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The hallmarks of COVID-19 are higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive immunological responses, induced by circulating human coronaviruses (hCoVs), is needed to understand such divergent clinical outcomes. Here we show analysis of coronavirus antibody responses of pre-pandemic healthy children (n = 89), adults (n = 98), elderly (n = 57), and COVID-19 patients (n = 50) by systems serology. Moderate levels of cross-reactive, but non-neutralizing, SARS-CoV-2 antibodies are detected in pre-pandemic healthy individuals. SARS-CoV-2 antigen-specific Fcγ receptor binding accurately distinguishes COVID-19 patients from healthy individuals, suggesting that SARS-CoV-2 infection induces qualitative changes to antibody Fc, enhancing Fcγ receptor engagement. Higher cross-reactive SARS-CoV-2 IgA and IgG are observed in healthy elderly, while healthy children display elevated SARS-CoV-2 IgM, suggesting that children have fewer hCoV exposures, resulting in less-experienced but more polyreactive humoral immunity. Age-dependent analysis of COVID-19 patients, confirms elevated class-switched antibodies in elderly, while children have stronger Fc responses which we demonstrate are functionally different. These insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics., Antibody responses to SARS-CoV-2 are critical in the immune response to infection, but the potential cross-reactivity to other human corona viruses is poorly appreciated. Here the authors apply a systems based approach to characterise the antibody response in pre-pandemic cohorts and assess heterotypic reactivity to SARS-CoV-2.

Although pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4+ and CD8+ T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.

ObjectivesSARS-CoV-2 can be transmitted by aerosols and the ocular surface may be an important route of transmission. Little is known about protective antibody responses to SARS-CoV-2 in tears after infection or vaccination. We analysed SARS-CoV-2 specific IgG and IgA responses in human tears after either COVID-19 infection or vaccination.MethodsWe recruited 16 subjects with COVID-19 infection an average of 7 months previously and 15 subjects before and 2 weeks after Comirnaty (Pfizer-BioNtech) vaccination. Plasma, saliva and basal tears were collected. Pre-pandemic plasma, saliva and basal tears from 11 individuals were included as healthy controls. Antibody responses to 5 SARS-CoV-2 antigens were measured via multiplex.ResultsIgG antibodies to Spike and Nucleoprotein were detected in tears, saliva and plasma from subjects with prior SARS-CoV-2 infection in comparison to uninfected controls. While RBD-specific antibodies were detected in plasma, minimal RBD-specific antibodies were detected in tears and saliva. In contrast, high levels of IgG antibodies to Spike and RBD, but not Nucleoprotein, were induced in tears, saliva and plasma of subjects receiving 2 doses of the Comirnaty vaccine. Increased levels of IgA1 and IgA2 antibodies to SARS-CoV-2 antigens were detected in plasma following infection or vaccination, but were unchanged in tears and saliva.ConclusionBoth infection and vaccination induce SARS-CoV-2-specific IgG antibodies in tears. RBD-specific IgG antibodies in tears were induced by vaccination but were not present 7 months post-infection. This suggests neutralising antibodies may be low in the tears late following infection.

Background HIV-1 infections occur following viral exposure at anogenital mucosal surfaces in the presence of semen. Semen contains immunosuppressive and pro-inflammatory factors. Semen from HIV-1-infected donors contains anti-HIV-1 antibodies. We assessed if passively infused anti-HIV-1 neutralizing antibody conferred protection from rectal SHIVSF162P3 challenge at semen exposed mucosae. Methods We pooled seminal plasma from HIV-1-infected donors. The pool was screened by ELISA for antibodies against HIV-1SF162 gp140. The ability of seminal plasma to inhibit macaque NK cells from responding to direct and antibody-dependent stimulation was assessed. The ability of seminal plasma to inhibit macaque granulocytes from mediating oxidative burst was also assessed. To demonstrate viral infectivity in the presence of seminal plasma, macaques (n = 4) were rectally challenged with SHIVSF162P3 following exposure to 2.5 mL of seminal plasma. To evaluate if anti-HIV-1 neutralizing antibody confers protection against rectal SHIV challenge at semen exposed mucosae, eight macaques were intravenously infused with PGT121, either wild type (n = 4) or the Fc receptor binding deficient LALA variant (n = 4), and rectally challenged with SHIVSF162P3 following exposure to 2.5 mL of seminal plasma. Findings Anti-HIV-1SF162 gp140 antibodies were detected in seminal plasma. Seminal plasma inhibited direct and antibody-dependent NK cell activation and granulocyte oxidative burst in vitro. Rectal SHIVSF162P3 challenge of control macaques following seminal plasma exposure resulted in infection of all animals. All macaques infused with wild type or LALA PGT121 and challenged with SHIVSF162P3 following seminal plasma exposure were protected. Interpretation PGT121 conferred protection against rectal SHIVSF162P3 challenge at semen exposed mucosae. Future research should investigate if semen alters protection conferred by antibodies more dependent on non-neutralizing functions. Funding This work was supported by a grant from the Australian National Health and Medical Research Council (APP1124680).

