On strategic choices faced by large pharmaceutical laboratories and their effect on innovation risk under fuzzy conditions.

OBJECTIVES: We develop a fuzzy evaluation model that provides managers at different responsibility levels in pharmaceutical laboratories with a rich picture of their innovation risk as well as that of competitors. This would help them take better strategic decisions around the management of their present and future portfolio of clinical trials in an uncertain environment. Through three structured fuzzy inference systems (FISs), the model evaluates the overall innovation risk of the laboratories by capturing the financial and pipeline sides of the risk. METHODS AND MATERIALS: Three FISs, based on the Mamdani model, determine the level of innovation risk of large pharmaceutical laboratories according to their strategic choices. Two subsystems measure different aspects of innovation risk while the third one builds on the results of the previous two. In all of them, both the partitions of the variables and the rules of the knowledge base are agreed through an innovative 2-tuple-based method. With the aid of experts, we have embedded knowledge into the FIS and later validated the model. RESULTS: In an empirical application of the proposed methodology, we evaluate a sample of 31 large pharmaceutical laboratories in the period 2008-2013. Depending on the relative weight of the two subsystems in the first layer (capturing the financial and the pipeline sides of innovation risk), we estimate the overall risk. Comparisons across laboratories are made and graphical surfaces are analyzed in order to interpret our results. We have also run regressions to better understand the implications of our results. CONCLUSIONS: The main contribution of this work is the development of an innovative fuzzy evaluation model that is useful for analyzing the innovation risk characteristics of large pharmaceutical laboratories given their strategic choices. The methodology is valid for carrying out a systematic analysis of the potential for developing new drugs over time and in a stable manner while managing the risks involved. We provide all the necessary tools and datasets to facilitate the replication of our system, which also may be easily applied to other settings.

Measuring the efficiency of large pharmaceutical companies: an industry analysis.

This paper evaluates the relative efficiency of a sample of 37 large pharmaceutical laboratories in the period 2008-2013 using a data envelopment analysis (DEA) approach. We describe in detail the procedure followed to select and construct relevant inputs and outputs that characterize the production and innovation activity of these pharmaceutical firms. Models are estimated with financial information from Datastream, including R&D investment, and the number of new drugs authorized by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) considering the time effect. The relative performances of these firms-taking into consideration the strategic importance of R&D-suggest that the pharmaceutical industry is a highly competitive sector given that there are many laboratories at the efficient frontier and many inefficient laboratories close to this border. Additionally, we use data from S&P Capital IQ to analyze 2071 financial transactions announced by our sample of laboratories as an alternative way to gain access to new drugs, and we link these transactions with R&D investment and DEA efficiency. We find that efficient laboratories make on average more financial transactions, and the relative size of each transaction is larger. However, pharmaceutical companies that simultaneously are more efficient and invest more internally in R&D announce smaller transactions relative to total assets.

Estrategia pedagógica para la formación profesional en ciencias biomédicas / Pedagogical strategy for the vocational training in biomedical sciences

Las insuficiencias en la orientación formativa de los contenidos científico-médicos en correspondencia con la comprensión, explicación e interpretación del ser humano, que limitan la lógica de actuación de los profesionales de la medicina y su desempeño futuro, fueron tratadas a través de la dinámica del proceso de formación profesional en las ciencias biomédicas, que tiene lugar en la Universidad de Ciencias Médicas de Santiago de Cuba. Por tal motivo, se ideó la elaboración de una estrategia pedagógica para la formación del profesional de las ciencias biomédicas, que contribuya al perfeccionamiento del ciclo básico de la carrera de medicina en cuanto al estudio del organismo humano con una visión holística. Se valoró la pertinencia científica de los resultados investigativos, se realizó la aplicación parcial de la estrategia pedagógica propuesta y se logró un impacto social en el perfeccionamiento del proceso de formación del médico general, lo cual lleva a la transformación de su desempeño, al ofrecer una solución a los problemas de salud que debe enfrentar en la atención al individuo, la familia y la comunidad(AU)

