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BACKGROUND: Even though antithrombotic therapy has probably little or even negative effects on the well-being of people with cancer during their last year of life, deprescribing antithrombotic therapy at the end of life is rare in practice. It is often continued until death, possibly resulting in excess bleeding, an increased disease burden and higher healthcare costs. METHODS: The SERENITY consortium comprises researchers and clinicians from eight European countries with specialties in different clinical fields, epidemiology and psychology. SERENITY will use a comprehensive approach combining a realist review, flash mob research, epidemiological studies, and qualitative interviews. The results of these studies will be used in a Delphi process to reach a consensus on the optimal design of the shared decision support tool. Next, the shared decision support tool will be tested in a randomised controlled trial. A targeted implementation and dissemination plan will be developed to enable the use of the SERENITY tool across Europe, as well as its incorporation in clinical guidelines and policies. The entire project is funded by Horizon Europe. RESULTS: SERENITY will develop an information-driven shared decision support tool that will facilitate treatment decisions regarding the appropriate use of antithrombotic therapy in people with cancer at the end of life. CONCLUSIONS: We aim to develop an intervention that guides the appropriate use of antithrombotic therapy, prevents bleeding complications, and saves healthcare costs. Hopefully, usage of the tool leads to enhanced empowerment and improved quality of life and treatment satisfaction of people with advanced cancer and their care givers.
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Fibrinolíticos , Neoplasias , Humanos , Fibrinolíticos/uso terapéutico , Calidad de Vida , Neoplasias/tratamiento farmacológico , Cuidados Paliativos , Muerte , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Electric vehicles demand high charge and discharge rates creating potentially dangerous temperature rises. Lithium-ion cells are sealed during their manufacture, making internal temperatures challenging to probe1. Tracking current collector expansion using X-ray diffraction (XRD) permits non-destructive internal temperature measurements2; however, cylindrical cells are known to experience complex internal strain3,4. Here, we characterize the state of charge, mechanical strain and temperature within lithium-ion 18650 cells operated at high rates (above 3C) by means of two advanced synchrotron XRD methods: first, as entire cross-sectional temperature maps during open-circuit cooling and second, single-point temperatures during charge-discharge cycling. We observed that a 20-minute discharge on an energy-optimized cell (3.5 Ah) resulted in internal temperatures above 70 °C, whereas a faster 12-minute discharge on a power-optimized cell (1.5 Ah) resulted in substantially lower temperatures (below 50 °C). However, when comparing the two cells under the same electrical current, the peak temperatures were similar, for example, a 6 A discharge resulted in 40 °C peak temperatures for both cell types. We observe that the operando temperature rise is due to heat accumulation, strongly influenced by the charging protocol, for example, constant current and/or constant voltage; mechanisms that worsen with cycling because degradation increases the cell resistance. Design mitigations for temperature-related battery issues should now be explored using this new methodology to provide opportunities for improved thermal management during high-rate electric vehicle applications.
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BACKGROUND: Despite recommendations for nutritional risk screening of all inpatients, outpatients and care home residents, as well as work to assess clinician's experiences and the validity of tools, little attention has been paid to the experiences of patients undergoing nutritional screening. This review aims to synthesise systematically the current evidence regarding nutritional risk screening with respect to the experiences and views of patients, their families and carers. METHODS: A systematic search was performed in MEDLINE, Embase, PsychINFO, CINAHL, Web of Science and British Nursing Database (inception - July 2019); with screening terms related to malnutrition, screening tools and experience. Titles, abstracts and full-text papers were independently reviewed by two reviewers and then quality-appraised. Qualitative papers and quantitative surveys were included. A narrative review of surveys and a thematic framework synthesis of interviews were used to identify themes. RESULTS: Nine studies, including five qualitative interview papers, were included. Qualitative and quantitative study results were combined using a matrix chart to allow comparison. Surveyed participants reported processes of nutritional screening as acceptable. Three key themes emerged from qualitative data: (i) experience of nutritional screening; (ii) misunderstanding of malnutrition: of causes, role of screening and poor self-perception of risk; and (iii) barriers to and opportunities for change. CONCLUSIONS: Although the screening process is acceptable, patients' misunderstanding and poor knowledge regarding causes and consequences of malnutrition result in reduced risk perception and disbelief or disregard of nutritional screening results. Findings should inform policy and clinical practice, as well as highlight the known paucity of data regarding the effectiveness of screening on clinical outcomes.
