Cost-effectiveness analysis with unordered decisions.

INTRODUCTION: Cost-effectiveness analysis (CEA) is used increasingly in medicine to determine whether the health benefit of an intervention is worth the economic cost. Decision trees, the standard decision modeling technique for non-temporal domains, can only perform CEAs for very small problems. Influence diagrams can model much larger problems, but only when the decisions are totally ordered. OBJECTIVE: To develop a CEA method for problems with unordered or partially ordered decisions, such as finding the optimal sequence of tests for diagnosing a disease. METHODS: We explain how to model those problems using decision analysis networks (DANs), a new type of probabilistic graphical model, somewhat similar to Bayesian networks and influence diagrams. We present an algorithm for evaluating DANs with two criteria, cost and effectiveness, and perform some experiments to study its computational efficiency. We illustrate the representation framework and the algorithm using a hypothetical example involving two therapies and several tests and then present a DAN for a real-world problem, the mediastinal staging of non-small cell lung cancer. RESULTS: The evaluation of a DAN with two criteria, cost and effectiveness, returns a set of intervals for the willingness to pay, separated by incremental cost-effectiveness ratios (ICERs). The cost, the effectiveness, and the optimal intervention are specific for each interval, i.e., they depend on the willingness to pay. CONCLUSION: Problems involving several unordered decisions can be modeled with DANs and evaluated in a reasonable amount of time. OpenMarkov, an open-source software tool developed by our research group, can be used to build the models and evaluate them using a graphical user interface.

BAFF, APRIL and BAFFR on the pathogenesis of Immunoglobulin-A vasculitis.

BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immune-mediated conditions, being BAFF GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGT>A, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV.

Multi-input convolutional neural network for breast cancer detection using thermal images and clinical data.

BACKGROUND AND OBJECTIVE: Breast cancer is the most common cancer in women. While mammography is the most widely used screening technique for the early detection of this disease, it has several disadvantages such as radiation exposure or high economic cost. Recently, multiple authors studied the ability of machine learning algorithms for early diagnosis of breast cancer using thermal images, showing that thermography can be considered as a complementary test to mammography, or even as a primary test under certain circumstances. Moreover, although some personal and clinical data are considered risk factors of breast cancer, none of these works considered that information jointly with thermal images. METHODS: We propose a novel approach for early detection of breast cancer combining thermal images of different views with personal and clinical data, building a multi-input classification model which exploits the benefits of convolutional neural networks for image analysis. First, we searched for structures using only thermal images. Next, we added the clinical data as a new branch of each of these structures, aiming to improve its performance. RESULTS: We applied our method to the most widely used public database of breast thermal images, the Database for Mastology Research with Infrared Image. The best model achieves a 97% accuracy and an area under the ROC curve of 0.99, with a specificity of 100% and a sensitivity of 83%. CONCLUSIONS: After studying the impact of thermal images and personal and clinical data on multi-input convolutional neural networks for breast cancer diagnosis, we conclude that: (1) adding the lateral views to the front view improves the performance of the classification model, and (2) including personal and clinical data helps the model to recognize sick patients.

Frequent and Rare HABP2 Variants Are Not Associated with Increased Susceptibility to Familial Nonmedullary Thyroid Carcinoma in the Spanish Population.

BACKGROUND/AIMS: A genomic HABP2 variant was proposed to be responsible for familial nonmedullary thyroid carcinoma (FNMTC). However, its involvement has been questioned in subsequent studies. We aimed to identify genetic HABP2 mutations in a series of FNMTC patients and investigate their involvement in the disease. METHODS: HABP2 was sequenced from 6 index patients. Presence of the variants was investigated in all members of one family. Somatic BRAF and RAS "hotspot" mutations were investigated by the IdyllaTM BRAF Mutation Test and/or Sanger sequencing. RESULTS: Two HABP2 variants (p.E393Q and p.G534E) were identified in the index patient from one family with papillary thyroid carcinoma (PTC) (follicular variant). The prevalence of p.E393Q in Spanish control alleles was 0.5% and that of p.G534E was 5.1%. However, neither change cosegregated with the phenotype in 3 affected members and 5 healthy members of the kindred. Interestingly, all 3 members affected by PTC harbored the p.V600E somatic mutation in BRAF. CONCLUSIONS: The variant G534E is prevalent in the Spanish population (5.1%); however, p.E393Q is rare (< 1%) and none cosegregated with the FNMTC phenotype. The presence of the noninheritable V600E BRAF mutation in this family supports Knudson's "double-hit" hypothesis for cancer development and suggests the involvement of more than 1 gene in the clinical expression of FNMTC.

Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With ST-Segment Elevation Myocardial Infarction and Left Ventricular Dysfunction.

RATIONALE: Allogeneic cardiac stem cells (AlloCSC-01) have shown protective, immunoregulatory, and regenerative properties with a robust safety profile in large animal models of heart disease. OBJECTIVE: To investigate the safety and feasibility of early administration of AlloCSC-01 in patients with ST-segment-elevation myocardial infarction. METHODS AND RESULTS: CAREMI (Safety and Efficacy of Intracoronary Infusion of Allogeneic Human Cardiac Stem Cells in Patients With STEMI and Left Ventricular Dysfunction) was a phase I/II multicenter, randomized, double-blind, placebo-controlled trial in patients with ST-segment-elevation myocardial infarction, left ventricular ejection fraction ≤45%, and infarct size ≥25% of left ventricular mass by cardiac magnetic resonance, who were randomized (2:1) to receive AlloCSC-01 or placebo through the intracoronary route at days 5 to 7. The primary end point was safety and included all-cause death and major adverse cardiac events at 30 days (all-cause death, reinfarction, hospitalization because of heart failure, sustained ventricular tachycardia, ventricular fibrillation, and stroke). Secondary safety end points included major adverse cardiac events at 6 and 12 months, adverse events, and immunologic surveillance. Secondary exploratory efficacy end points were changes in infarct size (percentage of left ventricular mass) and indices of ventricular remodeling by magnetic resonance at 12 months. Forty-nine patients were included (92% male, 55±11 years), 33 randomized to AlloCSC-01 and 16 to placebo. No deaths or major adverse cardiac events were reported at 12 months. One severe adverse events in each group was considered possibly related to study treatment (allergic dermatitis and rash). AlloCSC-01 elicited low levels of donor-specific antibodies in 2 patients. No immune-related adverse events were found, and no differences between groups were observed in magnetic resonance-based efficacy parameters at 12 months. The estimated treatment effect of AlloCSC-01 on the absolute change from baseline in infarct size was -2.3% (95% confidence interval, -6.5% to 1.9%). CONCLUSIONS: AlloCSC-01 can be safely administered in ST-segment-elevation myocardial infarction patients with left ventricular dysfunction early after revascularization. Low immunogenicity and absence of immune-mediated events will facilitate adequately powered studies to demonstrate their clinical efficacy in this setting. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT02439398.

Optimal sequence of tests for the mediastinal staging of non-small cell lung cancer.

BACKGROUND: Non-small cell lung cancer (NSCLC) is the most prevalent type of lung cancer and the most difficult to predict. When there are no distant metastases, the optimal therapy depends mainly on whether there are malignant lymph nodes in the mediastinum. Given the vigorous debate among specialists about which tests should be used, our goal was to determine the optimal sequence of tests for each patient. METHODS: We have built an influence diagram (ID) that represents the possible tests, their costs, and their outcomes. This model is equivalent to a decision tree containing millions of branches. In the first evaluation, we only took into account the clinical outcomes (effectiveness). In the second, we used a willingness-to-pay of € 30,000 per quality adjusted life year (QALY) to convert economic costs into effectiveness. We assigned a second-order probability distribution to each parameter in order to conduct several types of sensitivity analysis. RESULTS: Two strategies were obtained using two different criteria. When considering only effectiveness, a positive computed tomography (CT) scan must be followed by a transbronchial needle aspiration (TBNA), an endobronchial ultrasound (EBUS), and an endoscopic ultrasound (EUS). When the CT scan is negative, a positron emission tomography (PET), EBUS, and EUS are performed. If the TBNA or the PET is positive, then a mediastinoscopy is performed only if the EBUS and EUS are negative. If the TBNA or the PET is negative, then a mediastinoscopy is performed only if the EBUS and the EUS give contradictory results. When taking into account economic costs, a positive CT scan is followed by a TBNA; an EBUS is done only when the CT scan or the TBNA is negative. This recommendation of performing a TBNA in certain cases should be discussed by the pneumology community because TBNA is a cheap technique that could avoid an EBUS, an expensive test, for many patients. CONCLUSIONS: We have determined the optimal sequence of tests for the mediastinal staging of NSCLC by considering sensitivity, specificity, and the economic cost of each test. The main novelty of our study is the recommendation of performing TBNA whenever the CT scan is positive. Our model is publicly available so that different experts can populate it with their own parameters and re-examine its conclusions. It is therefore proposed as an evidence-based instrument for reaching a consensus.

Palliative care in children with spinal muscular atrophy type I: What do they need?

