RESUMEN
Even though it has been established that a hyetograph's shape affects the results of hydrological simulations, common engineering practice does not always account for this fact. Instead, a single design storm is often considered sufficient for designing a urban drainage system. This study examines the impact that this design paradigm, combined with the uncertainty introduced by subjective choices made during the design process, has on the robustness of a designed system. To do so, we evaluated a set of individual designs created by engineering students using the same Chicago hyetograph as a design storm. We then created ensembles of hyetographs with the same precipitation volume and duration as the Chicago hyetograph and evaluated the designs' hydrological responses. The results showed that designs, which performed equally well for the initial design storm, triggered varying responses for the storms in the ensembles and, consequently, showed different levels of robustness, hinting at a need to adapt the current design approach.
Asunto(s)
Drenaje de Agua , Ciudades , Modelos TeóricosRESUMEN
A primary goal in transplantation medicine is the induction of a tolerogenic environment for prevention of transplant rejection without the need for long-term pharmacological immunosuppression. Generation of alloantigen-specific regulatory T cells (Tregs) by transduction with chimeric antigen receptors (CARs) is a promising strategy to achieve this goal. This publication reports the preclinical characterization of Tregs (TR101) transduced with a human leukocyte antigen (HLA)-A*02 CAR lentiviral vector (TX200) designated to induce immunosuppression of allograft-specific effector T cells in HLA-A*02-negative recipients of HLA-A*02-positive transplants. In vitro results demonstrated specificity, immunosuppressive function, and safety of TX200-TR101. In NOD scid gamma (NSG) mice, TX200-TR101 prevented graft-versus-host disease (GvHD) in a xenogeneic GvHD model and TX200-TR101 Tregs localized to human HLA-A*02-positive skin transplants in a transplant model. TX200-TR101 persisted over the entire duration of a 3-month study in humanized HLA-A*02 NSG mice and remained stable, without switching to a proinflammatory phenotype. Concomitant tacrolimus did not impair TX200-TR101 Treg survival or their ability to inhibit peripheral blood mononuclear cell (PBMC) engraftment. These data demonstrate that TX200-TR101 is specific, stable, efficacious, and safe in preclinical models, and provide the basis for a first-in-human study.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Órganos , Receptores Quiméricos de Antígenos , Ratones , Animales , Humanos , Linfocitos T Reguladores , Leucocitos Mononucleares/trasplante , Antígenos HLA-ARESUMEN
Urban drainage systems are composed of subsystems. The ratio of the storage and discharge capacities of the subsystems determines the performance. The performance of the urban water system may deteriorate as a result of the change in the ratio of storage to discharge capacity due to aging, urbanisation and climate change. We developed the graph-based weakest link method (GBWLM) to analyse urban drainage systems. Flow path analysis from graph theory is applied instead of hydrodynamic model simulations to reduce the computational effort. This makes it practically feasible to analyse urban drainage systems with multi-decade rainfall series. We used the GBWLM to analyse the effect of urban water system aging and/or climate scenarios on flood extent and frequency. The case study shows that the results of the hydrodynamic models and the GBWLM are similar. The rainfall intensities of storm events are expected to increase by approximately 20% in the Netherlands due to climate change. For the case study, such an increase in load has little impact on the flood frequency and extent caused by gully pots and surface water. However, it could lead to a 50% increase in the storm sewer flood frequency and an increase in the extent of flooding.
Asunto(s)
Modelos Teóricos , Urbanización , Inundaciones , Cambio Climático , Agua , Ciudades , LluviaRESUMEN
OBJECTIVES: Transcutaneous posterior tibial nerve stimulation (TC-PTNS) is a validated option for lower urinary tract symptoms (LUTS) management, with a short-term success rate of around 60% and few adverse events. Our goal was to report the efficacy and safety results of TC-PTNS using the newly issued device TENSI+ for LUTS management. PATIENTS AND METHODS: A multicenter, retrospective study was conducted in 7 urology departments in France. All patients treated with TC-PTNS for LUTS using the TENSI+ device between September 2021 and February 2022 were included. All patients received supervised at-home training by a specialized nurse. All patients were asked to do daily, 20minutes sessions of TC-PTNS. Patient demographics, history, initial symptoms and previous treatment were collected at inclusion. A follow-up visit was scheduled at 3 months. Efficacy was evaluated through treatment persistence at 3 months and PGI-I (Patient Global Impression of Improvement) score. Adverse events were recorded. RESULTS: One hundred and three patients (86 women and 17 men) were included. All patients had overactive bladder symptoms, 64 suffered from urgency incontinence, and 24 had associated voiding symptoms. Eighteen patients had neurogenic background, and 30 previously received anticholinergics. After a median follow-up of 12 [10-21]weeks, 70 patients were still using the device (68%). PGI-I score reflected an improvement in 70.9% and was 1, 2 and 3 in 28, 26 and 19 patients respectively, while 24 were unchanged and 6 were worse. No clinical baseline parameter was predictive of success. Adverse events included pain at stimulation site (two cases) and pelvic pain (two patients), which rapidly resolved after treatment interruption. CONCLUSIONS: TC-PTNS with TENSI+ device is an effective option for LUTS management, with results that seem similar to other TC-PTNS approaches. Adverse events were mild and reversible after treatment interruption.
