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Aim: This study aimed to improve comparative effectiveness estimates and discuss challenges encountered through the application of Bayesian borrowing (BB) methods to augment an external control arm (ECA) constructed from real-world data (RWD) using historical clinical trial data in first-line non-small-cell lung cancer (NSCLC). Materials & methods: An ECA for a randomized controlled trial (RCT) in first-line NSCLC was constructed using ConcertAI Patient360™ to assess chemotherapy with or without cetuximab, in the bevacizumab-inappropriate subpopulation. Cardinality matching was used to match patient characteristics between the treatment arm (cetuximab + chemotherapy) and ECA. Overall survival (OS) was assessed as the primary outcome using Cox proportional hazards (PH). BB was conducted using a static power prior under a Weibull PH parameterization with borrowing weights from 0.0 to 1.0 and augmentation of the ECA from a historical control trial. Results: The constructed ECA yielded a higher overall survival (OS) hazard ratio (HR) (HR = 1.53; 95% CI: 1.21-1.93) than observed in the matched population of the RCT (HR = 0.91; 95% CI: 0.73-1.13). The OS HR decreased through the incorporation of BB (HR = 1.30; 95% CI: 1.08-1.54, borrowing weight = 1.0). BB was applied to augment the RCT control arm via a historical control which improved the precision of the observed HR estimate (1.03; 95% CI: 0.86-1.22, borrowing weight = 1.0), in comparison to the matched population of the RCT alone. Conclusion: In this study, the RWD ECA was unable to successfully replicate the OS estimates from the matched population of the selected RCT. The inability to replicate could be due to unmeasured confounding and variations in time-periods, follow-up and subsequent therapy. Despite these findings, we demonstrate how BB can improve precision of comparative effectiveness estimates, potentially aid as a bias assessment tool and mitigate challenges of traditional methods when appropriate external data sources are available.
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Teorema de Bayes , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/terapia , Masculino , Femenino , Persona de Mediana Edad , Cetuximab/uso terapéutico , Cetuximab/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano , Investigación sobre la Eficacia Comparativa/métodos , Ensayos Clínicos Controlados Aleatorios como Asunto/métodos , Modelos de Riesgos ProporcionalesRESUMEN
BACKGROUND: With the introduction of investigational human epidermal growth factor receptor 2 (HER2) targeting treatments, thorough understanding of breast cancer with different HER2 expression levels is critical. The aim of this study was to compare clinicopathologic characteristics and survival of patients with metastatic breast cancer according to the level of HER2 expression. METHODS: Women with distant metastatic breast cancer during 2008-2016 were selected from PALGA, the Dutch Pathology Registry, and linked to the PHARMO Database Network. Breast cancer samples were categorised as HER2 immunohistochemistry score 0 (IHC0), HER2-low or HER2+. RESULTS: Among women with hormone receptor (HR) positive metastatic breast cancer (n = 989), 373 (38%) cancers were HER2 IHC0, 472 (48%) were HER2-low and 144 (15%) were HER2+. Among HR negative patients (n = 272), the proportion of HER2 IHC0, HER2-low and HER2+ was 110 (40%), 104 (38%) and 58 (21%) respectively. Within the HR + cohort, patients with HER2 IHC0 or HER2-low cancer were significantly older compared to HER2+ patients. This age difference was not seen in the HR-cohort. The localisation of distant metastases differed significantly between HER2 IHC0 or HER2-low versus HER2+ cases. Survival rates did not differ markedly by subtypes. CONCLUSION: Substantial proportion of patients had a HER2-low breast cancer. No clear differences in survival were found when comparing HER2 and HR status. Getting more granular insights in the level of HER2 expression and addressing HER2-low as a separate category could help to assess the impact of emerging treatment strategies. Therefore, more detailed information on HER2 expression should be routinely reported.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Pronóstico , Estudios de Cohortes , Receptor ErbB-2/metabolismo , Mama/patologíaRESUMEN
OBJECTIVES: The development of accelerated approval programs for high morbidity and unmet need conditions has driven the use of single-arm studies in drug development. Regulatory and health technology assessment (HTA) agencies are recognizing that high-quality external control arms (ECAs), built using real-world data, can reduce uncertainties arising from single-arm studies. This review compared 7 case studies of regulatory and HTA agencies' evaluations of oncology ECAs. METHODS: Food and Drug Administration multidisciplinary reviews for oncology submissions from 2014 to 2021 were screened to identify 7 cases (2 blinatumomab indications, avelumab, and erdafitinib, entrectinib, trastuzumab deruxtecan, and idecabtagene vicleucel) with ECAs to support efficacy claims. Regulatory (Food and Drug Administration, European Medicines Agency, Health Canada) and HTA (pan-Canadian Oncology Drug Review, National Institute for Health and Care Excellence, Federal Joint Committee, Haute Autorité de Santé, and Pharmaceutical Benefits Advisory Committee) submissions for these cases were reviewed. The decision makers' ECA critiques and the level of influence on the decision were analyzed and categorized. RESULTS: Across case studies, selection bias and confounding were the most common ECA critiques. Nevertheless, agreement in critiques between and among regulators and HTA bodies was low. ECA influence on agencies' decisions also varied. CONCLUSIONS: Evaluating the same ECA evidence, agencies focused on methodologic issues (ie, selection bias and confounding), but were often not aligned on their critiques. Further research is needed to fully characterize how agencies evaluate ECAs. This study is a first step in critically evaluating agencies' critiques of ECAs and highlights the need for future guidance development around ECA design and generation.
