0 (0.25–4) [23]. The effects selleck of viral load and CD4 cell count when starting salvage therapy were classified as ‘possibly harmful’ and ‘possibly beneficial’ with median hazard ratios of 1.5 (95% CI 0.38–6) and 0.67 (95% CI 0.17–2.7) and with probabilities of being above 1 of 0.72 and 0.28, respectively. Poor adherence and overall GSS were classified as ‘probably harmful’ and ‘probably beneficial’ with median hazard ratios of 2.0 (95% CI 0.5–8) and 0.5 (95% CI 0.13–2) and with probabilities of being above 1 of 0.84 and 0.16, respectively. These priors

correspond to normal distributions for the log hazard ratio with variance 0.5 [23], and the normal cumulative distribution click here function was used to calculate the probability

of a hazard ratio above 1. When considering alternatives to the overall GSS, we compared models using twice the log Bayes factor (2logBF) with the integral of a posterior density calculated by Laplace’s method of approximation [24]. We used SAS version 9.1.3 (SAS Institute Inc., Cary, NC, USA) for our analyses. As of February 2009, 196 patients in the SHCS had started darunavir for the first time but only 130 patients started darunavir as part of a salvage therapy. Of these 130 patients, 115 (88%) had at least one viral load measured 12 weeks or more after starting. Patients starting darunavir as part of a salvage therapy (Table 1) had a median age of 47 years and had been living with HIV for a median of 16 years. Most (81%) received mono or dual antiretroviral therapy prior to starting highly active antiretroviral therapy and since then had experienced virological failure on a median of three PI-based regimens. Prior to starting

darunavir, 77% of patients had been given lopinavir, with 52% recording a viral load above 1000 copies/mL while on a regimen that included this drug. Typically, a considerable period had elapsed between assumed ‘triple class failure’ (i.e. first reporting a viral load above 1000 copies/mL given prior exposure to PI- and to NNRTI-based therapies for more than 90 days each) and starting darunavir (median 6.6 years), and much of this period (median 3.6 years) was spent at risk of developing resistant mutations, with the patient on therapy while having a viral load above 400 copies/mL. When starting darunavir, only 42% of patients had HIV considered fully susceptible to darunavir. Patients started in reasonable health (median CD4 count 250 cells/μL) given that many patients had an advanced infection [43% Centers for Disease Control and Prevention (CDC) group C] and a relatively high proportion (22%) were coinfected with hepatitis C virus.

Informal teaching and learning, shared experience, half measures in implementation, workarounds and resistance to change were reported with polarised views of technology evident. Pharmacy staff perceived their own digital literacy skills as basic with no formalised, related training. Increased reliance on IT in both community and hospital pharmacy may need to be formally reflected in future pharmacy buy AZD1208 curricula. Although limited by the unreliability of self-reporting and potential

recruitment, response and social desirability biases, these findings provide insight into a digital literacy related training gap in pharmacy practice. 1. Scottish Government. eHealth Strategy 2011–2017. Edinburgh: Scottish Government; 2011 2. Thomas G. How to do Your Case Study. London: SAGE Publications Ltd; 2011 The research team gratefully acknowledge funding provided by SGI-1776 in vivo NHS Education for Scotland. Thanks are also given to the participating pharmacy teams across the NHS Grampian area and colleagues at RGU for support with recruitment. Ed England South Central Ambulance Service, Oxfordshire, UK A

safe process for the administration of medicines in the emergency pre-hospital environment was required; The highest potential process risks were associated

with the double check of the medicine and the dose, and the potential mix up of unlabelled syringes; To address the risks, prefilled syringes and standard syringe labels are now used, and medicines are packed into a range of coloured bags in their original packaging so that they look and feel distinct; FMEA is a useful tool to prioritise risks and agree solutions. The safe administration of medicines relies on competent clinicians following guidelines and Tau-protein kinase procedures, however human error still occurs. FMEA is a proactive tool which enables teams to analyse processes, identify potential ‘failure modes’ and to prioritise process improvements. The aim of this project was to design and implement a safe process for the administration of medicines in the pre-hospital and emergency environment by standardising medicines and the medicines bags used across the Trust. The FMEA method was followed1: A team of paramedics and a pharmacist agreed the current processes for the supply and administration of medicines and identified potential failure modes; To prioritise process improvements a hazard analysis tool was agreed.

