The consequences of implementing non-invasive prenatal testing with cell-free foetal DNA for the detection of Down syndrome in the Spanish National Health Service: a cost-effectiveness analysis.

BACKGROUND: DNA-based non-invasive prenatal testing (NIPT) using maternal blood constitutes an emerging technology for the detection of Down syndrome (DS). The aim of the study was to conduct a cost-effectiveness analysis to evaluate the economic costs and health implications of the introduction of NIPT based on cell-free foetal DNA analysis through different screening strategies for the detection of DS. METHODS: An analytical short-term decision model was developed, from the payer´s perspective (Spanish National Health Service). The main outcome measure was the number of DS cases detected. Secondary measures included associated miscarriages, women undergoing current screening, women undergoing NIPT, positive NIPT and invasive procedures performed. The study setting was the Spanish National Health Service. Three strategies were compared: (a) first- and second-trimester screening (current screening); (b) NIPT as contingent testing; and (c) NIPT as first-line testing. Modelling was based on a hypothetical cohort of 100,000 Spanish pregnant women. Population data were obtained from the database of the Basque Antenatal Screening Programme. Deterministic sensitivity analyses were performed to assess variations in the cost of NIPT, screening risk cut-off, screening uptake-rate and rate of failure of NIPT. RESULTS: NIPT as contingent testing (strategy b) led to fewer miscarriages following invasive procedures and a slight reduction in the number of DS cases detected compared to current screening. However, lowering the screening cut-off to ≥ 1:500 would improve the overall effectiveness of NIPT as contingent testing, increasing the number of DS cases detected and decreasing foetal losses as compared to the current screening, despite there would be an extra-cost of 3.5%. When NIPT was used as first-line testing (strategy c), the screening would be more effective but also more expensive, with incremental cost-effectiveness ratios (ICERs) per additional case of DS detected of €1,299,763 and €1,232,763, compared with strategies a and b, respectively. Results were sensitive to the different parameters considered in the analysis. CONCLUSIONS: Both, as first-line testing and as contingent testing when screening cut-off was lowered ≥ 1:500, NIPT would lead to more favourable outcomes as compared to the current screening (both in terms of DS cases detected and miscarriages avoided), but at a greater cost.

Psychometric validation of the behavioral indicators of pain scale for the assessment of pain in mechanically ventilated and unable to self-report critical care patients.

OBJECTIVE: To assess the psychometric properties of the behavioral indicators of pain scale (ESCID) when applied to a wide range of medical and surgical critical patients. DESIGN: A multicentre, prospective observational study was designed to validate a scale measuring instrument. SETTING: Twenty Intensive Care Units of 14 hospitals belonging to the Spanish National Health System. PARTICIPANTS: A total of 286 mechanically ventilated, unable to self-report critically ill medical and surgical adult patients. PROCEDURE: Pain levels were measured by two independent evaluators simultaneously, using two scales: ESCID and the behavioral pain scale (BPS). Pain was observed before, during, and after two painful procedures (turning, tracheal suctioning) and one non-painful procedure. MAIN VARIABLES: ESCID reliability was measured on the basis of internal consistency using the Cronbach-α coefficient. Inter-rater and intra-rater agreement were measured. The Spearman correlation coefficient was used to assess the correlation between ESCID and BPS. RESULTS: A total of 4386 observations were made in 286 patients (62% medical and 38% surgical). High correlation was found between ESCID and BPS (r=0.94-0.99; p<0.001), together with high intra-rater and inter-rater concordance. ESCID was internally reliable, with a Cronbach-α value of 0.85 (95%CI 0.81-0.88). Cronbach-α coefficients for ESCID domains were high: facial expression 0.87 (95%CI 0.84-0.89), calmness 0.84 (95%CI 0.81-0.87), muscle tone 0.80 (95%CI 0.75-0.84), compliance with mechanical ventilation 0.70 (95%CI 0.63-0.75) and consolability 0.85 (95%CI 0.81-0.88). CONCLUSION: ESCID is valid and reliable for measuring pain in mechanically ventilated unable to self-report medical and surgical critical care patients. CLINICALTRIALS.GOV: NCT01744717.

Glucose pathways adaptation supports acquisition of activated microglia phenotype.