Asunto(s)
Síntomas del Sistema Urinario Inferior , Estimulación Eléctrica Transcutánea del Nervio , Vejiga Urinaria Hiperactiva , Masculino , Humanos , Femenino , Estimulación Eléctrica Transcutánea del Nervio/efectos adversos , Estimulación Eléctrica Transcutánea del Nervio/métodos , Estudios Retrospectivos , Vejiga Urinaria Hiperactiva/terapia , Síntomas del Sistema Urinario Inferior/etiología , Síntomas del Sistema Urinario Inferior/terapia , Nervio TibialRESUMEN
INTRODUCTION: Multidisciplinary team meetings (MTMs) in the field of pelvic floor diseases in women tend to generalize, as they are required as mandatory before mid-urethral sling implantation or sacrocolpopexy by recent decrees published by the French health authorities. However, access to these meetings is variable in the French territory. The goal of the present study was to describe the existence and the settings of these kinds of meetings in France. MATERIEL AND METHODS: An on-line survey was conducted between June and July 2020 (stage 1) then between November 2021 and January 2022 (stage 2). A 15-item questionnaire was sent to all members of the Association française d'urologie (AFU). A descriptive analysis was conducted. RESULTS: Three hundred and twenty-two completed questionnaires were sent back during stage 1 and 158 during stage 2. Early 2022, 61.3% of respondents had access to a pelviperineology MTM, with important difference according to geographical areas. Main activity of MTMs was case discussion of complex situations (68% of meetings). At the end of 2021, 22% of the respondents declared willing to stop partially or totally their pelviperineology activity, given the new regulations set in place by the authorities. CONCLUSION: Despite being absolutely mandatory in current clinical practice, MTMs in pelvic floor disease have spread slowly. MTMs implementation was still insufficient in 2022, and variable on the French territory. Some urologists declare having no access to such resources and about 1 out of 5 were considering to voluntary stop of decrease significantly their activity in this difficult context.
Asunto(s)
Trastornos del Suelo Pélvico , Cabestrillo Suburetral , Humanos , Femenino , Trastornos del Suelo Pélvico/terapia , Urólogos , FranciaRESUMEN
PURPOSE: Loss of brain synapses is an early pathological feature of Alzheimer's disease. The current study assessed synaptic loss in vivo with positron emission tomography and an 18F-labelled radiotracer of the synaptic vesicle protein 2A, [18F]UCB-H. METHODS: Twenty-four patients with mild cognitive impairment or Alzheimer's disease and positive [18F]Flutemetamol amyloid-PET were compared to 19 healthy controls. [18F]UCB-H brain uptake was quantified with Logan graphical analysis using an image-derived blood input function. SPM12 and regions-of-interest (ROI) analyses were used for group comparisons of regional brain distribution volumes and for correlation with cognitive measures. RESULTS: A significant decrease of [18F]UCB-H uptake was observed in several cortical areas (11 to 18% difference) and in the thalamus (16% difference), with the largest effect size in the hippocampus (31% difference). Reduced hippocampal uptake was related to patients' cognitive decline (ROI analysis) and unawareness of memory problems (SPM and ROI analyses). CONCLUSIONS: The findings thus highlight predominant synaptic loss in the hippocampus, confirming previous autopsy-based studies and a recent PET study with an 11C-labelled SV2A radiotracer. [18F]UCB-H PET allows to image in vivo synaptic changes in Alzheimer's disease and to relate them to patients' cognitive impairment.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Enfermedad de Alzheimer/diagnóstico por imagen , Animales , Encéfalo/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico por imagen , Hipocampo/diagnóstico por imagen , Humanos , Tomografía de Emisión de PositronesRESUMEN
Alzheimer's disease (AD) subtypes have been described according to genetics, neuropsychology, neuropathology, and neuroimaging. Thirty-one patients with clinically probable AD were selected based on perisylvian metabolic decrease on FDG-PET. They were compared to 25 patients with a typical pattern of decreased posterior metabolism. Tree-based machine learning was used on those 56 images to create a classifier that was subsequently applied to 207 Alzheimer's Disease Neuroimaging Initiative (ADNI) patients with AD. Machine learning was also used to discriminate between the two ADNI groups based on neuropsychological scores. Compared to AD patients with a typical precuneus metabolic decrease, the new subtype showed stronger hypometabolism in the temporoparietal junction. The classifier was able to distinguish the two groups in the ADNI population. Both groups could only be distinguished cognitively by Trail Making Test-A scores. This study further confirms that there is more than a typical metabolic pattern in probable AD with amnestic presentation.
