Quantitative justification for target concentration intervention - parameter variability and predictive performance using population pharmacokinetic models for aminoglycosides

Aims [1] To quantify the random and predictable components of variability for aminoglycoside clearance and volume of distribution [2] To investigate models for predicting aminoglycoside clearance in patients with low serum creatinine concentrations [3] To evaluate the predictive performance of initial dosing strategies for achieving an aminoglycoside target concentration. Methods Aminoglycoside demographic, dosing and concentration data were collected from 697 adult patients (>=20 years old) as part of standard clinical care using a target concentration intervention approach for dose individualization. It was assumed that aminoglycoside clearance had a renal and a nonrenal component, with the renal component being linearly related to predicted creatinine clearance. Results A two compartment pharmacokinetic model best described the aminoglycoside data. The addition of weight, age, sex and serum creatinine as covariates reduced the random component of between subject variability (BSVR) in clearance (CL) from 94% to 36% of population parameter variability (PPV). The final pharmacokinetic parameter estimates for the model with the best predictive performance were: CL, 4.7 l h(-1) 70 kg(-1); intercompartmental clearance (CLic), 1 l h(-1) 70 kg(-1); volume of central compartment (V-1), 19.5 l 70 kg(-1); volume of peripheral compartment (V-2) 11.2 l 70 kg(-1). Conclusions Using a fixed dose of aminoglycoside will achieve 35% of typical patients within 80-125% of a required dose. Covariate guided predictions increase this up to 61%. However, because we have shown that random within subject variability (WSVR) in clearance is less than safe and effective variability (SEV), target concentration intervention can potentially achieve safe and effective doses in 90% of patients.

Lead sulfide nanocrystal: conducting polymer solar cells

In this paper, we report photovoltaic devices fabricated from lead sulfide nanocrystals and the conducting polymer poly(2-methoxy-5-(2'-ethyl-hexyloxy)-p-phenylene vinylene). This composite material was produced via a new single-pot synthesis which solves many of the issues associated with existing methods. Our devices have white light power conversion efficiencies under AM 1.5 illumination of 0.7% and single wavelength conversion efficiencies of 1.1%. Additionally, they exhibit remarkably good ideality factors (n = 1.15). Our measurements show that these composites have significant potential as soft optoelectronic materials.

Seizure detection algorithm for neonates based on wave-sequence analysis

Objective: The description and evaluation of the performance of a new real-time seizure detection algorithm in the newborn infant. Methods: The algorithm includes parallel fragmentation of EEG signal into waves; wave-feature extraction and averaging; elementary, preliminary and final detection. The algorithm detects EEG waves with heightened regularity, using wave intervals, amplitudes and shapes. The performance of the algorithm was assessed with the use of event-based and liberal and conservative time-based approaches and compared with the performance of Gotman's and Liu's algorithms. Results: The algorithm was assessed on multi-channel EEG records of 55 neonates including 17 with seizures. The algorithm showed sensitivities ranging 83-95% with positive predictive values (PPV) 48-77%. There were 2.0 false positive detections per hour. In comparison, Gotman's algorithm (with 30 s gap-closing procedure) displayed sensitivities of 45-88% and PPV 29-56%; with 7.4 false positives per hour and Liu's algorithm displayed sensitivities of 96-99%, and PPV 10-25%; with 15.7 false positives per hour. Conclusions: The wave-sequence analysis based algorithm displayed higher sensitivity, higher PPV and a substantially lower level of false positives than two previously published algorithms. Significance: The proposed algorithm provides a basis for major improvements in neonatal seizure detection and monitoring. Published by Elsevier Ireland Ltd. on behalf of International Federation of Clinical Neurophysiology.

