Pharmacodynamic monitoring by residual gene expression of the nuclear factor of activated T cell-regulated genes in lung transplant recipients and its correlation with tacrolimus blood levels.

Introduction: Trough blood levels (C0) of tacrolimus are used to adjust drug dosage, but they do not consistently correlate with clinical outcomes. Measurement of residual gene expression of nuclear factor of activated T cell (NFAT)-regulated genes (NFAT-RGE) has been proposed as a pharmacodynamic biomarker to assess the degree of immunosuppression in certain solid organ transplantations, but little is known regarding lung transplant recipients (LTR). Our primary objective is to correlate tacrolimus blood levels with NFAT-RGE. Methods: NFAT-RGE and tacrolimus C0 and peak (C1.5) levels were determined in 42 patients at three, six and 12 months post-transplantation. Results: Tacrolimus C0 did not exhibit a correlation with NFAT-RGE, whereas C1.5 did. Besides, over 20% of measurements indicated high levels of immunosuppression based on the below 30% NFAT-RGE threshold observed in many studies. Among those measurements within the therapeutic range, 19% had an NFAT-RGE<30%. Conclusion: Consequently, a subset of patients within the tacrolimus therapeutic range may be more susceptible to infection or cancer, potentially benefiting from NFAT-RGE and tacrolimus peak level monitoring to tailor their dosage. Further quantitative risk assessment studies are needed to elucidate the relationship between NFAT-RGE and the risk of infection, cancer, or rejection.

Harmonization of indirect reference intervals calculation by the Bhattacharya method.

OBJECTIVES: The aim of this study was to harmonize the criteria for the Bhattacharya indirect method Microsoft Excel Spreadsheet for reference intervals calculation to reduce between-user variability and use these criteria to calculate and evaluate reference intervals for eight analytes in two different years. METHODS: Anonymized laboratory test results from outpatients were extracted from January 1st 2018 to December 31st 2019. To assure data quality, we examined the monthly results from an external quality control program. Reference intervals were determined by the Bhattacharya method with the St Vincent's hospital Spreadsheet firstly using original criteria and then using additional harmonized criteria defined in this study. Consensus reference intervals using the additional harmonized criteria were calculated as the mean of four users' lower and upper reference interval results. To further test the operation criteria and robustness of the obtained reference intervals, an external user validated the Spreadsheet procedure. RESULTS: The extracted test results for all selected laboratory tests fulfilled the quality criteria and were included in the present study. Differences between users in calculated reference intervals were frequent when using the Spreadsheet. Therefore, additional criteria for the Spreadsheet were proposed and applied by independent users, such as: to set central bin as the mean of all the data, bin size as small as possible, at least three consecutive bins and a high proportion of bins within the curve. CONCLUSIONS: The proposed criteria contributed to the harmonization of reference interval calculation between users of the Bhattacharya indirect method Spreadsheet.

Influence of initial clinical suspicion on the diagnostic yield of laboratory enzymatic testing in lysosomal storage disorders. Experience from a multispecialty hospital.

Lysosomal storage disorders (LSD) are a group of inherited metabolic diseases mainly caused by a deficiency of lysosomal hydrolases, resulting in a gradual accumulation of non-degraded substrates in different tissues causing the characteristic clinical manifestations of such disorders. Confirmatory tests of suspected LSD individuals include enzymatic and genetic testing. A well-oriented clinical suspicion can improve the cost-effectiveness of confirmatory tests and reduce the time expended to achieve the diagnosis. Thus, this work aims to retrospectively study the influence of clinical orientation on the diagnostic yield of enzymatic tests in LSD by retrieving clinical, biochemical, and genetic data obtained from subjects with suspicion of LSD. Our results suggest that the clinical manifestations at the time of diagnosis and the initial clinical suspicion can have a great impact on the diagnostic yield of enzymatic tests, and that clinical orientation performed in specialized clinical departments can contribute to improve it. In addition, the analysis of enzymatic tests as the first step in the diagnostic algorithm can correctly guide subsequent confirmatory genetic tests, in turn increasing their diagnostic yield. In summary, our results suggest that initial clinical suspicion plays a crucial role on the diagnostic yield of confirmatory enzymatic tests in LSD.

Vitamin C deficiency in critically ill COVID-19 patients admitted to intensive care unit.