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Cuidadores/psicología , Programas de Detección Diagnóstica , Dieta/psicología , Familia/psicología , Desnutrición/diagnóstico , Estado Nutricional , Pacientes/psicología , Actitud Frente a la Salud , Femenino , Humanos , Masculino , Evaluación NutricionalRESUMEN
OBJECTIVE: To develop a set of core outcomes to be minimally reported in trials on induction of labour. DESIGN: Two-round Delphi survey and consensus meeting. POPULATION: Four stakeholder groups: midwives, obstetricians, neonatologists, and women's representatives. METHODS: Protocol registered with COMET (Registration Number: 695). Stakeholders rated reported outcomes for importance (1-limited to 9-critical). The median rating of each outcome was calculated. The consensus criteria to include outcomes were as follows: ≥70% participants rated outcomes as critical and <15% rated outcomes as limited importance. Outcomes that did not achieve consensus were taken to round two and, if there was still no consensus, to the final consensus meeting. MAIN OUTCOME MEASURES: Outcomes in trials of induction of labour. RESULTS: Of the 159 invited participants, 54% (86/159) completed the first round, and 83% completed the second round (71/86). The core outcome set included 28 core outcomes in four domains: Short-term maternal outcomes (n = 18)-cardiorespiratory arrest, damage to internal organs, death, haemorrhage, hysterectomy, infection, intensive care admission, length of hospital stay, mode of delivery, need for more than one induction agent, oxytocin augmentation, postnatal depression, pulmonary embolus, satisfaction with care, stroke, time from induction to delivery, uterine hyperstimulation, uterine scar dehiscence/rupture; short-term offspring outcomes (n = 8)-admission to the neonatal unit, birth trauma, death, hypoxic ischaemic encephalopathy/need for therapeutic hypothermia, meconium aspiration syndrome, need for respiratory support, infection, and seizures; long-term maternal outcomes (n = 1)-operative pelvic floor repair; long-term offspring outcomes (n = 1)-disability including neurodevelopmental delay. CONCLUSION: Trials on induction of labour should include this core outcome set to standardise reporting. TWEETABLE ABSTRACT: International multistakeholder Delphi study identifies a core outcome set for trials on induction of labour.
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Ensayos Clínicos como Asunto , Determinación de Punto Final , Trabajo de Parto Inducido , Evaluación de Resultado en la Atención de Salud/métodos , Consenso , Técnica Delphi , Femenino , Humanos , Embarazo , Proyectos de Investigación/normas , Participación de los InteresadosRESUMEN
Essentials Congenital afibrinogenemia causes a potentially life-threatening bleeding and clotting tendency. Two human fibrinogen concentrates (HFCs) were compared in a randomized pharmacokinetic study. Bioequivalence was not shown for AUCnorm , which was significantly larger for the new HFC. Increases in clot strength were comparable, and no thromboses or deaths occurred in the study. SUMMARY: Background Human fibrinogen concentrate (HFC) corrects fibrinogen deficiency in congenital a-/hypofibrinogenemia. Objectives To assess pharmacokinetics (PK), effects on thromboelastometry maximum clot firmness (MCF), and safety of a new double virus-inactivated/eliminated, highly purified HFC vs. active control. Patients/Methods In this multinational, randomized, phase II, open-label, crossover study in 22 congenital afibrinogenemia patients aged ≥ 12 years, 70 mg kg-1 of new HFC (FIBRYGA, Octapharma AG) or control (Haemocomplettan® P/RiaSTAP™, CSL Behring GmbH) were administered, followed by crossover to the other concentrate. Fibrinogen activity, PK and MCF in plasma were assessed. Results The concentrates were not bioequivalent for the primary endpoint, AUCnorm (mean ratio, 1.196; 90% confidence interval [CI], 1.117, 1.281). Remaining PK parameters (Cmaxnorm , IVR, t1/2 , MRT) reflected bioequivalence between concentrates, except for clearance (mean ratio, 0.836; 90% CI, 0.781, 0.895) and Vss (mean ratio, 0.886; 90% CI, 0.791, 0.994). Mean AUCnorm was significantly larger for the new HFC (1.62 ± 0.45 vs. 1.38 ± 0.47 h kg g L-1 mg-1 , P = 0.0001) and mean clearance was significantly slower (0.665 ± 0.197 vs. 0.804 ± 0.255 mL h-1 kg-1 , P = 0.0002). Mean MCF increased from 0 mm to 9.68 mm (new HFC) and 10.00 mm (control) 1-hour post-infusion (mean difference, -0.32 mm; 95% CI, -1.70, 1.07, n.s.). No deaths, thromboses, viral seroconversions or serious related adverse events occurred. Conclusions Bioequivalence was not demonstrated for AUCnorm , clearance and Vss . Larger AUCnorm and slower clearance were observed for the new HFC. Remaining pharmacokinetic parameters reflected bioequivalence to control. Safety profiles and increases in clot strength were comparable between concentrates.