The inadequacies in the training orientation of the scientific-medical contents in correspondence to the understanding, explanation and interpretation of the human being that limit the logic of the medicine professionals performance and their future acting, were treated through the dynamics of the vocational training process in biomedical sciences taking place in the University of Medical Sciences from Santiago de Cuba. For such a reason, the elaboration of a pedagogical strategy was drawn for the training of the biomedical sciences professional, contributing to the improvement of the basic cycle of the medicine career as for the study of the human organism with a holistic vision. The scientific relevance of the investigative results was evaluated, the partial application of the pedagogical strategy proposed was carried out, and a social impact was achieved in the improvement of the general doctor training process, which brings the transformation of his acting, as it offers a solution to the health problems that he should face in the care to the individual, the family and the community(AU)

On macroeconomic characteristics of pharmaceutical generics and the potential for manufacturing and consumption under fuzzy conditions.

OBJECTIVE: The aim of this paper is to develop a methodology that is useful for analyzing, from a macroeconomic perspective, the aggregate demand and the aggregate supply features of the market of pharmaceutical generics. In order to determine the potential consumption and the potential production of pharmaceutical generics in different countries, two fuzzy decision support systems are proposed. METHODS AND MATERIALS: Two fuzzy decision support systems, both based on the Mamdani model, were applied in this paper. These systems, generated by Matlab Toolbox 'Fuzzy' (v. 2.0), are able to determine the potential of a country for the manufacturing or the consumption of pharmaceutical generics. The systems make use of three macroeconomic input variables. RESULTS: In an empirical application of our proposed methodology, the potential towards consumption and manufacturing in Holland, Sweden, Italy and Spain has been estimated from national indicators. Cross-country comparisons are made and graphical surfaces are analyzed in order to interpret the results. CONCLUSIONS: The main contribution of this work is the development of a methodology that is useful for analyzing aggregate demand and aggregate supply characteristics of pharmaceutical generics. The methodology is valid for carrying out a systematic analysis of the potential generics have at a macrolevel in different countries. The main advantages of the use of fuzzy decision support systems in the context of pharmaceutical generics are the flexibility in the construction of the system, the speed in interpreting the results offered by the inference and surface maps and the ease with which a sensitivity analysis of the potential behavior of a given country may be performed.

Respuesta. Síndrome de apnea obstructiva durante el sueño y cortocircuito derecha-izquierda late / Reply. Obstructive sleep apnea syndrome and right-to-left shunt

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Influencia de las condiciones medio ambientales en la tolerancia al Ocígeno en animales de experimentación / Influence of the environmental conditions in the oxygen toxicity

INTRODUCCIÓN:La toxicidad del oxígeno está condicionada por la presiónp arcial del gas y el tiempo de exposición al mismo, además de otros factores invariables o variables. Nuestro objetivo es determinar el rango de humedad relativa en una atmósfera hiperóxica y normobárica par que la tolerancia al oxígenos sea mayor. MÉTODO: Se realizaron 3 grupos de experimentación que se introdujeron en a cámara con la atmósfera deseada. El grupo 1 respiró oxígeno húmedo (humedad <50%)(n=27). el grupo 2 (humedad <50%)(n=22). el tercer grupo fue el control (humedad ambiental)(n=11). durante todo el experimento se toma registro de la concentración de O2, CO2, humedad, temperatura, flujo, presion de la botella y la sintomatología clínica asociada al consumo de O2. RESULTADOS: Los sujetos del grupo control presentaron una supervivencia media de 103.18+/-40,32 horas, superior a los otros dos grupos siendo el grupo húmedo el que menos supervivencia media presentó con 87,27+/-34,36 horas, siendo estas diferencias significativas (p=0,01). Las lesiones más graves aparecen en el grupo húmedo y seco. CONCLUSIONES:Estos datos indican que humedades relativas comprendidas entre 30%-60% son las óptimas para disminuir el riesgo de presentar un cuadro de intoxicación por oxígeno bajo condiciones de hiperoxia normobárica

