Potential Pitfalls in the Analysis and Structural Interpretation of Seismic Data from the Mars InSight Mission.

The Seismic Experiment for Interior Structure (SEIS) of the InSight mission to Mars, has been providing direct information on Martian interior structure and dynamics of that planet since it landed. Compared to seismic recordings on Earth, ground motion measurements acquired by SEIS on Mars are made under dramatically different ambient noise conditions, but include idiosyncratic signals that arise from coupling between different InSight sensors and spacecraft components. This work is to synthesize what is known about these signal types, illustrate how they can manifest in waveforms and noise correlations, and present pitfalls in structural interpretations based on standard seismic analysis methods. We show that glitches, a type of prominent transient signal, can produce artifacts in ambient noise correlations. Sustained signals that vary in frequency, such as lander modes which are affected by variations in temperature and wind conditions over the course of the Martian Sol, can also contaminate ambient noise results. Therefore, both types of signals have the potential to bias interpretation in terms of subsurface layering. We illustrate that signal processing in the presence of identified nonseismic signals must be informed by an understanding of the underlying physical processes in order for high fidelity waveforms of ground motion to be extracted. While the origins of most idiosyncratic signals are well understood, the 2.4 Hz resonance remains debated and the literature does not contain an explanation of its fine spectral structure. Even though the selection of idiosyncratic signal types discussed in this paper may not be exhaustive, we provide guidance on best practices for enhancing the robustness of structural interpretations.

Sequential treatment of cytomegalovirus infection or disease with a short course of intravenous ganciclovir followed by oral valganciclovir: efficacy, safety, and pharmacokinetics.

Oral (p.o.) or intravenous (IV) ganciclovir (GCV) has been the first-line agent for prevention and treatment of cytomegalovirus (CMV) infection and disease in solid organ transplantation (SOT). The introduction of p.o. valganciclovir, with higher bioavailability than p.o. GCV, has proven to be a suitable approach toward outpatient p.o. therapy for CMV infection/disease. The present single-arm, exploratory pilot trial performed with 21 patients investigates the efficacy and safety of a short therapeutic course (21 days) based on an initial IV treatment with GCV (5 mg/kg twice daily, for 5 days) followed by p.o. valganciclovir (900 mg twice daily, for 16 days) for CMV infection/disease in SOT patients. In all cases, doses were adjusted for renal function. Moreover, the study allowed comparison of exposure to GCV after p.o. valganciclovir with respect to IV GCV in the same patients. Response to treatment was monitored until day 180. Viral load eradication was achieved in 66.7% of patients, on day 21. Although not statistically significant, a trend was seen toward increased persistence of viral load on day 21 for patients with donor positive/recipient negative CMV serostatus or receiving either anti-rejection therapy or polyclonal anti-thymocyte globulin. CMV clinical infection recurred in 14.3% of patients, with higher recurrence rates in patients with risk factors for persistence of viremia. Exposures to GCV after using IV GCV or p.o. valganciclovir showed comparable values (P=0.054). This short course, combining initial IV GCV and subsequent p.o. valganciclovir, may provide effective exposure and therapeutic response in the treatment of CMV infection in SOT patients with adequate drug exposure and with the additional potential benefit of shortening the length of hospital stay, which may result in cost reduction and improved patient comfort.

Population pharmacokinetics of ganciclovir after intravenous ganciclovir and oral valganciclovir administration in solid organ transplant patients infected with cytomegalovirus.

A population pharmacokinetics analysis was performed after intravenous ganciclovir and oral valganciclovir in solid organ transplant patients with cytomegalovirus. Patients received ganciclovir at 5 mg/kg of body weight (5 days) and then 900 mg of valganciclovir (16 days), both twice daily with dose adjustment for renal function. A total of 382 serum concentrations from days 5 and 15 were analyzed with NONMEM VI. Renal function given by creatinine clearance (CL(CR)) was the most influential covariate in CL. The final pharmacokinetic parameters were as follows: ganciclovir clearance (CL) was 7.49.(CL(CR)/57) liter/h (57 was the mean population value of CL(CR)); the central and peripheral distribution volumes were 31.9 liters and 32.0 liters, respectively; intercompartmental clearance was 10.2 liter/h; the first-order absorption rate constant was 0.895 h(-1); bioavailability was 0.825; and lag time was 0.382 h. The CL(CR) was the best predictor of CL, making dose adjustment by this covariate important to achieve the most efficacious ganciclovir exposure.