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Afibrinogenemia/tratamiento farmacológico , Coagulación Sanguínea/efectos de los fármacos , Coagulantes/administración & dosificación , Coagulantes/farmacocinética , Fibrinógeno/administración & dosificación , Fibrinógeno/farmacocinética , Adolescente , Adulto , Afibrinogenemia/sangre , Afibrinogenemia/diagnóstico , Afibrinogenemia/genética , Asia , Niño , Coagulantes/efectos adversos , Estudios Cruzados , Europa (Continente) , Femenino , Fibrinógeno/efectos adversos , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Modelos Biológicos , Equivalencia Terapéutica , Tromboelastografía , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
Essentials High-quality data are lacking on use of prophylaxis in adults with hemophilia and arthropathy. SPINART was a 3-year randomized clinical trial of late/tertiary prophylaxis vs on-demand therapy. Prophylaxis improved function, quality of life, activity and pain but not joint structure by MRI. Prophylaxis improves function but must start before joint bleeding onset to prevent arthropathy. SUMMARY: Background Limited data exist on the impact of prophylaxis on adults with severe hemophilia A and pre-existing joint disease. Objectives To describe 3-year bleeding, joint health and structure, health-related quality-of-life (HRQoL) and other outcomes from the open-label, randomized, multinational SPINART study. Patients/Methods Males aged 12-50 years with severe hemophilia A, ≥ 150 factor VIII exposure days, no inhibitors and no prophylaxis for > 12 consecutive months in the past 5 years were randomized to sucrose-formulated recombinant FVIII prophylaxis or on-demand therapy (OD). Data collected included total and joint bleeding events (BEs), joint structure (magnetic resonance imaging [MRI]), joint health (Colorado Adult Joint Assessment Scale [CAJAS]), HRQoL, pain, healthcare resource utilization (HRU), activity, and treatment satisfaction. Results Following 3 years of prophylaxis, adults maintained excellent adherence, with a 94% reduction in BEs despite severe pre-existing arthropathy; 35.7% and 76.2% of prophylaxis participants were bleed-free or had fewer than two BEs per year, respectively. As compared with OD, prophylaxis was associated with improved CAJAS scores (least squares [LS] mean, - 0.31 [n = 42] versus + 0.63 [n = 42]) and HAEMO-QoL-A scores (LS mean, + 3.98 [n = 41] versus - 6.00 [n = 42]), less chronic pain (50% decrease), and approximately two-fold less HRU; activity, Euro QoL-5D-3L (EQ-5D-3L) scores and satisfaction scores also favored prophylaxis. However, MRI score changes were not different for prophylaxis versus OD (LS mean, + 0.79 [n = 41] versus + 0.96 [n = 38]). Conclusions Over a period of 3 years, prophylaxis versus OD in adults with severe hemophilia A and arthropathy led to decreased bleeding, pain, and HRU, better joint health, activity, satisfaction, and HRQoL, but no reduction in structural arthropathy progression, suggesting that pre-existing joint arthropathy may be irreversible.
