Low-Cost Pseudo-Anthropomorphic PVA-C and Cellulose Lung Phantom for Ultrasound-Guided Interventions.

A low-cost custom-made pseudo-anthropomorphic lung phantom, offering a model for ultrasound-guided interventions, is presented. The phantom is a rectangular solidstructure fabricated with polyvinyl alcohol cryogel (PVA-C) and cellulose to mimic the healthy parenchyma. The pathologies of interest were embedded as inclusions containing gaseous, liquid, or solid materials. The ribs were 3D-printed using polyethylene terephthalate, and the pleura was made of a bidimensional reticle based on PVA-C. The healthy and pathological tissues were mimicked to display acoustic and echoic properties similar to that of soft tissues. Theflexible fabrication process facilitated the modification of the physical and acoustic properties of the phantom. The phantom's manufacture offers flexibility regarding the number, shape, location, and composition of the inclusions and the insertion of ribs and pleura. In-plane and out-of-plane needle insertions, fine needle aspiration, and core needle biopsy were performed under ultrasound image guidance. The mimicked tissues displayed a resistance and recoil effect typically encountered in a real scenario for a pneumothorax, abscesses, and neoplasms. The presented phantom accurately replicated thoracic tissues (lung, ribs, and pleura) and associated pathologies providing a useful tool for training ultrasound-guided procedures.

Cost-effectiveness analysis of the daily HIV pre-exposure prophylaxis in men who have sex with men in Barcelona.

INTRODUCTION: Pre-Exposure Prophylaxis (PrEP) for HIV prevention has been implemented in several countries. Previous literature has shown that its cost-effectiveness (and, under some specifications, cost-saving character) is dependent on the reduction in price due to generics, the time-horizon and its effectiveness. The intervention has never been studied in Catalonia after the approval of the PrEP, a territory with extensive implementation. METHODS: Economic evaluation of the implementation of HIV pre-exposition prophylaxis using administrative data from Men who have Sex with Men (MSM) who receive the treatment (at the generic price) compared with non-implementation. A deterministic compartmental model and a social perspective with a micro-costing approach over the time horizon 2022-2062 are used. A baseline 86% effectiveness of PrEP is assumed. RESULTS: Daily oral PrEP is found to be cost-saving: discounted savings in costs are attained after 16 years, and after 40 years they reach 81 million euros. In terms of health indicators, 10,322 additional discounted QALYs are generated by the intervention. Results are sensitive to sexual behavioral patterns among MSM, the price of PrEP (reduced if offered on-demand), its effectiveness and the discount rate. CONCLUSIONS: The use and promotion of PrEP in Catalonia is predicted to result in substantial health and monetary benefits because of reductions in HIV infections. Short-term investments in the promotion of PrEP will result in important cost-savings in the long term.

Tigecycline population pharmacokinetics in critically ill patients with decompensated cirrhosis and severe infections.

OBJECTIVES: Physiopathological changes in advanced cirrhosis could alter tigecycline pharmacokinetics (PK), thus affecting serum drug concentrations and compromising target attainment. We aimed to describe tigecycline PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under tigecycline treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate tigecycline exposure to assess the PTA. RESULTS: Twenty critically ill patients were enrolled in the study. Data were best described by a two-compartment linear model. Mean ± SD parameter estimates for clearance (CL), intercompartmental clearance (Q), central and peripheral volumes of distribution (V1 and V2) were 14.8 ± 11 L/h, 38.4 ± 24 L/h, 63.7 ± 14 L and 233 ± 30 L, respectively. MELD score significantly influenced tigecycline CL, and total serum proteins significantly affected V1. Monte Carlo simulations showed that tigecycline elimination is hampered as MELD score values increase, consequently requiring lower drug doses. Patients with hypoproteinaemia would have lower peak tigecycline concentrations but similar steady-state concentrations compared with patients with normoproteinaemia. CONCLUSIONS: Our study confirms that tigecycline dose adjustment is needed in severe hepatic dysfunction and suggests using the MELD score for dose optimization since it is identified as a covariate that significantly influences tigecycline CL. Dosing regimens are recommended to reach several PK/PD targets considering this clinical variable and any MIC within the susceptibility range.

'Equity' and 'Justice' for patients with acute-on chronic liver failure: A call to action.