The experiences and perceptions of fathers attending the birth and immediate care of their baby

Fathers in the United Kingdom (UK) usually attend the birth and immediate care of their baby. They also have an increasing presence during complicated and preterm childbirth, newborn resuscitation and early neonatal unit(NNU) care. However, there is limited evidence about the effect of these experiences on them. The aim of this study was to gain an understanding of the experiences of fathers encountering these situations. The study consisted of three phases and was undertaken in one National Health Service trust in the UK. Qualitative semi-structured interviews using a phenomenological approach were undertaken with 20 first-time fathers present at the delivery, resuscitation and/or admission of their baby to the NNU. Direct observations were made of 22 normal and complicated deliveries and initial newborn care and qualitative semi-structured interviews using the critical incident approach were undertaken with 37 health care professionals (HCPs). The study generated qualitative and quantitative data that were analysed accordingly. The findings show that most fathers were involved for at least some of the time and often spontaneously initiated their involvement. Their most important need was for information. They were usually more concerned about their partner, irrespective of the baby?s need for resuscitation and NNU care. To facilitate their involvement, fathers needed guidance and support from HCPs, particularly delivery suite midwives. Most HCPs recognised the needs of fathers and ways in which they could be helped to connect with their experience. However, these needs were not always met, usually because of inadequate staffing levels, a lack of resources or a mother-centred philosophy of care. The findings suggest the service often determines the extent to which fathers are involved. It is anticipated that these findings will inform HCP education and training and the development of both policy and health education thereby enhancing the quality of care provision for fathers.

Avaliação comparativa da eficácia dos meios de diagnóstico das vulvovaginites: implantação de tecnologia no ensino prático da ginecologia

Inaccurate diagnosis of vulvovaginitis generates inadequate treatments that cause damages women's health. Objective: evaluate the effectiveness of methods when diagnosing vulvovaginitis. Method: a cross-sectional study was performed with 200 women who complained about vaginal discharge. Vaginal smear was collected for microbiological tests, considering the gram stain method as gold standard. The efficacy of the available methods for diagnosis of vaginal discharge was assessed (sensitivity, specificity, positive predictive value and negative predictive value). Data were inserted to Graphpad Prism 6, for statistical analysis. Results: the following results were obtained: wet mount for vaginal candidiasis: sensitivity = 31%; specificity = 97%; positive predictive value (PPV) = 54%; negative predictive value (NPV) =93%; accuracy = 91%. Wet mount for bacterial vaginosis: sensitivity = 80%; specificity =95%; positive predictive value (PPV) = 80%; negative predictive value (NPV) = 95%; accuracy = 92%. Syndromic approach for bacterial vaginosis: sensitivity = 95%; specificity=43%; positive predictive value (PPV) =30%; negative predictive value (NPV) = 97%; accuracy = 54%. Syndromic approach for vaginal candidiasis: sensitivity = 75%; specificity =91%; positive predictive value (PPV) = 26%; negative predictive value (NPV) = 98%; accuracy = 90%. Pap smear for vaginal candidiasis: sensitivity = 68%, specificity = 98%; positive predictive value (PPV) = 86%; negative predictive value (NPV) =96%; accuracy = 96%. Pap smear for bacterial vaginosis: sensitivity = 75%; specificity = 100%; positive predictive value (PPV) = 100%; negative predictive value (NPV) =94%; accuracy = 95%. There was only one case of vaginal trichomoniasis reported – diagnosed by oncological cytology and wet mount – confirmed by Gram. The syndromic approach diagnosed it as bacterial vaginosis. From the data generated and with support on world literature, the Maternidade Escola Januário Cicco’s vulvovaginitis protocol was constructed. Conclusion: Pap smear and wet mount showed respectively low and very low sensitivity for vaginal candidiasis. Syndromic approach presented very low specificity and accuracy for bacterial vaginosis, which implies a large number of patients who are diagnosed or treated incorrectly.

An evaluation of physician predictions of discharge on a general medicine service.

The goal of this study was to evaluate general medicine physicians' ability to predict hospital discharge. We prospectively asked study subjects to predict whether each patient under their care would be discharged on the next day, on the same day, or neither. Discharge predictions were recorded at 3 time points: mornings (7-9 am), midday (12-2 pm), or afternoons (5-7 pm), for a total of 2641 predictions. For predictions of next-day discharge, the sensitivity (SN) and positive predictive value (PPV) were lowest in the morning (27% and 33%, respectively), but increased by the afternoon (SN 67%, PPV 69%). Similarly, for same-day discharge predictions, SN and PPV were highest at midday (88% and 79%, respectively). We found that although physicians have difficulty predicting next-day discharges in the morning prior to the day of expected discharge, their ability to correctly predict discharges continually improved as the time to actual discharge decreased. Journal of Hospital Medicine 2015;10:808-810. © 2015 Society of Hospital Medicine.