OBJECTIVE: Our aim was to describe the clinical evolution and needs of children with spinal muscular atrophy type I treated in a domiciliary palliative care program. METHOD: We undertook a retrospective chart review of nine consecutive patients. Descriptions of the clinical and demographic profile of children with spinal muscular atrophy (SMA) type I were referred to a pediatric palliative care team (PPCT). RESULTS: Six males and three females were admitted to the PPCT, all before six months of age, except for one afflicted with SMA type I with respiratory distress. The median time of attention was 57 days (range 1-150). The domiciliary attention mainly consisted of respiratory care. The patient with SMA type I with respiratory distress required domiciliary mechanical ventilation by tracheotomy. In all cases, a nasogastric tube (NT) was indicated. As end-of-life care, eight required morphine to manage the dyspnea, four received it only by enteral (oral or NT) administration, and four received it first by enteral administration with continuous subcutaneous infusion (CSI) later. Three of the four patients with CSI also received benzodiazepines. While they were attended by the PPCT, none required hospital admission. All the patients died at home except for the one attended to for just one day. SIGNIFICANCE OF RESULTS: Domiciliary care for these patients is possible. The respiratory morbidity and its management are the main issues. Application of an NT is useful to maintain nutritional balance. Morphine administration is necessary to manage the dyspnea. Palliative sedation is not always necessary.

Características de una población co infectada por el VIH y los virus de las hepatitis B y C por medio de los resultados de la elastografía de transición / Characteristics of a cohort of HIV and hepatitis B and C co-infected patients through the results of transition elastography

Antecedentes y objetivos: El tratamiento de las hepatopatías crónicas en los pacientes VIH positivos es de especial importancia y la detección de fibrosis hepática resulta fundamental para la toma de decisiones. Los objetivos son: describir las características de los pacientes con VIH a los que se realizó elastografía detransición (ET) y analizar la prevalencia y la asociación de diversos factores en el subgrupo de pacientes con fibrosis significativa. Pacientes y métodos: Estudio retrospectivo-prospectivo, descriptivo y de un único centro, realizado en un hospital terciario universitario en el período comprendido entre enero de 2007 hasta febrero de 2010, con 240 pacientes con VIH coinfectados por el virus de la hepatitis B (VHB) o C (VHC), a los que se les realizó ET. Resultados: El 35% de los pacientes no tenía fibrosis, 29.5% presentaba fibrosis medianamente significativa, 10.7% mostraba fibrosis significativa y un 24.8% tenía cirrosis. El 93.3% de los pacientes estaba coinfectado por el VHC; el más frecuente fue el genotipo 1. Se ha encontrado relación significativa entre la fibrosis avanzada y la ausencia de respuesta viral sostenida (RVS), cifra de CD4 < 200 células/mm3 y el consumo de alcohol. Conclusiones: Uno de cada 3 pacientes presenta un estadio de fibrosis significativo y cerca de un cuarto del total tiene cirrosis. La fibrosis significativa se asoció con ausencia de RVS, cifras de CD4 < 200 células/mm3 y consumo de alcohol. Es recomendable tratar a un mayor número de pacientes y de manera más temprana y es en este aspecto donde disponer de una prueba como la ET facilita el diagnóstico del grado de fibrosis para indicar el momento del tratamiento...

The nit1C gene cluster of Pseudomonas pseudoalcaligenes CECT5344 involved in assimilation of nitriles is essential for growth on cyanide.

A proteomic approach was used to identify several proteins induced by cyanide in the alkaliphilic bacterium Pseudomonas pseudoalcaligenes CECT5344, two of them, NitB and NitG, encoded by genes that belong to the nit1C gene cluster. The predicted products of the nit1C gene cluster are a Fis-like σ(54) -dependent transcriptional activator (NitA), a nitrilase (NitC), an S-adenosylmethionine superfamily member (NitD), an N-acyltransferase superfamily member (NitE), a trifunctional polypeptide of the AIRS/GARS family (NitF), an NADH-dependent oxidoreductase (NitH) and two hypothetical proteins of unknown function (NitB and NitG). RT-PCR analysis suggested that nitBCDEFGH genes were co-transcribed, whereas the regulatory nitA gene was divergently transcribed. Real-time RT-PCR revealed that expression of the nitBCDEFGH genes was induced by cyanide and repressed by ammonium. The P. pseudoalcaligenes CECT5344 nit1C gene cluster was found to be involved in assimilation of free and organic cyanides (nitriles) as deduced for the inability to grow with cyanides showed by the NitA, NitB and NitC mutant strains. The wild-type strain CECT5344 showed a nitrilase activity that allows growth on cyanide or hydroxynitriles. The NitB and NitC mutants only presented low basal levels of nitrilase activity that were not enough to support growth on either free cyanide or aliphatic nitriles, suggesting that nitrilase NitC is specific and essential for cyanide and aliphatic nitriles assimilation.