INTRODUCTION:The oxygen toxicity is conditioned by the partial pressure of the gas and the time of exposure, besides other invariable or variable factors. Our objective is to determine the interval of relative humidity ina hyperoxic and normobaric atmosphere so that the tolerance of the oxygen is bigger. METHOD: 3 experimentation groups of rats were introduced in the chamber with the normobaric and hyperoxic atmosphere. Group 1 breathed humid oxygen (humidity>50%) (n=27). Group 2 (humidity <50%)(n=22). the third group was the control (environmental humidity)(n=11). the following data were written down. concentration of O2, CO2, humidity, temperature, flow, pressure of the bottle and the clinical symptomatologic which is associated with the consumption of CO2. RESULTS: The average survival of the control group was of 103.18+/-40.32 hours, it´s higher than the other two groups. The humid group has the survival the lowest survive rate of 87.27+/-34.36 hours, these differences are significant (p=0.01). the most serious injuries appeared in the humid and dry groups. CONCLUSIONS: These data indicate that relative humidy between 30%-60% are recommended in order to decrease the risk of an oxygen toxicity ina hyperoxic normobaric atmosphere

[Factors with influence on sleep apnea/hypopnea syndrome]. / Factores que influyen en el síndrome de apneas-hipopneas durante el sueño.

BACKGROUND AND OBJECTIVE: Evaluate the influence of some variables (gender, age, alcohol intake and obesity) on the apnea/hypopnea index (AHI) in patients with sleep apnea/hypopnea syndrome (SAHS). PATIENTS AND METHOD: We retrospectively reviewed medical records of patients with SAHS in the Hospital General Universitario of Murcia. We assessed demographic variables, alcohol intake, Epworth's scale, obesity and cardiorespiratory polygraphy or polysomnography. A multivariate regression model was used to explain the AHI in relation with other variables. RESULTS: We reviewed 127 medical records of patients with SAHS. Alcohol intake was the most powerful variable influencing the AHI, followed by the numeric value of the Epworth's Scale. No statistical significance was found with regard to the the rest of variables. CONCLUSIONS: In patients with SAHS, the AHI can be related to the alcohol intake and the numeric value of Epworth's Scale.

Factores que influyen en el síndrome de apneas-hipopneas durante el sueño / Factors with Influence on Sleep Apnea/Hypopnea Syndrome

Fundamento y objetivo: Evaluar la influencia de determinados factores, como el sexo, la edad, el consumo de alcohol y la obesidad, sobre el valor del índice de apneas-hipopneas (IAH) en pacientes con síndrome de apneas-hipopneas durante el sueño (SAHS). Pacientes y método: Se han revisado de forma retrospectiva las historias clínicas de pacientes diagnosticados de SAHS en el Hospital General Universitario de Murcia. Se tomaron datos sobre variables demográficas, obesidad, consumo de alcohol, somnolencia (escala de Epworth) y poligrafía cardiorrespiratoria o polisomnografía. A los datos obtenidos se les aplicó un modelo de regresión multivariante para explicar la variable IAH en función de diversas características. Resultados: Se estudió 127 historias clínicas de pacientes diagnosticados de SAHS. En nuestro trabajo, la variable que tiene mayor poder explicativo del comportamiento del IAH en pacientes diagnosticados de SAHS es el consumo de alcohol; la siguiente en importancia es el valor numérico de la escala de Epworth. Las demás variables tienen una influencia estadísticamente no significativa. Conclusiones: El valor del IAH en pacientes diagnosticados de SAHS podría estar relacionado con el consumo de alcohol y con el valor numérico de la escala de Epworth

Background and objective: Evaluate the influence of some variables (gender, age, alcohol intake and obesity) on the apnea/hypopnea index (AHI) in patients with sleep apnea/hypopnea syndrome (SAHS). Patients and Method: We retrospectively reviewed medical records of patients with SAHS in the Hospital General Universitario of Murcia. We assessed demographic variables, alcohol intake, Epworth's scale, obesity and cardiorespiratory polygraphy or polysomnography. A multivariate regression model was used to explain the AHI in relation with other variables. Results: We reviewed 127 medical records of patients with SAHS. Alcohol intake was the most powerful variable influencing the AHI, followed by the numeric value of the Epworth's Scale. No statistical significance was found with regard to the the rest of variables. Conclusions: In patients with SAHS, the AHI can be related to the alcohol intake and the numeric value of Epworth's Scale

Guidelines for the treatment of community-acquired pneumonia: predictors of adherence and outcome.

