Vitamin D supplementation and COVID-19 risk: a population-based, cohort study.

PURPOSE: To analyze the associations between cholecalciferol or calcifediol supplementation, serum 25-hydroxyvitamin D (25OHD) levels and COVID-19 outcomes in a large population. METHODS: All individuals ≥ 18 years old living in Barcelona-Central Catalonia (n = 4.6 million) supplemented with cholecalciferol or calcifediol from April 2019 to February 2020 were compared with propensity score-matched untreated controls. Outcome variables were SARS-CoV2 infection, severe COVID-19 and COVID-19 mortality occuring during the first wave of the pandemic. Demographical data, comorbidities, serum 25OHD levels and concomitant pharmacological treatments were collected as covariates. Associations between cholecalciferol or calcifediol use and outcome variables were analyzed using multivariate Cox proportional regression. RESULTS: Cholecalciferol supplementation (n = 108,343) was associated with slight protection from SARS-CoV2 infection (n = 4352 [4.0%] vs 9142/216,686 [4.2%] in controls; HR 0.95 [CI 95% 0.91-0.98], p = 0.004). Patients on cholecalciferol treatment achieving 25OHD levels ≥ 30 ng/ml had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19 and lower COVID-19 mortality than unsupplemented 25OHD-deficient patients (56/9474 [0.6%] vs 96/7616 [1.3%]; HR 0.66 [CI 95% 0.46-0.93], p = 0.018). Calcifediol use (n = 134,703) was not associated with reduced risk of SARS-CoV2 infection or mortality in the whole cohort. However, patients on calcifediol treatment achieving serum 25OHD levels ≥ 30 ng/ml also had lower risk of SARS-CoV2 infection, lower risk of severe COVID-19, and lower COVID-19 mortality compared to 25OHD-deficient patients not receiving vitamin D supplements (88/16276 [0.5%] vs 96/7616 [1.3%]; HR 0.56 [CI 95% 0.42-0.76], p < 0.001). CONCLUSIONS: In this large, population-based study, we observed that patients supplemented with cholecalciferol or calcifediol achieving serum 25OHD levels ≥ 30 ng/ml were associated with better COVID-19 outcomes.

Is a treat-to-target strategy in osteoporosis applicable in clinical practice? Consensus among a panel of European experts.

A panel of European experts was convened to establish consensus on a treat-to-target strategy in osteoporosis. Panellists agreed that the ultimate goals of treating osteoporosis are recovering pre-fracture functional level and reducing subsequent fracture risk; there was consensus that total hip bone mineral density is currently the most appropriate treatment target in clinical practice. INTRODUCTION: A modified Delphi approach was convened to establish consensus among European experts on best practice management for patients with fragility fractures and whether a treat-to-target (T2T) strategy is applicable in osteoporosis. METHODS: A panel of 12 clinical experts (from eight European countries) voted on 13 final statements relating to a T2T strategy for osteoporosis across three rounds of blinded, remotely conducted electronic surveys (Likert scale: 'strongly disagree', 'disagree', 'unable to answer', 'agree', 'strongly agree'). When panellists disagreed, they were asked how the statement could be adjusted to allow for a positive response, which was used to refine the statement for the following round. Consensus was defined as ≥ 75% agreement with a statement. Panellists were selected by UCB Pharma, which provided financial and logistical support. RESULTS: Consensus was reached for 13/13 statements. Panellists agreed that the most important goals for fragility fracture patients are recovery of pre-fracture functional level and reduction of subsequent fracture risk. There was also consensus that a T2T strategy is applicable to osteoporosis and that bone mineral density (BMD) is currently the most clinically appropriate target. With regard to the definition of a specific BMD treatment target and timeframes applicable to T2T in osteoporosis, no clear consensus was reached; panellists emphasised that these would need to be individually determined. CONCLUSIONS: According to a panel of European experts, the main goals of fracture management are to recover pre-fracture functional level and reduce fracture risk. Total hip BMD seems to be the most clinically appropriate treatment target within a T2T strategy.

Efficacy of teriparatide compared with risedronate on FRAX®-defined major osteoporotic fractures: results of the VERO clinical trial.