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Factor VIII/administración & dosificación , Hemartrosis/prevención & control , Hemofilia A/tratamiento farmacológico , Hemostasis/efectos de los fármacos , Hemostáticos/administración & dosificación , Articulaciones/efectos de los fármacos , Adolescente , Adulto , Artralgia/diagnóstico , Artralgia/etiología , Artralgia/prevención & control , Niño , Costo de Enfermedad , Esquema de Medicación , Factor VIII/efectos adversos , Hemartrosis/diagnóstico por imagen , Hemartrosis/etiología , Hemofilia A/sangre , Hemofilia A/complicaciones , Hemofilia A/diagnóstico , Hemostáticos/efectos adversos , Humanos , Articulaciones/diagnóstico por imagen , Imagen por Resonancia Magnética , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Dimensión del Dolor , Satisfacción del Paciente , Estudios Prospectivos , Calidad de Vida , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
Little is known about the impact of chronic breathlessness (modified Medical Research Council (mMRC) score ≥2 for most days, at least three of the last six months) on health-related quality of life (Short Form-12 (SF-12)). 3005 adults from randomly selected households were interviewed face-to-face in South Australia. mMRC ≥2 community prevalence was 2.9%. Adjusted analyses showed clinically meaningful and statistically significant decrements of physical and mental components of SF-12 (mean SF-12 summary scores in physical (-13.0 (-16.0 to -10.2)) and mental (-10.7 (-13.7 to -7.8)) components compared with people with mMRC=0) as chronic breathlessness severity increased, across five age groupings.
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Disnea/rehabilitación , Calidad de Vida , Adulto , Anciano , Enfermedad Crónica , Femenino , Estado de Salud , Humanos , Masculino , Salud Mental , Persona de Mediana Edad , Psicometría , Índice de Severidad de la EnfermedadRESUMEN
A Needs Assessment Tool (NAT) was developed previously to help clinicians identify the supportive/palliative needs of people with interstitial lung disease (ILD) (NAT:ILD). This letter presents barriers and facilitators to clinical implementation. Data from (1) a focus group of respiratory clinicians and (2) an expert consensus group (respiratory and palliative clinicians, academics, patients, carers) were analysed using Framework Analysis. Barriers related to resources and service reconfiguration, and facilitators to clinical need, structure, objectiveness, flexibility and benefits of an 'aide-memoire'. Identified training needs included communication skills and local service knowledge. The NAT:ILD was seen as useful, necessary and practical in everyday practice.
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Grupos Focales , Enfermedades Pulmonares Intersticiales/terapia , Evaluación de Necesidades , Consenso , Humanos , Cuidados PaliativosRESUMEN
OBJECTIVES: Home is considered the preferred place of death for many, but patients with haematological malignancies (leukaemias, lymphomas and myeloma) die in hospital more often than those with other cancers and the reasons for this are not wholly understood. We examined preferred and actual place of death among people with these diseases. METHODS: The study is embedded within an established population-based cohort of patients with haematological malignancies. All patients diagnosed at two of the largest hospitals in the study area between May 2005 and April 2008 with acute myeloid leukaemia, diffuse large B-cell lymphoma or myeloma, who died before May 2010 were included. Data were obtained from medical records and routine linkage to national death records. RESULTS: 323 deceased patients were included. A total of 142 (44%) had discussed their preferred place of death; 45.8% wanted to die at home, 28.2% in hospital, 16.9% in a hospice, 5.6% in a nursing home and 3.5% were undecided; 63.4% of these died in their preferred place. Compared to patients with evidence of a discussion, those without were twice as likely to have died within a month of diagnosis (14.8% vs 29.8%). Overall, 240 patients died in hospital; those without a discussion were significantly more likely to die in hospital than those who had (p≤0.0001). Of those dying in hospital, 90% and 75.8% received haematology clinical input in the 30 and 7â days before death, respectively, and 40.8% died in haematology areas. CONCLUSIONS: Many patients discussed their preferred place of death, but a substantial proportion did not and hospital deaths were common in this latter group. There is scope to improve practice, particularly among those dying soon after diagnosis. We found evidence that some people opted to die in hospital; the extent to which this compares with other cancers is of interest.