Assessment of Two Diabetes Point-of-Care Analyzers Measuring Hemoglobin A1c in the Peruvian Amazon

Aims: Measurement of glycated hemoglobin (HbA1c) is an important indicator of glucose control over time. Point-of-care (POC) devices allow for rapid and convenient measurement of HbA1c, greatly facilitating diabetes care. We assessed two POC analyzers in the Peruvian Amazon where laboratory-based HbA1c testing is not available.

Methods: Venous blood samples were collected from 203 individuals from six different Amazonian communities with a wide range of HbA1c, 4.4-9.0% (25-75 mmol/mol). The results of the Afinion AS100 and the DCA Vantage POC analyzers were compared to a central laboratory using the Premier Hb9210 high-performance liquid chromatography (HPLC) method. Imprecision was assessed by performing 14 successive tests of a single blood sample.

Results: The correlation coefficient r for POC and HPLC results was 0.92 for the Afinion and 0.93 for the DCA Vantage. The Afinion generated higher HbA1c results than the HPLC (mean difference = +0.56% [+6 mmol/mol]; p < 0.001), as did the DCA Vantage (mean difference = +0.32% [4 mmol/mol]). The bias observed between POC and HPLC did not vary by HbA1c level for the DCA Vantage (p = 0.190), but it did for the Afinion (p < 0.001). Imprecision results were: CV = 1.75% for the Afinion, CV = 4.01% for the DCA Vantage. Sensitivity was 100% for both devices, specificity was 48.3% for the Afinion and 85.1% for the DCA Vantage, positive predictive value (PPV) was 14.4% for the Afinion and 34.9% for the DCA Vantage, and negative predictive value (NPV) for both devices was 100%. The area under the receiver operating characteristic (ROC) curve was 0.966 for the Afinion and 0.982 for the DCA Vantage. Agreement between HPLC and POC in classifying diabetes and prediabetes status was slight for the Afinion (Kappa = 0.12) and significantly different (McNemar’s statistic = 89; p < 0.001), and moderate for the DCA Vantage (Kappa = 0.45) and significantly different (McNemar’s statistic = 28; p < 0.001).

Conclusions: Despite significant variation of HbA1c results between the Afinion and DCA Vantage analyzers compared to HPLC, we conclude that both analyzers should be considered in health clinics in the Peruvian Amazon for therapeutic adjustments if healthcare workers are aware of the differences relative to testing in a clinical laboratory. However, imprecision and bias were not low enough to recommend either device for screening purposes, and the local prevalence of anemia and malaria may interfere with diagnostic determinations for a substantial portion of the population.

Economic crisis and national health system

The text analyzes the impact of the economic crisis in some critical aspects of the National Health System: outcomes, health expenditure, remuneration policy and privatization through Private Public Partnership models. Some health outcomes related to social inequalities are worrying. Reducing public health spending has increased the fragility of the health system, reduced wage income of workers in the sector and increased heterogeneity between regions. Finally, the evidence indicates that privatization does not mean more efficiency and better governance. Deep reforms are needed to strengthen the National Health System.

Validation of Electronic Health Record Phenotyping of Bipolar Disorder Cases and Controls

Objective: The study was designed to validate use of elec-tronic health records (EHRs) for diagnosing bipolar disorder and classifying control subjects. Method: EHR data were obtained from a health care system of more than 4.6 million patients spanning more than 20 years. Experienced clinicians reviewed charts to identify text features and coded data consistent or inconsistent with a diagnosis of bipolar disorder. Natural language processing was used to train a diagnostic algorithm with 95% specificity for classifying bipolar disorder. Filtered coded data were used to derive three additional classification rules for case subjects and one for control subjects. The positive predictive value (PPV) of EHR-based bipolar disorder and subphenotype di- agnoses was calculated against diagnoses from direct semi- structured interviews of 190 patients by trained clinicians blind to EHR diagnosis. Results: The PPV of bipolar disorder defined by natural language processing was 0.85. Coded classification based on strict filtering achieved a value of 0.79, but classifications based on less stringent criteria performed less well. No EHR- classified control subject received a diagnosis of bipolar dis- order on the basis of direct interview (PPV=1.0). For most subphenotypes, values exceeded 0.80. The EHR-based clas- sifications were used to accrue 4,500 bipolar disorder cases and 5,000 controls for genetic analyses. Conclusions: Semiautomated mining of EHRs can be used to ascertain bipolar disorder patients and control subjects with high specificity and predictive value compared with diagnostic interviews. EHRs provide a powerful resource for high-throughput phenotyping for genetic and clinical research.