Acute-on-chronic liver failure (ACLF) occurs in hospitalised patients with cirrhosis and is characterised by multiorgan failures and high rates of short-term mortality. Without liver transplantation (LT), the 28-day mortality rate of patients with ACLF ranges from 18-25% in those with ACLF grade 1 to 68-89% in those with ACLF grade 3. It has become clear that patients with ACLF do not have equitable access to LT because of current allocation policies, which are based on prognostic scores that underestimate their risk of death and a lack of appreciation of the clear evidence of transplant benefit in carefully selected patients (who can have excellent post-LT outcomes). In this expert opinion, we provide evidence supporting the argument that patients with ACLF should be given priority for LT based on prognostic models that define the risk of death for these patients. We also pinpoint risk factors for poor post-LT outcomes, identify unanswered questions and describe the design of a global study, the CHANCE study, which will provide answers to the outstanding issues. We also propose the worldwide adoption of new organ allocation policies for patients with ACLF, as have been initiated in the UK and recommended in Spain.

Meropenem population pharmacokinetics in patients with decompensated cirrhosis and severe infections.

OBJECTIVES: Meropenem pharmacokinetics (PK) may be altered in patients with cirrhosis, hampering target attainment. We aimed to describe meropenem PK in patients with decompensated cirrhosis and severe bacterial infections, identify the sources of PK variability and assess the performance of different dosing regimens to optimize the PK/pharmacodynamic (PD) target. METHODS: Serum concentrations and covariates were obtained from patients with severe infections under meropenem treatment. A population PK analysis was performed using non-linear mixed-effects modelling and the final model was used to simulate meropenem exposure to assess the PTA. RESULTS: Fifty-four patients were enrolled in the study. Data were best described by a one-compartment linear model. The estimated typical mean value for clearance (CL) was 8.35 L/h and the estimated volume of distribution (V) was 28.2 L. Creatinine clearance (CLCR) and MELD score significantly influenced meropenem CL, and acute-on-chronic liver failure (ACLF) significantly affected V. Monte Carlo simulations showed that a lower meropenem dose would be needed as CLCR decreases and as the MELD score increases. Patients with ACLF would have lower peak meropenem concentrations but similar steady-state concentrations compared with patients with no ACLF. CONCLUSIONS: Our study identified two new covariates that influence meropenem PK in patients with decompensated cirrhosis in addition to CLCR: MELD score and ACLF. Dosing regimens are recommended to reach several PK/PD targets considering these clinical variables and any MIC within the susceptibility range.

Correction to: The cost-effectiveness of albumin in the treatment of decompensated cirrhosis in Germany, Italy, and Spain.

Following publication of the original article [1], the authors reported that one of the numbers within Fig. 6 contains a mistake.

The cost-effectiveness of albumin in the treatment of decompensated cirrhosis in Germany, Italy, and Spain.

BACKGROUND: Albumin is frequently prescribed in cirrhotic patients with acute decompensation. However, the true cost effectiveness of albumin use in cirrhotic patients is still under debate. OBJECTIVE: To evaluate the cost-effectiveness of albumin in the treatment of decompensated cirrhosis in Germany, Italy, and Spain. METHODS: A decision-tree economic model was developed to evaluate treatments for decompensated cirrhosis from the hospital perspective over a typical inpatient admission. The treatments for large volume paracentesis (LVP) were albumin vs saline, gelatin, or no fluid. The treatments for spontaneous bacterial peritonitis (SBP) were albumin plus antibiotics vs antibiotics alone. The treatments for hepatorenal syndrome (HRS) were albumin plus a vasoconstrictor vs a vasoconstrictor alone. Effectiveness inputs were literature-based. Cost inputs included pharmacy costs and medical complication costs of decompensated cirrhosis. The primary model assessments were incremental cost-effectiveness ratios (ICERs) per life saved and per quality-adjusted life-year (QALY). RESULTS: Albumin was found to be both less costly and more effective relative to saline, gelatin, and no fluid for the treatment of LVP across all 3 countries. For SBP, albumin plus antibiotics was more clinically effective than antibiotics alone in all 3 countries. The combination of albumin plus antibiotics was less costly than antibiotics alone in Germany and Italy, making albumin a dominant treatment (ie, less costly and more effective). In the management of SBP in Spain, albumin plus antibiotics compared to antibiotics alone resulted in ICERs of €1516 per life saved and €3369 per QALY gained. Albumin plus a vasoconstrictor was both less costly and more effective than vasoconstrictor alone in the treatment of HRS across all 3 countries. CONCLUSION: This analysis demonstrates that albumin is cost-effective in terms of lives saved and QALYs gained in the management of decompensated cirrhosis associated with LVP, SBP, or HRS.