Impact of valganciclovir on Epstein-Barr Virus polymerase chain reaction in pediatric liver transplantation: preliminary report.

UNLABELLED: Preemptive therapy with ganciclovir has been recommended in the pediatric liver transplant strategy to avoid the development of posttransplant lymphoproliferative disorder (PTLD) from an high Epstein-Barr virus (EBV) is detected. We sought viral load to analyze the response to preemptive therapy with valganciclovir (VGC) in children with liver transplantations and an high quantitative EBV-PCR. METHODS: From June 2005 to December 2007, we tested 979 EBV-PCR among 80 pediatric liver transplant recipients, from those 21/80 PCR were tested from the date of transplantation and 59/80 belonged to the historical cohort (7/59 had a prior history of PTLD). Patients were divided into 2 groups depending upon whether they did (n = 22) or did not (n = 19) receive VGC treatment. The response to VGC was considered complete, if the PCR was negative at 30 and 60 days of treatment; and partial, when the PCR decreased at least 50%. Ganciclovir blood levels tested in 109 cases instances and correlated with the EBV-PCR. RESULTS: A total of 369 (33%) positive PCR were detected in 36/80 patients (mean, 75,000 copies; range = 5000-4,200,000). Among the 22 episodes treated for 30 days, 34% showed complete responses, 41%, partial, and 23%, no response. Among the non-treated group the rates were 6%, 25%, and 68%, respectively (P = .01). However, no differences were observed among those episodes treated for 60 days. At the administered doses, hardly any patient reached the recommended ganciclovir therapeutic level at 2 hours (6 micro/mL). However, the mean PCR was lower when the ganciclovir levels were greater than 4 mg/L when compared with lower levels (P = .03). CONCLUSION: After 30 days of treatment there was a response to VGC in the EBV viral load. There was high interpatient variability of ganciclovir serum concentrations, suggesting the need for pharmacokinetic monitoring to optimize treatment. There was a relationship between the concentration of ganciclovir and the EBV viral load.

Amphotericin B determination in respiratory secretions by reversed-phase liquid chromatography.

Direct delivery of amphotericin B (AMB) to the respiratory tract may be an alternative to intravenous administration. The use of inhalation allows high AMB concentrations to be achieved at the site of infection. A reversed-phase high-performance liquid chromatographic method with a 30-mm-long column is described for assaying AMB in respiratory secretions obtained by bronchoaspiration (BAS) and bronchoalveolar lavage (BAL). Sample clean-up involved treatment with methanol (BAS) and solid-phase extraction onto Sep-Pak C18 cartridges (BAL). The mobile phase consisted of 2.5 mM Na2EDTA-acetonitrile (70:30, v/v). The retention time of AMB was 1.5 min. The range of the assay was from 0.1 to 5 micrograms/ml. The mean recovery was over 90% for both fluids. Within-day and between-day RSDs ranged from 3.10 to 11.87%. AMB in the BAS samples was stable for two days at 20-25 degrees C and for three months at -20 degrees C. The drug in the BAL fluid was stable for one day at 20-25 degrees C, seven days at 4 degrees C and for one month at -20 degrees C.

Stability of amphotericin B in an extemporaneously prepared i.v. fat emulsion.