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Oncología Médica , Evaluación de la Tecnología Biomédica , Humanos , Estados Unidos , Canadá , InvestigaciónRESUMEN
Aim: To describe initial treatment patterns and survival of patients diagnosed with non-small-cell lung cancer (NSCLC) in Denmark, before immune checkpoint inhibitor and later-generation tyrosine kinase inhibitor use. Patients & methods: Adults diagnosed with incident NSCLC (2005-2015; follow-up: 2016). Initial treatments and overall survival (OS) are reported. Results: 31,939 NSCLC patients (51.6% stage IV) were included. Increasing use of curative radiotherapy/chemoradiation for stage I, II/IIIA and IIIB NSCLC coincided with improved 2-year OS. Systemic anticancer therapy use increased for patients with stage IV non-squamous NSCLC (53.0-60.6%) but not squamous NSCLC (44.9-47.3%). 1-year OS improved in patients with stage IV non-squamous NSCLC (23-31%) but not squamous NSCLC (22-25%). Conclusion: Trends indicated improved OS as treatments evolved between 2005 and 2015, but the effect was limited to 1-year OS in stage IV disease.
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Carcinoma de Pulmón de Células no Pequeñas/terapia , Neoplasias Pulmonares/terapia , Mortalidad/tendencias , Adolescente , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/diagnóstico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Quimioradioterapia Adyuvante/métodos , Quimioradioterapia Adyuvante/estadística & datos numéricos , Dinamarca/epidemiología , Femenino , Estudios de Seguimiento , Historia del Siglo XXI , Humanos , Pulmón/patología , Pulmón/cirugía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Mortalidad/historia , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/estadística & datos numéricos , Estadificación de Neoplasias , Neumonectomía/estadística & datos numéricos , Estudios Retrospectivos , Resultado del Tratamiento , Adulto JovenRESUMEN
INTRODUCTION: SCAN-LEAF, part of the I-O Optimise initiative, is a retrospective, longitudinal study investigating the epidemiology, clinical care, and outcomes for patients with NSCLC in Scandinavia. We report overall survival (OS) trends for patients diagnosed with NSCLC in Sweden and Denmark between 2005 and 2015. METHODS: Swedish and Danish cohorts were established by linking national registries. Data on all adults diagnosed with incident NSCLC from January 1, 2005, to December 31, 2015, were included. For temporal analyses of OS trends, patients were stratified by TNM stage and histology. RESULTS: Between 2005 and 2015, a total of 30,067 and 31,939 patients from Sweden and Denmark, respectively, were diagnosed with NSCLC; the most common histological subtype was nonsquamous cell carcinoma (56.9% and 53.0%) and 48.4% and 51.6% were diagnosed at stage IV. Over the study period, significant improvements in short-term survival (1 y) were observed for patients with nonsquamous cell carcinoma in both countries, regardless of disease stage at diagnosis; however, improvements in longer-term survival (5 y) were limited to patients with stage I and II disease only. Conversely, among patients with squamous cell histology, improvements in short-term survival were only observed for stage I disease in Sweden and stage IIIA disease in Denmark, while significant improvements in longer-term survival were seen only for stage IIIA NSCLC in both countries. CONCLUSIONS: Despite some survival improvements between 2005 and 2015, an unmet need remains for patients with advanced NSCLC, particularly those with squamous cell histology. Future analyses will evaluate the impact of newer treatments on OS in NSCLC.