RATIONALE: Some studies highlight the association of better clinical responses with adherence to guidelines for empiric treatment of community-acquired pneumonia (CAP), but little is known about factors that influence this adherence. OBJECTIVES: Our objectives were to identify factors influencing adherence to the guidelines for empiric treatment of CAP, and to evaluate the impact of adherence on outcome. METHODS: We studied 1,288 patients with CAP admitted to 13 Spanish hospitals. Collected variables included the patients' clinical and demographic data, initial severity of the disease, antibiotic treatment, and specialty and training status of the prescribing physician. MEASUREMENTS AND MAIN RESULTS: Adherence to guidelines was high (79.7%), with significant differences between hospitals (range, 47-97%) and physicians (pneumologists, 81%; pneumology residents, 84%; nonpneumology residents, 82%; other specialists, 67%). The independent factors related to higher adherence were hospital, physician characteristics, and initial high-risk class of Fine, whereas admission to intensive care unit decreased adherence. Seventy-four patients died (6.1%), and treatment failure was found in 175 patients (14.2%). After adjusting for Fine risk class, adherence to the guidelines was found protective for mortality (odds ratio [OR], 0.55; 95% confidence interval [CI], 0.3-0.9) and for treatment failure (OR, 0.65; 95% CI, 0.5-0.9). Treatment prescribed by pneumologists and residents was associated with lower treatment failure (OR, 0.6; 95% CI, 0.4-0.9). CONCLUSIONS: Adherence to guidelines mainly depends on the hospital and the specialty and training status of prescribing physicians. Nonadherence was higher in nonpneumology specialists, and is an independent risk factor for treatment failure and mortality.

Effect of N-acetylcysteine on antioxidant status in glycerol-induced acute renal failure in rats.

Myoglobinuric acute renal failure has three pathogenic mechanisms: tubular obstruction, renal vasoconstriction, and oxidative stress. The latter is generated through the iron released from the group hemo of the myoglobin. Iron induces the formation of high-activity oxygen free radicals that increase oxidative stress and provoke lipid peroxidation and cellular death. This oxidative stress can be measured in several ways, both total or partially with the total antioxidant status or the intermediate enzymes. On the other hand, N-acetylcysteine is a demonstrated substance with antioxidant properties. The aim of the present work was to assess the effect of N-acetylcysteine on the oxidative stress in the glycerol-induced acute renal failure in rats model. We observed that the animals treated with N-acetylcysteine showed an improvement in the antioxidant activity given by an increase in the total antioxidant status and glutathione reductase levels in serum. This improvement was greater when treatment was administered before the induction of rhabdomyolysis. Nevertheless, the observed increase in antioxidant status was only statistically significant for glutathione reductase but not for total antioxidant status. Our results support an important role for N-acetylcysteine in the treatment of this form of acute renal failure, although we think that oxidative stress is not the main pathogenic mechanism of the tubular necrosis induced by rhabdomyolysis, tubular obstruction and renal vasoconstriction being still more important.

Reaching stability in community-acquired pneumonia: the effects of the severity of disease, treatment, and the characteristics of patients.