The stability of amphotericin B in an extemporaneously prepared i.v. fat emulsion was studied. Admixtures of amphotericin B 0.5, 1, and 2 mg/mL were prepared by adding 10, 20, and 40 mL of amphotericin B 5 mg/mL to 90, 80, and 60 mL, respectively, of 20% fat emulsion. The admixtures were stored in glass vacuum containers at 20-25 degrees C and exposed to fluorescent light, 20-25 degrees C and protected from light, or 4-8 degrees C and protected from light. A sample was withdrawn from each container at 0, 4, 12, and 24 hours and at 2, 4, 7, and 15 days for analysis of amphotericin B concentration by high-performance liquid chromatography and for visual evaluations; these samples were immediately frozen until analyzed. A sample was withdrawn from one container of amphotericin B 1 and 2 mg/mL for each storage condition at 0, 7, and 15 days for immediate determination of particle-size distribution with a fluorescinated-antibody cell sorter. Amphotericin B 0.5 mg/mL in 20% fat emulsion was stable for one week under all the storage conditions. Amphotericin B in the 1- and 2-mg/mL admixtures was stable for up to four days at 20-25 degrees C exposed to fluorescent light, and for up to one week at 20-25 degrees C protected from light and at 4-8 degrees C protected from light. There was no visible evidence of incompatibility. There were no substantial changes in particle-size distribution for the 1-mg/mL admixtures; appreciable changes were detected for the 2-mg/mL admixtures. Amphotericin B 1 and 2 mg/mL was stable in 20% fat emulsion for four days at 20-25 degrees C exposed to fluorescent light and for seven days at 20-25 degrees C protected from light or at 4-8 degrees C; amphotericin B 0.5 mg/mL was stable in 20% fat emulsion for seven days under the three storage conditions.

Blood cyclosporine C0 and C2 concentrations and cytomegalovirus infections following lung transplantation.

The aim of this study was to determine whether cyclosporine levels predose (C0) and at two hours postdose (C2) were higher among patients presenting with cytomegalovirus (CMV) infection or disease. Between days 40 and 365 posttransplantation serial C0 and C2 levels were measured in 15 lung transplant recipients. Nine developed 13 episodes of CMV infection or disease. Both C0 and C2 levels were higher during CMV infection or disease episodes. Eleven of the 13 CMV episodes (84%) displayed C0 >220 ng/mL and none had C0 <200 ng/mL. For C2, 11 of 13 CMV episodes (84%) showed C2 >1200 ng/mL and none had C2 <1000 ng/mL. Among determinations that did not coincide with a CMV episode, 7 of 21 (33%) showed C0 >220 and 9 of 21 (42%) showed C2 >1200, respectively (P<.05). In conclusion, cyclosporine blood levels are higher among patients presenting with CMV infection or disease.

[Theophyllines of 12- and 24-hour sustained-release. Comparative study]. / Teofilinas de liberación sostenida de 12 y 24 horas. Estudio comparativo.

To compare 24-h and 12-h delayed-release theophylline in asthmatic patients, in terms of clinical stability and respiratory function, side effects and required dose, clinical tolerance and plasma concentrations. Patients with bronchial asthma in stable phase taking theophylline every 12 h were selected. Each patient received 12-h (treatment A) and 24-h (treatment B) theophylline formulas in a prospective, cross-over study with paired data for periods of 15 days. We evaluated theophylline doses, blood levels, clinical course, lung function and side effects. Twenty patients were enrolled. No significant differences between the two treatments were observed in mean dose of theophylline per kg body weight required to obtain therapeutic plasma concentrations (treatment A: 9.36 +/- 1.88 mg/kg/day; treatment B: 9.6 +/- 1.7 mg/kg/day). Mean blood level just before administration of a the next dose was lower with the 24-h formula, but still within therapeutic margins (treatment A: 7.31 +/- 2.27 micrograms/ml; treatment B: 10.66 +/- 2.86 micrograms/ml; p = 0.002). There were no differences in side effects after the adjustment period or in FEV1 after each treatment period. Peak expiratory flow remained stable during the study. The 24-h delayed release theophylline formula was similar to the 12-h formula in dose required by asthmatic patients and in therapeutic plasma concentrations throughout the day.