Similarly, amphetamine infusions into the NAc shell at the time of PIT significantly enhanced the transfer effect (Wyvell & Berridge, 2000). However, in both of these circumstances, the drug was present at the time of transfer, whereas in the present study and others (Ranaldi et al., 2009), animals were drug abstinent for 1 week prior to testing. Thus, the present findings suggest that repeated cocaine exposure may change the sensitivity of shell

neurons to PIT-related stimuli, a mechanism that may be gated by prolonged exposure to phasic DA release. Intriguingly, SB431542 chemical structure previous studies have shown that DA release in the NAc following cocaine infusions is largely confined to the shell (Aragona Cabozantinib mouse et al., 2008). Cocaine self-administration may thus result in inducing a shell-specific DA-dependent process in which animals become exquisitely sensitive to task-related stimuli and rewards, and thus may be at greater risk for subsequent relapse. Given these converging data, one model for these results that is in line with the present findings suggests a role of the NAc core

neurons in learning the motivational significance of cues early in learning, whereas the core may become less important after the associations are fully learned. The naive animals reported here show such a pattern; core neurons reliably encoded cue-related information and, further, the degree to which this was learned predicted success on later transfer. However, these neural representations did not appear Carbohydrate to modulate lever-pressing activity during PIT, suggesting a less essential role in expressing that behavior. Shell neurons showed a different pattern of activity in line with this model. Although not as involved with the encoding of cue-related information as the core, cells that were cue-modulated at the time of press were significantly correlated with performance

on transfer. If this model is correct, we would predict that transient inactivation of the core, but not shell, during learning would impair subsequent transfer, whereas inactivation of the shell, but not core, at the time of transfer would have a similar transfer-inhibiting effect. Previous work in this laboratory has also shown that, following cocaine abstinence, cue and task-related encoding are selectively potentiated in the core, but not the shell (Hollander & Carelli, 2005, 2007). However, in those studies, modulation was found for drug-related stimuli and responses, whereas in the present study, drug exposure altered encoding for non-drug (natural) reward during novel learning. Notably, in the earlier study, associative encoding for drug-related stimuli necessarily occurred while the cocaine was onboard, whereas in the present study, all animals had the opportunity to learn about Pavlovian and instrumental responses for natural reward while drug naive.

, 2007). It illustrates that Csps and CSD fold proteins have retained a high degree of functional similarity.

In addition we observed that CspD expression in Ant5-2 increased at 37 °C and upon UV exposure (Fig. 2b and c), and as described previously (Yamanaka et al., 2001; Kim & Wood, 2010), the cells also become elongated at 37 °C (data not shown), indicating that the CspD in Ant5-2 is a ATM/ATR inhibitor stress-inducible protein. Because CspD in Ant5-2 shares structural similarity with E. coli CspD, it might retain the same function as DNA replication inhibitor at 37 °C. It has also been reported that PprM, a homolog of Csp and a homodimer like E. coli CspD, is involved in the expression of many protein(s) that are important for the radioresistance of Deinococcus radiodurans (Ohba et

al., 2009). In this study, we have shown that the overall fold of the predicted CspD monomer from Ant5-2 did not closely resemble those of Venetoclax mw other bacterial cold-shock proteins. In both E. coli CspA and Bs-CspB, each chain is folded into an independent three-dimensional biological unit whereas the predicted Ant5-2 CspD dimer is composed of the N-terminal residues 1–36 from one chain and the C-terminal residues 37–67 from the other chain. The stable dimer prediction was performed with the help of the hex 5.1 docking software, which is considered to be a more reliable platform for ‘protein–protein’ compared with ‘protein–ligand’ docking. The predicted CspD dimer from Ant5-2 was formed by the exchange of two β-strands between protein monomers, but formed a symmetric unit of 2 five-stranded β-barrels unlike Nm-Csp that form two asymmetric five-stranded β-barrels. Despite differences, the predicted CspD dimer in Ant5-2 had significant structural similarities with the Nm-Csp and Bs-CspB dimers (Ren et al., 2008), sharing the same folds as Selleckchem Rucaparib that of monomeric Csps. This implies that it binds to ssDNA in a similar fashion. As evident