With its capacity to survey the environment and phagocyte debris, microglia assume a diversity of phenotypes to respond specifically through neurotrophic and toxic effects. Although these roles are well accepted, the underlying energetic mechanisms associated with microglial activation remain largely unclear. This study investigates microglia metabolic adaptation to ATP, NADPH, H(+) , and reactive oxygen species production. To this end, in vitro studies were performed with BV-2 cells before and after activation with lipopolysaccharide + interferon-γ. Nitric oxide (NO) was measured as a marker of cell activation. Our results show that microglial activation triggers a metabolic reprogramming based on an increased glucose uptake and a strengthening of anaerobic glycolysis, as well as of the pentose pathway oxidative branch, while retaining the mitochondrial activity. Based on this energy commitment, microglial defense capacity increases rapidly as well as ribose-5-phosphate and nucleic acid formation for gene transcription, essential to ensure the newly acquired functions demanded by central nervous system signaling. We also review the role of NO in this microglial energy commitment that positions cytotoxic microglia within the energetics of the astrocyte-neuron lactate shuttle.

Preparation of carboxylic arylphosphines by hydrolysis of the trifluoromethyl group.

Triarylphosphines substituted with carboxylic and trifluoromethlyl groups have been prepared by the hydrolysis of trifluoromethyl groups using fuming sulfuric acid and boric acid. The reaction has been studied in a set of homoleptic and heteroleptic trifluoromethylated triarylphosphines and offers a new synthetic procedure for the preparation of carboxylic phosphines with a relatively simple methodology. The degree of carboxylation is modulated by the reaction conditions and is sensitive to the substitution pattern of the starting trifluoromethylated phosphines. A pH-dependent procedure based on the amphiphilic character of these phosphines was developed for their separation and purification. The electronic properties of the synthesized carboxylic-trifluoromethylated phosphines have been analyzed by 31P NMR of the corresponding selenide derivatives. Finally, the structures of two palladium complexes, containing the para and meta carboxylic-trifluoromethylated phosphines are also described, showing different dimeric structures.

Design and construction of an experimental pervious paved parking area to harvest reusable rainwater.

Pervious pavements are sustainable urban drainage systems already known as rainwater infiltration techniques which reduce runoff formation and diffuse pollution in cities. The present research is focused on the design and construction of an experimental parking area, composed of 45 pervious pavement parking bays. Every pervious pavement was experimentally designed to store rainwater and measure the levels of the stored water and its quality over time. Six different pervious surfaces are combined with four different geotextiles in order to test which materials respond better to the good quality of rainwater storage over time and under the specific weather conditions of the north of Spain. The aim of this research was to obtain a good performance of pervious pavements that offered simultaneously a positive urban service and helped to harvest rainwater with a good quality to be used for non potable demands.

Performance of pervious pavement parking bays storing rainwater in the north of Spain.

Pervious pavements are drainage techniques that improve urban water management in a sustainable manner. An experimental pervious pavement parking area has been constructed in the north of Spain (Santander), with the aim of harvesting good quality rainwater. Forty-five pervious pavement structures have been designed and constructed to measure stored water quantity and quality simultaneously. Ten of these structures are specifically constructed with different geotextile layers for improving water storage within the pavements. Following the confirmation in previous laboratory experiments that the geotextile influenced on water storage, two different geosynthetics (Inbitex and a One Way evaporation control membrane) and control pervious pavements with no geotextile layers were tested in the field. Weather conditions were monitored in order to find correlations with the water storage within the pervious pavement models tested. During one year of monitoring the three different pervious pavement types tested remained at their maximum storage capacity. The heavy rain events which occurred during the experimental period caused evaporation rates within the pervious pavements to be not significant, but allowed the researchers to observe certain trends in the water storage. Temperature was the most closely correlated weather factor with the level of the water stored within the pervious pavements tested.

(R)-2'-Benz-yloxy-5,5',6,6',7,7',8,8'-octa-hydro-1,1'-binaphthyl-2-ol.

