Stability of tedizolid phosphate-sodium rifampicin and tedizolid phosphate-meropenem admixtures in intravenous infusion bags stored at different temperatures.

This is a report on the chemical stability and physical compatibility of intravenous tedizolid phosphate 0.8 mg/mL-sodium rifampicin 2.4 mg/mL and tedizolid phosphate 0.8 mg/mL-meropenem 4 mg/mL combinations in polypropylene 0.9% sodium chloride infusion bags stored at different storage conditions. Triplicate solutions of both admixtures were prepared in 0.9% sodium chloride polypropylene infusion bags and stored under light protection at room temperature (25±2 °C), refrigeration (2-8 °C) or freezing (-15 - -25 °C) conditions. The study was performed using a validated and stability-indicating liquid chromatography (LC) method. For both admixtures and for all storage conditions, at least 90% of the initial drug concentration of tedizolid phosphate remained unchanged throughout the entire study period. Stability of sodium rifampicin at 25±2 °C was determined to be seven hours and six days when it was stored at 2-8 °C. Under the same storage conditions, meropenem was stable for 12 h or 6 days, respectively. Under freezing conditions, sodium rifampicin was stable throughout all 28 days, while stability of meropenem was only 8 days. Solutions of 0.8 mg/mL tedizolid phosphate admixtured with 2.4 mg/mL rifampicin or 4 mg/mL meropenem, in polypropylene 0.9% sodium chloride infusion bags, are stable for at least 7 or 12 hours, respectively, when stored at 25±2 °C. When stored at 2-8 °C, stability was increased to 6 days for both admixtures.

Fusion of genomic, proteomic and phenotypic data: the case of potyviruses.

Data fusion has been widely applied to analyse different sources of information, combining all of them in a single multivariate model. This methodology is mandatory when different omic data sets must be integrated to fully understand an organism using a systems biology approach. Here, a data fusion procedure is presented to combine genomic, proteomic and phenotypic data sets gathered for Tobacco etch virus (TEV). The genomic data correspond to random mutations inserted in most viral genes. The proteomic data represent both the effect of these mutations on the encoded proteins and the perturbation induced by the mutated proteins to their neighbours in the protein-protein interaction network (PPIN). Finally, the phenotypic trait evaluated for each mutant virus is replicative fitness. To analyse these three sources of information a Partial Least Squares (PLS) regression model is fitted in order to extract the latent variables from data that explain (and relate) the significant variables to the fitness of TEV. The final output of this methodology is a set of functional modules of the PPIN relating topology and mutations with fitness. Throughout the re-analysis of these diverse TEV data, we generated valuable information on the mechanism of action of certain mutations and how they translate into organismal fitness. Results show that the effect of some mutations goes beyond the protein they directly affect and spreads on the PPIN to neighbour proteins, thus defining functional modules.

Acute renal failure according to the RIFLE and AKIN criteria: a multicenter study.

OBJECTIVE: To determine the incidence of acute renal failure (ARF) in critically ill patients using the RIFLE and AKIN criteria. DESIGN: A prospective, multicenter observational study with a duration of one year from February 2010 was carried out. RIFLE and AKIN were employed using the urinary (UC) and creatinine criteria (CC) jointly and separately. SCOPE: Nine polyvalent Critical Care Units (CCUs) in Argentina. PATIENTS: A total of 627 critical patients over 18 years of age were admitted to the CCU for more than 48h. EXCLUSION CRITERIA: inability to quantify diuresis, surgical instrumentation of the urinary tract, and need for renal support therapy (RST). VARIABLES OF INTEREST: Calculated hourly diuresis (CHD) was used to apply the UC. RESULTS: The incidence of ARF was 69.4% and 51.8% according to RIFLE and AKIN, respectively. UC detected ARF in 59.5% of cases, while CC identified ARF in 34.7% (RIFLE) and 25.3% (AKIN). The mortality rate was 40.9% and 44.6% according to RIFLE and AKIN respectively, was significantly higher than in patients without ARF, and increased with disease severity (Data processing: Excel, SQL and SPSS. Levene test, comparison of means with Student t and chi-squared, with 95% confidence interval). CONCLUSIONS: RIFLE identified more cases of ARF. UC proved more effective than CC. The presence of ARF and severity levels were correlated to mortality but not to days of stay in the CCU. Implementation of the unified CHD was useful for implementing UC and achieving comparable results.