Background: Given the scale of the ongoing COVID-19 pandemic, the development of vaccines based on different platforms is essential, particularly in light of emerging viral variants, the absence of information on vaccine-induced immune durability, and potential paediatric use. We aimed to assess the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a novel molecular clamp (spike glycoprotein-clamp [sclamp]). Methods: We did a phase 1, double-blind, placebo-controlled, block-randomised trial of the sclamp subunit vaccine in a single clinical trial site in Brisbane, QLD, Australia. Healthy adults (aged ≥18 to ≤55 years) who had tested negative for SARS-CoV-2, reported no close contact with anyone with active or previous SARS-CoV-2 infection, and tested negative for pre-existing SARS-CoV-2 immunity were included. Participants were randomly assigned to one of five treatment groups and received two doses via intramuscular injection 28 days apart of either placebo, sclamp vaccine at 5 μg, 15 μg, or 45 μg, or one dose of sclamp vaccine at 45 μg followed by placebo. Participants and study personnel, except the dose administration personnel, were masked to treatment. The primary safety endpoints included solicited local and systemic adverse events in the 7 days after each dose and unsolicited adverse events up to 12 months after dosing. Here, data are reported up until day 57. Primary immunogenicity endpoints were antigen-specific IgG ELISA and SARS-CoV-2 microneutralisation assays assessed at 28 days after each dose. The study is ongoing and registered with ClinicalTrials.gov, NCT04495933. Findings: Between June 23, 2020, and Aug 17, 2020, of 314 healthy volunteers screened, 120 were randomly assigned (n=24 per group), and 114 (95%) completed the study up to day 57 (mean age 32·5 years [SD 10·4], 65 [54%] male, 55 [46%] female). Severe solicited reactions were infrequent and occurred at similar rates in participants receiving placebo (two [8%] of 24) and the SARS-CoV-2 sclamp vaccine at any dose (three [3%] of 96). Both solicited reactions and unsolicited adverse events occurred at a similar frequency in participants receiving placebo and the SARS-CoV-2 sclamp vaccine. Solicited reactions occurred in 19 (79%) of 24 participants receiving placebo and 86 (90%) of 96 receiving the SARS-CoV-2 sclamp vaccine at any dose. Unsolicited adverse events occurred in seven (29%) of 24 participants receiving placebo and 35 (36%) of 96 participants receiving the SARS-CoV-2 sclamp vaccine at any dose. Vaccination with SARS-CoV-2 sclamp elicited a similar antigen-specific response irrespective of dose: 4 weeks after the initial dose (day 29) with 5 μg dose (geometric mean titre [GMT] 6400, 95% CI 3683–11 122), with 15 μg dose (7492, 4959–11 319), and the two 45 μg dose cohorts (8770, 5526–13 920 in the two-dose 45 μg cohort; 8793, 5570–13 881 in the single-dose 45 μg cohort); 4 weeks after the second dose (day 57) with two 5 μg doses (102 400, 64 857–161 676), with two 15 μg doses (74 725, 51 300–108 847), with two 45 μg doses (79 586, 55 430–114 268), only a single 45 μg dose (4795, 2858–8043). At day 57, 67 (99%) of 68 participants who received two doses of sclamp vaccine at any concentration produced a neutralising immune response, compared with six (25%) of 24 who received a single 45 μg dose and none of 22 who received placebo. Participants receiving two doses of sclamp vaccine elicited similar neutralisation titres, irrespective of dose: two 5 μg doses (GMT 228, 95% CI 146–356), two 15 μg doses (230, 170–312), and two 45 μg doses (239, 187–307). Interpretation: This first-in-human trial shows that a subunit vaccine comprising mammalian cell culture-derived, MF59-adjuvanted, molecular clamp-stabilised recombinant spike protein elicits strong immune responses with a promising safety profile. However, the glycoprotein 41 peptide present in the clamp created HIV diagnostic assay interference, a possible barrier to widespread use highlighting the criticality of potential non-spike directed immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response. Funding: Coalition for Epidemic Preparedness Innovations, National Health and Medical Research Council, Queensland Government, and further philanthropic sources listed in the acknowledgments.

Steam generators (SGs) used in power plants have several hundreds of ferromagnetic SG tubes which are periodically inspected using non-destructive testing (NDT) methods. Pre-service and in-service inspections of these magnetic tubes are carried out using RFEC technique for plant safety and structural integrity. In this paper, a 3D numerical model was developed for SG tube inspection using remote field eddy current (RFEC) technique. The numerical model was used to estimate the electrical properties of the SG tube using RFEC signals gathered from a SG tube with machined defects. The influence of magnetic coupling between the surrounding SG tubes on defect detection was investigated for the estimated SG tube electrical properties. Simulations in the presence of six neighbouring SG tubes were carried out for centre to centre tube spacing of 32.2 mm with respect to the centre tube. Numerical simulations for the SG tube with machined defects indicated very good agreement with measurements for tube electrical conductivity σ of 2 MS/m and relative magnetic permeability \({\mu }_{r}\) of 30. Numerical simulations carried out to study the influence of magnetic coupling with the surrounding SG tubes indicated negligibly small perturbation in the simulated RFEC signal for a 2D groove defect in the centre tube and no false call in the centre tube for a 2D grove defect in the neighbouring tube.

Background: We assessed the safety and immunogenicity of an MF59-adjuvanted subunit vaccine for COVID-19 based on recombinant SARS-CoV-2 spike glycoprotein stabilised in a prefusion conformation by a novel molecular clamp (Sclamp). Methods: Phase 1, double-blind, placebo-controlled trial conducted in Australia (July 2020–ongoing; ClinicalTrials.gov NCT04495933). Healthy adults (18-55 years) received two doses of placebo, 5-μg, 15-μg, or 45-μg SARS-CoV-2 Sclamp, or one 45-μg dose of SARS-CoV-2 Sclamp followed by placebo, 28 days apart (n=120; 24 per group). Safety, humoral immunogenicity (ELISA, microneutralisation, pseudovirus neutralisation), and cellular immunogenicity (antigen-specific CD4+/CD8+ T-cells, antibody-secreting cells) were assessed up to 56 days after the first dose. Findings: The SARS-CoV-2 Sclamp vaccine was very well tolerated with few systemic reactions. All two-dose regimens elicited robust, broadly neutralising humoral responses. Geometric mean titres were higher than in sera from convalescent COVID-19 patients and strongly neutralised spike variants of concern, including N501Y. Moreover, humoral and cellular responses were highly correlated. However, antibodies elicited to a peptide sequence used in the molecular clamp derived from human immunodeficiency virus-1 (HIV-1) gp41 cross-reacted weakly with some HIV diagnostic screening tests. Interpretation: These first-in-human results demonstrate that a subunit vaccine comprising mammalian cell culture-derived, molecular clamp-stabilised recombinant spike protein formulated in a squalene-in-oil adjuvant elicits strong immune responses with an excellent safety profile. However, the gp41 peptide induced diagnostic interference, creates a likely barrier to widespread use and highlights the criticality of potential off-target immunogenicity during vaccine development. Studies are ongoing with alternative molecular clamp trimerisation domains to ameliorate this response. Clinical Trial Registration: ClinicalTrials.gov (NCT04495933). Funding: Coalition for Epidemic Preparedness Innovations; National Health and Medical Research Council, Queensland Government, and philanthropic sources. Declaration of Interests: KJC and DW report grants from the Coalition for Epidemic Preparedness Innovations, the National Health and Medical Research Council of Australia, and the Queensland Government, during the conduct of the study; other from ViceBio Limited, outside the submitted work; and has patents pending (AU 2018241252; BR112019019813.0; CA 3057171; CH 201880022016.9; EP 18775234.0; IN 201917038666; ID P00201909145; IL 269534; JP 2019-553883; MX/a/2019/011599; NZ 757178; KR 0-2019-7031415; SG 11201908280S; US 16/498865). JB reports personal fees from CSL Limited, during the conduct of the study, and other from CSL Limited, outside the submitted work. WZ reports grants from the National Health and Medical Research Council of Australia, the Research Grants Council of the Hong Kong Special Administrative Region, China, and the Jack Ma Foundation, during the conduct of the study. SM-H reports grants from Canarian Foundation Doctor Manuel Morales, during the conduct of the study. KJS reports grants from the the Australian Medical Research Future Fund, during the conduct of the study. AWC reports grants from the Australian Medical Research Future Fund and a National Health and Medical Research Council of Australia Career Development Fellowship, during the conduct of the study. BDW reports grants from the National Health and Medical Research Council of Australia, the Australian Medical Research Future Fund, and the Victorian State Government, during the conduct of the study. PMH reports grants from the Australian Medical Research Future Fund, during the conduct of the study. DP reports grants from the National Health and Medical Research Council of Australia, the A2 Milk Foundation, and the Jack Ma Foundation, during the conduct of the study. CR reports grants from the Coalition for Epidemic Preparedness Innovations, during the conduct of the study. PRY reports grants from the Coalition for Epidemic Preparedness Innovations, the National Health and Medical Research Council of Australia, and the Queensland Government, during the conduct of the study; grants from ViceBio Limited, outside the submitted work; and a patent issued (US 2020/0040042). FLM, Zl, DKW, PE, JAL, STMC, NM, SA, CLH, KH, PG, LH, THON, MHT, PT, JB, PCR, SN, SC, TH, KK, KS, and TPM have nothing to disclose. Ethics Approval Statement: The protocol was approved by the Alfred Health Human Research Ethics Committee (2020001376/334/20).