FRAX® calculates the 10-year probability of major osteoporotic fractures (MOF), which are considered to have a greater clinical impact than other fractures. Our results suggest that, in postmenopausal women with severe osteoporosis, those treated with teriparatide had a 60% lower risk of FRAX®-defined MOF compared with those treated with risedronate. INTRODUCTION: The VERO trial was an active-controlled fracture endpoint clinical trial that enrolled postmenopausal women with severe osteoporosis. After 24 months, a 52% reduction in the hazard ratio (HR) of clinical fractures was reported in patients randomized to teriparatide compared with risedronate. We examined fracture results restricted to FRAX®-defined major osteoporotic fractures (MOF), which include clinical vertebral, hip, humerus, and forearm fractures. METHODS: In total, 1360 postmenopausal women (mean age 72.1 years) were randomized to receive subcutaneous daily teriparatide (20 µg) or oral weekly risedronate (35 mg). Patient cumulative incidence of ≥ 1 FRAX®-defined MOF and of all clinical fractures were estimated by Kaplan-Meier analyses, and the comparison between treatments was based on the stratified log-rank test. Additionally, an extended Cox model was used to estimate HRs at different time points. Incidence fracture rates were estimated at each 6-month interval. RESULTS: After 24 months, 16 (2.6%) patients in the teriparatide group had ≥ 1 low trauma FRAX®-defined MOF compared with 40 patients (6.4%) in the risedronate group (HR 0.40; 95% CI 0.23-0.68; p = 0.001). Clinical vertebral and radius fractures were the most frequent FRAX®-defined MOF sites. The largest difference in incidence rates of both FRAX®-defined MOF and all clinical fractures between treatments occurred during the 6- to 12-month period. There was a statistically significant reduction in fractures between groups as early as 7 months for both categories of clinical fractures analyzed. CONCLUSION: In postmenopausal women with severe osteoporosis, treatment with teriparatide was more efficacious than risedronate, with a 60% lower risk of FRAX®-defined MOF during the 24-month treatment period. Fracture risk was statistically significantly reduced at 7 months of treatment. CLINICAL TRIAL INFORMATION: ClinicalTrials.gov Identifier: NCT01709110 EudraCT Number: 2012-000123-41.

Spanish consensus on treat to target for osteoporosis.

To reach a Spanish expert consensus on a treat-to-target strategy in osteoporosis, a Delphi Consensus Study has been developed. Most of the experts (59.8%) were rheumatologist with a mean clinical experience of 21.3 years (SD 8.5). Consensus was achieved for 70% of the items. Therapeutic objectives, patient follow-up scheme, treatment failure criteria, and appropriate treatment choice for use in T2T strategy in Spain have been defined. INTRODUCTION: The paper aims to achieve a Spanish expert consensus on a treat-to-target (T2T) strategy in osteoporosis. METHODS: A scientific committee led the project and was involved in expert panel identification and Delphi questionnaire development. Two Delphi rounds were completed. The first-round questionnaire included 24 items and assessed, using a seven-point Likert scale, the experts' wish (W) and prognosis (P) in 5 years for each topic (applicability, therapeutic objectives, patient follow-up, and possible treatment to be prescribed). Items for which there was no consensus in the first round were included in the second round. Consensus was defined as ≥75% agreement (somewhat/mostly/entirely agree) or disagreement (somewhat/mostly/entirely disagree) responses. RESULTS: Of the experts, 112 and 106 completed the first and second rounds, respectively. 59.8% were rheumatologists with a mean clinical experience of 21.3 years (SD 8.5). Consensus was achieved for 70% of the items, and was established regarding the utility of a T2T strategy to define therapeutic objectives, optimal follow-up, and therapeutic algorithm. Participants agreed on the utility of the bone mineral density (BMD) value (T-score >-2.5 SD for spine and >-2.5/-2.0 SD for femoral neck), lack of fractures, and fracture risk (FRAX) as therapeutic objectives. For measuring BMD changes, consensus was achieved on the suitability of hip and femoral neck locations. Experts agreed to consider treatment failure as when a significant BMD gain could not be achieved, or when a new fracture occurs within 2-3 years. There was consensus that all proposed therapies should achieve a therapeutic target through T2T strategy (treatments with the highest consensus scores were denosumab and teriparatide). CONCLUSION: The therapeutic objectives, patient follow-up scheme, treatment failure criteria, and appropriate treatment choice for use in T2T strategy in Spain have been established by a panel of experts. Some aspects nevertheless still require further analysis.

Comparison of total, free and bioavailable 25-OH vitamin D determinations to evaluate its biological activity in healthy adults: the LabOscat study.