from the electrostatic properties, the only DNA-binding region in the predicted tertiary structure of CspD dimer of Ant5-2 is the side of the β-barrel, which corresponds to the DNA-binding site in OB-fold proteins such as E. coli CspA and B. subtilis CspB. Although its theoretical pI is 5.6, the attractive potential for nucleic acids is created by the solvent-exposed basic amino acids located on the nucleic acid-binding surface. The solvent-exposed aromatic residues on the surface of these molecules also bind and melt nucleic acid secondary structure to facilitate transcription and translation at low temperatures (Phadtare et al., 2004). The phylogenetic relationship of the CspD from Ant5-2 and Csps from three classes of phylum Proteobacteria, i.e. Betaproteobacteria, Gammaproteobacteria and Firmicutes, revealed that they distinctly form orthologous protein groups indicating a speciation event at each node except E. coli CspD.

, 2007). It illustrates that Csps and CSD fold proteins have retained a high degree of functional similarity.

In addition we observed that CspD expression in Ant5-2 increased at 37 °C and upon UV exposure (Fig. 2b and c), and as described previously (Yamanaka et al., 2001; Kim & Wood, 2010), the cells also become elongated at 37 °C (data not shown), indicating that the CspD in Ant5-2 is a Screening Library solubility dmso stress-inducible protein. Because CspD in Ant5-2 shares structural similarity with E. coli CspD, it might retain the same function as DNA replication inhibitor at 37 °C. It has also been reported that PprM, a homolog of Csp and a homodimer like E. coli CspD, is involved in the expression of many protein(s) that are important for the radioresistance of Deinococcus radiodurans (Ohba et

al., 2009). In this study, we have shown that the overall fold of the predicted CspD monomer from Ant5-2 did not closely resemble those of DAPT other bacterial cold-shock proteins. In both E. coli CspA and Bs-CspB, each chain is folded into an independent three-dimensional biological unit whereas the predicted Ant5-2 CspD dimer is composed of the N-terminal residues 1–36 from one chain and the C-terminal residues 37–67 from the other chain. The stable dimer prediction was performed with the help of the hex 5.1 docking software, which is considered to be a more reliable platform for ‘protein–protein’ compared with ‘protein–ligand’ docking. The predicted CspD dimer from Ant5-2 was formed by the exchange of two β-strands between protein monomers, but formed a symmetric unit of 2 five-stranded β-barrels unlike Nm-Csp that form two asymmetric five-stranded β-barrels. Despite differences, the predicted CspD dimer in Ant5-2 had significant structural similarities with the Nm-Csp and Bs-CspB dimers (Ren et al., 2008), sharing the same folds as Cyclic nucleotide phosphodiesterase that of monomeric Csps. This implies that it binds to ssDNA in a similar fashion. As evident

from the electrostatic properties, the only DNA-binding region in the predicted tertiary structure of CspD dimer of Ant5-2 is the side of the β-barrel, which corresponds to the DNA-binding site in OB-fold proteins such as E. coli CspA and B. subtilis CspB. Although its theoretical pI is 5.6, the attractive potential for nucleic acids is created by the solvent-exposed basic amino acids located on the nucleic acid-binding surface. The solvent-exposed aromatic residues on the surface of these molecules also bind and melt nucleic acid secondary structure to facilitate transcription and translation at low temperatures (Phadtare et al., 2004). The phylogenetic relationship of the CspD from Ant5-2 and Csps from three classes of phylum Proteobacteria, i.e. Betaproteobacteria, Gammaproteobacteria and Firmicutes, revealed that they distinctly form orthologous protein groups indicating a speciation event at each node except E. coli CspD.

Information on TMC125 resistance is still scarce: a set of 13 baseline reverse transcriptase mutations was previously

identified in the DUET studies as having an effect on virological response to TMC125 [7–12]. Poveda et al. [12] suggested that efavirenz (EFV) might be less capable of inducing Staurosporine molecular weight TMC125 resistance than nevirapine (NVP). Moreover, a longer duration of initial NNRTI treatment has been associated with increased evidence of in vitro TMC125 resistance [13] and the inclusion of NVP within the initial highly active antiretroviral therapy (HAART) regimen could result in a higher risk of virological failure and drug resistance compared with EFV [14]. This could limit the future use of TMC125 [15]. Recently, Tambuyzer et al. examined two TMC125 weighted genotypic scores (WGSs) Selleckchem Y 27632 [TBT (Tibotec, Mechelen, Belgium) and MGR (Monogram, San Francisco, CA, USA)], which produced similar results in defining susceptibility to TMC125 in treatment-experienced