Asunto(s)
Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Anciano , Anciano de 80 o más Años , Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Femenino , Humanos , Interpretación de Imagen Asistida por Computador , Aprendizaje Automático , Masculino , Neuroimagen/métodos , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
Motor neurons appear to be activated with a common input signal that modulates the discharge activity of all neurons in the motor nucleus. It has proven difficult for neurophysiologists to quantify the variability in a common input signal, but characterization of such a signal may improve our understanding of how the activation signal varies across motor tasks. Contemporary methods of quantifying the common input to motor neurons rely on compiling discrete action potentials into continuous time series, assuming the motor pool acts as a linear filter, and requiring signals to be of sufficient duration for frequency analysis. We introduce a space-state model in which the discharge activity of motor neurons is modeled as inhomogeneous Poisson processes and propose a method to quantify an abstract latent trajectory that represents the common input received by motor neurons. The approach also approximates the variation in synaptic noise in the common input signal. The model is validated with four data sets: a simulation of 120 motor units, a pair of integrate-and-fire neurons with a Renshaw cell providing inhibitory feedback, the discharge activity of 10 integrate-and-fire neurons, and the discharge times of concurrently active motor units during an isometric voluntary contraction. The simulations revealed that a latent state-space model is able to quantify the trajectory and variability of the common input signal across all four conditions. When compared with the cumulative spike train method of characterizing common input, the state-space approach was more sensitive to the details of the common input current and was less influenced by the duration of the signal. The state-space approach appears to be capable of detecting rather modest changes in common input signals across conditions.NEW & NOTEWORTHY We propose a state-space model that explicitly delineates a common input signal sent to motor neurons and the physiological noise inherent in synaptic signal transmission. This is the first application of a deterministic state-space model to represent the discharge characteristics of motor units during voluntary contractions.
Asunto(s)
Modelos Neurológicos , Neuronas Motoras/fisiología , Animales , Retroalimentación Fisiológica , Probabilidad , Tiempo de Reacción , Potenciales SinápticosRESUMEN
Self-unawareness concerning current symptoms remains a clinical challenge in Alzheimer's disease. Reduced self-awareness likely depends on complex biopsychosocial mechanisms that comprise multiple cognitive processes, regulated by personal goals and values. We specifically reviewed the cognitive processes impaired in unaware participants with AD by emphasizing the related impaired brain activity observed during task-based fMRI. Unawareness can be explained by a failure in functioning of or in connection between brain regions that intervene in access, retrieval and updating of (present or extended) self-information (posterior midline, medial temporal, inferior parietal cortices), or in its monitoring, evaluation, or control (medial and lateral prefrontal cortices). Although one must be cautious when relating function to brain regions, impaired processes were tentatively related to the Cognitive Awareness Model. Although brain function depends on neural networks, impaired brain activity during cognitive processes was discussed according to previous studies reporting correlations between brain regions and scores of anosognosia. The review provides a framework to help clinicians considering processes that can explain unawareness in dementia. In patients at early stages of AD, different levels of awareness of cognitive or social clinical changes might be described as impairment in the interaction between specific cognitive processes and contents.