Although the respiratory tract is the primary site of SARS-CoV-2 infection and the ensuing immunopathology, respiratory immune responses are understudied and urgently needed to understand mechanisms underlying COVID-19 disease pathogenesis. We collected paired longitudinal blood and respiratory tract samples (endotracheal aspirate, sputum or pleural fluid) from hospitalized COVID-19 patients and non-COVID-19 controls. Cellular, humoral and cytokine responses were analysed and correlated with clinical data. SARS-CoV-2-specific IgM, IgG and IgA antibodies were detected using ELISA and multiplex assay in both the respiratory tract and blood of COVID-19 patients, although a higher receptor binding domain (RBD)-specific IgM and IgG seroconversion level was found in respiratory specimens. SARS-CoV-2 neutralization activity in respiratory samples was detected only when high levels of RBD-specific antibodies were present. Strikingly, cytokine/chemokine levels and profiles greatly differed between respiratory samples and plasma, indicating that inflammation needs to be assessed in respiratory specimens for the accurate assessment of SARS-CoV-2 immunopathology. Diverse immune cell subsets were detected in respiratory samples, albeit dominated by neutrophils. Importantly, we also showed that dexamethasone and/or remdesivir treatment did not affect humoral responses in blood of COVID-19 patients. Overall, our study unveils stark differences in innate and adaptive immune responses between respiratory samples and blood and provides important insights into effect of drug therapy on immune responses in COVID-19 patients.

Objectives SARS‐CoV‐2 can be transmitted by aerosols, and the ocular surface may be an important route of transmission. Little is known about protective antibody responses to SARS‐CoV‐2 in tears after infection or vaccination. We analysed the SARS‐CoV‐2‐specific IgG and IgA responses in human tears after either COVID‐19 infection or vaccination. Methods We measured the antibody responses in 16 subjects with COVID‐19 infection for an average of 7 months before, and 15 subjects before and 2 weeks post‐Comirnaty (Pfizer‐BioNtech) vaccination. Plasma, saliva and basal tears were collected. Eleven pre‐pandemic individuals were included as healthy controls. Results IgG antibodies to spike and nucleoprotein were detected in tears, saliva and plasma from subjects with prior SARS‐CoV‐2 infection in comparison with uninfected controls. While receptor‐binding domain (RBD)‐specific antibodies were detected in plasma, minimal RBD‐specific antibodies were detected in tears and saliva. By contrast, high levels of IgG antibodies to spike and RBD, but not nucleoprotein, were induced in tears, saliva and plasma of subjects receiving 2 doses of the Comirnaty vaccine. Increased levels of IgA1 and IgA2 antibodies to SARS‐CoV‐2 antigens were detected in plasma following infection or vaccination but were unchanged in tears and saliva. Comirnaty vaccination induced high neutralising Abs in the plasma, but limited neutralising antibodies were detected in saliva or tears. Conclusion Both infection and vaccination induce SARS‐CoV‐2‐specific IgG antibodies in tears. RBD‐specific IgG antibodies in tears were induced by vaccination but were not present 7 months post‐infection. This suggests the neutralising antibodies may be low in the tears late following infection., The ocular surface may be an important route of SARS‐CoV‐2 transmission. We found SARS‐CoV‐2‐specific antibodies in tears, saliva and plasma from participants either convalescent from COVID‐19 or receiving the Pfizer Comirnaty vaccine.

Compared to adults, children with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have predominantly mild or asymptomatic infections, but the underlying immunological differences remain unclear. Here, we describe clinical features, virology, longitudinal cellular, and cytokine immune profile, SARS-CoV-2-specific serology and salivary antibody responses in a family of two parents with PCR-confirmed symptomatic SARS-CoV-2 infection and their three children, who tested repeatedly SARS-CoV-2 PCR negative. Cellular immune profiles and cytokine responses of all children are similar to their parents at all timepoints. All family members have salivary anti-SARS-CoV-2 antibodies detected, predominantly IgA, that coincide with symptom resolution in 3 of 4 symptomatic members. Plasma from both parents and one child have IgG antibody against the S1 protein and virus-neutralizing activity detected. Using a systems serology approach, we demonstrate higher levels of SARS-CoV-2-specific antibody features of these family members compared to healthy controls. These data indicate that children can mount an immune response to SARS-CoV-2 without virological confirmation of infection, raising the possibility that immunity in children can prevent the establishment of SARS-CoV-2 infection. Relying on routine virological and serological testing may not identify exposed children, with implications for epidemiological and clinical studies across the life-span., Children with SARS-CoV-2 infection are more likely to have mild symptoms and may be asymptomatic, but underlying reasons remain unclear. Here, the authors show cellular, cytokine and antibody response to SARS-CoV-2 infection in three children who repeatedly tested negative for the virus by PCR, despite high exposure in the household.