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Actitud Frente a la Muerte , Neoplasias Hematológicas/epidemiología , Prioridad del Paciente , Estudios de Cohortes , Inglaterra/epidemiología , Femenino , Neoplasias Hematológicas/psicología , Humanos , Leucemia Mieloide Aguda/epidemiología , Leucemia Mieloide Aguda/psicología , Linfoma de Células B Grandes Difuso/epidemiología , Linfoma de Células B Grandes Difuso/psicología , Masculino , Mieloma Múltiple/epidemiología , Mieloma Múltiple/psicología , Cuidados Paliativos , Medicina EstatalRESUMEN
INTRODUCTION: The implementation of early long-term, regular clotting factor concentrate (CFC) replacement therapy ('prophylaxis') has made it possible to offer boys with haemophilia a near normal life. Many different regimens have reported favourable results, but the optimum treatment regimens have not been established and the cost of prophylaxis is very high. Both for optimizing treatment and reimbursement issues, there is a need to provide objective evidence of both short- and long-term results and benefits of prophylactic regimens. AIMS: This report presents a critical review of outcome measures for use in the assessment of musculoskeletal health in persons with haemophilia according to the International Classification of Functioning, Disability and Health (ICF). This framework considers structural and functional changes, activities and participation in a context of both personal and environmental factors. METHODS: Results were generated by a combination of a critical review of available literature plus expert opinion derived from a two day consensus conference between 48 health care experts from different disciplines involved in haemophilia assessment and care. Outcome tools used in haemophilia were reviewed for reliability and validity in different patient groups and for resources required. RESULTS AND CONCLUSION: Recommendations for choice of outcome tools were made according to the ICF domains, economic setting, and reason for use (clinical or research). The next step will be to identify a 'core' set of outcome measures for use in clinical care or studies evaluating treatment.
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Hemofilia A/terapia , Evaluación de Resultado en la Atención de Salud/métodos , HumanosRESUMEN
Essentials Studies characterizing neutralizing antibodies (inhibitors) in hemophilia B (HB) are lacking. The current study describes anti-factor (F) IX antibody profiles in 37 patients who have HB. Anti-FIX IgG4 levels exhibited a strong positive correlation with Nijmegen-Bethesda results. These data will help to more clearly define, predict, and treat alloantibody formation in HB. SUMMARY: Background Hemophilia B (HB) is an inherited bleeding disorder caused by the absence or dysfunction of coagulation factor IX (FIX). A subset of patients who have HB develop neutralizing alloantibodies (inhibitors) against FIX after infusion therapy. HB prevalence and the proportion of patients who develop inhibitors are much lower than those for hemophilia A (HA), which makes studies of inhibitors in patients with HB challenging due to the limited availability of samples. As a result, there is a knowledge gap regarding HB inhibitors. Objective Evaluate the largest group of patients with inhibitor-positive HB studied to date to assess the relationship between anti-FIX antibody profiles and inhibitor formation. Methods A fluorescence immunoassay was used to detect anti-FIX antibodies in plasma samples from 37 patients with HB. Results Assessments of antibody profiles showed that anti-FIX IgG1-4 , IgA, and IgE were detected significantly more often in patients with a positive Nijmegen-Bethesda assay (NBA). All NBA-positive samples were positive for IgG4 . Anti-FIX IgG4 demonstrated a strong correlation with the NBA, while correlations were significant, yet more moderate, for anti-FIX IgG1-2 and IgA. Conclusions The anti-FIX antibody profile in HB patients who develop inhibitors is diverse and correlates well with the NBA across immunoglobulin (sub)class, and anti-FIX IgG4 is particularly relevant to functional inhibition. The anti-FIX fluorescence immunoassay may serve as a useful tool to confirm the presence of antibodies in patients who have low positive NBA results and to more clearly define, predict, and treat alloantibody formation against FIX.