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BACKGROUND: Comorbidity is of significant concern in multiple sclerosis (MS). Few population-based studies have reported conditions occurring in MS after diagnosis, especially in contemporary cohorts. OBJECTIVE: To explore incident comorbidity, mortality and hospitalizations in MS, stratified by age and sex. METHODS: In a Swedish population-based cohort study 6602 incident MS patients (aged ≥18 years) and 61,828 matched MS-free individuals were identified between 1 January 2008 and 31 December 2016, using national registers. Incidence rates (IRs) and incidence rate ratios (IRRs) with 95% CI were calculated for each outcome. RESULTS: IRs of cardiovascular disease (CVD) were higher among MS patients than MS-free individuals, (major adverse CVD: IRR 1.42; 95% CI 1.12-1.82; hemorrhagic/ischemic stroke: 1.46; 1.05-2.02; transient ischemic attack: 1.65; 1.09-2.50; heart failure: 1.55; 1.15-2.10); venous thromboembolism: 1.42; 1.14-1.77). MS patients also had higher risks of several non-CVDs such as autoimmune conditions (IRR 3.83; 3.01-4.87), bowel dysfunction (2.16; 1.86-2.50), depression (2.38; 2.11-2.68), and fractures (1.32; 1.19-1.47), as well as being hospitalized and to suffer from CVD-related deaths ((1.91; 1.00-3.65), particularly in females (3.57; 1.58-8.06)). CONCLUSION: MS-patients experience a notable comorbidity burden which emphasizes the need for integrated disease management in order to improve patient care and long-term outcomes of MS.
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BACKGROUND: Multiple sclerosis (MS) patients have an increased risk of infections, but few population-based studies have reported infections occurring in MS in the years immediately after diagnosis. OBJECTIVE: To explore incident infections in MS, stratified by age and sex. METHODS: In a Swedish population-based cohort study 6602 incident MS patients (aged ≥18 years), matched at diagnosis with 61,828 matched MS-free individuals were identified between 1st January 2008 and 31st December 2016, using national registers. Incidence rates (IR) and incidence rate ratios (IRR) with 95% CI were calculated for each outcome. RESULTS: The IRRs were 2.54 (95% CI 2.28-2.83) for first serious infection and 1.61 (1.52-1.71) for first non-serious infection. Compared with MS-free individuals, MS patients had higher IRs for skin, respiratory/throat infections, pneumonia/influenza, bacterial, viral, and fungal infections, with the highest IRR observed for urinary tract/kidney infections (2.44; 2.24-2.66). The cumulative incidence for most of these infections was higher among MS patients than MS-free individuals, both 0 to <5 and 5 to <9 years after index date. CONCLUSION: The burden of infections around the time of MS diagnosis and subsequent infection risk, underscore the need for careful considerations regarding the risk-benefit across different disease-modifying therapies.
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Esclerosis Múltiple , Adolescente , Adulto , Estudios de Cohortes , Humanos , Incidencia , Esclerosis Múltiple/epidemiología , Medición de Riesgo , Factores de Riesgo , Suecia/epidemiologíaRESUMEN
PURPOSE: Estimating disease incidence based on secondary data requires a look-back period to exclude patients with pre-existing disease from the incidence risk set. However, the optimal length of the look-back period and its impact on incidence rates are often unknown. We studied the impact of the length of the look-back period on incidence rates of 24 different chronic diseases. METHODS: Everyone residing in Sweden between January 1, 2005 and December 31, 2013 were identified from national registries and followed up to 2 years (through December 31, 2015). Outcome events were identified from inpatient and outpatient hospital contacts and incidence rates were calculated per 100 000 person-years. The length of the look-back period was varied with 6-month increments, starting at 6 months. The maximum look-back period of 9 years was used as reference period. RESULTS: There were 7 943 807 individuals with a look-back period of at least 9 years (mean age 46.5 years) and a mean follow-up time of 1.97 years. Incidence rates were higher across all diseases when restricting the look-back to 1 year compared to 9 years, with a magnitude of overestimation of the incidence rates between 13% (temporal arteritis) and 174% (type 1 diabetes). However, for most diseases the effect of extending the look-back period beyond 3-5 years appeared comparably small. CONCLUSIONS: This study illustrates how short look-back periods cause overestimation of the incidence rates of chronic diseases, suggesting that sensitivity analyses with respect to look-back period are considered, particularly using data sources with limited information on past medical history.
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Enfermedad Crónica/epidemiología , Farmacoepidemiología/métodos , Adulto , Estudios de Cohortes , Conjuntos de Datos como Asunto , Humanos , Incidencia , Persona de Mediana Edad , Sistema de Registros/estadística & datos numéricos , Suecia/epidemiología , Factores de Tiempo , Adulto JovenRESUMEN
BACKGROUND: The electronic medical record (EMR) offers unique possibilities for clinical research, but some important patient attributes are not readily available due to its unstructured properties. We applied text mining using machine learning to enable automatic classification of unstructured information on smoking status from Swedish EMR data. METHODS: Data on patients' smoking status from EMRs were used to develop 32 different predictive models that were trained using Weka, changing sentence frequency, classifier type, tokenization, and attribute selection in a database of 85,000 classified sentences. The models were evaluated using F-score and accuracy based on out-of-sample test data including 8500 sentences. The error weight matrix was used to select the best model, assigning a weight to each type of misclassification and applying it to the model confusion matrices. The best performing model was then compared to a rule-based method. RESULTS: The best performing model was based on the Support Vector Machine (SVM) Sequential Minimal Optimization (SMO) classifier using a combination of unigrams and bigrams as tokens. Sentence frequency and attributes selection did not improve model performance. SMO achieved 98.14% accuracy and 0.981 F-score versus 79.32% and 0.756 for the rule-based model. CONCLUSION: A model using machine-learning algorithms to automatically classify patients' smoking status was successfully developed. Such algorithms may enable automatic assessment of smoking status and other unstructured data directly from EMRs without manual classification of complete case notes.