Objectives: To determine vitamin C plasma kinetics, through the measurement of vitamin C plasma concentrations, in critically ill Coronavirus infectious disease 2019 (COVID-19) patients, identifying eventually the onset of vitamin C deficiency. Design: Prospective, observational, single-center study. Setting: Intensive Care Unit (ICU), Vall d'Hebron University Hospital, Barcelona. Study period from November 12th, 2020, to February 24th, 2021. Patients: Patients who had a severe hypoxemic acute respiratory failure due to COVID-19 were included. Interventions: Plasma vitamin C concentrations were measured on days 1, 5, and 10 of ICU admission. There were no vitamin C enteral nor parenteral supplementation. The supportive treatment was performed following the standard of care or acute respiratory distress syndrome (ARDS) patients. Measurement: Plasma vitamin C concentrations were analyzed using an ultra-performance liquid chromatography (UPLC) system with a photodiode array detector (wavelength set to 245 nm). We categorized plasmatic levels of vitamin C as follows: undetectable: < 1,5 mg/L, deficiency: <2 mg/L. Low plasma concentrations: 2-5 mg/L; (normal plasma concentration: > 5 mg/L). Main results: Forty-three patients were included (65% men; mean age 62 ± 10 years). The median Sequential Organ Failure Assessment (SOFA) score was 3 (1-4), and the Acute Physiology and Chronic Health disease Classification System (APACHE II) score was 13 (10-22). Five patients had shock. Bacterial coinfection was documented in 7 patients (16%). Initially all patients required high-flow oxygen therapy, and 23 (53%) further needed invasive mechanical ventilation during 21 (± 10) days. The worst PaO2/FIO2 registered was 93 (± 29). ICU and hospital survival were 77 and 74%, respectively. Low or undetectable levels remained constant throughout the study period in the vast majority of patients. Conclusion: This observational study showed vitamin C plasma levels were undetectable on ICU admission in 86% of patients with acute respiratory failure due to COVID-19 pneumonia requiring respiratory support. This finding remained consistent throughout the study period.

Indirect determination of biochemistry reference intervals using outpatient data.

The aim of this study was to determine reference intervals in an outpatient population from Vall d'Hebron laboratory using an indirect approach previously described in a Dutch population (NUMBER project). We used anonymized test results from individuals visiting general practitioners and analysed during 2018. Analytical quality was assured by EQA performance, daily average monitoring and by assessing longitudinal accuracy between 2018 and 2020 (using trueness verifiers from Dutch EQA). Per test, outliers by biochemically related tests were excluded, data were transformed to a normal distribution (if necessary) and means and standard deviations were calculated, stratified by age and sex. In addition, the reference limit estimator method was also used to calculate reference intervals using the same dataset. Finally, for standardized tests reference intervals obtained were compared with the published NUMBER results. Reference intervals were calculated using data from 509,408 clinical requests. For biochemical tests following a normal distribution, similar reference intervals were found between Vall d'Hebron and the Dutch study. For creatinine and urea, reference intervals increased with age in both populations. The upper limits of Gamma-glutamyl transferase were markedly higher in the Dutch study compared to Vall d'Hebron results. Creatine kinase and uric acid reference intervals were higher in both populations compared to conventional reference intervals. Medical test results following a normal distribution showed comparable and consistent reference intervals between studies. Therefore a simple indirect method is a feasible and cost-efficient approach for calculating reference intervals. Yet, for generating standardized calculated reference intervals that are traceable to higher order materials and methods, efforts should also focus on test standardization and bias assessment using commutable trueness verifiers.

Rapid and accurate method for quantifying busulfan in plasma samples by isocratic liquid chromatography-tandem mass spectrometry (LC-MS/MS).

Objectives: Administration of busulfan is extending rapidly as a part of a conditioning regimen in patients undergoing hematopoietic stem cell transplantation (HSCT). Monitoring blood plasma levels of busulfan is recommended for identifying the optimal dose in patients and for minimizing toxicity. The aim of this research was to validate a simple, rapid, and cost-effective analytical tool for measuring busulfan in human plasma that would be suitable for routine clinical use. This novel tool was based on liquid chromatography coupled to mass spectrometry. Methods: Human plasma samples were prepared using a one-step protein precipitation protocol. These samples were then resolved by isocratic elution in a C18 column. The mobile phase consisted 2 mM ammonium acetate and 0.1% formic acid dissolved in a 30:70 ratio of methanol/water. Busulfan-d8 was used as the internal standard. Results: The run time was optimized at 1.6 min. Standard curves were linear from 0.03 to 5 mg/L. The coefficient of variation (%CV) was less than 8%. The accuracy of this method had an acceptable bias that fell within 85-115% range. No interference between busulfan and the interfering compound hemoglobin, lipemia, or bilirubin not even at the highest concentrations of compound was tested. Neither carryover nor matrix effects were observed using this method. The area under the plasma drug concentration-time curves obtained for 15 pediatric patients who received busulfan therapy prior to HSCT were analyzed and correlated properly with the administered doses. Conclusions: This method was successfully validated and was found to be robust enough for therapeutic drug monitoring in a clinical setting.