SARS-CoV-2, the pandemic coronavirus that causes COVID-19, has infected millions worldwide, causing unparalleled social and economic disruptions. COVID-19 results in higher pathogenicity and mortality in the elderly compared to children. Examining baseline SARS-CoV-2 cross-reactive coronavirus immunological responses, induced by circulating human coronaviruses, is critical to understand such divergent clinical outcomes. The cross-reactivity of coronavirus antibody responses of healthy children (n=89), adults (n=98), elderly (n=57), and COVID-19 patients (n=19) were analysed by systems serology. While moderate levels of cross-reactive SARS-CoV-2 IgG, IgM, and IgA were detected in healthy individuals, we identified serological signatures associated with SARS-CoV-2 antigen-specific Fcγ receptor binding, which accurately distinguished COVID-19 patients from healthy individuals and suggested that SARS-CoV-2 induces qualitative changes to antibody Fc upon infection, enhancing Fcγ receptor engagement. Vastly different serological signatures were observed between healthy children and elderly, with markedly higher cross-reactive SARS-CoV-2 IgA and IgG observed in elderly, whereas children displayed elevated SARS-CoV-2 IgM, including receptor binding domain-specific IgM with higher avidity. These results suggest that less-experienced humoral immunity associated with higher IgM, as observed in children, may have the potential to induce more potent antibodies upon SARS-CoV-2 infection. These key insights will inform COVID-19 vaccination strategies, improved serological diagnostics and therapeutics.

Background and importance Adalimumab is an anti-TNFα monoclonal antibody used in inflammatory bowel disease (IBD). Its efficacy can benefit from therapeutic drug monitoring (TDM). However, because there are several population pharmacokinetic models (PopPK) published, it is necessary to perform an evaluation of these models in the target population before being used in clinical practice. Aim and objectives To evaluate the predictive performance and adequacy of four PopPK of adalimumab in adult patients diagnosed with IBD, using TDM in a clinical setting. Material and methods A retrospective observational study (2014–2018) was conducted. Inclusion criteria were adult patients with IBD treated with adalimumab, with at least one trough concentration (TC). Four different PopPK were evaluated: Mod-A (FDA-2007), Mod-B Ternant-2015, Mod-C Sharma-2015 and Mod-D Berends-2018. The models were implemented in NONMEM V.7.3. The individual and population predictions of TCs were estimated from the four PopPK models. Two datasets were created; DATASET-1 was used to evaluate the model adequacy, all patients and TCs were included, and their population predictions were compared with the observed TCs; DATASET-2 was used to assess the predictive performance and only patients with two or more TCs were included. Only the first TC of these patients was used to estimate the Bayesian estimates, and the individual predictions were compared with observed TCs. To validate these models, bias and precision of estimated concentrations were calculated as the mean predictive error and the mean square predictive error in the population, respectively. Results A total of 171 patients with 245 TCs in DATASET-1 and 55 patients with 74 TCs in DATASET-2 were included; 5.85% of patients in DATASET-1 and 3.64% in DATASET-2 developed anti-adalimumab antibodies. Conclusion and relevance Mod-B performed better both in the evaluation of adequacy (DATASET-1) and for predictive performance (DATASET-2). All four models overestimated TC although Mod-B had better bias and precision (ie, closer to zero). Implementation of this PopPK in clinical practice should be done with caution. References and/or acknowledgements No conflict of interest.

Background Voriconazole is an antifungal drug used for invasive fungal infection with high pharmacokinetic variability and narrow therapeutic range and, therefore, therapeutic drug monitoring (TDM) is recommended. Purpose The objective was to evaluate the standard dosage regimen of voriconazole in a paediatric and adult population through TDM. Material and methods Retrospective observational study (January 2015 and October 2017). Inclusion criteria: adult and paediatric patients treated with voriconazole (oral/intravenous) with at least one trough plasma concentrations (C_trough) of voriconazole at steady state (>5 days) with the standard dosage and without concomitant use of potent inducers or inhibitors. Standard dose was: paediatric 8 mg/kg IV BID or 9 mg/kg PO BID, and adult 4 mg/kg IV BID or 200 mg PO BID. Variables: age, weight, indication (treatment or prophylaxis) and C_trough at steady state. Data was stratified by paediatric and adult patients. Primary outcome was: percentage of patients with C_trough at steady state of voriconazol within the therapeutic range at the standard dose (therapeutic window by indication: treatment: 1–5 mg/L; prophylaxis: 0.5–5 mg). Results A total of 56 patients were included (26.7% children and 73.2% adults). In the paediatric group, the mean age and weight was 6.4 years (95% CI: 3.9 to 9.0) and 25.5 kg (95% CI: 16.4 to 34.5). The mean age and weight for the adult patients were 61.0 years (95% CI: 56.4 to 65.6) and 69.9 kg (95% CI: 65.3 to 74.5). 17.7% of the patients were treated with voriconazole for prophylaxis and 82.2% for treatment. The median C_trough in paediatrics was lower than in adults: 0.7 mg/L (p25–75: 0–5.5) vs 2.5 mg/L (p25–75: 0.1–8.0), respectively (p 66.7% and 22% of patients had infra-therapeutic C_trough in paediatrics and adults (p Conclusion The C_trough with the standard maintenance dose of voriconazol were within the therapeutic range in only 26.7% in paediatrics, while in the adult group it was 70.7%. Given the high variability observed in the C_trough, it was necessary to perform TDM at the beginning of the treatment to make an individualised dosage adjustment in both paediatric and adult patients. References and/or acknowledgements https://www.ema.europa.eu/documents/product-information/vfend-epar-product-information_es.pdf No conflict of interest.