Safety auxiliary feedback element for the artificial pancreas in type 1 diabetes.

The artificial pancreas aims at the automatic delivery of insulin for glycemic control in patients with type 1 diabetes, i.e., closed-loop glucose control. One of the challenges of the artificial pancreas is to avoid controller overreaction leading to hypoglycemia, especially in the late postprandial period. In this study, an original proposal based on sliding mode reference conditioning ideas is presented as a way to reduce hypoglycemia events induced by a closed-loop glucose controller. The method is inspired in the intuitive advantages of two-step constrained control algorithms. It acts on the glucose reference sent to the main controller shaping it so as to avoid violating given constraints on the insulin-on-board. Some distinctive features of the proposed strategy are that 1) it provides a safety layer which can be adjusted according to medical criteria; 2) it can be added to closed-loop controllers of any nature; 3) it is robust against sensor failures and overestimated prandial insulin doses; and 4) it can handle nonlinear models. The method is evaluated in silico with the ten adult patients available in the FDA-accepted UVA simulator.

Tumor marker kinetics predict outcome in patients with relapsed disseminated non-seminomatous germ-cell tumors.

BACKGROUND: An early serum tumor marker (TM) decline during chemotherapy was shown to independently predict survival in patients with poor-prognosis disseminated non-seminomatous germ-cell tumors (NSGCTs). The aim of this study was to assess whether a TM decline (TMD) also correlates with the outcome in the salvage setting. PATIENTS AND METHODS: Data regarding 400 patients with progressive or relapsed disseminated NSGCTs after first-line chemotherapy prospectively accrued onto two phase III clinical trials were obtained. Serum alpha-fetoprotein (AFP) and/or human chorionic gonadotropin (hCG) were assessed at baseline and after 6 weeks of chemotherapy. A total of 297 patients, 185 and 112 in the training and validation sets, with initially abnormal TMs for whom a change from baseline could be established were used for this analysis. RESULTS: An unfavorable decline in either AFP or hCG was predictive of progression-free survival (PFS) [hazard ratio, HR = 2.15, (95% CI 1.48-3.11); P < 0.001; 2-year PFS rate: 50% versus 26%] as was the Lorch prognostic score (LPS). In the multivariate analysis, an unfavorable TMD, stratified based on the LPS, was an independent adverse prognostic factor for PFS and OS. CONCLUSION: An unfavorable TMD during the first 6 weeks after chemotherapy is associated with a poorer outcome in patients with relapsed disseminated NSGCTs.

Neurotoxicidad asociada a oxaliplatino en la práctica clínica asistencial / Oxaliplatin-associated neurotoxicity in clinical practice

Objetivos: Determinar la presencia de neurotoxicidad asociada a oxaliplatino en la práctica clínica asistencial, la gravedad de la misma y el manejo clínico relacionado con este efecto adverso. Método Estudio observacional retrospectivo que incluyó pacientes diagnosticados de cáncer colorrectal y que iniciaron un esquema de quimioterapia basada en oxaliplatino durante el año 2008 en un hospital de segundo nivel. Los datos se obtuvieron del programa de prescripción de Onco-Hematología propio del hospital y de las historias clínicas informatizadas. Se recogieron variables relacionadas con las características clínicas de los pacientes, con el tratamiento antineoplásico, con la neurotoxicidad asociada a oxaliplatino, así como con su manejo clínico. Resultados Se incluyó un total de 64 pacientes. La presencia de neurotoxicidad se situó en un 65,6%, presentándose mayoritariamente de forma leve o moderada. Alrededor de una tercera parte de los pacientes que presentaron este efecto adverso requirió un cambio en la prescripción de oxaliplatino. Se determinó una relación estadísticamente significativa (p=0,0004) entre dosis acumuladas de oxaliplatino y presencia de toxicidad neurológica. Conclusiones La presencia de neurotoxicidad asociada a oxaliplatino y su distribución en función de su gravedad, es similar a la descrita en literatura médica. El número de pacientes que requiere un cambio en la prescripción de oxaliplatino podría justificar la necesidad de diseñar estudios que valoren las consecuencias clínicas asociadas a estas modificaciones. Consideramos que es necesario el desarrollo de estrategias neuroprotectoras efectivas que garanticen la seguridad y calidad de vida de estos pacientes (AU)