Revisiting molecular diagnostics of Streptococcus pneumoniae

Streptococcus pneumoniae is a human pathobiont that colonizes the nasopharynx. S. pneumoniae is responsible for causing non-invasive and invasive disease such as otitis, pneumonia, meningitis, and sepsis, being a leading cause of infectious diseases worldwide. Due to similarities with closely related species sharing the same niche, it may be a challenge to correctly distinguish S. pneumoniae from its relatives when using only non-culture based methods such as real time PCR (qPCR). In 2007, a molecular method targeting the major autolysin (lytA) of S. pneumoniae by a qPCR assay was proposed by Carvalho and collaborators to identify pneumococcus. Since then, this method has been widely used worldwide. In 2013, the gene encoding for the ABC iron transporter lipoprotein PiaA, was proposed by Trzcinzki and collaborators to be used in parallel with the lytA qPCR assay. However, the presence of lytA gene homologues has been described in closely related species such as S. pseudopneumoniae and S. mitis and the presence of piaA gene is not ubiquitous between S. pneumoniae. The hyaluronate lyase gene (hylA) has been described to be ubiquitous in S. pneumoniae. This gene has not been used so far as a target for the identification of S. pneumoniae. The aims of our study were to evaluate the specificity, sensitivity, positive predicted value (PPV) and negative predicted value (NPV) of the lytA and piaA qPCR methods; design and implement a new assay targeting the hylA gene and evaluate the same parameters above described; analyze the assays independently and the possible combinations to access what is the best approach using qPCR to identify S. pneumoniae. A total of 278 previously characterized strains were tested: 61 S. pseudopneumoniae, 37 Viridans group strains, 30 type strains from other streptococcal species and 150 S. pneumoniae strains. The collection included both carriage and disease isolates. By Mulilocus Sequence Analysis (MLSA) we confirmed that strains of S. pseudopneumoniae could be misidentified as S. pneumoniae when lytA qPCR assay is used. The results showed that as a single target, lytA had the best combination of specificity, sensitivity, PPV and NPV being, 98.5%, 100.0%, 98.7% and 100.0% respectively. The combination of targets with the best values of specificity, sensibility, PPV and NPV were lytA and piaA, with 100.0%, 93.3%, 97.9% and 92.6%, respectively. Nonetheless by MLSA we confirmed that strains of S. pseudopneumoniae could be misidentified as S. pneumoniae and some capsulated (23F, 6B and 11A) and non-capsulated S. pneumoniae were not Identified using this assay. The hylA gene as a single target had the lowest PPV. Nonetheless it was capable to correctly identify all S. pneumoniae.

Giza papilomabirusa eta umetoki lepoko minbizia: aldakortasun genetikoa, biomarkatzaileak eta epidemiologia

148 p.

Renal- and calcium-dependent vascular effects of Polybia paulista wasp venom

In the present study, the effects of Polybia paulista venom (PPV) on renal and vascular tissues were investigated. Isolated kidneys perfused with PPV (1 and 3 mu g/mL) had increased perfusion pressure, renal vascular resistance, urinary flow, and glomerular filtration rate; and reduced sodium tubular transport. Histological evaluation demonstrated deposits of proteins in Bowman's space and tubular lumen, and focal areas of necrosis. The venom promoted a cytotoxic effect on Madin-Darby canine kidney (MDCK) cells. A significant increase in lactic dehydrogenase levels was observed in response to venom exposure. In isolated mesenteric vascular beds, pressure and vascular resistance augmented in a dose-dependent manner. PPV increased the contractility of aortic rings maintained under basal tension. This contractile response was inhibited when preparations were maintained in Ca2+-free medium. Likewise, verapamil, a voltage-gated calcium channel blocker, also inhibited the contractile response. In this study, phentolamine, a blocker of a-adrenergic receptor blocker, significantly reduced the contractile effect of PPV in the aortic ring. In conclusion, PPV produced nephrotoxicity, which suggests a direct effect on necrotic cellular death in renal tubule cells. The vascular contractile effect of PPV appears to involve calcium influx through voltage-gated calcium channels via adrenergic regulation.