Asunto(s)
Agnosia , Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Concienciación , Pruebas Neuropsicológicas , Encéfalo/diagnóstico por imagen , Corteza PrefrontalRESUMEN
BACKGROUND AND OBJECTIVE: Our aim was to report the first clinical trial of TENSI+, a new device for transcutaneous posterior tibial nerve stimulation (TNS) for treatment of overactive bladder (OAB). METHODS: A prospective, multicentre clinical trial was conducted in adults with OAB in seven French centres. The main exclusion criteria were prior percutaneous or transcutaneous TNS or invasive OAB treatment, current antimuscarinic use, 24-h polyuria, known bladder disease, postvoid residual volume >150 ml, and pelvic organ prolapse stage >2. Patients self-administered daily TTNS sessions of 20 min with TENSI+ at home after education by a specialized nurse. A bladder diary, Urinary Symptom Profile and OAB-q questionnaires, and Patient Global Impression of Improvement (PGI-I) scores were evaluated at baseline and 3 and 6 mo. The primary endpoint was efficacy, based on PGI-I and variations in bladder diary parameters. Success was defined as a PGI-I score ≤3 and any improvement ≥30% in bladder diary parameters. KEY FINDINGS AND LIMITATIONS: The study included 78 patients (13 males). Nine patients had neurological disease, 21 had previously tried antimuscarinics, and 41 had wet OAB at baseline. At 3 mo, 65/78 patients had a full analysis set. Treatment was successful in 44/65 patients (67%), with 25/65 (38%) reporting both an objective improvement and high satisfaction. All OAB-related endpoints were significantly improved, except bladder capacity and total voided volume per 24 h. At 6 mo, only five of 44 patients had interrupted their treatment. No factor predictive of success was identified. Two adverse events (pain at stimulation site and/or pelvic pain) were reported and spontaneously resolved without treatment interruption. CONCLUSIONS AND CLINICAL IMPLICATIONS: TENSI+ is a safe and effective TTNS treatment option for OAB management. PATIENT SUMMARY: TENSI+ is a new device for nerve stimulation in patients with overactive bladder. Patients use the device at home every day. In our short-term trial, TENSI+ use improved symptoms in 67% of patients. Further evaluation over a longer period of time is needed.
RESUMEN
Although some studies have reported associations between serum vitamin D level and prognosis in several cancers, others have found associations between genetic sequence variants (GSVs) in the vitamin D metabolism pathway genes and outcomes in various cancers including head and neck cancer (HNC). We comprehensively evaluated the association and interaction of GSVs in vitamin D metabolism pathway genes and their regulatory effects on circulatory serum vitamin D level in HNC outcome. We systemically evaluated the association of 89 tagging and candidate-based GSVs in six major vitamin D metabolism pathway genes (VDR, GC, CYP24A1, CYP27A1, CYP27B1 and CYP2R1) and the circulating serum vitamin D level with overall survival (OS) and second primary cancer (SPC) in 522 Stages I-II radiation-treated patients with HNC. For OS: median follow-up time was 8 years; for SPC, 4.4 years. The most common subsite was the larynx (84%). Three hundred and twelve patients were alive at the end of follow-up for OS. SPCs were diagnosed in 108 patients and were primarily of lung (46%). Serum vitamin D levels were significantly lower in patients carrying the minor alleles of GC:rs4588 and CYP2R1:rs10500804. CYP24A1:rs2296241 was significantly associated with OS and CYP2R1:rs1993116 was with SPC. These two GSVs remained significantly associated after adjusting for serum vitamin D level and important clinical factors. GSVs in the vitamin D metabolism pathway genes were associated with disease outcomes in HNC patients; however, these GSVs are different from those affecting serum vitamin D levels.