Objectives: To evaluate the presence and severity of oxaliplatin-associated neurotoxicity inclinical practice and the clinical management of this adverse side effect. Method: Observational retrospective study including patients diagnosed with colorectal cancer that started an oxaliplatin-based chemotherapy regimen during 2008 at a secondary hospital. Data were obtained from an onco-haematological prescription programme at the hospital and from digital clinical histories. We compiled variables related to the clinical characteristics of the patients, antineoplastic treatment, neurotoxicity associated with oxaliplatin, and clinical management of this issue. Results: Our study included a total of 64 patients. Neurotoxicity was recorded in 65.6% of cases, usually in mild or moderate forms. In approximately one third of patients who developed this adverse effect, the oxaliplatin prescription had to be modified. We observed a statistically significant relationship between cumulative oxaliplatin doses and the presence of neurological toxicity (P=.0004).Conclusions: The presence of oxaliplatin-associated neurotoxicity and its distribution based onits severity was similar to rates published in the literature. The number of patients requiring a change in the oxaliplatin prescription could justify the need for studies that assess the clinical consequences of these modifications. We believe that effective strategies for neurological protection need to be developed in order to guarantee the safety and quality of life in these patients (AU)

[Clinical pathways in acute pancreatitis: recommendations for early multidisciplinary management. Scientific Committee of the SEMICYUC. Working Group on Infectious Diseases (GTEI-SEMICYUC)]. / Hoja de ruta de los cuidados clínicos para la pancreatitis aguda: recomendaciones para el manejo anticipado multidisciplinar (clinical pathways).

There is a growing body of evidence that early management of patients with acute pancreatitis may alter the natural course of disease and improve outcomes of patients. The aim of this paper is to optimize the management of patients with acute pancreatitis during the first 72 h after hospital admission by proposing several clinical care pathways. The proposed pathways are based on the SEMICYUC 2005 Recommendations with incorporation of the latest developments in the field, particularly the determinants-based classification of acute pancreatitis severity. The pathways also incorporate the "alarm signs", the use of therapeutic modalities known as PANCREAS, and the "call to ICU" criteria. Further studies will need to assess whether the adoption of these pathway reduces mortality and morbidity in patients with acute pancreatitis. The previous SEMICYUC guidelines on management of patients with acute pancreatitis in Intensive Care will need to be revised to reflect the recent developments in the field.

[Oxaliplatin-associated neurotoxicity in clinical practice]. / Neurotoxicidad asociada a oxaliplatino en la práctica clínica asistencial.

OBJECTIVES: To evaluate the presence and severity of oxaliplatin-associated neurotoxicity in clinical practice and the clinical management of this adverse side effect. METHOD: Observational retrospective study including patients diagnosed with colorectal cancer that started an oxaliplatin-based chemotherapy regimen during 2008 at a secondary hospital. Data were obtained from an onco-haematological prescription programme at the hospital and from digital clinical histories. We compiled variables related to the clinical characteristics of the patients, antineoplastic treatment, neurotoxicity associated with oxaliplatin, and clinical management of this issue. RESULTS: Our study included a total of 64 patients. Neurotoxicity was recorded in 65.6% of cases, usually in mild or moderate forms. In approximately one third of patients who developed this adverse effect, the oxaliplatin prescription had to be modified. We observed a statistically significant relationship between cumulative oxaliplatin doses and the presence of neurological toxicity (P=.0004). CONCLUSIONS: The presence of oxaliplatin-associated neurotoxicity and its distribution based on its severity was similar to rates published in the literature. The number of patients requiring a change in the oxaliplatin prescription could justify the need for studies that assess the clinical consequences of these modifications. We believe that effective strategies for neurological protection need to be developed in order to guarantee the safety and quality of life in these patients.