patients and were able to predict nonresponse to TMC125 in ∼60% of subjects enrolled in the DUET trials [16]. Nevertheless, there is a difference between mutations associated with TMC125 use (L100I, E138G, V179F/I, Y181C/I and H221Y), i.e. mutations that emerge with use of TMC125, and mutations associated with an altered response to TMC125 (V90I, A98G, L100I, K101E/H/P, Ceramide glucosyltransferase V106I, E138A, V179D/T/F, Y181C/I/V and G190A/S). To evaluate whether etravirine might be effective in patients failing therapy with current NNRTIs, we analysed the prevalence of etravirine mutations and possible determinants of genotypic resistance to this drug among sequences reported to a large Italian database. We retrospectively considered

HIV-1 reverse transcriptase sequences obtained from the Italian Antiretroviral Resistance Cohort Analysis (ARCA; available at http://www.hivarca.net) database for a total of 2955 patients experiencing therapy failure with an NNRTI-based regimen at the time of blood drawing, and with complete treatment history available. These subjects had been selected on the basis of having a resistance test while failing their antiretroviral regimen (viral load>1000 HIV-1 RNA copies/mL). Patients were TMC125-naïve. Inclusion criteria were NNRTI-based regimen for at least 3 months, and an HIV RNA measurement and CD4 cell count available within 1 month. Drug resistance mutations were interpreted following the latest International AIDS Society-USA (IAS-USA) panel list of mutations proposed to be TMC125-specific (http://www.iasusa.org; update in December 2008) [17]: V90I, A98G, L100I, K101E, K101P, K101H, V106I, E138A, V179D, V179F, V179T, Y181C, Y181I, Y181V, G190A, G190S and M230L.

Only the simultaneous presence of psmrAB, but not the single gene alone, conferred the tolerance of E. coli KNabc to up to 0.6 M NaCl and at alkaline pH. pH-dependent Na+(Li+)/H+ antiport activity was detected from everted membrane vesicles prepared from E. coli KNabc cells carrying learn more psmrAB, which had the highest activity at pH 9.0. However, a detailed

test for antimicrobial drugs showed that E. coli DH5α with psmrAB only exhibited slight resistance to chloramphenicol, but not other representative antimicrobial drugs especially ethidium bromide. Protein sequence alignment showed that neither PsmrA nor PsmrB has homology with known single-gene or multiple-gene Na+/H+ antiporters, or such proteins as TetA(L) and MdfA with Na+/H+ antiport activity. Taken together, PsmrAB should function mainly as a novel two-component Na+/H+ antiporter. This is the first example of a PSMR family member that exhibits Na+/H+ antiporter activity. In bacteria, Na+/H+ antiporters are ABT-737 molecular weight ubiquitous secondary transporters that catalyze the efflux of intracellular alkali cations in exchange for external protons, which play a vital role in reducing the cytoplasmic concentration of toxic alkali cations

and supporting Na+(Li+)/K+-dependent intracellular pH homeostasis under alkaline conditions (Ito et al., 1999; Padan et al., 2005). Na+/H+ antiporter genes or the genes with Na+/H+ antiporter activity have been increasingly cloned and functionally identified in Escherichia coli mutants KNabc or EP432 lacking major antiporters (Padan et al., 2004). So far, Na+/H+ antiporters are sorted into two main kinds based on the number of genes: One kind of Na+/H+ antiporters are encoded by a single gene including nhaA (Karpel et al., 1988), nhaB (Pinner et al., 1992), nhaC (Nakamura et al., 1996), nhaD (Ito et al., 1997), napA (Waser et al., 1992), nhaP (Utsugi et al., 1998), nhaG (Gouda et al., 2001) and nhaH (Yang et al., 2006c). The other kind of Na+/H+ antiporters containing multiple subunits are encoded by an operon or a gene cluster such as mrp operon from Bacillus subtilis (Ito et al., 1999), mnh gene cluster from Staphylococcus aureus (Hiramatsu