Background Abnormal liver functioning is associated with long term treatment with total parenteral nutrition (TPN). Purpose To assess the influence of a lipid emulsion based exclusively on omega-3 fatty acids on the progress of abnormal liver functioning in a patient receiving long term TPN. Material and methods This was a descriptive retrospective study regarding a case of parenteral nutrition. The case was a 52-year-old woman with cyclic TPN at home due to intestinal obstruction secondary to a recurrent appendix tumour. The patient had external gallbladder flush and oral intake was impossible. Lipid input was founded on a solution based exclusively on omega-3 fatty acids. Clinical, analytical and nutritional variables were gathered. Results The patient was initially administered a lipid formulation made up of medium chain triglycerides, soy oil and AG-omega3 (1 g/kg/day), ratio of carbohydrates–lipids 60:40 and 15 g nitrogen/day. Liver function parameters: ALP 150 U/L, TB 0.32 mg/dL, GGT 92 U/L, AST 26 U/L and ALT 28 U/L. After the worsening of cholestasis pattern ALP was 499 U/L, TB 0.89 mg/dL, GGT 608 U/L, AST 354 U/L and ALT 280 U/L. The composition of TPN was modified, replacing the lipid emulsion with another one containing medium chain triglycerides, soy oil, olive oil and omega-3 fatty acids. The nitrogenated solution was also replaced with a taurine enriched solution. As liver function did not normalise, the lipid input was reduced, and its administration was eventually suspended. Due to a sudden worsening of cholestasis (ALP 1619 U/L, TB 0.7 mg/dL, GGT 1324 U/L, AST 77 U/L, ALT 247 U/L and marked jaundice), the lipid formulation was replaced with another formulation based exclusively on omega-3 fatty acids ( 1g/kg/day). After 6 weeks, an improvement in the cholestasis pattern was observed, with a decrease in ALP and GGT by 68.5% and 67%, respectively: ALP 510 U/L, TB 0.4 mg/dL, GGT 435 U/L, AST 33 U/L and ALT 47U/L. The patient tolerated the treatment and no adverse effects were observed in relation to fish oil, such as thrombocytopenia or INR increases. The deficit in essential fatty acids was monitored, and values were found to be within normal limits. The clinical and analytical parameters remained stable until the patient died due to progression of her condition. Conclusion Administration of this formulation for 7 months as the only lipid formulation was well tolerated by the patient and no deficit in essential fatty acids was detected. References and/or acknowledgements Pharmacy and endocrinology department. No conflict of interest

Background A triple regimen with tacrolimus constitutes the basis of immunosuppressive protocols after orthotopic liver transplantation (OLT). Purpose The aim was to analyse the efficacy and safety of once daily tacrolimus (TAC-OD) (Advagraf) individualised dosing through a Bayesian approach in de novo OLT patients. Material and methods This was a retrospective study (September 2012–April 2016). Inclusion criteria: adult OLT patients with a minimum follow-up of 7 days. Immunosuppressive protocol: TAC-OD (first dose: 0.15 mg/kg/day), mycophenolate mofetil (1 g/24 hours orally) and steroids within the first 24 hours after OLT. Patients with renal dysfunction were treated with interleukin-2 receptor antagonists and tacrolimus was delayed. Blood trough levels of tacrolimus were monitored every 24 hours during hospitalisation and every outpatient visit. Dose adjustments were performed with every blood withdrawn through calculation of the empirical Bayesian estimates of the pharmacokinetic parameters. Population pharmacokinetics models were implemented in NONMEM V.7.3. Tacrolimus target trough levels were 8–10 ng/mL during the first month, reducing progressively to 5–8 ng/mL. Efficacy variables: tacrolimus trough levels, hospital stay and survival. Safety variables: serum creatinine (SCr). Results 2515 concentrations were collected from 99 patients (83 men/16 women). Mean age was 57.0 years (95% CI 53.9–60.14), IMC 16.07±4.7 kg/m 2 and MELD 15 (95% CI 12–18). Median (p25–p75) trough concentrations (ng/mL) of tacrolimus were 8.9 (5.3–11.6), 7.5 (5.4–9.7), 8.78 (6.9–10.65) and 9.7 (8.17–11.9) at 2, 7, 15 and 30 days, and 8.43 (7.38–10.02), 7.9 (6.45–9.04), 7.53 (6–9.17), 7.22 (6–8.7), 6.37 (5–7.25), 6.1 (5.2–7.48), 4.4 (3.8–6.35) and 4.5 (4–5.3) at 2, 3, 6, 12, 18, 24, 36 and 42 months after transplantation (statistically significant decrease after the second month, p 0.05). Median hospital stay after transplantation was 4 days (p25–p75: 3–6). Patient survival at 1, 3 and 4 years was 85%, 83.4% and 79.6%, respectively. Mean time of survival was 41 months (95% CI 37.6–44.4). Conclusion Our dosing protocol of TAC-OD based on Bayesian methodology was feasible in routine clinical practice, the target concentration was achieved at 48 hours in 75% of patients and it showed favourable outcomes in terms of survival and safety. No conflict of interest

Objective To assess the safety and effectiveness of oral propranolol (OP) in the treatment of infantile hemangiomas. Material and method We conducted a prospective study of infantile hemangiomas (IHs) treated with oral propranolol between October 2008 and March 2011. We included fast-growing IHs in the proliferative phase, IHs affecting vital structures, ulcerated IHs, and IHs that could cause functional or aesthetic problems after the proliferative phase. The patients received oral propranolol 2 mg/kg/d and were monitored on an outpatient basis. Response to treatment was assessed by volume reduction, lightening of color, improvement of symptoms, and parent satisfaction. Time of initial and peak response, as well as side effects and sequelae, were recorded. Results We analyzed 20 IHs, corresponding to 17 girls and 3 boys. The main sites of involvement were around the eyes (20%), the nose (15%), the neck (15%), and the trunk (15%). Ninety percent of the hemangiomas were focal and in the proliferative phase. Treatment was started between the ages of 2 and 19 months and the main reason for starting treatment was rapid growth (50% of cases). Initial response was observed in 70% of cases and only in 2 of them it took over a month. Peak response occurred at 3 months. All the IHs responded to treatment; response was excellent in 55% of cases, good in 35%, and minimal in 10%. The following factors were predictive of response: focal IH, proliferative phase, periorbital location, and ulceration. No serious side effects were observed. Conclusion Oral propranolol was clinically effective in reducing the volume and color of infantile hemangiomas, although the reduction was not complete and telangiectasia and scarring persisted after treatment. Oral propranolol also proved to be safe for use in outpatients.