Asunto(s)
Biomarcadores de Tumor/genética , Sistema Enzimático del Citocromo P-450/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias Primarias Secundarias/genética , Polimorfismo de Nucleótido Simple/genética , Vitamina D/sangre , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/sangre , ADN de Neoplasias/genética , Femenino , Estudios de Seguimiento , Predisposición Genética a la Enfermedad , Genotipo , Neoplasias de Cabeza y Cuello/sangre , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/sangre , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/radioterapia , Reacción en Cadena de la Polimerasa , Pronóstico , Receptores de Calcitriol/genética , Factores de Riesgo , Tasa de SupervivenciaRESUMEN
BACKGROUND: Secondary primary cancers (SPCs), a major cause of morbidity and mortality in head and neck cancers (HNCs), are commonly associated with field cancerization. We comprehensively evaluated 23 germline sequence variants (from published literature) in 17 genes from 7 biological pathways associated with the HNC survival. Because cancer prognosis correlates with disease aggressiveness, the factors that determine aggressive disease may influence field cancerization process to favor SPC development. We thus hypothesized that the same sequence variants associated with HNC survival can also be associated with SPC. METHODS: Germline DNA from 531 stage I-II radiation-treated HNC patients (originally recruited for an alpha-tocopherol/beta-carotene placebo-controlled secondary prevention clinical trial) were genotyped, and analyzed using Cox proportional hazards models, stratified by treatment arm, adjusting for clinical prognostic factors. RESULTS: The majority of SPCs were of lung and HNCs. Median follow-up time was 5 years. SPCs were diagnosed in 21% of patients. The 5-year SPC-free survival was 79%. All but 1 evaluated sequence variant were not associated with SPC. There was a strong association of the DNA (cytosine-5-)-methyltransferase 3 beta (DNMT3B) sequence variant, DNMT3B:C149T (rs2424913) with SPC: the adjusted hazard ratio (aHR) for TT versus CC was 2.23 (1.32-3.78; P = .003), whereas each variant T allele was associated with an aHR of 1.49 (1.15-1.95; P = .003). CONCLUSIONS: A functional sequence variant in DNMT3B is associated with the development of SPCs in HNC early stage patients treated with radiation. Aberrant DNA methylation may be an important modulator of SPC development in at-risk individuals with HNCs.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/genética , Neoplasias de Cabeza y Cuello/genética , Neoplasias Primarias Secundarias/genética , Adulto , Anciano , Anciano de 80 o más Años , Metilación de ADN , Femenino , Genotipo , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Polimorfismo de Nucleótido Simple , Modelos de Riesgos Proporcionales , ADN Metiltransferasa 3BRESUMEN
BACKGROUND: The purpose of the study was to identify factors associated with weight loss during radiotherapy (RT) in patients with stage I or II head and neck (HN) cancer. METHODS: This study was conducted as part of a phase III chemoprevention trial. A total of 540 patients were randomized. The patients were weighed before and after RT. Patients' characteristics, dietary intake, health-related quality of life (HRQOL), tumor characteristic, treatment characteristics, and acute adverse effects of RT were evaluated at baseline and during RT. Factors independently associated with weight loss during RT were identified using the multiple linear regression (P ≤ 0.05). RESULTS: The mean weight loss during RT was 2.2 kg (standard deviation, 3.4). In bivariate analyses, the occurrence of adverse effects of RT and most of the HRQOL dimensions evaluated during RT were correlated with weight loss. In the multivariate analysis, eight factors were associated with a greater weight loss: all HN cancer sites other than the glottic larynx (P < 0.001), TNM stage II disease (P = 0.01), higher pre-RT body weight (P < 0.001), dysphagia before RT (P < 0.005), higher mucosa adverse effect of RT (P = 0.03), lower dietary energy intake during RT (P < 0.001), lower score of the digestive dimension on the Head and Neck Radiotherapy Questionnaire (P < 0.001) and a higher score of the constipation symptom on the EORTC QLQ-C30 during RT (P = 0.02). CONCLUSIONS: The results underline the importance of maintaining energy intake in early stage HN cancer patients during RT and the importance of preventing and treating adverse effects.