Low-Cost FPGA-Based Electronic Control Unit for Vehicle Control Systems.

The development of new control algorithms in vehicles requires high economic resources, mainly due to the use of generic real-time instrumentation and control systems. In this work, we proposed a low-cost electronic control unit (ECU) that could be used for both development and implementation. The proposed electronic system used a hybrid system on chip (SoC) between a field-programmable gate array (FPGA) and an Advanced RISC (reduced instruction set computer) Machine (ARM) processor that allowed the execution of parallel tasks, fulfilling the real-time requirements that vehicle controls demand. Another feature of the proposed electronic system was the recording of measured data, allowing the performance of the implemented algorithm to be evaluated. All this was achieved by using modular programming that, without the need for a real-time operating system, executed the different tasks to be performed, exploiting the parallelism offered by the FPGA as well as the dual core of the ARM processor. This methodology facilitates the transition between the designing, testing, and implementation stages in the vehicle. In addition, our system is programmed with a single binary file that integrates the code of all processors as well as the hardware description of the FPGA, which speeds up the updating process. In order to validate and demonstrate the performance of the proposed electronic system as a tool for the development and implementation of control algorithms in vehicles, a series of tests was carried out on a test bench. Different traction control system (TCS) algorithms were implemented and the results were compared.

Neutrophil Gelatinase-Associated Lipocalin for Assessment of Acute Kidney Injury in Cirrhosis: A Prospective Study.

Kidney biomarkers appear to be useful in differential diagnosis between acute tubular necrosis (ATN) and other types of acute kidney injury (AKI) in cirrhosis, particularly hepatorenal syndrome (HRS-AKI). Distinction is important because treatment is different. However, kidney biomarkers are still not used in clinical practice. The aim of the current study was to investigate the accuracy of several biomarkers in differential diagnosis of AKI and in predicting kidney outcome and patient survival. This was a prospective study of 320 consecutive cases of AKI in patients hospitalized for decompensated cirrhosis. Evaluation of AKI was made with a diagnostic algorithm that included identification and removal/treatment of precipitating factors and albumin administration (1 g/kg for 2 days) to patients with AKI stage 1B or greater. Urinary neutrophil gelatinase-associated lipocalin (NGAL), monomeric NGAL (mNGAL), interleukin-18, and standard biomarkers were measured at diagnosis and on days 3, 7, and 14. Of the 320 cases, 153 were hypovolemia-induced AKI (48%), 93 were HRS-AKI (29%), 39 were ATN (12%), and 35 were due to miscellaneous causes (11%). Among all biomarkers, urinary NGAL measured at day 3 had the greatest accuracy for differential diagnosis between ATN and other types of AKI (area under the receiver operating characteristic curve, 0.87; 95% confidence interval, 0.78-0.95). The cutoff with the best predictive accuracy for ATN diagnosis was 220 µg/g creatinine. Progression of AKI during hospitalization was associated with persistently high NGAL levels, and NGAL was an independent predictive factor of AKI progression. Likewise, NGAL was also an independent predictive factor of 28-day mortality together with Model for End-Stage Liver Disease score. Conclusion: These results support the use of NGAL in clinical practice within the context of a diagnostic algorithm for differential diagnosis of AKI and outcome prediction in cirrhosis.

Hidden Conformations in Aspergillus niger Monoamine Oxidase are Key for Catalytic Efficiency.

Enzymes exist as an ensemble of conformational states, whose populations can be shifted by substrate binding, allosteric interactions, but also by introducing mutations to their sequence. Tuning the populations of the enzyme conformational states through mutation enables evolution towards novel activity. Herein, Markov state models are used to unveil hidden conformational states of monoamine oxidase from Aspergillus niger (MAO-N). These hidden conformations, not previously observed by any other technique, play a crucial role in substrate binding and enzyme activity. This reveals how distal mutations regulate MAO-N activity by stabilizing these hidden, catalytically important conformational states, but also by modulating the communication pathway between both MAO-N subunits.