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Registros Electrónicos de Salud , Aprendizaje Automático , Procesamiento de Lenguaje Natural , Fumar , Tabaquismo/diagnóstico , Algoritmos , Automatización , Teorema de Bayes , Minería de Datos , Reacciones Falso Positivas , Humanos , Informática Médica , Variaciones Dependientes del Observador , Reconocimiento de Normas Patrones Automatizadas , Curva ROC , Reproducibilidad de los Resultados , Proyectos de Investigación , Programas Informáticos , Máquina de Vectores de Soporte , Suecia/epidemiología , Tabaquismo/epidemiologíaRESUMEN
Objectives: Lisdexamfetamine dimesylate (LDX) is approved in some European countries for the second-line treatment of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents when response to previous methylphenidate (MPH) treatment is considered clinically inadequate, and as a first-line treatment in adults. Limited evidence exists on the real-world use of LDX across Europe. This retrospective study evaluated LDX drug utilization patterns from eight European countries for up to 5 years. Methods: Data were collected from national registries (Denmark, Finland, Norway, Sweden), electronic medical records (Germany, Spain, United Kingdom), and prescription databases (Switzerland) in eight European countries. Patients were included if they were prescribed LDX at least once since the LDX launch date in each country. Demographic and clinical characteristics, and LDX prescription data included patient age and gender, a recorded diagnosis of ADHD, the number of prescriptions per participant, previous MPH prescription recorded, average daily dose, treatment persistence, discontinuation, and switching of medications. Results: Overall, information for 59,292 patients (437,272 LDX prescriptions) was analyzed. Most patients were male (58.1%-84.3%) and fewer than 1% were under 6 years of age. Extensive use of LDX in adults was observed in four countries (Denmark, Finland, Norway, and Sweden), including countries where LDX was not approved for this age group. Most patients had a recorded diagnosis of ADHD (61.9%-95.4%). The mean number of prescriptions per patient ranged from 5.4 to 10.0. At least 79.6% of patients with ADHD had a recorded previous MPH prescription. Mean duration of LDX exposure ranged from 233.1 to 410.8 days. The average daily dose of LDX was ≤70 mg/day for most patients (79.4%-99.7%). The 5-year discontinuation rate ranged from 22.8% to 70.6% and was below 40% for most countries. The proportion of patients switching from LDX to other medications was ≤33.8. Conclusions: This study provides the first long-term, real-world information related to LDX use by children, adolescents, and adults in Europe in the 5 years since its first launch in the region. Most LDX prescriptions fulfilled label requirements regarding a recorded diagnosis of ADHD before treatment initiation, previous MPH use, and an average daily dose of ≤70 mg/day. LDX was largely prescribed within the indicated age range, although adult use of LDX was high in some countries where LDX is not approved for this population.
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Trastorno por Déficit de Atención con Hiperactividad/tratamiento farmacológico , Estimulantes del Sistema Nervioso Central/uso terapéutico , Utilización de Medicamentos/estadística & datos numéricos , Dimesilato de Lisdexanfetamina/uso terapéutico , Adolescente , Adulto , Niño , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND Improved understanding of the impact of kidney transplantation on healthcare resource use/costs and loss of productivity could aid decision making about funding allocation and resources needed for the treatment of chronic kidney disease in stage 5. MATERIAL AND METHODS This was a retrospective study utilizing data from Swedish national health registers of patients undergoing kidney transplantation. Primary outcomes were renal disease-related healthcare resource utilization and costs during the 5 years after transplantation. Secondary outcomes included total costs and loss of productivity. Regression analysis identified factors that influenced resource use, costs, and loss of productivity. RESULTS During the first year after transplantation, patients (N=3120) spent a mean of 25.7 days in hospital and made 21.6 outpatient visits; mean renal disease-related total cost was 66,014. During the next 4 years, resource use was approximately 70% (outpatient) to 80% (inpatient) lower, and costs were 75% lower. Before transplantation, 62.8% were on long-term sick leave, compared with 47.4% 2 years later. Higher resource use and costs were associated with age <10 years, female sex, graft from a deceased donor, prior hemodialysis, receipt of a previous transplant, and presence of comorbidities. Higher levels of sick leave were associated with female sex, history of hemodialysis, and type 1 diabetes. Overall 5-year graft survival was 86.7% (95% CI 85.3-88.2%). CONCLUSIONS After the first year following transplantation, resource use and related costs decreased, remaining stable for the next 4 years. Demographic and clinical factors, including age <10 years, female sex, and type 1 diabetes were associated with higher costs and resource use.