Asunto(s)
Peso Corporal/efectos de la radiación , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/radioterapia , Radioterapia/efectos adversos , Pérdida de Peso , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/epidemiología , Causalidad , Quimioprevención , Quimioradioterapia , Comorbilidad , Método Doble Ciego , Ingestión de Alimentos , Femenino , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/epidemiología , Humanos , Masculino , Persona de Mediana Edad , Mucositis/epidemiología , Estadificación de Neoplasias , Neoplasias Primarias Secundarias/tratamiento farmacológico , Neoplasias Primarias Secundarias/epidemiología , Neoplasias Primarias Secundarias/prevención & control , Vigilancia de la Población , Calidad de Vida , Factores de Riesgo , Encuestas y Cuestionarios , alfa-Tocoferol/administración & dosificación , beta Caroteno/administración & dosificaciónRESUMEN
Low pretreatment vitamin D status has been associated with worsened disease outcomes in patients with cancer at various sites. Its prognostic significance in head and neck cancer (HNC) patients has not been studied. Patients with HNC who participated in a randomized trial were evaluated for: (i) total intake of vitamin D from diet and supplements using a validated food frequency questionnaire (all trial participants, n = 540) and (ii) pretreatment serum 25-hydroxyvitamin D through a radioimmunoassay (n = 522). The association of dietary/serum measures of vitamin D status with HNC recurrence, second primary cancer (SPC) incidence, and overall mortality was evaluated using multivariate Cox proportional hazard models. There was no significant association between dietary or serum vitamin D measures and the three HNC outcomes. The hazard ratios (HRs) comparing the highest with the lowest quartile of dietary/supplemental vitamin D intake were 1.10 (95% confidence interval (CI): 0.66-1.84) for recurrence, 1.05 (95% CI: 0.63-1.74) for SPC, and 1.27 (95% CI: 0.87-1.84) for overall mortality. HRs comparing the uppermost to the lowest quartile of serum 25-hydroxyvitamin D levels were 1.12 (95% CI: 0.65-1.93) for recurrence, 0.72 (95% CI: 0.40-1.30) for SPC, and 0.85 (95% CI: 0.57-1.28) for overall mortality. There was no effect modification by cancer stage, season of initial treatment, or trial arm. Among patients with HNC, vitamin D status before treatment does not influence disease outcomes. Our results contrast with those from most published studies, which suggest prognostic significance of vitamin D status in cancer patients at least in subgroups.
Asunto(s)
Suplementos Dietéticos , Neoplasias de Cabeza y Cuello/sangre , Vitamina D/análogos & derivados , Anciano , Dieta , Femenino , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/terapia , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Modelos de Riesgos Proporcionales , Radioterapia/métodos , Recurrencia , Encuestas y Cuestionarios , Resultado del Tratamiento , Vitamina D/sangreRESUMEN
OBJECTIVES: Post-listing assessment of pharmaceuticals depends on national habits. In England, the assessment is based on estimates of cost per quality-adjusted life-year. These are made some considerable time after listing (negative list). In France, effectiveness, and then efficiency, is assessed immediately after listing (positive list). We propose a new formal method--the REAL method--that can help make early comparisons of the effectiveness of medical treatments. METHODS: Relative efficacies are first obtained from randomized controlled trials (RCTs). Members of the Transparency Committee (French National Authority for Health) are then consulted by questionnaire on the transposability of these results to real life. The RCT results and experts' ratings are entered into an effect model to obtain estimates of relative effectiveness, using unidimensional scaling, and bootstrap procedures. RESULTS: Application of the REAL method to the example of a new drug to treat Parkinson's disease and three comparators used in the same indication provided graphs of the distributions of their relative efficacy and relative effectiveness. The new drug was found to provide no added value. CONCLUSIONS: The REAL method is a rational, transparent, and practical procedure for comparing the effectiveness of pharmaceuticals in an immediate post-listing setting.
Asunto(s)
Medicamentos bajo Prescripción/economía , Medicamentos bajo Prescripción/uso terapéutico , Años de Vida Ajustados por Calidad de Vida , Evaluación de la Tecnología Biomédica/métodos , Investigación sobre la Eficacia Comparativa , Análisis Costo-Beneficio , Humanos , Ensayos Clínicos Controlados Aleatorios como Asunto , Proyectos de InvestigaciónRESUMEN
Comparison of graph structure is a ubiquitous task in data analysis and machine learning, with diverse applications in fields such as neuroscience, cyber security, social network analysis, and bioinformatics, among others. Discovery and comparison of structures such as modular communities, rich clubs, hubs, and trees yield insight into the generative mechanisms and functional properties of the graph. Often, two graphs are compared via a pairwise distance measure, with a small distance indicating structural similarity and vice versa. Common choices include spectral distances and distances based on node affinities. However, there has of yet been no comparative study of the efficacy of these distance measures in discerning between common graph topologies at different structural scales. In this work, we compare commonly used graph metrics and distance measures, and demonstrate their ability to discern between common topological features found in both random graph models and real world networks. We put forward a multi-scale picture of graph structure wherein we study the effect of global and local structures on changes in distance measures. We make recommendations on the applicability of different distance measures to the analysis of empirical graph data based on this multi-scale view. Finally, we introduce the Python library NetComp that implements the graph distances used in this work.