A Specific Tubular ApoA-I Distribution Is Associated to FSGS Recurrence after Kidney Transplantation.

A major complication of primary focal segmental glomerulosclerosis (FSGS) is its recurrence after kidney transplantation that happens in 30 to 40% of the patients. The diagnosis of these relapses is not always easy as the histological lesions are not highly specific and appear after the proteinuria increase. Currently, there are no accurate biomarkers to detect FSGS recurrence. Our group identified a modified form of Apolipoprotein A-I (ApoA-I), named ApoA-Ib, specifically present in the urine of recurrent FSGS patients after kidney transplantation. Aberrant forms of ApoA-I have also been described in the urine of native primary FSGS patients; this feature has been associated with prominent staining of ApoA-I at the apical membrane of the tubular cells. In this study, we aim to analyze the ApoA-I distribution in kidney allograft biopsies of recurrent FSGS patients. We detected ApoA-I by immunohistochemistry in kidney allograft biopsies of patients with FSGS relapse after kidney transplantation and in kidney allograft biopsies of patients with a disease different from FSGS in the native kidney (non-FSGS). In recurrent FSGS patients, ApoA-I was prominently localized at the brush border of the tubular cells, while in the non-FSGS patients, ApoA-I was found along the cytoplasm of the tubular cells. The localization of ApoA-I at the brush border of the tubular cells is a specific feature of primary FSGS in relapse. This suggests that ApoA-I staining in kidney biopsies, coupled with ApoA-Ib measurement in urine, could be used as a diagnostic tool of primary FSGS relapse after kidney transplantation due to its highly specific tubular distribution.

A descriptive and validation study of a predictive model of severity of SARS-COV-2 infection.

Objectives: The strain the SARS-COV-2 pandemic is putting on hospitals requires that predictive values are identified for a rapid triage and management of patients at a higher risk of developing severe COVID-19. We developed and validated a prognostic model of COVID-19 severity. Methods: A descriptive, comparative study of patients with positive vs. negative PCR-RT for SARS-COV-2 and of patients who developed moderate vs. severe COVID-19 was conducted. The model was built based on analytical and demographic data and comorbidities of patients seen in an Emergency Department with symptoms consistent with COVID-19. A logistic regression model was designed from data of the COVID-19-positive cohort. Results: The sample was composed of 410 COVID-positive patients (303 with moderate disease and 107 with severe disease) and 81 COVID-negative patients. The predictive variables identified included lactate dehydrogenase, C-reactive protein, total proteins, urea, and platelets. Internal calibration showed an area under the ROC curve (AUC) of 0.88 (CI 95%: 0.85-0.92), with a rate of correct classifications of 85.2% for a cut-off value of 0.5. External validation (100 patients) yielded an AUC of 0.79 (95% CI: 0.71-0.89), with a rate of correct classifications of 73%. Conclusions: The predictive model identifies patients at a higher risk of developing severe COVID-19 at Emergency Department, with a first blood test and common parameters used in a clinical laboratory. This model may be a valuable tool for clinical planning and decision-making.

Interpretability of Aviation Weather Information Displays for General Aviation.

BACKGROUND: General Aviation (GA) pilots who encounter hazardous weather inflight have a high probability of incurring fatal accidents. To mitigate this problem, previous research investigated pilot decision making and the effects of new technology. Limited investigations have examined usability and interpretability of observation and forecast weather products available to pilots. Therefore, this study examined the interpretability of weather observation and forecast reports that GA pilots use for preflight weather planning and the impact of pilot certification level on the interpretability of these displays.METHOD: There were 204 GA pilots (Mean age = 22.50 yr; Median flight hours = 131.0) who completed a 90-item multiple choice Aviation Weather Product Test. The questions portrayed static weather displays available on the NOAA/National Weather Service Aviation Weather Center website. The questions were designed to have high cognitive fidelity in comparison with preflight weather planning tasks.RESULTS: The results revealed overall low mean interpretability scores (Mean percent correct= 59.29%, SD = 16.01%). The scores for observation products and product attributes were lower for student pilots than experienced pilots. Forecast product scores for student and private pilots did not differ, however, student pilot scores were significantly lower than instrument rated private and commercial pilots.DISCUSSION: The low interpretability scores indicate that GA pilots misinterpret weather information provided by most weather observation and forecast products. Possible contributing factors to the low product interpretation scores include poor usability and a lack of training. Future research should measure the usability of weather displays designed for pilots.Blickensderfer BL, Guinn TA, Lanicci JM, Ortiz Y, King JM, Thomas RL, DeFilippis N. Interpretability of aviation weather information displays for general aviation. Aerosp Med Hum Perform. 2020; 91(4):318-325.