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Utilización de Instalaciones y Servicios/tendencias , Costos de la Atención en Salud/tendencias , Trasplante de Riñón/economía , Ausencia por Enfermedad/tendencias , Adolescente , Adulto , Anciano , Niño , Preescolar , Utilización de Instalaciones y Servicios/economía , Utilización de Instalaciones y Servicios/estadística & datos numéricos , Femenino , Estudios de Seguimiento , Supervivencia de Injerto , Costos de la Atención en Salud/estadística & datos numéricos , Humanos , Lactante , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Estudios Retrospectivos , Ausencia por Enfermedad/economía , Ausencia por Enfermedad/estadística & datos numéricos , Suecia , Adulto JovenRESUMEN
OBJECTIVE: To estimate the cost of dementia care and its relation to dependence. METHOD: Disease severity and health care resource utilization was retrieved from the Swedish National Study on Aging and Care. Informal care was assessed with the Resource Utilization in Dementia instrument. A path model investigates the relationship between annual cost of care and dependence, cognitive ability, functioning, neuropsychiatric symptoms, and comorbidities. RESULTS: Average annual cost among patients diagnosed with dementia was 43,259, primarily incurred by accommodation. Resource use, that is, institutional care, community care, and accommodation, and corresponding costs increased significantly by increasing dependency. Path analysis showed that cognitive ability, functioning, and neuropsychiatric symptoms were significantly correlated with dependence, which in turn had a strong impact on annual cost. DISCUSSION: This study confirms that cost of dementia care increases with dependence and that the impact of other disease indicators is mainly mediated by dependence.
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Costo de Enfermedad , Demencia/economía , Actividades Cotidianas , Anciano , Anciano de 80 o más Años , Cognición , Demencia/terapia , Femenino , Costos de la Atención en Salud , Humanos , Masculino , Autonomía Personal , SueciaRESUMEN
BACKGROUND AND OBJECTIVES: Acute otitis media (AOM) not only affects childhood quality of life (QoL), but can also affect parental QoL. We adapted a previously published questionnaire on the effect of childhood recurrent ear, nose and throat infections on parental QoL for use with AOM and used it in an observational, multicentre, prospective study of children with AOM. METHODS: The AOM-specific parental QoL questionnaire grouped 15 items into emotional, daily disturbance, total and overall parental QoL impact scores. The questionnaire was assessed using item-convergent and item-discriminant validity criteria and internal consistency reliability; and then used with parents of children aged <6 years diagnosed with AOM at 73 practices in Germany, Italy, Spain, Sweden and the UK. Bivariate analyses explored the differences in mean parental QoL impact scores by various characteristics. RESULTS: The questionnaire demonstrated good to excellent internal consistency reliability for the various components (Cronbach's α 0.82-0.97). There were 1419 AOM episodes among 5882 healthy children over 1 year, of which 1063 episodes (74.9%) among 852 children had a questionnaire. Parents reported interrupted sleep (68.4%), worry (51.0%), altered daily schedule (44.6%) and less leisure time (41.5%) with a score ≥ 3 (1 = least to 5 = most impact). Factors that adversely affected parental QoL included: increased parental perception of AOM severity, younger child age and multiple AOM episodes. CONCLUSIONS: The AOM-specific parental QoL questionnaire demonstrated good performance across five European countries. Parental QoL was affected by childhood AOM proportionally to severity, number of episodes and younger child age.
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Costo de Enfermedad , Otitis Media/psicología , Padres/psicología , Calidad de Vida , Enfermedad Aguda , Niño , Preescolar , Europa (Continente) , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Estudios Prospectivos , Recurrencia , Reproducibilidad de los Resultados , Encuestas y Cuestionarios , Reino UnidoRESUMEN
Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting preinvasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type-distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type-distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N = 49), adenosquamous carcinoma (ASC, N = 104), and various adenocarcinoma subtypes (ADC, N = 461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV-positivity rates were observed in AIS (93.9%), ASC (85.6%), and usual-type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear-cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric-type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV-positive ADC. There were variations in HPV prevalence and ADC type-distribution by country. Age at diagnosis differed by ADC subtype, with usual-type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57 and 66 years). Moreover, HPV-positive ADC cases were younger than HPV-negative ADC. The six years difference in median age for women with AIS compared to those with usual-type ADC suggests that cytological screening for AIS may be suboptimal. Since the great majority of CGN are HPV16/18/45-positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV.