BACKGROUND: The natural history of the resolution of infectious parameters in patients with community-acquired pneumonia (CAP) is not completely known. The aim of our study was to identify those factors related to host characteristics, the severity of pneumonia, and treatment that influence clinical stability. METHODS: In a prospective, multicenter, observational study, we observed 1424 patients with CAP who were admitted to 15 Spanish hospitals. The main outcome variable was the number of days needed to reach clinical stability (defined as a temperature of or=90 mm Hg, and oxygen saturation >or=90% or arterial oxygen partial pressure of >or=60 mm Hg). RESULTS: The median time to stability was 4 days. A Cox proportional hazard model identified 6 independent variables recorded during the first 24 h after hospital admission related to the time needed to reach stability: dyspnea (hazard ratio [HR], 0.76), confusion (HR, 0.66), pleural effusion (HR, 0.67), multilobed CAP (HR, 0.72), high pneumonia severity index (HR, 0.73), and adherence to the Spanish guidelines for treatment of CAP (HR, 1.22). A second Cox model was performed that included complications and response to treatment. This model identified the following 10 independent variables: chronic bronchitis (HR, 0.81), dyspnea (HR, 0.79), confusion (HR, 0.61), multilobed CAP (HR, 0.84), initial severity of disease (HR, 0.73), treatment failure (HR, 0.31), cardiac complications (HR, 0.66), respiratory complications (HR, 0.77), empyema (HR, 0.57), and admission to the intensive care unit (HR, 0.57). CONCLUSIONS: Some characteristics of CAP are useful at the time of hospital admission to identify patients who will need a longer hospital stay to reach clinical stability. Empirical treatment that follows guidelines is associated with earlier clinical stability. Complications and treatment failure delay clinical stability.

Factores de insatisfacción de los médicos internos residentes / Unsatisfaction factors of resident physicians

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Evolution of total antioxidant status in a model of acute renal insufficiency in rats.

BACKGROUND: Accurate estimation of the Total Antioxidant Status (TAS) in the myoglobinuric acute renal failure (ARF) is necessary because its pathogenesis is believed to be mediated, at least in part, by the development of oxidative stress resulting from the generation of oxygen free radicals and reduced antioxidant defense system. The purpose of this study is to examine the TAS 24 and 72 h after glycerol injection in a model of myoglobinuric-ARF. EXPERIMENTAL DESIGN: The study was conduced in 28 Sprague-Dawley rats. In group 1 (n = 7) rats were placed into individual metabolic cages and deprived of water during 24 h. afterwards an intramuscular injection of glycerol was administrated (50% vol/vol in sterile saline) 10 mg/100 g of body weight and 24 h later blood samples were collected for biochemical measurements (urea, creatinine, creatine-kinase, and TAS levels). In group 2 (n = 7), rats followed the same conditions than group 1 ones but blood samples were collected 72 h after glycerol injection. In groups 3 (n = 7) and 4 (n = 7) rats didn't receive glycerol injection, and blood samples were collected within 24 and 72 h respectively after they were placed into metabolic cages. RESULTS: In groups 1 and 2 we observed a renal function decrease, with higher serum levels of urea and creatinine in group 2 (urea levels: 269 +/- 16 mg/dL vs. 586 +/- 147 mg/dL; p < 0.001. Creatinine levels: 2.8 +/- 0.2 mg/dL vs. 5.8 +/- 0.7 mg/dL; p < 0.001). TAS levels in groups 2, 3, and 4 were similar, but in group 1 was significantly lower (group 1: 0.81 +/- 0.2 mmol/L; group 2: 1.3 +/- 0.1 mmol/L; group 3: 1.2 +/- 0.3 mmol/L, and group 4: 1.2 +/- 0.2 mmol/L; p < 0.005). CONCLUSION: In the model of glycerol induced myoglobinuric-ARF we observed a decrease of serum TAS level within 24 h with spontaneous recuperation 72 h after.

[Significance and management of testicular microlithiasis]. / Significado y manejo de la microlitiasis testiculares.