Indicadores biológicos en los procesos de esterilización / Biological indicators in sterilization process

El objetivo de este estudio fue determinar la frecuencia del uso de indicadores biológicos de esterilidad en las Centrales de Equipos y Esterilización de los Hospitales de Oncología, Pediatría y Especialidades del Centro Médico Nacional Siglo XXI. El diseño fue una serie de casos. Fueron incluidos todos los procesos de purificación en esterilizadores de vapor o gas óxido de etileno, durante un periodo de seis meses. Las variables analizadas fueron el número de cargas, tipo de esterilización e indicador utilizado. El promedio diario de cargas de esterilización en el Hospital de Oncología fue de 7.72, en Pediatría 10.92 y en Especialidades 8.26. La esterilización por vapor es el método más utilizado (más de 90%). El uso de los indicadores biológicos fue bajo a pesar de que ofrecen doble factor de seguridad para verificar la eficacia del proceso: 32% en Pediatría, 4% en Especialidades y 3% en Oncología.

The objectives were to assess the amount, type and sterility indicators in the sterilization process. Design: series of cases. Study site: Central Equipment and Sterilization Service at the Oncology, Pediatrics and Specialties Hospitals of the 21st Century National Medical Center Mexican Institute of Social Security (IMSS), Mexico City, Mexico. Material and methods: all sterilization processes, whether vapor of ethylene oxide gas sterilizes were studied during a six-month period from three hospitals at the National Medical Center. Variables analyzed: number of loads, sterilize processes and indicator of sterility used. Results: the daily average sterilization loads were: Oncology 7.72, Pediatrics 10.92, Specialties 8.26. The vapor sterilize method was the type most frequently used (>90%). The percentage of utilization of the biological indicators of sterility showed: 32% pediatrics, 4% specialties and oncology 3%. Conclusions: in spite of the fact that the sterilization indicators are twice as safe, they are underused.

Factibilidad de la utilización de la evaluación y manejo de riesgo; mesa redonda

Exposiciones de los distintos participantes del congreso a modo de clausura

Factibilidad de la utilización de la evaluación y manejo de riesgo; mesa redonda

Exposiciones de los distintos participantes del congreso a modo de clausura

Cuantificación, codificación y sistematización de los diagnósticos histopatológicos

El conocimiento de las patologías más frecuentemente diagnosticadas en nuestros servicios de histopatología permite una mejor orientación de programas preventivos y de servicios. En el laboratorio de patología de la Facultad de Odontología de la Universidad Nacional de Colombia, se tomaron 295 historias clínicas. Los diagnósticos allí consignados fueron cuantificados, sistematizados y codificados de acuerdo a la Organización Mundial de la Salud. Se tuvieron en cuenta variables de persona, tiempo y lugar

La lepra en Mexico

La lepra es un problema importante en México, tanto desde el punto de vista médico como social. Se conoce oficialmente la existencia de l5,000 enfermos, pero se supone que existam de 30,000 a 50,000. La prevalencia nacional es de 0,42 pero hay zonas con 12 por 1000. La enfermedad fué introducida probablemente por los conquistadores españoles en el siglo XVI y fué el propio Hernán Cortés quien estableció la primeira leprosería en l521. Desde el punto de vista científico las contribuciones mexicanas han sido numerosas destacándose entre ellas la de Lucio y Alvarado quienes en l851 describieron la llamada lepra manchada o lazarina actualmente conocida como lepromatosis difusa, muy frecuente en México, pero existente también en otros países. Gonzáles-Urueña fundó em l930 el Servicio Federal de Profilaxix de la lepra sobre bases legales muy drásticas que no fueron jamás aplicadas. Se establecieron dispensários y se abrió una leprosaria en l939..