[Scientific evidence and legal liability in occupational health: indemnity claim based on lack of safety and hygiene controls after a worker's death due to mesothelioma]. / Evidencia científica y responsabilidad legal en salud laboral: recargo de prestaciones por falta de medidas de seguridad e higiene tras la muerte por mesotelioma de un trabajador.

The aim of this paper is to reflect, under the precautionary principle, on the relationship between scientific causation and legal liability in connection with a lawsuit regarding compensation for lack of occupational safety and hygiene controls following the death of a worker with mesothelioma that had been previously accepted as an occupational disease. The worker had spent 28 years as a shipyard welder, with a diagnosis of occupationally-related mesothelioma in 2007, and who died in 2009. After reviewing the advances in a) scientific knowledge on the health effects of asbestos exposure, which were consolidated between 1955 and 1976, and b) the development of a regulatory framework for the protection of workers in Spain that began generically in 1940 and became more specific in 1982, we conclude that our case probably would have benefited from application of the precautionary principle, which is now widely accepted.

El objetivo es reflexionar, bajo el principio de precaución, sobre la relación entre causalidad científica y responsabilidad legal, a propósito de una demanda en materia de recargo de prestación por falta de medidas de seguridad e higiene tras la muerte de un trabajador por mesotelioma, reconocida previamente como enfermedad profesional. Se trata de un trabajador que tras 28 años como soldador en unos astilleros, se le reconoció en 2007 un mesotelioma como enfermedad profesional, falleciendo en 2009. Después de valorar que a) el conocimiento científico de la relación de la exposición a amianto y el mesotelioma se consolida entre 1955 y 1976, y b) que la normativa legal para la protección de los trabajadores en España se inicia en 1940 con carácter genérico y en 1982 de manera específica, concluimos que nuestro caso posiblemente se hubiera beneficiado si el principio de precaución, que ahora está ampliamente aceptado, se hubiera aplicado.

The cyanotrophic bacterium Pseudomonas pseudoalcaligenes CECT5344 responds to cyanide by defence mechanisms against iron deprivation, oxidative damage and nitrogen stress.

Two-dimensional (2-D) electrophoresis approach has been used to test protein expression changes in response to cyanide in the alkaliphilic bacterium Pseudomonas pseudoalcaligenes CECT5344. This is a cyanide-assimilating strain which also grows in media containing cyanide-enriched effluent from the jewellery industry. The bacterium efficiently uses this residue as the sole nitrogen source for aerobic growth under alkaline pH with negligible nitrogen losses as HCN. Cell-free extracts isolated from P. pseudoalcaligenes grown with a jewellery residue, free cyanide or ammonium chloride as nitrogen source were subjected to 2-D electrophoresis and the spot patterns were examined to determine differential protein expression. Electrophoretic plates exhibiting an average of 1000 spots showed significant differences in the expression of about 44 proteins depending on the nitrogen source. Some of these protein spots were analysed by Matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS). Characterization of five of these proteins reveals that cyanide shock induces proteins related to iron acquisition, regulation of nitrogen assimilation pathways and oxidative stress repairing and protection.

High prevalence of secondary hypertension and insulin resistance in patients with refractory hypertension.

OBJECTIVE: To determine causes of treatment resistance in patients with refractory hypertension, and to estimate the prevalence of true resistant hypertension. METHODS: We studied 50 consecutive patients referred with refractory hypertension after exclusion of hypokalemia and stenosis of the renal artery. Ambulatory blood pressure monitoring was performed in all patients to detect white-coat effect. The patients were hospitalized, antihypertensive drugs were withdrawn and a screening for secondary hypertension was performed. In addition, these patients, and a control group of essential hypertensives controlled with three antihypertensive drugs, underwent a OGTT with 75 g of glucose. RESULTS: Primary normokalemic hyperaldosteronism was diagnosed in seven patients. Two patients had a pheochromocytoma and six had white-coat effect. The 35 remaining patients with true resistant hypertension shown significant differences in serum insulin and HOMA IR when compared with the control group. CONCLUSIONS: These findings show that among normokalemic treatment-resistant hypertension, the presence of hyperaldosteronism and pheochromocytoma is quite high. Moreover, treatment resistance in hypertensive patients appears to be associated with insulin resistance.