Determination of different forms of 25-OHD (total, free and bioavailable) in healthy young women does not offer additional advantages over standard 25-OHDT for evaluating vitamin D deficiency. In these subjects 25-OHDT values <15 ng/ml would be more appropriate for defining this deficiency. INTRODUCTION: Determination of 25-OH vitamin D serum levels (25-OHD) constitutes the method of choice for evaluating vitamin D deficiency. However, vitamin D-binding protein (DBP) may modulate its bioavailability thereby affecting correct evaluation of 25-OHD status. We analysed the impact of the determination of 25-OHD (total, free and bioavailable) on the evaluation its biologic activity (estimated by serum PTH determination) in healthy young women. METHODS: 173 premenopausal women (aged 35-45 yrs.) were included. We analysed serum values of total 25-OHD (25-OHDT), DBP, albumin, PTH and bone formation (PINP,OC) and resorption (NTx,CTx) markers. Free(25-OHDF) and bioavailable (25-OHDB) serum 25-OHD levels were estimated by DBP and albumin determinations and also directly by ELISA (25-OHDF-2). We analysed threshold PTH values for the different forms of 25-OHD and the correlations and differences according to 25-OHDT levels <20 ng/ml. RESULTS: 62% of subjects had 25-OHD values <20 ng/ml and also had significantly lower 25-OHDF and 25-OHDB values, with no significant differences in bone markers and PTH values. The PTH threshold value was similar for all forms of 25-OHD (∼70 pg/ml). Women with PTH values >70 had lower 25-OHDT (15.4 ± 1.4 vs. 18.3 ± 2.7, p < 0.05) and 25OHDB values (1.7 ± 0.2 vs. 2.2 ± 0.09, p < 0.05). The different forms of 25OHD were significantly intercorrelated, with marginal correlations between PTH and 25-OHDT (r = -0.136, p = 0.082). CONCLUSIONS: Determination of different forms of 25-OHD in healthy young women does not offer additional advantages over standard 25-OHDT for evaluating vitamin D deficiency. In these subjects 25-OHDT values <15 ng/ml would be more appropriate for defining this deficiency.

Dynamic soluble changes in sVEGFR1, HGF, and VEGF promote chemotherapy and bevacizumab resistance: A prospective translational study in the BECOX (GEMCAD 09-01) trial.

Despite initial responsiveness, acquired resistance to both bevacizumab and chemotherapy in metastatic colorectal cancer is universal. We have recently published that in vitro, chronically oxaliplatin resistance upregulates soluble vascular endothelial growth factor receptor 1, downregulates vascular endothelial growth factor, and also promotes c-MET, b-catenin/transcription factor 4, and AKT activation. We tested whether variation in three serum biomarkers such as the natural c-MET ligand (hepatocyte growth factor), soluble vascular endothelial growth factor receptor 1, and vascular endothelial growth factor-A was associated with efficacy in metastatic colorectal cancer patients treated in the prospective BECOX study. Serum levels of vascular endothelial growth factor-A165, soluble vascular endothelial growth factor receptor 1, and hepatocyte growth factor were assessed by enzyme-linked immunosorbent assay method basally and every 3 cycles (at the time of computed tomography evaluation) in a preplanned translational study in the first-line BECOX trial in metastatic colorectal cancer patients treated with CAPOX plus bevacizumab. Response was evaluated by routine contrast-enhanced computed tomography by RECIST 1.1 by investigator assessment and by three blinded independent radiologists. Ratios between soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A and hepatocyte growth factor/vascular endothelial growth factor-A were established and variations through time were related to RECIST 1.1 by investigator assessment and independent radiologist. The BECOX trial included 68 patients, and 27 patients were analyzed in the translational trial. A total of 80 RECIST 1.1 evaluations were done by investigator assessment and 56 by independent radiologist. We found that a 3.22-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by investigator assessment and a 3.06-fold increase in soluble vascular endothelial growth factor receptor 1/vascular endothelial growth factor-A by independent radiologist from previous determination were associated with responses compared with 1.38-fold increase by investigator assessment and 1.59 by independent radiologist in non-responders (p = 0.0009 and p = 0.03, respectively). Responders had a 3.36-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A from previous determination by investigator assessment and 3.66-fold increase in hepatocyte growth factor/vascular endothelial growth factor-A by independent radiologist compared with 1.43-fold increase by investigator assessment and 1.53 by independent radiologist for non-responders (p = 0.002 and 0.003, respectively). In conclusion, a decrease in vascular endothelial growth factor-A and an increase in soluble vascular endothelial growth factor receptor 1 during chemotherapy and bevacizumab exposure can contribute to both chemotherapy (due to c-MET/b-catenin activation) and bevacizumab (due to low vascular endothelial growth factor requirements) resistance. Because hepatocyte growth factor levels decrease also during acquired resistance, alternative strategies to hepatocyte growth factor-ligand inhibition should be investigated.

First-line bevacizumab and capecitabine-oxaliplatin in elderly patients with mCRC: GEMCAD phase II BECOX study.