et al., 1998) and pha2 gene cluster from Sinorhizobium fredii (Jiang et al., 2004; Yang et al., 2006a). G protein-coupled receptor kinase Moreover, an unique tetracycline/H+ antiporter TetA(L) was reported to possess Na+/H+ antiporter activity (Cheng et al., 1994). Another E. coli multidrug resistance (MDR) protein MdfA with a broad-specificity MDR phenotype (Edgar & Bibi, 1997) was also characterized to exhibit Na+(K+)/H+ antiporter activity (Lewinson et al., 2004). In our previous studies, a novel species Halobacillus dabanensis D-8T was isolated and characterized from Daban Salt Lake in Xinjiang Province, China (Liu et al., 2005), and two genes nhaH (Yang et al., 2006c) and nap (Yang et al., 2006b) were cloned from H. dabanensis and found to possess Na+/H+ antiporter activity.

Sulfate was quantified turbidimetrically as a suspension of BaSO4 (Sörbo, 1987). 3-Sulfolactate find more was quantified by ion chromatography (IC) with the conditions described for sulfoacetate (Denger et al., 2004). DHPS was assayed qualitatively by the reaction of DHPS dehydrogenase [HpsN (EC 1.1.1.308) catalyzes the NAD+-dependent oxidation of DHPS to sulfolactate] from the soluble fraction of C. pinatubonensis JMP134 (Mayer et al., 2010). The reaction mixture contained in 50 mM Tris/HCl,

pH 9.0, 2 mM NAD+, soluble fraction (about 0.3 mg protein mL−1) and outgrown medium of K. oxytoca TauN1 after growth with sulfoquinovose. Standard methods were used for the Gram reaction and to assay catalase or cytochrome c-oxidase activity (Gerhardt et al., 1994). SQ was assayed with a colorimetric assay for reducing sugars (2,3-dinitrosalicylic acid method; Sturgeon, 1990). SQ was quantified by HPLC after separation on a Nucleodur HILIC (hydrophylic-interaction liquid chromatography) column (125 × 3 mm) (Macherey-Nagel, Düren, Germany) and evaporative light-scattering detection (ELSD). The isocratic eluent was 0.1 M

ammonium acetate in 80 % acetonitrile with a flow rate of 0.5 mL min−1. Samples were dissolved in the eluent. Under those conditions, DHPS, taurine (2-aminoethanesulfonate), and glucose could also be analyzed directly in culture medium, which did not interfere with the analyses (Fig. 2); sulfolactate could also be quantified, but it interfered with the peak of sulfoquinovose. The chemical synthesis of SQ is simple: two hydroxyl groups of glucose are protected, and the hydroxyl group at C-6 tosylated Selleck Erastin and the tosyl group are displaced by sulfite. This yields two organic products, SQ and 4-toluenesulfonate, and, finally, Rebamipide sodium sulfate. The problem is to separate the two organic products, in which we were not fully successful. The consequence was that all organisms, with which we worked, had to be checked for growth with 4-toluenesulfonate. No organism used in the work utilized (or was inhibited by) 4-toluenesulfonate. We initially assayed SQ, a reducing sugar, with a standard method (Sturgeon, 1990) (e.g. Fig. 3). At low concentrations

of sugar, the standard curve is, indeed, a curve and the interpolation had to be made manually. We required a different method, IC, for the metabolic product, 3-sulfolactate (Fig. 3), which eluted on the tail of the peak for sulfate (not shown). These methods were just adequate (Fig. 3), but inadequate for the next product, DHPS, which we could not detect by IC. What was needed was a detector which was sensitive for nonchromophores and a column which could separate highly polar compounds. The ELSD detector and the HILIC column met our demands (Fig. 2). We optimized the system for our purposes and had linear standard curves between 0 and 5 pmol per injection (R2 > 0.99); a fresh standard curve was needed with each set of experiments.

