medical plausibility, seriousness, and prevalence, while significant benefit is also assessed when there are authorised medicinal products for the sought indication. This review attempts to clarify the specific concepts currently used in that regard and discusses how the available data can be used to justify the criteria for designation. Moving away from theoretical expectations or assumptions, it stresses that the applications have to be complemented with nosological and epidemiological justifications pertaining to the proposed condition, as well as relevant data in specific non-clinical in vivo models or in affected patients to support inclusion into the orphan scheme.
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Since the implementation of the EU Orphan Regulation in 2000, the Committee for Orphan Medicinal Products at the European Medicines Agency has been evaluating the benefits of proposed orphan medicines vs. satisfactory treatment methods. This type of evaluation is foreseen in the Orphan Regulation as the orphan designation criterion called the "significant benefit." In this article, based on 20 years of experience, we provide a commentary explaining what is considered a satisfactory method of treatment in the context of the EU Orphan Regulation and for the purpose of the assessment of significant benefit. We discuss the challenges posed by continuously changing clinical practise, which is associated with the increasing number of treatment options, evolving nature of medicinal therapeutic indications and our understanding of them.
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Difficulties with emotion regulation have been identified as an underlying mechanism in mental health. This pilot study aimed at examining whether group skills training in emotion regulation for adolescents and parents as an add-on intervention was feasible in an outpatient child and adolescent psychiatric clinic. We also investigated if the treatment increased knowledge and awareness of emotions and their functions, increased emotion regulation skills and decreased self-reported symptoms of anxiety and depression. Six skills training groups were piloted with a total of 20 adolescents and 21 adults. The treatment consisted of five sessions dealing with psychoeducation about emotions and emotion regulation skills training. Paired-samples t test was used to compare differences between before-and-after measures for adolescents and parents separately. The primary outcome measure, Difficulties in Emotion Regulation Scale, showed significant improvement after treatment for both adolescents and parents. For adolescents, measures of alexithymia were significantly reduced. Also, emotional awareness was significantly increased. Measures of depression and anxiety did not change. In conclusion, group skills training as an add-on treatment can be feasible and effective but further studies are needed.
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Regulação Emocional , Transtornos Mentais/psicologia , Psicoterapia de Grupo , Adolescente , Adulto , Depressão/psicologia , Feminino , Humanos , Masculino , Pais , Projetos PilotoRESUMO
BACKGROUND: Emotion regulation difficulties appear to play a role in the development and maintenance of several eating disorders. This pilot study aimed at examining whether a short add-on group skills training in emotion regulation for young adults with different eating disorders was feasible in a psychiatric clinical setting. We also investigated if the treatment increased knowledge of emotions, and decreased self-reported difficulties with emotion regulation, alexithymia, symptoms of eating disorder, anxiety and depression, as well as clinical impairment. METHODS: Six skills training groups were piloted with a total of 29 participants (M = 21.41 years, SD = 1.92). The treatment consisted of five sessions dealing with psychoeducation about emotions and emotion regulation skills training. Paired samples t-test was used to compare differences between before-and-after measures. RESULTS: The primary outcomes measures difficulties in emotion regulation (p < 0.001) and alexithymia (p < 0.001) showed significant improvement after treatment. The total eating disorder score (p = 0.009) was also significantly reduced, as was clinical impairment (p < 0.001). Acceptance/valued direction, identifying primary emotions and learning about secondary emotions was rated as especially helpful. CONCLUSIONS: This preliminary pilot study showed that group training targeting emotion regulation skills was feasible and appreciated by participants, as well as being potentially promising as an adjunctive treatment for different eating disorders. Further controlled studies are needed. TRIAL REGISTRATION: The study was retrospectively registered NCT04148014 on October 30th 2019.
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An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Most rare diseases still lack approved treatments despite major advances in research providing the tools to understand their molecular basis, as well as legislation providing regulatory and economic incentives to catalyse the development of specific therapies. Addressing this translational gap is a multifaceted challenge, for which a key aspect is the selection of the optimal therapeutic modality for translating advances in rare disease knowledge into potential medicines, known as orphan drugs. With this in mind, we discuss here the technological basis and rare disease applicability of the main therapeutic modalities, including small molecules, monoclonal antibodies, protein replacement therapies, oligonucleotides and gene and cell therapies, as well as drug repurposing. For each modality, we consider its strengths and limitations as a platform for rare disease therapy development and describe clinical progress so far in developing drugs based on it. We also discuss selected overarching topics in the development of therapies for rare diseases, such as approval statistics, engagement of patients in the process, regulatory pathways and digital tools.
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Aprovação de Drogas , Desenvolvimento de Medicamentos , Reposicionamento de Medicamentos/estatística & dados numéricos , Produção de Droga sem Interesse Comercial/estatística & dados numéricos , Doenças Raras/tratamento farmacológico , HumanosRESUMO
To maintain orphan drug status at the time of market authorization, orphan medicinal products (OMPs) need to be assessed for all criteria, including significant benefit, by the Committee for Orphan Medicinal Products (COMP) of the European Medicines Agency (EMA). Subsequently, health technology assessment (HTA) organizations evaluate the same OMPs in their relative effectiveness assessments (REAs). This review investigates the similarities and differences between the two frameworks for six HTA organizations, including the European Network for HTA. We discuss differences between both assessment frameworks within five domains (clinical evidence used, patient population, intervention, comparators, and outcome measures) for all drugs. Five illustrative cases studies were selected for a qualitative review.
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Produção de Droga sem Interesse Comercial/legislação & jurisprudência , Avaliação da Tecnologia Biomédica/legislação & jurisprudência , Europa (Continente) , Política de Saúde/legislação & jurisprudência , HumanosRESUMO
This review provides an overview of nonclinical in vivo models that can be used to support orphan designation in selected rare infectious diseases in Europe, with the aim to inform and stimulate the planning of nonclinical development in this area of often neglected diseases.
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Doenças Transmissíveis/tratamento farmacológico , Doenças Negligenciadas/tratamento farmacológico , Produção de Droga sem Interesse Comercial , Doenças Raras/tratamento farmacológico , Animais , HumanosRESUMO
BACKGROUND: Dendritic cells (DCs) are central in allergy as regulators of the Th1/Th2 balance. We have recently demonstrated a unique transcriptional profile of DCs in patients with ongoing allergy compared with healthy subjects and shown that crosstalk between DCs and memory T cells affects the transcriptional profile of T cells. However, the transcriptional profile of DCs educated by T cells in allergy is unknown. METHODS: In the present study, we have examined the transcriptional profiles of DCs after stimulation with grass pollen allergens, Phleum pratense and coculture with autologous CD4+ memory T cells using high-density microarray. Protein analysis was performed using flow cytometry and recombinant antibody protein microarrays. Patients with allergic rhinitis and healthy subjects were compared. RESULTS: The results reveal a distinct T-cell-induced DC profile in atopic individuals. Accordingly, about 170 genes were upregulated and 40 genes downregulated. For example, the chemokine receptor CXCR4 and the tumor necrosis factor receptor CD30 were upregulated in DCs derived from atopic donors, and this could also be verified at the protein level. CONCLUSION: We conclude that crosstalk between CD4+ memory T cells and autologous DCs induces transcriptional reprogramming in DCs. This finding suggests that T cells have a key instructive role in educating DCs in Th2-type responses.