The mol-ecules of the title compound, C(27)H(28)O(2), exhibit axial chirality. The planes of the aromatic rings of the tetra-lin ring systems make an angle of 85.72 (11)°. The non-aromatic rings adopt distorted half-chair conformations. In one of them, two C atoms of the four-atom aliphatic chain are disordered over two sites in a 0.75 (2):0.25 (2) ratio. The substituent phenyl ring is also disordered over two positions in a 0.59 (3):0.41 (3) ratio. There are no conventional hydrogen bonds joining the mol-ecules.

Antimicrobial activity of ceftolozane-tazobactam against multidrug-resistant and extensively drug-resistant Pseudomonas aeruginosa clinical isolates from a Spanish hospital.

OBJECTIVE: Our objective was to evaluate the in vitro activity of ceftolozane-tazobactam against multidrug resistant (MDR) and extensively drug-resistant (XDR) non metallo-ß-lactamase producing Pseudomonas aeruginosa clinical isolates at Hospital Universitario Miguel Servet (Zaragoza, Spain) from February 2016 to October 2017. METHODS: We evaluated the in vitro activity of ceftolozane-tazobactam and other antipseudomonal antibiotics against 12 MDR and 117 XDR non metallo-ß-lactamase producing P. aeruginosa isolates. Ceftolozane-tazobactam minimal inhibitory concentrations (MICs) were determined by MIC gradient diffusion test strip. RESULTS: Among the 129 MDR/XDR isolates included, 119 (92.2%) were susceptible to ceftolozane-tazobactam, and ten (7.8%) were resistant. MIC50 was 2 mg/L, and MIC90 4 mg/L. Ceftolozane-tazobactam was the second most active antibiotic after colistin, overtaking amikacin. CONCLUSIONS: Ceftolozane-tazobactam is a valuable treatment option for MDR and XDR P. aeruginosa infections in our setting.

Lewis super-acid catalyzed cyclizations: a new route to fragrance compounds.

This review deals with the application of Lewis super acids such as Al(III), In(III), and Sn(IV) triflates and triflimidates as catalysts in the synthesis of fragrance materials. Novel catalytic reactions involving C-C and C-heteroatom bond-forming reactions, as well as cycloisomerization processes are presented. In particular, Sn(IV) and Al(III) triflates were employed as catalysts in the selective cyclization of unsaturated alcohols to cyclic ethers, as well as in the cyclization of unsaturated carboxylic acids to lactones. The addition of thiols and thioacids to non-activated olefins, both in intra- and intermolecular versions, was efficiently catalyzed by In(III) derivatives. Sn(IV) Triflimidates catalyzed the cycloisomerization of highly substituted 1,6-dienes to gem-dimethyl-substituted cyclohexanes bearing an isopropylidene substituent. The hydroformylation of these unsaturated substrates, catalyzed by a Rh(I) complex with a bulky phosphite ligand, selectively afforded the corresponding linear aldehydes. The olfactory evaluation of selected heterocycles, carbocycles, and aldehydes synthesized is also discussed.

Eye lens dose levels in interventional rooms using simple phantom simulation, dose management software and Monte Carlo method of uncertainty assessment.

This paper presents a fast method to estimate the annual eye lens dose levels for interventional practitioners applying the Monte Carlo method of uncertainty assessment. The estimation was performed by placing an anthropomorphic phantom in the typical working position, and applying the habitually employed protocol. No radiation protection devices were considered in the simulation. The results were compatible with the measurements performed during interventions by placing dosimeters in the vicinity of the eyes of two paediatric interventional cardiologists working with a fluoroscopic biplane system.

Eye lens dose correlations with personal dose equivalent and patient exposure in paediatric interventional cardiology performed with a fluoroscopic biplane system.