Immediate post-procedure bridging with unfractioned heparin versus low molecular weight heparin in patients undergoing radiofrequency ablation for atrial fibrillation with an interrupted oral anticoagulation strategy.

PURPOSE: Many centers perform catheter ablation for atrial fibrillation (AF) with periprocedural interruption of oral vitamin K antagonists. In this scenario, the optimal post-procedural anticoagulation strategy is still under debate. We sought to compare the incidence of major complications associated with post-procedural use of low molecular weight heparin (LMWH) versus unfractioned heparin (UFH) as a bridge to reinitiation of oral anticoagulation after an AF ablation procedure. METHODS: We retrospectively reviewed medical history data of all patients undergoing catheter ablation for AF at three Spanish referral centers between January 2009 and January 2014. A total of 702 patients were included in the analysis. We compared the incidence of major complications (a combination of major bleeding and thromboembolic events) between patients receiving UFH (291) and those receiving LMWH (411) after the procedure. RESULTS: The overall incidence of major complications was 4.1%, including five thromboembolic events (0.7%) and 24 major bleeding events (3.4%), with no significant differences in patients treated with LMWH vs. UFH (2.9 vs. 4.1%; P = NS). The presence of peripheral vascular disease emerged as the only independent predictor of major complications (adjusted odds ratio (OR) 9.1; confidence interval (CI) 95% 1.7-49.3; P < 0.01). CONCLUSIONS: Immediate post-procedural bridging with UFH or with LMWH are equally safe strategies in patients undergoing catheter ablation for AF in whom oral anticoagulation is interrupted for the procedure. Due to its greater simplicity of use, LMWH may be the preferred option. The presence of peripheral vascular disease is a potent predictor of major post-procedural complications.

Analysis of a urinary biomarker panel for clinical outcomes assessment in cirrhosis.

BACKGROUND: Biomarkers are potentially useful in assessment of outcomes in patients with cirrhosis, but information is very limited. Given the large number of biomarkers, adequate choice of which biomarker(s) to investigate first is important. AIM: Analysis of potential usefulness of a panel of urinary biomarkers in outcome assessment in cirrhosis. PATIENTS AND METHODS: Fifty-five patients with acute decompensation of cirrhosis were studied: 39 had Acute Kidney Injury (AKI) (Prerenal 12, type-1 HRS (hepatorenal syndrome) 15 and Acute Tubular Necrosis (ATN) 12) and 16 acute decompensation without AKI. Thirty-four patients had Acute-on-chronic liver failure (ACLF). A panel of 12 urinary biomarkers was assessed, using a multiplex assay, for their relationship with ATN, ACLF and mortality. RESULTS: Biomarker with best accuracy for ATN diagnosis was NGAL (neutrophil-gelatinase associated lipocalin): 36 [26-125], 104 [58-208] and 1807 [494-3,716] µg/g creatinine in Prerenal-AKI, type-1 HRS and ATN, respectively; p<0.0001 (AUROC 0.957). Other attractive biomarkers for ATN diagnosis were IL-18, albumin, trefoil-factor-3 (TFF-3) and glutathione-S-transferase-π (GST-π) Biomarkers with less accuracy for ATN AUCROC<0.8 were ß2-microglobulin, calbindin, cystatin-C, clusterin and KIM-1 (kidney injury molecule-1). For ACLF, the biomarker with the best accuracy was NGAL (ACLF vs. No-ACLF: 165 [67-676] and 32 [19-40] µg/g creatinine; respectively; p<0.0001; AUROC 0.878). Interestingly, other biomarkers with high accuracy for ACLF were osteopontin, albumin, and TFF-3. Biomarkers with best accuracy for prognosis were those associated with ACLF. CONCLUSIONS: A number of biomarkers appear promising for differential diagnosis between ATN and other types of AKI. The most interesting biomarkers for ACLF and prognosis are NGAL, osteopontin, albumin, and TFF-3. These results support the role of major inflammatory reaction in the pathogenesis of ACLF.

[New technologies in minimally invasive surgery training: what do surgeons demand?]. / Nuevas tecnologías en formación de cirugía de mínima invasión: ¿qué demandan los cirujanos?