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Carcinoma Adenoescamoso/epidemiología , Infecciones por Papillomavirus/epidemiología , Displasia del Cuello del Útero/epidemiología , Neoplasias del Cuello Uterino/epidemiología , Adulto , Anciano , Carcinoma Adenoescamoso/virología , Estudios Transversales , Europa (Continente)/epidemiología , Femenino , Papillomavirus Humano 16/genética , Humanos , Persona de Mediana Edad , Infecciones por Papillomavirus/virología , Prevalencia , Estudios Retrospectivos , Neoplasias del Cuello Uterino/virología , Adulto Joven , Displasia del Cuello del Útero/virologíaRESUMEN
OBJECTIVE: Human papillomavirus (HPV) genotype distribution in invasive cervical cancers may differ by geographic region. The primary objective of this study was to estimate HPV-genotype distribution in Danish women with a diagnosis of invasive cervical cancer. DESIGN: Observational, cross-sectional. POPULATION: Danish data from a multi-center study undertaken in 12 European countries. METHODS: A total of 342 archived fixed tissue samples with diagnosis of invasive cervical cancer from the Departments of Pathology in the University Hospitals in Hvidovre and Odense, Denmark, were anonymized and shipped to a central laboratory for histopathology review and PCR testing for HPV DNA. A standardized HPV-test methodology was used to enable comparison of HPV-type distribution. MAIN OUTCOME MEASURES: Occurrence of HPV genotypes in Danish women with cervical cancer. RESULTS: There were 261 samples evaluated as histologically adequate and 251 (96%) of these were HPV-positive (HPV+). The most frequent diagnosis was squamous cell carcinoma (78.9% of histological adequate and 79.3% of HPV+). Adenocarcinoma, adenosquamous carcinoma and other types were found in 14.9, 3.4 and 2.7% of the histologically adequate group and 14.7, 3.6 and 2.4% of the HPV+ group, respectively. In 92.8% of HPV+ women only a single HPV type was diagnosed. HPV-type distribution in the latter population was as follows: HPV-16: 62.2%; HPV-18: 14.6%; HPV-33: 6.9%; HPV-45: 6.4% and HPV-31: 3.4%. Of the HPV+ women, 6.4% were diagnosed with multiple HPV types and 0.8% had unknown HPV types. CONCLUSION: HPV-16 and -18 are detected in 74.3% of Danish women with diagnosis of invasive cervical cancer, while HPV-16, -18, -31, -33, -45 and 58 are detected in 90.0% of women with invasive cervical disease.
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Adenocarcinoma/virología , Alphapapillomavirus/genética , Carcinoma de Células Escamosas/virología , ADN Viral/genética , Genotipo , Neoplasias del Cuello Uterino/virología , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Escamosas/patología , Estudios Transversales , Dinamarca , Femenino , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/patologíaRESUMEN
BACKGROUND: Rotavirus is a leading worldwide cause of acute gastroenteritis in young children. This retrospective hospital-based study assessed the burden of rotavirus gastroenteritis in children younger than 6 years in Japan. METHODS: Children admitted to eight hospitals for acute gastroenteritis between 2008 and 2009 were identified from hospital admission databases. Diagnosis of acute gastroenteritis/rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis was confirmed based on either the International Classification of Diseases and Related Health Problems 10th revision (ICD10) codes (intestinal infectious diseases [AA00-AA09] and rotavirus gastroenteritis [A08.0]) or from rapid rotavirus diagnostic test results. RESULTS: Of 13,767 hospitalized children, 11.9% (1,644), 4.8% (665) and 0.6% (81) were diagnosed with acute gastroenteritis, rotavirus gastroenteritis and hospital-acquired rotavirus gastroenteritis, respectively. Among acute gastroenteritis hospitalizations, 40.5% (665/1,644; ICD10 and rapid test) and 57.7% (645/1,118; rapid test only) were confirmed as rotavirus positive. Of 1,563 children with community-acquired acute gastroenteritis, 584 (37.4%) cases were confirmed as rotavirus positive. The median durations of hospitalization for all and community-acquired rotavirus gastroenteritis were 5.0 days (range: 2.0-133.0 days) and 5.0 days (range: 2.0-34.0 days), respectively. Among rotavirus gastroenteritis hospitalizations, 12.2% (81/665) of cases were hospital-acquired and the median duration of hospitalization was 10.0 days (range: 2.0-133.0 days). The median duration of additional hospitalization due to hospital-acquired rotavirus gastroenteritis was 3.0 days (range: 0-14 days). The overall incidence rate of hospital-acquired rotavirus gastroenteritis was 1.0 per 1,000 children hospital-days. The number of rotavirus gastroenteritis cases peaked between February and May in both 2008 and 2009, and the highest number of cases was reported in March 2008 (21.8%; 145/665). The highest number of rotavirus gastroenteritis hospitalizations (24.1%; 160/665) was observed in children aged 12-18 months. The proportion of hospital-acquired rotavirus gastroenteritis was higher in children aged below 18 months as compared to children at least 18 months of age (0.94 [95% CI: 0.71-1.21] vs. 0.39 [95% CI: 0.25-0.58]) and for children hospitalized for at least 5 days compared to those hospitalized for less than 5 days (0.91 [95% CI: 0.72-1.14] vs. 0.15 [95% CI: 0.05-0.32]). CONCLUSIONS: Both community- and hospital-acquired rotavirus gastroenteritis are significant public health problems in Japan. Data from this study justify the need for the introduction and implementation of rotavirus vaccination in the Japanese national immunization program. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01202201.