[The use of the determination of plasma theophylline concentrations in the hospital]. / Uso de la determinación de las concentraciones plasmáticas de teofilina en el hospital.

BACKGROUND: The evaluation of the determination of plasmatic concentrations of theophylline (PCT) in clinical practice is scarce. An observational study was carried out with the aim of discerning the reasons why PCT determinations are requested, the theophyllinemias obtained and the attitude of the medical staff in a hospital. METHODS: PCT determinations obtained in 113 patients over a period of 3 months were analyzed. Information concerning treatment and daily doses of theophylline, reasons for theophylline determination, apart from those included in the request for theophyllinemia determination, clinical history and treatment sheets were collected. RESULTS: Treatment with theophylline had been indicated in 78 patients (69%) with chronic bronchitis, and 30 (26%) with asthma. All the patients received medication in addition to theophylline. Daily dosage (SD) was 734 (260) mg and the daily doses as to body weight (SD) was 11 (4) mg/kg/day. 188 DNPT were performed, however 22 (12%) were inadequate; of the remaining 166 PCT determinations 117 (69%) had been requested with no indication of insufficient clinical response, suspicion of undesirable effects or modifying factors of the pharmacokinetics of theophylline. The mean plasmatic concentration (SD) was 11.3 (7) micrograms/ml. PCT was infratherapeutic in 74 PCT determinations (44%), therapeutic in 73 (44%) and toxic in 19 (11%). Therapeutic concentrations were obtained in only 16 (35%) of the 45 patients in whom a second PCT determination had been carried out. CONCLUSIONS: In this study scarce individualization in the indication of treatment and the doses of theophylline administered are observed. The reason for soliciting determination of theophyllinemia and dosage adjustment in terms of plasmatic concentrations are also commented upon.

Determination of ganciclovir in human plasma by ultra performance liquid chromatography-UV detection.

OBJECTIVES: Implement a sensitive UHPLC method for the assay of ganciclovir in human plasma. DESIGN AND METHODS: We developed and validated a chromatographic method coupled to ultraviolet detection for quantification of ganciclovir, with a short run time using a small volume of human plasma. Comparison of system performance was made with respect to analysis time, efficiency and sensitivity. RESULTS: Correlation coefficients (r) of the calibration curves ranged from 0.999744 to 0.999784. Within-day and between-day imprecision and inaccuracy, specificity and recovery were also evaluated for validation. The method was precise and accurate and the retention time was 0.7 min. The calibration curves were linear between 0.5 and 30 µg/mL. There was a good correlation between HPLC and UHPLC techniques. CONCLUSIONS: We developed a method that is currently applied in a clinical study assessing GCV plasma concentration variability after ganciclovir and valganciclovir administration.

Indications and management of everolimus after liver transplantation.

OBJECTIVE: Our aim was to assess our experience with the use and management of everolimus after orthotopic liver transplantation (OLT). MATERIALS AND METHODS: Among the 759 patients who underwent transplantation from 1988 to 2008, 25 (3.2%) received immunosuppression with everolimus. Their mean age was 55.6 years. We analyzed indications for use, time between transplantation and introduction of everolimus, as well as its efficacy, side effects, and patient survival. RESULTS: The indications for everolimus treatment were: extended hepatocellular carcinoma (HCC) in the explanted liver (n = 6; 24%); HCC recurrence during follow-up (n = 4; 16%); de novo tumor (n = 6; 24%); refractory rejection (n = 3; 12%); side effects of calcineurin inhibitors (CNI; n = 3; 12%); and other causes (n = 3; 12%). Mean time between OLT and everolimus treatment was 40 +/- 33 months (range, 10 days-178 months). Mean follow-up after conversion was 10 +/- 9 months (range, 1.5-25 months). More than half of the patients resolved the event for which the drug was indicated: 75% of patients with refractory rejection; 60% of those with renal insufficiency; and 100% of those converted for neurotoxicity or hepatotoxicity. Two patients with recurrent HCC and 1 with extended HCC died at a mean time of 10.5 months. The 6 cases of de novo tumors were operated and are healthy. Side effects were dyslipidemia in 8 and infection in 2. Five patients (20%) discontinued the drug. CONCLUSIONS: In the early posttransplantation period, everolimus is indicated for refractory rejection or as prophylaxis for recurrence of extended tumors. In any time but especially in the late period, everolimus is indicated for patients with serious side effects due to a CNI or to a de novo tumor.