BACKGROUND: Minimally invasive surgery might greatly benefit from the Information and Communications Technologies. The objective of this work is to determine the better approach to include those technologies, in particular an e-Learning platform, into an in-person training course. METHODS: An online survey was sent to all participants in any of the laparoscopic training courses at Jesús Usón Minimally Invasive Surgery Centre. This survey included questions regarding new technologies used for training. Once all data were gathered, a descriptive analysis was performed. RESULTS: 382 questionnaires were sent of which 102 were correctly received back. This means a response rate equal to 30%. Current theoretical training means are watching surgical videos (85-83.3%) and assisting to in-person training courses (77-75.5%). Participants rated as useful the use of new technologies for training (4.1 ± 0.9) and they would mainly use it both before and after assisting to an in-person training course (80-78.4%). CONCLUSIONS: It is proposed a methodology that provides participants with didactic resources based on surgical videos, both before and after assisting to an in-person training course. Through the application of this methodology, an improvement and reduction of the time that surgeons expend in training is aimed.

Antecedentes: las tecnologías de la información y comunicación pueden aportar beneficios a la formación en cirugía de mínima invasión. Objetivo: determinar la manera más adecuada de incluir las tecnologías de la información y comunicación, en particular una plataforma de e-Learning, en un programa de formación presencial. Material y métodos: se realizó una encuesta en línea entre los asistentes al Centro de Cirugía de Mínima Invasión Jesús Usón, con preguntas relativas a las nuevas tecnologías aplicadas a la formación. Con los datos recopilados se efectuó un estudio descriptivo. Resultados: se enviaron 382 cuestionarios y se recibieron 102 (30%) correctamente respondidos. Los medios para formación teórica más empleados en la actualidad en la población estudiada son: visualización de videos quirúrgicos (85-83.3%) y la asistencia a cursos (77-75.5%). Los usuarios consideran útiles las nuevas tecnologías en formación (4.1 ± 0.9) y sobre todo usarían una plataforma de e-Learning personalizada antes y después de asistir a un curso de formación presencial (80-78.4%). Conclusiones: se propone una metodología de recursos didácticos basados en videos quirúrgicos antes y después que los alumnos asistan a un curso de formación presencial, para que mediante la aplicación de esta metodología se mejore y optimice el tiempo que los cirujanos dedican a su formación.

Assessment and management of infants with apparent life-threatening events in the paediatric emergency department.

OBJECTIVE: To report our experience with a guideline approach for the assessment of apparent life-threatening events (ALTE) at our paediatric emergency department (PED). METHODS: Prospective observational case series study of a guideline approach for infants under the age of 12 months who suffered an ALTE between 1 April 2005 and 31 June 2006. RESULTS: A total of 66 infants with ALTE were included. Fourteen had perinatal risk factors and 16 previous ALTE. Only 14 presented significant abnormalities at examination at the PED. Eight had recurrent ALTE at the PED. Laboratory investigations were abnormal in 35 infants. A total of 45 infants were admitted. Associated conditions (secondary ALTE) were reported in 24 infants (36%), mostly respiratory infections and gastroesophageal reflux. Laboratory investigations contributed to a related diagnosis in nine cases. Compared with idiopathic group, the secondary ALTE sufferers had more perinatal risk factors, more abnormal examination findings, higher risk of recurrence and more frequent need for intervention in the PED. CONCLUSION: Most infants with a first episode of ALTE have normal physical examination. The absence of data suggesting underlying disease, after detailed history and examination, identifies a pool of infants who may be handled conservatively. This group may be monitored as outpatients after keeping them under watch for a short time at the emergency unit, thus avoiding unnecessary admissions. The low yield of laboratory tests in this group suggests that they could be safely omitted in most ALTE and restricted to cases with risk factors and/or whose progress at the observation unit is not satisfactory.

4-Phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives, a novel class of selective delta-opioid agonists.

A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for delta-, mu-, and kappa-opioid receptors, as well as the functional activity in the [(35)S]GTPgammaS assay are reported. The most potent and selective delta-opioid agonist 18a exhibited a K(i) of 18 nM, and was >258-fold and 28-fold selective over mu- and kappa-receptors, respectively; the compound is a full agonist with an EC(50) value of 14 nM.