Objetivo: La purificacion del preparado comercial de triamcinolona acetonido disponible es importante para evitar el efecto potencialmente toxico del disolvente alcohol bencilico. Presentamos una nueva tecnica de preparacion de triamcinolona en polvo, a partir de su forma pura, sin disolventes y diluida con agua destilada esteril. Dada su escasa solubilidad en agua se describe como preparar y controlar dicha suspension. Material y metodo: El acetonido de triamcinolona es preparado por el Servicio de Farmacia del Hospital, en condiciones de maxima esterilidad, bajo campana de flujo laminar. La suspension de triamcinolona es envasada en un vial primario, capsulado y posteriormente esterilizado en autoclave a 121 .C. Del vial primario se obtienen dosis individualizadas de 4 mg/0,1 ml. Resultados: Se obtiene la dosis real administrada (3,77 mg/0,1 ml) mediante cuantificacion de triamcinolona por cromatografia liquida de alta resolucion (HPLC). La estabilidad fisica, quimica y microbiologica conservando el vial entre 2-8. se mantiene a los 6 meses. Concusion: Se presenta un metodo de preparacion de triamcinolona en estado puro, obteniendo una concentracion muy proxima a la dosis optima, evitando el uso de disolventes y con maxima garantia de esterilidad

Objective: To design a therapeutic exchange protocol for antidepressants and clinically assess variables, such as compliance level, frequency of cases with clinically significant increase on the Udvalg-fur-Kliniske-Undersogelser (UKU) psychopharmacological scale, adverse effects analysis, overall analysis of UKU rating development and patients’ level of acceptance. Secondary objectives were to correlate psychopharmacological treatment aspects with the pharmacological morbidity level, and evaluate the clinical impact of pharmacotherapeutic optimisation measures. Method: The protocol is designed in accordance with a bibliographical review, which was approved by the Pharmacy and Therapeutics Commission. Sequential study was carried out with a sample of 30 patients. Three measurements were taken (base line, at 48---72 h and at 1---3 weeks) to calculate the pharmacotherapeutic morbidity with the UKU rating scale and the Global Clinical Impression. Pharmacotherapeutic optimisation measures were used for those patients with high pharmacotherapeutic morbidity levels. Results: The compliance level was 73.3%. One patient experienced ≥25% increase on the UKU rating scale and another patient suffered from an adverse effect. The final UKU rating reached statistical significance compared with the measurements taken at 48---72 h (P=.032) and with the base line measurement (P=.007). Patient acceptance was 90%. The impact of optimisation measurements on the pharmacotherapeutic morbidity level was clinically and statistically significant (P

Objective: To design a therapeutic exchange protocol for antidepressants and clinically assess variables, such as: compliance level, frequency of cases with clinically significant increase on the Udvalg-fur-Kliniske-Undersogelser (UKU) psychopharmacological scale, adverse effects analysis, overall analysis of UKU rating development and patients’ level of acceptance. Secondary objectives were to correlate psychopharmacological treatment aspects with the pharmacological morbidity level, and evaluate the clinical impact of pharmacotherapeutic optimisation measures. Method: The protocol is designed in accordance with a bibliographical review, which was approved by the Pharmacy and Therapeutics Commission. Sequential study was carried out with a sample of 30 patients. Three measurements were taken (base line, at 48-72 hours and at 1-3 weeks) to calculate the pharmacotherapeutic morbidity with the UKU rating scale and the Global Clinical Impression. Pharmacotherapeutic optimisation measures were used for those patients with high pharmacotherapeutic morbidity levels. Results: The compliance level was 73.3%. One patient experienced ≥25% increase on the UKU rating scale and another patient suffered from an adverse effect. The final UKU rating reached statistical significance compared with the measurements taken at 48-72 hours (P = .032) and with the base line measurement (P = .007). Patient acceptance was 90%. The impact of optimisation measurements on the pharmacotherapeutic morbidity level was clinically and statistically significant (P < .001). Conclusions: The proposed protocol has been widely accepted and it is quite certain that it is to be introduced in at a general hospital level.

Objective To evaluate the effectiveness of 100% autologous serum eye drops for the treatment of various ocular surface disorders. Methods A descriptive prospective observational study carried out from May 2005 to February 2009 which included patients with ocular surface disorders treated with single-dose autologous serum eye drops. Treatment effectiveness was evaluated by using a clinical questionnaire in order to assess symptoms experienced by patients at the beginning and end of treatment. Results A total of 15 patients (24 eyes) were evaluated. Clinical symptoms such as redness, burning, sharp pain and tired eyes improved in 100% of the patients, whereas dryness and sandy/gritty sensation improved in 92% of the patients. The overall improvement of clinical symptoms was worth the inconvenience of venipuncture according to 66.7% of the patients. Regarding tolerance for autologous serum eye drops, only one patient experienced some discomfort when using the single-dose eye drops. Conclusion The treatment with 100% autologous serum eye drops improved ocular symptoms for most patients.

Objective: To evaluate the effectiveness of 100% autologous serum eye drops for the treatment of various ocular surface disorders. Methods: A descriptive prospective observational study carried out from May 2005 to February 2009 which included patients with ocular surface disorders treated with single-dose autologous serum eye drops. Treatment effectiveness was evaluated by using a clinical questionnaire in order to assess symptoms experienced by patients at the beginning and end of treatment. Results: A total of 15 patients (24 eyes) were evaluated. Clinical symptoms such as redness, burning, sharp pain and tired eyes improved in 100% of the patients, whereas dryness and sandy/gritty sensation improved in 92% of the patients. The overall improvement of clinical symptoms was worth the inconvenience of venipuncture according to 66.7% of the patients. Regarding tolerance for autologous serum eye drops, only one patient experienced some discomfort when using the single-dose eye drops. Conclusion: The treatment with 100% autologous serum eye drops improved ocular symptoms for most patients.

Achieving new heights in object detection and image classification was made possible because of Convolution Neural Network(CNN). However, compared to image classification the object detection tasks are more difficult to analyze, more energy consuming and computation intensive. To overcome these challenges, a novel approach is developed for real time object detection applications to improve the accuracy and energy efficiency of the detection process. This is achieved by integrating the Convolutional Neural Networks (CNN) with the Scale Invariant Feature Transform (SIFT) algorithm. Here, we obtain high accuracy output with small sample data to train the model by integrating the CNN and SIFT features. The proposed detection model is a cluster of multiple deep convolutional neural networks and hybrid CNN-SIFT algorithm. The reason to use the SIFT featureis to amplify the model‟s capacity to detect small data or features as the SIFT requires small datasets to detect objects. Our simulation results show better performance in accuracy when compared with the conventional CNN method. As the resources like RAM, graphic card, ROM, etc. are limited we propose a pipelined implementation on an aggregate Central Processing Unit(CPU) and Graphical Processing Unit(GPU) platform.