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Anticuerpos Neutralizantes/inmunología , Factor IX/inmunología , Técnica del Anticuerpo Fluorescente , Hemofilia B/inmunología , Inmunoglobulinas/inmunología , Adolescente , Adulto , Anciano , Coagulación Sanguínea , Estudios de Casos y Controles , Niño , Preescolar , Estudios Transversales , Humanos , Inmunoglobulina G/inmunología , Lactante , Isoanticuerpos/inmunología , Persona de Mediana Edad , Prevalencia , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
PURPOSE: Breathlessness is a major cause of suffering in advanced cancer. We aimed to determine the symptom trajectory in people with advanced cancer and to identify those at increased risk of experiencing higher or increasing breathlessness over time in advanced cancer. PATIENTS AND METHODS: This was an analysis of the multinational, prospective, longitudinal European Palliative Care Cancer Symptom (EPCCS) study. We included adults with confirmed incurable cancer enrolled in palliative care, with prospective monthly assessments for up to 6 months, withdrawal or death, whichever came first. Symptom severity (0-10 numerical rating scales) was analyzed using multivariate random coefficients regression. RESULTS: A total of 1689 patients (50 % women; mean age 65.7 ± [standard deviation; SD] 12.4 years) were included. Main diagnoses were digestive (31 %), lung (20 %), and breast (17 %) cancers. During a median follow-up of 62 (interquartile range, 0 to 133) days, 65 % were breathless at some point and 36 % of all patients reported moderate/severe breathlessness. The group mean (1.6 points; SD, 2.4) was unchanged over time, but the severity varied markedly between patients and over time. Independent predictors for worse breathlessness were COPD, lung cancer, living alone, lung metastases, anxiety, pain, depression, and lower performance status. Predictors of worsening breathlessness over time were low performance status (p = 0.039) and moderate to severe pain (p = 0.012). CONCLUSION: In the largest longitudinal clinical study to date in advanced cancer alone, breathlessness was frequent and associated with factors including respiratory disease, other concurrent unpleasant symptoms, and impaired performance status. Increase in severity over time was predicted by performance status and pain.
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Disnea/etiología , Neoplasias/complicaciones , Anciano , Femenino , Humanos , Internacionalidad , Estudios Longitudinales , Masculino , Neoplasias/mortalidad , Neoplasias/patología , Estudios Prospectivos , Factores de RiesgoRESUMEN
INTRODUCTION: Haemophilia A is treated with FVIII, either prophylactically or on demand. Prophylaxis is the gold standard in children and evidence is accumulating in adults. AIMS/METHODS: The aim of this analysis was to compare prophylaxis vs. on-demand treatment with Nuwiq(®) (Human-cl rhFVIII), a new-generation rFVIII expressed in a human cell line, in previously treated patients (PTPs) with severe haemophilia A. Data were analysed from two similarly designed, multinational, prospective, open-label studies with similar inclusion and exclusion criteria and comparable patient demographics. Human-cl rhFVIII was administered either prophylactically in a study of 32 adults or on-demand in a study of 22 patients (20 adults and two adolescents). RESULTS: Patients treated prophylactically experienced 36 bleeds compared with 997 bleeds in patients treated on-demand (mean observation periods: 180 and 335 days respectively). Based on a negative binomial regression model, annualized bleeding rate (ABR) during prophylaxis was 2.30 (95% CI: 1.54, 3.44) compared with 57.74 (95% CI: 43.36, 76.91) during on-demand treatment, which equates to a 96% lower ABR during prophylaxis. 'Excellent' or 'good' efficacy in the treatment of bleeds was achieved with Human-cl rhFVIII in 100% of 28 evaluated bleeds during the prophylaxis study and 94.5% of 985 evaluated bleeds during the on-demand study. No inhibitors, treatment-related serious adverse events or severe adverse events were recorded during prophylaxis or or-demand treatment. CONCLUSIONS: Prophylaxis with Human-cl rhFVIII reduces recurrent bleeding in adult PTPs with severe haemophilia A and adds further supportive evidence for the benefits of prophylaxis in adults.