Asunto(s)
Macrodatos , Gráficos por Computador , Modelos TeóricosRESUMEN
A central goal in neuroscience is to understand how dynamic networks of neural activity produce effective representations of the world. Advances in the theory of graph measures raise the possibility of elucidating network topologies central to the construction of these representations. We leverage a result from the description of lollipop graphs to identify an iconic network topology in functional magnetic resonance imaging data and characterize changes to those networks during task performance and in populations diagnosed with psychiatric disorders. During task performance, we find that task-relevant subnetworks change topology, becoming more integrated by increasing connectivity throughout cortex. Analysis of resting state connectivity in clinical populations shows a similar pattern of subnetwork topology changes; resting scans becoming less default-like with more integrated sensory paths. The study of brain network topologies and their relationship to cognitive models of information processing raises new opportunities for understanding brain function and its disorders.
RESUMEN
PURPOSE: Cyclooxygenase-2 (COX-2) overexpression has been associated with a poor prognosis in many cancers. However, the role of COX-2 overexpression in head and neck cancers remains undetermined. The objective of this study was to evaluate whether COX-2 is a prognostic factor in glottic cancer. EXPERIMENTAL DESIGN: This study was part of a phase III placebo-controlled randomized trial evaluating the efficacy of alpha-tocopherol in reducing second primary cancers (SPC) in head and neck cancer patients. Immunohistochemical analyses were conducted on pretreatment biopsies of 301 patients with early-stage glottic cancer treated by radiotherapy. The median value of 50% of positive tumor cells was the cutoff point used to define COX-2 overexpression. Outcomes considered in the statistical analysis were recurrence, SPC, and death. The Cox proportional hazards model was used to estimate the hazard ratios (HR) and their 95% confidence intervals (95% CI). RESULTS: The HR associated with COX-2 overexpression was 0.94 (95% CI, 0.55-1.62) for recurrence. The HR associated with SPC was 2.63 (95% CI, 1.32-5.23) for the first 3.5 years of follow-up and 0.55 (95% CI, 0.22-1.32) for the following 3.5 years. The HR associated with COX-2 overexpression was 1.57 (95% CI, 1.01-2.45) for overall mortality. CONCLUSIONS: COX-2 overexpression in glottic cancer was associated with increased overall mortality and an increased risk of SPC during the early follow-up period. Future studies are needed to explain observed effects on SPC. COX-2 expression may prove helpful in defining an individual patient's prognosis.
Asunto(s)
Biomarcadores de Tumor/análisis , Ciclooxigenasa 2/biosíntesis , Glotis/patología , Neoplasias Laríngeas/metabolismo , Anciano , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/patología , Método Doble Ciego , Femenino , Glotis/metabolismo , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Neoplasias Laríngeas/mortalidad , Neoplasias Laríngeas/patología , Masculino , Persona de Mediana Edad , Neoplasias Primarias Secundarias/mortalidad , Neoplasias Primarias Secundarias/prevención & control , Placebos , Pronóstico , Vitaminas/uso terapéutico , alfa-Tocoferol/uso terapéuticoRESUMEN
This study evaluated the efficacy and safety of intramuscular administration of NV1FGF, a plasmid-based angiogenic gene delivery system for local expression of fibroblast growth factor 1 (FGF-1), versus placebo, in patients with critical limb ischemia (CLI). In a double-blind, randomized, placebo-controlled, European, multinational study, 125 patients in whom revascularization was not considered to be a suitable option, presenting with nonhealing ulcer(s), were randomized to receive eight intramuscular injections of placebo or 2.5 ml of NV1FGF at 0.2 mg/ml on days 1, 15, 30, and 45 (total 16 mg: 4 x 4 mg). The primary end point was occurrence of complete healing of at least one ulcer in the treated limb at week 25. Secondary end points included ankle brachial index (ABI), amputation, and death. There were 107 patients eligible for evaluation. Improvements in ulcer healing were similar for use of NV1FGF (19.6%) and placebo (14.3%; P = 0.514). However, the use of NV1FGF significantly reduced (by twofold) the risk of all amputations [hazard ratio (HR) 0.498; P = 0.015] and major amputations (HR 0.371; P = 0.015). Furthermore, there was a trend for reduced risk of death with the use of NV1FGF (HR 0.460; P = 0.105). The adverse event incidence was high, and similar between the groups. In patients with CLI, plasmid-based NV1FGF gene transfer was well tolerated, and resulted in a significantly reduced risk of major amputation when compared with placebo.