OBJECTIVES: Testicular microlithiasis is an infrequent urologic diagnosis of non well-known etiology; it has been observed in patients with infertility, testicular atrophy, chromosomopathies, etc., and it had been considered as a benign non progressive disease for a long time. Recent reports have shown its occasional association with malignant tumors. We look for evidences about the significance of testicular microlithiasis and its relationship with gonadal pathologies. METHODS: We perform an electronic bibliographic search in both The Cochrane library and MEDLINE. We performed a manual search in the AUA Update Series, Current Opinion Urology, and bibliographic citations from selected studies. We report one case of bilateral testicular microlithiasis studied at our center which is illustrative. Most published articles are case reports with bibliographic review. RESULTS: The real incidence is unknown, although depending on the series varies from 0.04% in autopsies to 18.1% in testicular ultrasound series. It is more frequent in chryptorchidism, infertility, varicocele, testicular torsion, brain and sympathetic nervous system calcifications, pseudohermaphroditism, Down's syndrome, Klinefelter and Carney, cystic fibrosis, germ cell tumors and carcinoma in situ. There are series which report testicular tumor up to 46% of patients with testicular microlithiasis. It has been described tumor development during follow-up of testicular microlithiasis between 15 months and 11 years, so that it is believed to be a predisposing factor, a possible indirect indicator of premalignant disease, or a tumor marker. It has been also described in normal testicles. CONCLUSIONS: The presence of testicular microlithiasis and its association to both benign diseases and malignant tumors makes a careful evaluation and follow-up necessary, mainly in patients with chryptorchidism, infertility, testicular atrophy, and contralateral testicular tumor; it is recommended testicular ultrasound each semester/year, physical examination, and testicular markers determination; to proceed with testicular biopsy is reasonable in patients of high risk (focal unilateral microlithiasis without mass, or the aforementioned chryptorchidism, infertility, testicular atrophy, and testicular tumor).

Significado y manejo de la microlitiasis testiculares / Testicular microlithiasis: significance and management

OBJETIVOS: la Microlitiasis Testicular (MT) es un diagnóstico urológico infrecuente de etiología poco clara, que se ha observado en pacientes con infertilidad, atrofia testicular, cromosomopatías, etc., y se había considerado durante mucho tiempo una afección benigna no progresiva. Publicaciones recientes han puesto de manifiesto la asociación en ocasiones con tumores malignos. Buscamos evidencias sobre el significado de la MT y la relación con la patología gonadal. MÉTODOS: Realizamos una búsqueda bibliográfica electrónica en la Cochrane Library y MEDLINE. Hacemos una búsqueda manual en las AUA Update Series, Current Opinion Urology y de citas bibliográficas de estudios identificados . Aportamos un caso de MT bilateral estudiado en nuestro Centro que sirve para realizar las ilustraciones. La gran mayoría de las publicaciones corresponden a aportación de casos nuevos con revisión de la literatura. RESULTADOS: La incidencia real es desconocida, aunque según las series oscila desde el 0,04 por ciento en autopsias al 18,1 por ciento de series de ecografías testiculares. Es más frecuente en teste criptorquídico, infertilidad, varicocele, torsión de testículo, calcificaciones del sistema nervioso simpático y del cerebro, pseudohermafroditismo, síndrome de Down, Klinefelter y Carney, fibrosis quística, y en tumores de células germinales y carcinoma in situ. Hay series que presentan tumor testicular hasta en un 46 por ciento de varones con MT. Hay descrito el desarrollo de tumores en el seguimiento de testículos con MT entre 15 meses a 11 años, por ello se cree que es un factor predisponente, un posible indicador indirecto de enfermedad premaligna o un marcador tumoral. También se ha descrito en testículos normales. CONCLUSIONES: La presencia de MT y su asociación tanto a afecciones benignas como con tumores malignos hace necesario una evaluación y seguimiento cuidadoso, especialmente indicado en pacientes con criptorquidia, infertilidad, atrofia testicular y en tumor testicular contralateral, siendo preciso el control con ecografía testicular semestral/anual, exploración física y determinación de marcadores testiculares, siendo razonable la práctica de biopsia en pacientes de alto riesgo (microlitiasis focal y unilateral sin masa o los anteriormente expresados: criptorquidia, infértiles, testesatróficos y tumor testicular) (AU)