We report the results of our ten-year experience in the Centre for Study and Conservation of Human Semen (CECOS) in Paris-Bicêtre. A total of 676 potential semen donors were interviewed by a geneticist and karyotyped; 6.0% were excluded, i.e. 2.6% for a cytogenetic reason and 3.4% for a genic reason. Our experience stresses the subjectivity and difficulty of the exclusion decision. It also shows how useful it is to take into account the recipient's familial pathology when choosing the donor. Finally, it reveals the importance of the geneticist's participation in the functioning of a centre.

Summary Background: Mycophenolate mofetil (MMF) has been used successfully in patients with various forms of uveitis not responsive to other immunosuppressants. Nevertheless, for these patients neither recommendations for optimal dosage of MMF nor data concerning drug exposure of MMF are available. Objective: To describe the results of the therapeutic drug monitoring (TDM) of MMF trough concentrations in a cohort of patients with uveitis, with the aim of optimizing the dosage of this drug, by maintaining a target concentration to achieve adequate immunosuppression with a minimal risk of therapeutic failure or toxicity. Patients and methods: This study describes the results of monitoring trough plasma concentrations of MMF in 12 patients with uveitis during a mean period of 21·4 months. Patients included one with Stevens–Johnson syndrome, one with Graves–Basedow's disease, one with Behcet's disease, one with idiopathic thombocytopenic purpura and the rest with idiopathic uveitis. All patients were treated with steroids and additional therapy prior to treatment with MMF. Results: Pharmacokinetic monitoring of mycophenolic acid (MPA) was performed with 108 trough plasma samples using an EMIT assay. Mean daily MMF dose was 24·5 ± 6·3 mg/kg and mean trough MPA concentration was 2·9 ± 1·9μg/mL. Therapy was effective in 10 patients (83%). There were few side-effects: diarrhoea, excitement, agitation and cough that disappeared with daily dose reduction of MMF. Conclusions: MMF was effective in the majority of patients with uveitis with an acceptable profile of side-effects. TDM of MMF in patients with uveitis is clinically practicable and may help to optimize individual immunosuppressive therapy. We estimated that MMF dosages in the range of 0·5–1·5 g/day might be sufficient for treating uveitis and we recommend an initial target range of 2–4 μg/mL, which included 50% of our results. Randomized controlled trials are essential to confirm the efficacy of MMF in uveitis.

pilonidal sinus (PS) is a common recurrent disease, often inflamed, usually located on sacral area, and causing high levels of morbidity. The incidence is estimated around 26 cases per 100,000, and it is more common in men (2:1). PS usually develops during the 2nd - 3rd decade of life.1 This article is protected by copyright. All rights reserved.

Objective: To assess pregnancies and conceptus after artificial insemination (AID) or IVF with frozen semen donor (IVF-D) on sufficiently large study population in order to distinguished minor variations. Study design: From 1987 to 1994, all pregnancies obtained after AID or IVF-D were registered prospectively in the French CECOS Federation data base. Different factors were recorded for this study: first menarche age of the recipient women, cycle length, insemination date in the conception cycle, maternal age at delivery, hormonal treatments, donor age, sperm conservation length and follow up of the pregnancy: miscarriage, tubal pregnancy, time at delivery, sex of the foetus, weight, malformation. Results: 21 597 pregnancies obtained after AID and 3381 after IVF-D were registered. 2% were lost to follow up. Foetal loss rate is 18% after AID and 21.5% after IVF-D (p

One of the main problems posed by complete dentures is retention and stability. In order to solve this problem, dentists and the dental industry for a long time have attempted to improve denture adhesion by developing a range of "glues" of highly varied composition and efficacy. The present in vivo clinical study evaluates whether the adhesives used to improve complete denture retention are truly effective and able to increase denture adhesion to the mucosa covering the edentulous alveolar ridge.of the mandibular dentures. An in vivo clinical study is made of 30 patients with complete mandibular dentures to evaluate the retention afforded by three commercial complete denture adhesives (Benfix®, Fittydent® and Supercorega®). A spring scale was used to measure retention strength (in grams). The purpose was to determine whether the use of complete denture adhesives is effective, and to establish which commercial brands offer the highest retention strengths. The results obtained indicate that retention is enhanced by the use of such adhesives, and that Fittydent® offers the best retention performance, followed by Benfix® and Supercorega®. The study of denture adhesives and his efficiency are necessary to improve the edentulous patient satisfaction. More in vivo investigations are necessary in dental literature. 0.537 SJR (2011) Q1, 26/107 Dentistry (miscellaneous); Q2, 504/1832 Medicine (miscellaneous), 133/362 Surgery, 42/91 Otorhinolaryngology

Objective. Most research on comprehensive primary care interventions for children with chronic health conditions has been conducted in large urban areas, where child health and related services are readily available. The purpose of this study was to evaluate the feasibility and impact of a medical home demonstration project in a more rural part of the country.Methods. Fifty-one parents of children with special health care needs participated in a pre-/posttreatment assessment of a program designed to enhance comprehensive and coordinated care. Participants were recruited from 3 primary care practices in a central Midwest state and remained in the program for ∼12 months.Results. Parents reported significant increases in satisfaction with care coordination and access to mental health services after the intervention. They also noted decreases in family needs, caregiver strain, parents’ missed work days, children’s school absences, and utilization of ambulatory services. Satisfaction with primary care declined slightly but remained in the “very good” range. Families of children with more complex conditions were more likely to report a decrease in needs after intervention, but other factors, such as geographic location or socioeconomic status, were not related to key outcome variables.Conclusions. Comprehensive care has a positive effect on children with chronic health conditions and their families, including those who live in more rural areas. Additional study is needed to learn more about rural service delivery strategies that promote implementation of this approach in general practice.

Objective To examine unmet needs among families of children with chronic health conditions treated in primary care settings and to identify predictors of these needs. Method Primary care physicians referred 83 caregivers of children with chronic health conditions. Mothers completed the Family Needs Survey, as well as other measures of child and family functioning. Results Mothers reported a high prevalence and broad range of unmet family needs. The most frequent area of need was for information about services and ways to promote child health and development. Predictors of total number of family needs included demographic characteristics, ratings of social support, and appraisals of family burden. Predictors of specific types of family needs varied according to category of need. Conclusions Innovative psychosocial intervention programs are needed in primary care settings to reduce family needs and promote child health. More intensive family supports may be indicated for those with minority-group or low socioeconomic status, limited social support, or high perceived burden.

In this paper measurements and modeling results obtained in the course of an European Space Agency, ESA, project (2002-2003) entitled "Navigation signal measurement campaign for critical environments" carried out by Joanneum Research (Austria) with subcontracts to DLR (Germany) and the University of Vigo (Spain), are presented.