Portable “lab-on-chip” platform for bovine mastitis diagnosis in raw milk

Tese de Doutoramento em Ciências Veterinárias, Especialidade de Ciências Biológicas e Biomédicas

Pre-Discharge Screening Trans-Cutaneous Bilirubinometry in Healthy Newborns in Mahdieh Hospital, Tehran

Background: Incidence of jaundice is high in newborn infants. Since well appearing newborns are rapidly and routinely discharged from hospital, performing an inexpensive noninvasive pre-discharge screening test for evaluation of jaundice seems to be necessary. Objectives: This study was conducted to compare the accuracy of cutaneous v/s serum bilirubin measurements in this regard. Patients and Methods: This was a prospective cross sectional study conducted in Mahdieh hospital, Tehran. 613 neonates weighing ≥ 1,800 g with gestational age of ≥ 35 weeks were enrolled. A pre discharge transcutaneous bilirubin test (TcB) was performed in all. Serum samples were taken from neonates with TcB ≥ 5 mg/dL in first and > 8 mg/dL in second 24 hours. Decision for treatment or recheck of bilirubin level after discharge was made based on serum bilirubin results. Results: Based on the study protocol, among 613 studied neonates, 491 (80%) revealed high TcB, of them 240 (49%) cases showed TBC ≥ 5 mg/dL in first and 251 (51 %) in second pre-discharge 24 hours. TcB ranged 3.3 - 17.1, mean TcB in first 24 hours was 6.9 ± 1 .7 (mode 6) and in second 24 hours 9.1 ± 2.1 (mode 10). Of 491 neonates with high TcB, capillary serum sample was taken as the second step and 398 neonates revealed high total serum bilirubin (TsB) with the same protocol for TcB. 108 (27.1%) neonates showed TsB ≥ 5 mg/dL in first and 290 (72.9%) in second 24 hours. According to the study results TcB has a 81% positive predictive value (PPV) in diagnosis of hyperbilirubinemia. Correlation coefficient of TcB and TsB in highest rate is equal to 72% (P value < 0.001). Conclusions: TcB is an inexpensive, noninvasive and precise pre-discharge screening test for evaluation of hyperbilirubinemia, with a high PPV. It is highly recommended to be performed routinely due to high incidence of hyperbilirubinemia in neonates.

Evaluación del desempeño de pruebas diagnósticas de tuberculosis en pacientes VIH positivo en dos hospitales públicos de Bogotá

La tuberculosis TB es una de las principales causas de muerte en el mundo en individuos con infección por VIH. En Colombia esta coinfección soporta una carga importante en la población general convirtiéndose en un problema de salud pública. En estos pacientes las pruebas diagnósticas tienen sensibilidad inferior y la enfermedad evoluciona con mayor frecuencia hacia formas diseminadas y rápidamente progresivas y su diagnóstico oportuno representa un reto en Salud. El objetivo de este proyecto es evaluar el desempeño de las pruebas diagnósticas convencionales y moleculares, para la detección de TB latente y activa pacientes con VIH, en dos hospitales públicos de Bogotá. Para TB latente se evaluó la concordancia entre las pruebas QuantiFERON-TB (QTF) y Tuberculina (PPD), sugiriendo superioridad del QTF sobre la PPD. Se evaluaron tres pruebas diagnósticas por su sensibilidad y especificidad, baciloscopia (BK), GenoType®MTBDR plus (Genotype) y PCR IS6110 teniendo como estándar de oro el cultivo. Los resultados de sensibilidad (S) y especificidad (E) de cada prueba con una prevalencia del 19,4 % de TB pulmonar y extrapulmonar en los pacientes que participaron del estudio fue: BK S: 64% E: 99,1%; Genotype S: 77,8% E: 94,5%; PCRIS6110 S: 73% E: 95,5%, de la misma forma se determinaron los valores predictivos positivos y negativos (VPP y VPN) BK: 88,9% y 94,8%, Genotype S: 77,8% E: 94,5%; PCRIS6110 S: 90% y 95,7%. Se concluyó bajo análisis de curva ROC que las pruebas muestran un rendimiento diagnóstico similar por separado en el diagnóstico de TB en pacientes con VIH, aumentando su rendimiento diagnostico cuando se combinan