PURPOSE: To analyse the correlations between the eye lens dose estimates performed with dosimeters placed next to the eyes of paediatric interventional cardiologists working with a biplane system, the personal dose equivalent measured on the thorax and the patient dose. METHODS: The eye lens dose was estimated in terms of Hp(0.07) on a monthly basis, placing optically stimulated luminescence dosimeters (OSLDs) on goggles. The Hp(0.07) personal dose equivalent was measured over aprons with whole-body OSLDs. Data on patient dose as recorded by the kerma-area product (PKA) were collected using an automatic dose management system. The 2 paediatric cardiologists working in the facility were involved in the study, and 222 interventions in a 1-year period were evaluated. The ceiling-suspended screen was often disregarded during interventions. RESULTS: The annual eye lens doses estimated on goggles were 4.13±0.93 and 4.98±1.28mSv. Over the aprons, the doses obtained were 10.83±0.99 and 11.97±1.44mSv. The correlation between the goggles and the apron dose was R2=0.89, with a ratio of 0.38. The correlation with the patient dose was R2=0.40, with a ratio of 1.79µSvGy-1cm-2. The dose per procedure obtained over the aprons was 102±16µSv, and on goggles 40±9µSv. The eye lens dose normalized to PKA was 2.21±0.58µSvGy-1cm-2. CONCLUSIONS: Measurements of personal dose equivalent over the paediatric cardiologist's apron are useful to estimate eye lens dose levels if no radiation protection devices are typically used.

[Analysis of tracheostomies in a pediatric intensive care unit during the period 2003-2013]. / Análisis de las traqueotomías en cuidados intensivos pediátricos durante el periodo 2003-2013.

INTRODUCTION: Tracheotomy in pediatric patients is a rare procedure. In this pediatric series, perioperative complications, mortality related to surgical procedure and overall mortality are analyzed. PATIENTS AND METHODS: This is a retrospective study conducted from January 2003 to December 2013. Data were retrieved from patients who were tracheotomized and admitted to our PICU in the postoperative period. RESULTS: Data were collected from 25 tracheotomized patients admitted during the study period. The mean age was 3.3 months (median 14 months, range 1-144 months), and PICU length of stay was 53 days (median 37 days, range 1-338 days). Most patients (68%) had comorbidities before their admission, with a higher prevalene of craniofacial anomalies/polymalformative syndromes (32%) and prematurity related disorders (12%) being obserevd. The most common etiologies related to the procedure were congenital airway obstruction (16%) and several types of spinal cord injury (16%), followed by tracheobronchomalacia (12%) and subglottic stenosis (12%). Some kind of complication was detected in 40% of patients, with accidental decannulation being the most frequent. Accidental or unexpected decannulation was present in a percentage as high as 20% of our patients, mainly in the first 24 hours after surgery. One of the patients died as a result of this. CONCLUSIONS: The postoperative course of a tracheotomy is associated with a high rate of complications, some of them related to life-threatening events.

Diazoxide enhances excitotoxicity-induced neurogenesis and attenuates neurodegeneration in the rat non-neurogenic hippocampus.

Diazoxide, a well-known mitochondrial KATP channel opener with neuroprotective effects, has been proposed for the effective and safe treatment of neuroinflammation. To test whether diazoxide affects the neurogenesis associated with excitotoxicity in brain injury, we induced lesions by injecting excitotoxic N-methyl-d-aspartate (NMDA) into the rat hippocampus and analyzed the effects of a daily oral administration of diazoxide on the induced lesion. Specific glial and neuronal staining showed that NMDA elicited a strong glial reaction associated with progressive neuronal loss in the whole hippocampal formation. Doublecortin immunohistochemistry and bromo-deoxyuridine (BrdU)-NeuN double immunohistochemistry revealed that NMDA also induced cell proliferation and neurogenesis in the lesioned non-neurogenic hippocampus. Furthermore, glial fibrillary acidic protein (GFAP)-positive cells in the injured hippocampus expressed transcription factor Sp8 indicating that the excitotoxic lesion elicited the migration of progenitors from the subventricular zone and/or the reprograming of reactive astrocytes. Diazoxide treatment attenuated the NMDA-induced hippocampal injury in rats, as demonstrated by decreases in the size of the lesion, neuronal loss and microglial reaction. Diazoxide also increased the number of BrdU/NeuN double-stained cells and elevated the number of Sp8-positive cells in the lesioned hippocampus. These results indicate a role for KATP channel activation in regulating excitotoxicity-induced neurogenesis in brain injury.

[Plastic bronchitis. A case report and review of the literature]. / Bronquitis plástica. A propósito de un caso y revisión de los casos asociados a cirugía de Fontan.