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Gastroenteritis/epidemiología , Infecciones por Rotavirus/epidemiología , Enfermedad Aguda , Distribución por Edad , Niño , Preescolar , Infecciones Comunitarias Adquiridas/diagnóstico , Infecciones Comunitarias Adquiridas/epidemiología , Costo de Enfermedad , Infección Hospitalaria/diagnóstico , Infección Hospitalaria/epidemiología , Bases de Datos Factuales , Femenino , Gastroenteritis/diagnóstico , Encuestas Epidemiológicas , Hospitalización/estadística & datos numéricos , Humanos , Incidencia , Lactante , Recién Nacido , Japón/epidemiología , Tiempo de Internación/estadística & datos numéricos , Masculino , Estudios Retrospectivos , Infecciones por Rotavirus/diagnóstico , Estaciones del AñoRESUMEN
OBJECTIVE: A study was undertaken to assess the distribution of high-risk HPV-genotypes in high-grade cervical intraepithelial neoplastic lesions in Danish women. DESIGN: Observational, cross-sectional. SETTING: Danish data from a multi-centre study undertaken in 13 European countries. POPULATION: 290 archived fixed biopsies with high-grade cervical lesions from the Departments of Pathology at the University Hospitals in Hvidovre and Odense, Denmark. METHODS: Relevant histological samples were anonymized and shipped to a central laboratory for histopathology review and PCR-testing for HPV-DNA. A standardised HPV-test methodology was utilised to enable comparison of HPV-genotype distribution. RESULTS: Of 290 Danish cervical samples, 276 were evaluated as histologically adequate and all of these were HPV-positive (HPVâº). Of the HPV⺠samples 77.9% were diagnosed with a single HPV-type, with cervical intraepithelial neoplasia (CIN)3 diagnosed in 82.3% and CIN2, CIN2/3, adenocarcinoma in situ (AIS) and AIS⺠other high-grade lesion diagnosed in the remaining 17.7%. The most prevalent HPV-types were: HPV16 (54.0%), HPV33 (13.5%), HPV31 (10.7%), HPV18 (7.9%) and HPV52 (4.7%). Of the HPV⺠samples, 21.4% were diagnosed with multiple HPV-types, with CIN3 diagnosed in 79.6% and CIN2, CIN2/3, AIS and AIS⺠other high-grade lesion diagnosed in the remaining 20.4%. The most prevalent HPV-types were: HPV16 (49.2%), HPV31 (30.5%), HPV52 (27.1%), HPV51 (20.3%), HPV18 (16.9%), HPV33 (13.6%), HPV45 (11.9%), with 0.7% unknown types. CONCLUSIONS: HPV16 and HPV18 were detected in approximately 75% of high-grade intraepithelial cervical lesions in a Danish population (single or multiple infections); these two genotypes are considered causative in at least 61.9% of the high-grade intraepithelial lesions (single infection).
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Alphapapillomavirus/genética , ADN Viral/genética , Genotipo , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/virología , Adulto , Anciano , Anciano de 80 o más Años , Estudios Transversales , Dinamarca , Femenino , Humanos , Persona de Mediana Edad , Neoplasias del Cuello Uterino/patología , Displasia del Cuello del Útero/patologíaRESUMEN
Knowledge of differences in human papillomavirus (HPV)-type prevalence between high-grade cervical intraepithelial neoplasia (HG-CIN) and invasive cervical cancer (ICC) is crucial for understanding the natural history of HPV-infected cervical lesions and the potential impact of HPV vaccination on cervical cancer prevention. More than 6,000 women diagnosed with HG-CIN or ICC from 17 European countries were enrolled in two parallel cross-sectional studies (108288/108290). Centralised histopathology review and standardised HPV-DNA typing were applied to formalin-fixed paraffin-embedded cervical specimens dated 2001-2008. The pooled prevalence of individual HPV types was estimated using meta-analytic methods. A total of 3,103 women were diagnosed with HG-CIN and a total of 3,162 with ICC (median ages: 34 and 49 years, respectively), of which 98.5 and 91.8% were HPV-positive, respectively. The most common HPV types in women with HG-CIN were HPV16/33/31 (59.9/10.5/9.0%) and in ICC were HPV16/18/45 (63.3/15.2/5.3%). In squamous cell carcinomas, HPV16/18/33 were most frequent (66.2/10.8/5.3%), and in adenocarcinomas, HPV16/18/45 (54.2/40.4/8.3%). The prevalence of HPV16/18/45 was 1.1/3.5/2.5 times higher in ICC than in HG-CIN. The difference in age at diagnosis between CIN3 and squamous cervical cancer for HPV18 (9 years) was significantly less compared to HPV31/33/'other' (23/20/17 years), and for HPV45 (1 year) than HPV16/31/33/'other' (15/23/20/17 years). In Europe, HPV16 predominates in both HG-CIN and ICC, whereas HPV18/45 are associated with a low median age of ICC. HPV18/45 are more frequent in ICC than HG-CIN and associated with a high median age of HG-CIN, with a narrow age interval between HG-CIN and ICC detection. These findings support the need for primary prevention of HPV16/18/45-related cervical lesions.