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Coagulantes/uso terapéutico , Factor VIII/uso terapéutico , Hemofilia A/tratamiento farmacológico , Adolescente , Adulto , Anciano , Niño , Esquema de Medicación , Factor VIII/genética , Factor VIII/metabolismo , Hemofilia A/patología , Hemorragia/epidemiología , Hemorragia/prevención & control , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Proteínas Recombinantes/biosíntesis , Proteínas Recombinantes/genética , Proteínas Recombinantes/uso terapéutico , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: Immune tolerance induction (ITI) in patients with congenital hemophilia A is successful in up to 70%. Although there is growing understanding of predictors of response to ITI, the probability and predictors of inhibitor recurrence after successful ITI are not well understood. OBJECTIVES: To determine the association of clinical characteristics, particularly adherence to factor VIII (FVIII) prophylaxis after ITI, with inhibitor recurrence in patients with hemophilia A who were considered tolerant after ITI. METHODS: In this multicenter retrospective cohort study, 64 subjects with FVIII level < 2% who were considered successfully tolerant after ITI were analyzed to estimate the cumulative probability of inhibitor recurrence using the Kaplan-Meier method. The association of clinical characteristics with inhibitor recurrence was assessed using logistic regression. RESULTS: A recurrent inhibitor titer ≥ 0.6 BU mL(-1) occurred at least once in 19 (29.7%) and more than once in 12 (18.8%). The probability of any recurrent inhibitor at 1 and 5 years was 12.8% and 32.5%, respectively. Having a recurrent inhibitor was associated with having received immune modulation during ITI (odds ratio [OR] 3.8, 95% confidence interval [CI] 1.2-22.4) and FVIII recovery of < 85% at the end of ITI (OR 2.6, 95% CI 1.3-5.9) but was not associated with adherence to post-ITI prophylactic FVIII infusion (OR 0.5, 95% CI 0.06-4.3). CONCLUSIONS: The use of immune modulation therapy during ITI and lower FVIII recovery at the end of ITI appear to be associated with an increased risk of inhibitor recurrence after successful ITI. Adherence to post-ITI prophylactic FVIII infusions is not a major determinant of recurrence.
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Factor VIII/inmunología , Hemofilia A/inmunología , Terapia de Inmunosupresión , Isoanticuerpos/biosíntesis , Niño , Preescolar , Factor VIII/administración & dosificación , Factor VIII/uso terapéutico , Femenino , Hemofilia A/tratamiento farmacológico , Humanos , Inmunosupresores/uso terapéutico , Lactante , Isoanticuerpos/sangre , Isoanticuerpos/inmunología , Estimación de Kaplan-Meier , Modelos Logísticos , Masculino , Cumplimiento de la Medicación , Modelos Inmunológicos , Plasmaféresis , Puntaje de Propensión , Proteínas Recombinantes/inmunología , Proteínas Recombinantes/uso terapéutico , Recurrencia , Estudios Retrospectivos , Factores de TiempoRESUMEN
BACKGROUND: Randomized controlled trials (RCTs) on pediatric venous thromboembolism (VTE) treatment have been challenged by unsubstantiated design assumptions and/or poor accrual. Pilot/feasibility (P/F) studies are critical to future RCT success. METHODS: The Kids-DOTT trial is a multicenter RCT investigating non-inferiority of a 6-week (shortened) versus 3-month (conventional) duration of anticoagulation in patients aged < 21 years with provoked venous thrombosis. Primary efficacy and safety endpoints are symptomatic recurrent VTE at 1 year and anticoagulant-related, clinically relevant bleeding. In the P/F phase, 100 participants were enrolled in an open, blinded-endpoint, parallel-cohort RCT design. RESULTS: No eligibility violations or randomization errors occurred. Of the enrolled patients, 69% were randomized, 3% missed the randomization window, and 28% were followed in prespecified observational cohorts for completely occlusive thrombosis or persistent antiphospholipid antibodies. Retention at 1 year was 82%. Interobserver agreement between local and blinded central determination of venous occlusion by imaging at 6 weeks after diagnosis was strong (k-statistic = 0.75; 95% confidence interval [CI] 0.48-1.0). The primary efficacy and safety event rates were 3.3% (95% CI 0.3-11.5%) and 1.4% (95% CI 0.03-7.4%). CONCLUSIONS: The P/F phase of the Kids-DOTT trial has demonstrated the validity of vascular imaging findings of occlusion as a randomization criterion, and defined randomization, retention and endpoint rates to inform the fully powered RCT.