Plastic bronchitis is a rare complication in which bronchial casts of lymphatic origin develop in the tracheobronchial tree and cause airway obstruction. The main feature is expectoration of bronchial casts. This condition usually occurs in the postoperative period after the Fontan operation for congenital heart disease. Treatment modalities include mucolytics and chest physiotherapy, and in the most severe cases bronchoscopy to remove the casts and aerosolized urokinase or r-TPA. We describe a 12-year-old boy with pulmonary atresia with intact ventricular septum and severely hypoplastic right ventricle who underwent a modified Fontan operation at the age of 7 years. At the age of 12 years the patient started to present frequent episodes of coughing, dyspnea, and desaturation followed by difficult emission of white bronchial casts. An extracardiac Fontan conversion was performed to improve hemodynamics and symptoms. During the postoperative period frequent episodes of airway obstruction required bronchoscopy and finally improved with administration of aerosolized urokinase.

[Pulmonary reperfusion syndrome after pulmonary stent implants in a patient with vascular tortuosity syndrome]. / Síndrome de reperfusión pulmonar tras implante de stents pulmonares en un paciente con síndrome de tortuosidad vascular.

Vascular tortuosity syndrome is a rare genetic disorder that causes tortuosity and stenosis of the pulmonary, systemic and / or coronary circulations. As a result of treatment of pulmonary stenosis, symptoms of pulmonary edema, known as lung reperfusion syndrome, may occur. The case is presented of an adolescent patient with vascular tortuosity syndrome who presented with a pulmonary reperfusion syndrome after multiple stent implants in the left pulmonary artery. After the procedure, the patient immediately developed an acute pulmonary edema with severe clinical deterioration, which required assistance with extracorporeal membrane oxygenation for recovery.

Excretion of foetal bilirubin by the rat placenta-maternal liver tandem.

Using plasma membrane vesicles from human trophoblast, carrier-mediated transport of unconjugated bilirubin (UCBR) has been reported. In the present work, using the in situ perfused rat placenta-maternal liver tandem, the relevance of this pathway in vivo was investigated. After single-pass perfusion of rat placenta through the umbilical artery with 0.25 micromol [(3)H]-UCBR, approximately 15 per cent of it was taken up by the placenta, detected in maternal serum (>96 per cent was unconjugated) and subsequently secreted into maternal bile (approximately 15 per cent of administered dose; >88 per cent was glucuronidated bilirubin). Co-administration through the umbilical artery of 0.25 micromol [(3)H]-UCBR and 2.5 micromol unlabelled UCBR, bromosulfophthalein, cholic acid or biliverdin IXalpha, reduced [(3)H]-UCBR placenta uptake, and the amount of radioactivity found in the maternal serum and bile. Co-administration into maternal jugular vein of 0.1 micromol [(3)H]-UCBR-a dose 3-fold higher than that reaching the maternal compartment in placenta perfusion experiments-and 1.0 micromol bromosulfophthalein, cholic acid or biliverdin IXalpha, resulted in no marked inhibition of the amount of radioactivity bile output. When antipyrine and [(3)H]-UCBR were continuously co-infused to the mother, similar antipyrine concentrations in maternal and foetal serum were reached in approximately 15 min, while progressive increase in [(3)H]-bilirubin concentrations in maternal serum above 70 microM was accompanied by a very low transfer of this compound into foetal compartment where [(3)H]-bilirubin concentrations were always <10 microM. These results suggest that the transfer of UCBR across the rat placenta occurs, without biotransformation, via a foetal-to-maternal mainly unidirectional pathway that can be cis-inhibited by UCBR and other cholephilic organic anions.

Evidence for carrier-mediated transport of unconjugated bilirubin across plasma membrane vesicles from human placental trophoblast.