Gangrena simétrica periférica vinculada a coagulación intravascular diseminada, shock séptico e infusión de noradrenalina / Symmetric peripheral gangrene linked to coagulation disseminated intravascular septic shock and infusion of noradrenaline

Introducción: Los intensivistas se enfrentan habitualmente con cuadros clínicos que pueden producir el síndrome de gangrena simétrica periférica. Al reconocer esta posibilidad, pueden prevenirlo, atenuarlo o revertirlo y reducir la morbimortalidad. Presentación del caso: Varón de 34 años con antecedentes de alcoholismo que se presenta con sepsis grave secundaria a absceso de pulmón derecho. Evolucionó con coagulación intravascular diseminada, requirió altas dosis de noradrenalina y tuvo gangrena acral en las cuatro extremidades. Finalmente falleció. Conclusiones: La combinación de shock e hipoperfusión, altas dosis de vasopresores y coagulación intravascular diseminada se vincula con la gangrena simétrica periférica que sufrió nuestro paciente. El manejo terapéutico de la gangrena simétrica periférica es multidisciplinario. (AU)

Introduction: Intensivists are confronted regularly with clinical and therapeutic conditions that can produce symmetrical peripheral gangrene syndrome. Knowing this possibility, they may prevent, attenuate and/or reverse it, and reduce its morbidity and mortality. Case presentation: A 34 years old man with history of alcoholism who presented with severe sepsis due to right lung abscess. The patient developed disseminated intravascular coagulation, he required high doses of noradrenaline infusion and he had acral gangrene in the four limbs. Finally he died. Conclusions: The combination of shock and hypoperfusion, high doses of vasopressors and disseminated intravascular coagulation is associated with the symmetrical peripheral gangrene presented by our patient. The therapeutic management of the symmetrical peripheral gangrene is multidisciplinary.(AU)

On-line monitoring of batch processes based on PCA: does the modelling structure matter? [corrected].

Much work has been devoted to the on-line multivariate statistical process control (MSPC) of batch processes based on bilinear models such as principal component analysis (PCA). The data collected from a batch process have 3-way structure and they have to be arranged in 2-way matrices prior to PCA. Several transformation methods have been proposed reporting contradictory conclusions regarding monitoring performance. The aim of this paper is to run an objective research to assess the influence of 3-way to 2-way transformations on the monitoring performance. Batch-wise, variable-wise, batch-dynamic, local and multi-phase approaches are compared using simulated data from a pair of 'toy' processes with quite different and perfectly known dynamics. Several realistic types of faults are simulated. The main conclusions regarding fault detection performance are: (i) the best monitoring approach depends more on the type of fault than on the process dynamics; (ii) the information considered in the model structure will determine which faults are detectable; (iii) in general, a good monitoring performance is achieved with a parsimonious model; (iv) proper identification of the changes in the correlation structure--the phases of the process--is crucial for parsimonious models; (v) it can be advisable to combine several unfolding methods to improve the detection ability of predefined types of faults. These results were coherently explained from the theoretically known features of the models and validate the conclusions in previous investigations with real batch processes and realistic simulations.

An interval approach for dealing with flux distributions and elementary modes activity patterns.