It is also noteworthy that patients traveling to western countries to access advanced treatment unobtainable in their home country may also import MRB.[3] There is also an increase of patients traveling from developed countries to other areas offering care at a lower cost, without delay, or with greater privacy Lumacaftor clinical trial for cosmetic and other procedures.[18-22] Certainly, these two

populations can also import MRB; we did not consider either group in our study. The occurrence of MRB among patients repatriated from foreign hospitals is noted in a significant minority of such individuals transferred back to their home country. The typical MRB patient was admitted to a high-risk unit in the foreign hospital prior EPZ015666 in vivo to repatriation; in addition, longer foreign hospital admissions and antibiotic administration during the initial hospital admission were also seen more frequently in these MRB patients. While these factors are associated with MRB presence, their absence does not rule out highly resistant bacterial colonization. The prospective identification

of these patients prior to transport is difficult yet extremely important to aid in the selection of the most appropriate transfer hospital location as well as the protection of the local population from MRB. Lastly, existing guidelines and system of consideration are not consistently applied; the impact of and reasons for this non-compliance EGFR inhibitor are unknown. A systematic review of this important medical issue is warranted with the development of guidelines. The authors state they have no conflicts of interest to declare. “
“Background. Many studies have found acute gastrointestinal infections to be among the most likely reason for clinic visits among forward deployed soldiers and are considered a significant contributor to morbidity in this population. This occurs

despite the controlled food and water distribution systems under which military populations operate. Furthermore, recent studies have indicated that providers often fail to appropriately identify and treat the typical causes of these infections. To adequately address this issue, an assessment of gaps in knowledge, practice, and management of acute diarrhea in deployed troops was conducted. Methods. A multiple-choice survey was developed by clinical researchers with expertise in travelers’ diarrhea (TD) and provided to a convenience sample of clinical providers with a broad range of training and operational experience. The survey evaluated provider’s knowledge of TD along with their ability to identify etiologies of various syndromic categories of acute gastrointestinal infections. Providers were also queried on selection of treatment approaches to a variety of clinical-based scenarios. Results. A total of 117 respondents completed the survey.

parapsilosis (Kurnatowski et al., 2007; Medeiros et al., 2008; Pires-Goncalves et al., 2008). Addition of saliva

significantly promoted Candida growth (P < 0.0001) as compared with control values (Fig. 1). A 1–2.3 log(10) increase in CFU was observed in C. parapsilosis incubated with 1–20% (v/v) saliva (P < 0.0001). No difference in the survival of C. parapsilosis with either 1% or 5% (v/v) saliva was seen, whereas 20% saliva induced a significant increase in CFU counts [> 2 vs. 1 log(10) CFU mL−1 increase; P < 0.0001]. Survival of C. albicans without saliva steadily decreased with time; a 3 log(10) CFU mL−1 decrease was observed after 15 days selleckchem (P < 0.0001) (Fig. 1b). As expected, tap water was not an appropriate medium for C. albicans, which required

a more protected environment to optimize its growth. Our results suggested that addition of saliva to the medium could provide some essential components to C. albicans: when compared with control, at each time point, a low increase [<1 log(10) CFU mL−1; P < 0.0001] was indeed observed during the 360 h of incubation in the presence of 1% (v/v) saliva. In fact, our results suggested that 1% (v/v) saliva promoted C. albicans yeast survival but was not able to induce their proliferation. On the other hand, 5% and 20% (v/v) saliva induced a strong growth increase of about 1–2.5 and 2–3.5 log(10) CFU mL−1, respectively (P < 0.0001); the log(10) increase in CFU observed with 5% and, in particular, 20% [2–3.5 log(10) CFU mL−1] was obvious from the first day of the test and was then stable and persistent throughout the 15-day period. Finally, Cobimetinib C. glabrata was the most susceptible species in tap water and was unable to survive for more than 192 h if saliva concentration was <20% (v/v) (Fig. 1c). The addition of 20% (v/v) saliva to tap water induced an increase of 2.3–4.5 log(10) CFU mL−1 (P < 0.0001), whereas the effect of 1% and 5% saliva, although clearly positive

during the first 72 h, then became less clear. The effect of saliva on C. albicans has been investigated in the mouth environment by click here several authors who suggested potential interactions but also highlighted conflicting observations. For example, it has been shown that whole saliva promoted adherence to silicon in a dose-dependent manner (Holmes et al., 2006). Other authors showed decreased biofilm formation in the presence of saliva (Jin et al., 2004). More recently, Elguezabal et al. (2008) showed a dual role played by whole saliva in decreasing the adhesion of germ-tubes but increasing that of yeast cells to polymethylmetacrylate. On the other hand, Leito et al. (2009) demonstrated that saliva could induce transition of hyphae to yeast forms in the mouth and may thus contribute to the oral defence against candidiasis; however, inhibition of the germination of C. albicans by whole saliva was not confirmed by Elguezabal et al.