Unconjugated bilirubin (UCB) is currently believed to cross the placenta only by passive diffusion. To assess whether carrier-mediated transport might be involved, the uptake of [(3)H]-UCB by basal (bTPM) and apical (aTPM) plasma membrane vesicles from human placental trophoblast at term was investigated. In both types of vesicles, the uptake of [(3)H]-UCB into an osmotically sensitive space was temperature-dependent, independent of the presence of Na(+), and not affected by changes in membrane potential. The uptake of [(3)H]-UCB by aTPM, but not bTPM, was activated by ATP hydrolysis and inhibited by vanadate. Thus, the exact contribution of both inside out and right-side out bTPM to UCB uptake could not be distinguished, while only inverted aTPM were expected to carry out ATP-dependent UCB uptake. In bTPM and aTPM, uptake of free (unbound) [(3)H]-UCB (B(f)) consisted of a dominant, saturable, presumably carrier-mediated process and a diffusional component that became predominant only at B(f) near or above aqueous solubility limit for UCB (70 nM ). For bTPM, K(m)=7.2 nM; V(max)=9.8 pmol/20s/mg protein; and diffusion coefficient (K(D))=0.14 ml/20s/mg protein. For aTPM in the presence of 9.5m M ATP, K(m)=18 n M; V(max)=131 pmol/20s/mg protein; and K(D)=0.47 ml/20s/mg protein. The uptake of [(3)H]-UCB by bTPM was cis-inhibited by estrone-3-sulfate and estradiol-17 beta-glucuronide and trans-stimulated by unlabelled UCB and bromosulphopthalein. ATP-dependent UCB uptake by aTPM was cis-inhibited by doxorubicin, cholic acid, methotrexate and pronenecid. These findings suggest the presence of distinct transporters in the two domains of human placental trophoblast that could cooperate to transfer UCB from the foetus to the maternal circulation.

Development of a headspace solid-phase microextraction procedure for the determination of free volatile fatty acids in waste waters.

An analytical procedure based on headspace solid-phase microextraction (SPME) coupled to GC-flame ionization detection/Negative Chemical Ionization Mass Spectrometry has been developed for the determination of free volatile fatty acids (C2-C7) in waste water samples. Five different coatings have been evaluated and polydimethylsiloxane-Carboxen was the only fiber that allows a successful extraction of the shortest chain fatty acids (acetic and propionic). Several parameters such as extraction time and temperature, desorption conditions, agitation speed and sample volume have been optimized using the polydimethylsiloxane-Carboxen fiber. The linear dynamic range was over two-four orders of magnitude, depending on the acid. Procedural detection limits were in the low to medium microg/l levels and the RSDs were between 5.6% and 13.3%. To evaluate the applicability of the developed SPME procedure on real samples, fermented urban wastewaters were analysed.

Time trends in acute childhood asthma in Basque Country, Spain.

To investigate recent changes in the epidemiology of acute asthma in children in a hospital setting, data from the Basque region of Bizkaia, Spain were reviewed for the period between 1987 and 1992. Over this period there was a 18% drop in hospital emergency visits for asthma in children aged 2-14 years from 1,697/100,000 to 1,382/100,000. It was associated with a decline in the number of annual episodes per patient and in the number of patients needing further hospital treatment for the same episode. Paradoxically, hospital admission rates rose by 35.9% from 298/100,000 to 405/100,000. A trend toward decreasing length of hospital stay, a fall in the number of intensive care unit admissions, and an absence of in-hospital deaths were observed. Comparing data from September 1987 with those of September 1992, a trend has been noticed toward greater intensity of emergency room treatment with increases in the number of doses of nebulized beta 2-agonists administered and in courses of oral prednisolone given. In September 1992 more patients were on maintenance "anti-inflammatory" inhaled therapy than in 1987.

Macroscopic and microscopic ionization constants of the thiol and amine groups in 1-methyl-4-mercaptopiperidine.

The acid dissociation constants of 1-methyl-4-mercaptopiperidine (pK(1) = 9.51, pK(2) = 11.33), the 1,1-dimethyl-4-mercaptopiperidinium ion (pK(A) = 9.59) and 1-methyl-4-(methylthio)piperidine (pK(B) = 10.18) have been determined potentiometrically in 3M sodium perchlorate (10% methanol) medium. The ultraviolet absorption of the mercaptide ion has been used to determine the relative proton affinity of the sulphur and nitrogen functions in 1-methyl-4-mercaptopiperidine under the same conditions, and its four microscopic constants (pK(a) = 9.49, pK(b) = 10.23, pK(c) = 11.34, pK(d) = 10.60) have been calculated; pK(A) has also been determined spectrophotometrically. From the results obtained, it can be concluded that the thiol group is more acidic than the amine group and that the Adams relation, K(a) + K(b) = K(1), holds very well when it is assumed that the spectrophotometric values for K(a), and K(b), can be replaced by K(A) and K(B) respectively.