This work introduces the use of an interval representation of fluxes. This representation can be useful in two common situations: (a) when fluxes are uncertain due to the lack of accurate measurements and (b) when the flux distribution is partially unknown. In addition, the interval representation can be used for other purposes such as dealing with inconsistency or representing a range of behaviour. Two main problems are addressed. On the one hand, the translation of a metabolic flux distribution into an elementary modes or extreme pathways activity pattern is analysed. In general, there is not a unique solution for this problem but a range of solutions. To represent the whole solution region in an easy way, it is possible to compute the alpha-spectrum (i.e., the range of possible values for each elementary mode or extreme pathway activity). Herein, a method is proposed which, based on the interval representation of fluxes, makes it possible to compute the alpha-spectrum from an uncertain or even partially unknown flux distribution. On the other hand, the concept of the flux-spectrum is introduced as a variant of the metabolic flux analysis methodology that presents some advantages: applicable when measurements are insufficient (underdetermined case), integration of uncertain measurements, inclusion of irreversibility constraints and an alternative procedure to deal with inconsistency. Frequently, when applying metabolic flux analysis the available measurements are insufficient and/or uncertain and the complete flux distribution cannot be uniquely calculated. The method proposed here allows the determination of the ranges of possible values for each non-calculable flux, resulting in a flux region called flux-spectrum. In order to illustrate the proposed methods, the example of the metabolic network of CHO cells cultivated in stirred flasks is used.

Comprehensive pharmacokinetic model of insulin Glargine and other insulin formulations.

In this paper, a comprehensive pharmacokinetic model for different insulin formulations including insulin Glargine is developed based on the model proposed by Trajanoski et al. (1993). Current models show limitations for insulin Glargine due to the appearance of an uncharacteristic peak in the concentration-time evolution of plasma insulin that does not coincide with real experimental data. This important limitation has been solved in this paper by introducing a new virtual insulin state called the bound state, in addition to the dimeric and hexameric ones. Trying to describe the retarded action of insulin Glargine, the modeling idea behind this approach is that immediately after the subcutaneous injection all the insulin resides in the bound state, and only then small amounts of insulin in the hexameric form disengage from the bound state. For the model evaluation different simulation results are compared. Using experimental data published by Lepore et al. (2000), the developed model turned out to be capable of at least qualitatively predicting the concentration-time profile of plasma insulin. Both exogenous insulin flow simulations and spatial diffusion simulations show the plausibility and correct implementation of the derived model. Considering all these simulation results, the here presented new pharmacokinetic model demonstrates to be able to reproduce real patient behavior simulating even complete insulin regimes including long-acting, intermediate and short-acting insulin formulations.

Burkitt lymphoma in adults: a prospective study of 72 patients treated with an adapted pediatric LMB protocol.

BACKGROUND: We conducted a phase II study to evaluate in 72 adult patients the efficacy of the intensive LMB chemotherapy regimen, previously reported by the Société Française d'Oncologie Pédiatrique for children with Burkitt lymphoma and L3 acute lymphoblastic leukemia. PATIENTS AND METHODS: Treatment began with a prephase (low-dose steroids, vincristine and cyclophosphamide), except in patients with low tumor burden. Group A (resected stage I and abdominal stage II disease) received three courses of vincristine, cyclophosphamide, doxorubicin and prednisone. Group B (not eligible for groups A or C) received five courses of chemotherapy comprising high-dose methotrexate, infusional cytarabine and intrathecal (IT) methotrexate. Group C (patients with central nervous system and/or bone marrow involvement with < 30% of blast cells) received eight courses containing intensified high-dose methotrexate, high-dose cytarabine, etoposide and triple IT injections. RESULTS: The 2 year event-free survival and overall survival rates for the 72 patients were 65% and 70%, respectively. Age > or = 33 years and high lactate dehydrogenase value were associated with a shorter survival. No response to COP was also associated with a poor outcome in group B. CONCLUSION: Patients with advanced-stage Burkitt lymphoma, including those with bone marrow and/or central nervous system involvement, can be cured with a short-term intensive chemotherapy regime tailored to the tumor burden.