Efficacy and safety of 'rescue therapy' with mycophenolate mofetil in resistant primary glomerulonephritis--a multicenter study.

BACKGROUND: Studies of mycophenolate mofetil (MMF) in primary glomerulonephritis have varied in their inclusion criteria, regimen and follow-up compromising assessments of efficacy and optimal dose. METHOD: This multicentre study analysed the safety and efficacy of MMF monotherapy in a large cohort with primary glomerulonephritis that was resistant to other conventional therapies. A total of 98 patients with biopsy-proven primary glomerulonephritis resistant to other drugs received MMF monotherapy for 1 year. Primary outcome measures were urinary protein excretion and the number of patients with complete or partial remission of proteinuria. Secondary analyses were time to remission and changes in the slope of creatinine clearance. RESULTS: Fifty-four percent of the patients achieved either complete or partial remission of proteinuria with no significant differences between glomerulonephritis types. Median (range) dose of MMF was 2 g/day (1.5-2 g/day) Mean (SD) treatment time to remission was 141.5 (+/-61.1) days with no significant differences between glomerulonephritis types. Serum albumin increased (P<0.01), whereas proteinuria (P<0.01) serum LDL-cholesterol (P<0.01) and mean blood pressure (P<0.05) decreased post-treatment. No significant changes were observed in glomerular filtration rate (GFR), serum creatinine or slopes of GFR. The reduction of urinary protein excretion was significantly higher in patients with basal nephrotic proteinuria and preserved renal function; it did not arise from an increased dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, since, among responders, mean blood pressure significantly decreased and the number of anti-hypertensive drugs could be reduced. CONCLUSIONS: MMF monotherapy causes a moderate decrease in proteinuria in >50% of the patients who do not have other treatment options. The response to therapy is largely influenced by a preserved renal function and requires sustained MMF treatment.

[Influence of organizational climate on job satisfaction among health professionals]. / Influencia del clima laboral en la satisfacción de los profesionales sanitarios.

OBJECTIVE: To describe the quality of professional life (QPL) as perceived by primary care workers and to measure the organizational climate (OC). To identify the influence of OC on QPL and the variables that explain this relationship. DESIGN: Cross-sectional study. SETTING: Primary care centres in the Menorca Health Area (Balearic Islands, Spain). PATIENTS: One hundred and sixty six primary care, including health-workers and others. MAIN MEASUREMENTS: Two anonymous, self-administered, PC-validated questionnaires were filled in: QPL-35 (dimensions: perception of demands, support from managers, and motivation) and OC (dimensions: team-work, cohesion, and commitment). Age, seniority, professional group, job relationship, and the health centre were analysed. RESULTS: Positive answers: 67.4%. Average QPL was 5.78, lower for older workers and higher among those perceiving more cohesion. Average score for perceived demands was 5.53, higher among physicians and less if there is high commitment. Support from managers was 4.9, positively associated with cohesion and team-work and negatively associated with permanent workers and clerical staff. Intrinsic motivation was 7.43, greater if commitment was higher. Regardless of age, professional category and seniority, there was a significant association between OC and QPL (strongest in the motivation [r2=0.26] and managerial support [r2=0.476] dimensions). CONCLUSIONS: OC influences QPL, especially in motivation and managerial support. Commitment enhances motivation and perception of demands. Where there is better cohesion and team-work, the manager s support is also rated more highly.

Determination of lamotrigine in human serum by liquid chromatography.