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Alphapapillomavirus/clasificación , Infecciones por Papillomavirus/epidemiología , Infecciones por Papillomavirus/virología , Displasia del Cuello del Útero/virología , Neoplasias del Cuello Uterino/virología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alphapapillomavirus/genética , Alphapapillomavirus/aislamiento & purificación , Cuello del Útero/patología , Cuello del Útero/virología , Estudios Transversales , ADN Viral/análisis , Europa (Continente)/epidemiología , Femenino , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Neoplasias del Cuello Uterino/patología , Adulto Joven , Displasia del Cuello del Útero/patologíaRESUMEN
OBJECTIVES: Influenza can be a serious illness, especially for older people, and reducing the impact of influenza in elderly is important. The objective of this study was to estimate the prevalence and postinfection outcomes of influenza among the over-50 population in Japan. DESIGN: An observational study was designed to ascertain the proportion of influenza cases in a population aged ≥ 50 years with acute respiratory infection (ARI) and to determine the postinfection outcomes of their illness during the 2008-09 influenza season in Japan. Respiratory specimens obtained from a total of 401 patients were tested by PCR for influenza viruses, respiratory syncytial virus (RSV) and human metapneumovirus (hMPV). The effectiveness of the seasonal trivalent influenza vaccine was estimated by a test-negative case control analysis. SETTING: Seventeen outpatient clinics located in four separate areas of Japan. SAMPLE: Respiratory swab specimens from the ARI patients aged ≥ 50 years. MAIN OUTCOME MEASURES: Laboratory confirmed influenza in patients presenting with ARI. RESULTS: In all, 89 (22.2%) of the patients were positive for one of the tested viruses; 70 (78.7%) with influenza, 17 (19.1%) with RSV, and 2 (2.2%) with hMPV. Cough (95.7% vs 73.4%), loss of appetite (67.1% vs 35.5%), absence from work (50.0% vs 23.0%), impact on daily activity (90.0% vs 62.5%), and caregiver absence from work (5.7% vs 0.6%) were observed higher in influenza patients. The duration of feeling weakness (6.3 ± 5.4 vs 3.6 ± 1.9 days) and average days of reduced activity (5.2 vs 3.6 days) were longer for influenza patients. Vaccine effectiveness was estimated to be 32.1% (95% CI: -14.9, 59.9%). CONCLUSIONS: Influenza was the dominant ARI-causing virus and the clinical and socio-economic outcomes imposed on patients over 50 years of age was high for influenza.
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Gripe Humana/epidemiología , Infecciones del Sistema Respiratorio/epidemiología , Enfermedad Aguda/economía , Enfermedad Aguda/epidemiología , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Femenino , Humanos , Gripe Humana/economía , Gripe Humana/virología , Japón/epidemiología , Masculino , Persona de Mediana Edad , Infecciones del Sistema Respiratorio/economía , Infecciones del Sistema Respiratorio/virología , Factores Socioeconómicos , TrabajoRESUMEN
The epidemiology of meningococcal disease in Europe since 1945 has shown fluctuations in incidence, serogroup distribution and case-fatality rate. Outbreaks and epidemics driven by the introduction of new virulent strains into Europe have occurred unpredictably. Epidemics associated with serogroups A and B have occurred in all regions of the continent. Additionally, there have been periods of increased outbreak frequency, such as those associated with serogroup C in the 1980s and 1990s, against an endemic disease incidence of around one to two cases per 100,000 population. Serogroup W135 disease was observed in the 1970s and again in 2000, while serogroup Y has recently emerged in Sweden and the Czech Republic. This article describes the changing epidemiology of meningococcal disease in Europe. An understanding of this is important for informed decision-making about different meningococcal vaccines that may be considered for use in Europe.