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Anticoagulantes/uso terapéutico , Trombosis de la Vena/tratamiento farmacológico , Adolescente , Anticoagulantes/administración & dosificación , Anticoagulantes/efectos adversos , Niño , Preescolar , Colorado/epidemiología , Diagnóstico por Imagen , Determinación de Punto Final/métodos , Estudios de Factibilidad , Femenino , Florida/epidemiología , Hemorragia/inducido químicamente , Hemorragia/epidemiología , Humanos , Lactante , Masculino , Variaciones Dependientes del Observador , Proyectos Piloto , Garantía de la Calidad de Atención de Salud , Recurrencia , Reproducibilidad de los Resultados , Proyectos de Investigación , Método Simple Ciego , Factores de Tiempo , Trombosis de la Vena/diagnóstico , Adulto JovenRESUMEN
Current guidelines recommend delaying the start of immune tolerance induction (ITI) until the inhibitor titre is <10 Bethesda units (BU) to improve success. This study was conducted to evaluate ITI outcome relative to time to start ITI from inhibitor detection irrespective of inhibitor titre. Data were retrospectively collected from two U.S. haemophilia treatment centres (HTCs) on subjects with severe/moderate factor VIII (FVIII) deficiency with inhibitors who underwent ITI. Outcomes were defined pragmatically: success--negative inhibitor titre and ability to use FVIII concentrate for treatment/bleed prevention; partial success--inhibitor titre 1 to <5 BU with ability to use FVIII concentrate for treatment of bleeding; failure--ITI ongoing >3 years without achieving success/partial success, or ITI discontinuation. Fifty-eight subjects were included; 32 of 39 (82%) with high-responding inhibitor (HRI) achieved success, 7 failed. HRI subjects were subdivided based on ITI start time: 23/39 subjects started within 1 month of detection and 22/23 (96%) achieved success. Of these 23, 13 started ITI with an inhibitor titre ≥10 BU; all were successes. Eleven of 39 HRI subjects had an interval >6 months until ITI start; 7 (64%) achieved success. Time from inhibitor detection to ITI start may play a critical role in outcome. A titre ≥10 BU at ITI start did not influence outcome in subjects when ITI was initiated within 1 month of detection. Prompt ITI should be considered a viable therapeutic option in newly identified patients with inhibitors regardless of current inhibitor titre.
Asunto(s)
Inhibidores de Factor de Coagulación Sanguínea/inmunología , Factor VIII/inmunología , Hemofilia A/tratamiento farmacológico , Hemofilia A/inmunología , Tolerancia Inmunológica , Isoanticuerpos/inmunología , Adolescente , Adulto , Inhibidores de Factor de Coagulación Sanguínea/sangre , Niño , Preescolar , Factor VIII/genética , Factor VIII/uso terapéutico , Hemofilia A/complicaciones , Hemofilia A/diagnóstico , Humanos , Lactante , Isoanticuerpos/sangre , Mutación , Recurrencia , Índice de Severidad de la Enfermedad , Resultado del Tratamiento , Estados Unidos , Adulto JovenRESUMEN
OBJECTIVE: To develop and implement a methodology for capturing complete haematological malignancy pathway data and use it to identify variations in specialist palliative care (SPC) referrals. METHODS: In our established UK population-based patient cohort, 323 patients were diagnosed with acute myeloid leukaemia, diffuse large B-cell lymphoma or myeloma between May 2005 and April 2008, and died before April 2010. A day-by-day calendar approach was devised to collect pathway data, including SPC referrals, to supplement routinely collected information on clinical presentation, diagnosis, treatment, response, and date and place of death. RESULTS: 155 (47.9%) of the 323 patients had at least one SPC referral. The likelihood of referral increased with survival (OR 6.58, 95% CIs 3.32 to 13.03 for patients surviving ≥1â year compared to ≤1â month from diagnosis), and varied with diagnosis (OR 1.96, CIs 1.15 to 3.35 for myeloma compared to acute myeloid leukaemia). Compared to patients dying in hospital, those who died at home or in a hospice were also more likely to have had an SPC referral (OR 3.07, CIs 1.59 to 5.93 and 4.74, CIs 1.51 to 14.81, respectively). No associations were found for age and sex. CONCLUSIONS: Our novel approach efficiently captured pathway data and SPC referrals, revealing evidence of greater integration between haematology and SPC services than previously reported. The likelihood of referral was much higher among those dying outside hospital, and variations in practice were observed by diagnosis, emphasising the importance of examining diseases individually.