A rapid high-performance liquid chromatographic method was developed using a short silica column (30 mm x 4.6 mm) with an aqueous methanol mobile phase consisting of methanol-water-NH4H2PO4 (94:5.96:0.04) adjusted to a final apparent pH of 5.0 and pumped at a flow-rate of 1 ml/min. Ultraviolet detection was carried out at a wavelength of 280 nm, and serum samples were prepared for HPLC analysis by extraction into dichloromethane after basification. Lamotrigine was eluted at 0.96 min. Within-day variation of the method was 4.46% at 0.75 microg/ml and 2.37% at 6.0 microg/ml, and day-to-day variation was 9.10% at 0.75 microg/ml and 7.28% at 6.0 microg/ml.

Changes in vancomycin pharmacokinetics during treatment.

Using data gathered in routine monitoring, the pharmacokinetics of vancomycin during the first 10 days of treatment were compared with the pharmacokinetics after 10 days of treatment in 46 adult patients with normal renal function, ages 17-85 years old (mean +/- SD: 50.8 +/- 17.5). The mean time from initiation of treatment to the first sample determination was 5.5 days, and the mean time to the second determination was 13.4 days. Statistical differences between the two periods were observed for all pharmacokinetic parameters, except for the steady-state distribution volume. After 10 days of treatment, the mean +/- SD of the vancomycin clearance and elimination rate constant decreased from 1.31 +/- 0.82 to 1.13 +/- 0.72 ml/kg/min (p = 0.0044) and from 0.13 +/- 0.08 to 0.10 +/- 0.06 h-1 (p = 0.091), respectively. The half-life (t1/2) increased from 8.01 +/- 6.82 to 10.02 +/- 8.00 h (p = 0.012). The median percentage of the increment of t1/2 was 9.4%. The increase in t1/2 was > 50% in 12 patients and > 100% in nine cases. No association was found between the increment of t1/2 and the cumulative vancomycin dose. Frequent monitoring of serum vancomycin seems indicated, given the risk of decreased elimination during prolonged treatment.

Effect of gentamicin dosing interval on therapy of viridans streptococcal experimental endocarditis with gentamicin plus penicillin.

This study compares the effects of a total daily dose of gentamicin given once a day (q.d.) or three times a day (t.i.d.) in the therapy of experimental endocarditis in rabbits caused by penicillin-susceptible, penicillin-tolerant, or penicillin-resistant viridans streptococci. Four isolates were used in vivo: one penicillin susceptible (MIC < or = 0.03 microgram/ml), one penicillin tolerant (MBC/MIC, < or = 0.03/ > 32 micrograms/ml), and two penicillin resistant (MICs = 0.5 and 2 micrograms/ml). Animals were infected with one of the four isolates and assigned to one of the following treatment regimens: no treatment, procaine penicillin at 1.2 million IU intramuscularly (i.m.) t.i.d., procaine penicillin plus gentamicin at 1 mg/kg of body weight i.m. t.i.d., procaine penicillin plus gentamicin at 3 mg/kg i.m. q.d., or procaine penicillin plus gentamicin at 1 mg/kg i.m. q.d. (only animals infected with the penicillin-susceptible isolate). Serum drug concentrations measured 30 min after administration of 1.2 million IU of penicillin and 1 or 3 mg of gentamicin per kg were 22.6, 3.8, and 8.5 micrograms/ml, respectively. The reduced total daily dose of gentamicin was ineffective among animals infected with penicillin-susceptible viridans streptococci; treatment with 1 mg of gentamicin per kg per day plus penicillin was less effective (P < 0.05) than was treatment with 3 mg of gentamicin per kg per day plus penicillin. The 1-mg/kg/day gentamicin treatment regimen was not further studied. The gentamicin dosing interval did not significantly affect (q.d. versus t.i.d., P > 0.05) the relative efficacy of penicillin plus gentamicin for treatment of experimental endocarditis among animals infected with each of the four isolates tested.