Background The standard treatment for chronic viral hepatitis C (VHC) infection is peginterferon alfa 2a 180 μg or peginterferon alfa 2b 1.5 μg/kg once a week and ribavirin once a day. One of the most important side effects of the treatment is neutropenia due to peginterferon, which is sometimes a reason to discontinue the treatment. Purpose To record the incidence of neutropenia due to the use of peginterferon in patients who are being treated for chronic VHC infection and to analyse from which neutrophil count doctors introduce neutrophil granulocyte colony-stimulating drugs, change or discontinue the treatment. Materials and methods Retrospective observational study of patients with chronic VHC infection who were receiving treatment with peginterferon alpha 2a or peginterferon alfa 2b between January 2010 and December 2010. Demographic data such as sex, age and body weight were collected. Other data collected were the viral genotype, initial and final treatment and neutrophil count during the treatment period (neutropenia was defined as neutrophil count less than 1.5 × 10 3 μL). Results 65 patients were included, 42% women and 58% men with average age of 46.6 years. 48 patients were excluded due to being younger than 18 years or having renal disease and because some patients were lost during the follow-up period. In relation to viral genotype, 56.9%, 1.5%, 40% and 1.5% were genotype 1, 2, 3 and 4 respectively. 74% of patients were treated with peginterferon alfa 2a and 26% of patients were treated with peginterferon alfa 2b. The incidence of neutropenia was 66% (48.8% developed grade 2 neutropenia (1.5 - 1 × 10 3 μL) and 51.2% grade 3 (1 - 0.5 × 10 3 μL)). Modifications of the treatment were compiled in 23% of patients who developed neutropenia: the peginterferon dose was reduced in 5 patients, filgrastim was added in 2 patients and both measures were used in 3 patients. A relationship between the neutrophil count and the type of corrective measure was not observed. Conclusions The incidence of neutropenia during the treatment with peginterferon is significant (66%) and corrective measures were taken in 23% of the patients who developed this side effect. However there was no relationship between the neutrophil count and the decision to start a corrective measure or the type of measure taken. This suggests that symptoms of neutropenia are the most important reason to start corrective measures. No conflict of interest.

Background Switching from intravenous (IV) to oral (PO) treatment as soon as patients are clinically stable can reduce the costs associated with IV administration. In this study, we selected levetiracetam, a drug with high bioavailability oral (100%) and a significant cost difference between IV and PO forms. Purpose To estimate avoidable IV levetiracetam use and analyse the potential effect on the hospital drugs budget associated with changing levetiracetam from intravenous to oral treatment. Materials and methods Retrospective observational study performed in patients admitted to the neurosurgical service treated with IV levetiracetam from March 2013 to August 2013 (6 months). We divided levetiracetam-days (LD), into IV levetiracetam days (all doses of levetiracetam were administered IV), and PO levetiracetam days (at least 1 dose administered PO). And we considered IV levetiracetam avoidable when a patient received at least one other oral drug. Data source for costs were the average wholesale prices in 2013. Results A total of 38 patients (24 men, 63%) were included in the study with a mean age of 54.3 (95% CI, 49.1–59.4) years. During study 303 LD were counted, 107 (35%) IV levetiracetam days and 196 (65%) PO levetiracetam days and a median of 2 days IV treatment (interquartile range 1–3). In this period 84 (78.5%) IV levetiracetam days were potentially avoidable, and the cost savings for conversion from IV to PO levetiracetam were calculated to be 2,066 € and the total annual cost savings in the neurosurgery unit 4,132 €. Conclusions Early switching from IV to oral levetiracetam is possible and leads to a substantial reduction in the drugs bill. Explicit physiological criteria should be recorded to serve as a benchmark for successfully switching treatment. No conflict of interest.

Background The management of anaemia and secondary hyperparathyroidism (SHPT) in haemodialysis patients with chronic kidney disease means a significant consumption of drugs with high economic and health consequences. Purpose To evaluate the potential economic impact of the different erythropoiesis stimulating agents (ESA) and active vitamin D analogues in haemodialysis patients in terms of cost minimisation. Materials and methods Retrospective observational study, in adult haemodialysis patients treated with ESA and active vitamin D analogues between January 2011 and February 2012. The sources of drug use data included drug acquisition costs and the prescribed monthly dose (PMD) defined as the average maintenance dose. Therapeutic equivalence was assumed in compliance with KDOQI and KDIGO quality criteria guidelines (haemoglobin, parathyroid hormone, calcium-phosphorus product). Statistical analysis was done using SPSS. The comparisons of averages were done using Student’s T test with a CI95% p Results 473 patients were included, 59% of them men. The total cost of the medicines dispensed was 1,207,225 €. For anaemia 328 patients were treated with epoetin: average PMD of 58,427 ± 38,989 IU and a total cost of 535,907 €; 145 patients were treated with darbepoetin: average PMD of 272 ± 213 mcg and a total cost of 222.214 €. The conversion ratio epoetin/darbepoetin was 214 IU:mcg, the PMDs cost 169 ± 113 € and 192 ± 150 €, respectively, and no significant differences were found (p = 0.07). To manage SHPT, 220 patients were treated with alfacalcidol: average PMD of 12.6 mcg and a cost of 16.965 €; 130 patients were treated with paricalcitol: average PMD of 24.3 mcg and a cost of 71.739 €. The conversion ratio alfacalcidol/paricalcitol was 1:2 mcg, and the PMDs cost 12.4 ± 6.8 € and 81.5 ± 33.8 €, respectively, reaching statistical significance (p Conclusions Alfacalcidol seems to be the best cost alternative, even with a conversion ratio higher than the one recommended by the manufacturer (1:3 mcg). Epoetin and darbepoetin generate similar costs. This data supports the therapeutic positioning of these medicines in our field. No conflict of interest.

A detailed numerical study of the flow and the heat transfer inside high-pressure-ratio transonic/supersonic turbine blade rows is described. A high-order upwinding relaxation method is used to solve the Reynoldsaveraged Navier-Stokes equation inside three different turbine blade rows. A two-equation turbulence model with a low-Reynolds-n umber modification is used to describe turbulent shear stress and turbulent heat flux. The numerical results are compared with available experimental data on two-dimensional geometries. It is found that very complex flow phenomena near the trailing edge of transonic turbine blade rows can be very well predicted numerically, and the method can be used in the development of new designs for HP turbines.