BACKGROUND: Subgroup analyses of clinical studies suggest that bevacizumab plus XELOX is effective and tolerable in elderly patients with metastatic colorectal cancer (mCRC). The prospective BECOX study examined the efficacy and safety of bevacizumab plus XELOX, followed by bevacizumab plus capecitabine in elderly patients with mCRC. METHODS: Patients aged ⩾70 years with Eastern Cooperative Oncology Group performance status 0 out of 1 and confirmed mCRC were included. Patients received bevacizumab 7.5 mg kg(-1) and oxaliplatin 130 mg m(-2) on day 1, plus capecitabine 1000 mg m(-2) bid orally on days 1-14 every 21 days; oxaliplatin was discontinued after 6 cycles. The primary end point was time to progression (TTP). RESULTS: The intent-to-treat population comprised 68 patients (65% male, median age 76 years). Median TTP was 11.1 months; median overall survival was 20.4 months; overall response rate was 46%. Grade 3 or 4 adverse events included diarrhoea (18%) and asthenia (16%). Grade 3 or 4 adverse events of special interest for bevacizumab included deep-vein thrombosis (6%) and pulmonary embolism (4%). CONCLUSIONS: Bevacizumab plus XELOX was effective and well tolerated in elderly patients in the BECOX study. The adverse-event profile was similar to previous reports; no new safety concerns were identified. Fit elderly patients with mCRC should be considered for treatment with bevacizumab plus XELOX.

Multicenter phase II study of oxaliplatin and sorafenib in advanced gastric adenocarcinoma after failure of cisplatin and fluoropyrimidine treatment. A GEMCAD study.

BACKGROUND: Cisplatin and fluoropyrimidine (CF) are standard first- line treatment in advanced gastric cancer, but no second-line treatment has yet been established. We present a phase II study in which we evaluated the efficacy and toxicity of the combination of Sorafenib (S), and Oxaliplatin as second-line therapy. METHODS: Patients with progressive gastric adenocarcinoma after CF- first-line, ECOG 0-2, and measurable disease were included. The primary objective was PFS. Treatment doses were Oxaliplatin 130 mg/m²/3 weeks and Sorafenib 800 mg/bid/d. RESULTS: We included 40 patients. CR was 2.5% and SD was 47.2%. Grade 3-4 toxic effects were neutropenia (9.8%), thrombocytopenia (7.3%), neurotoxicity (4.9%) and diarrhea (4.9%). Median PFS was 3 months (95%CI: 2.3-4.1) and median OS was 6.5 months (95% CI: 5.2-9.6). Time to progression (TTP) to first line therapy was a prognosis factor. Median OS was 9.7 months when time-to-progression during first-line chemotherapy was >6 months and 5.6 m when it was <6 months (p = 0.04). CONCLUSIONS: Time-to-progression under a CF-based first-line therapy determines subgroups of GC patients with different prognosis. The combination of Oxaliplatin-Sorafenib in advanced GC patients previously treated with CF appears safe, but our results do not support the implementation of a phase III trial.

Improving the safety of viral DNA vaccines: development of vectors containing both 5' and 3' homologous regulatory sequences from non-viral origin.

Although some DNA vaccines have proved to be very efficient in field trials, their authorisation still remains limited to a few countries. This is in part due to safety issues because most of them contain viral regulatory sequences to driving the expression of the encoded antigen. This is the case of the only DNA vaccine against a fish rhabdovirus (a negative ssRNA virus), authorised in Canada, despite the important economic losses that these viruses cause to aquaculture all over the world. In an attempt to solve this problem and using as a model a non-authorised, but efficient DNA vaccine against the fish rhabdovirus, viral haemorrhagic septicaemia virus (VHSV), we developed a plasmid construction containing regulatory sequences exclusively from fish origin. The result was an "all-fish vector", named pJAC-G, containing 5' and 3' regulatory sequences of ß-acting genes from carp and zebrafish, respectively. In vitro and in vivo, pJAC-G drove a successful expression of the VHSV glycoprotein G (G), the only antigen of the virus conferring in vivo protection. Furthermore, and by means of in vitro fusion assays, it was confirmed that G protein expressed from pJAC-G was fully functional. Altogether, these results suggest that DNA vaccines containing host-homologous gene regulatory sequences might be useful for developing safer DNA vaccines, while they also might be useful for basic studies.

Internet use by cancer patients: should oncologists 'prescribe' accurate web sites in combination with chemotherapy? A survey in a Spanish cohort.

BACKGROUND: Cancer patients search for information about prognosis and treatment. Internet has become a major source of medical information. Its impact on oncology patients is not well known. PATIENTS AND METHODS: Three hundred and eighty questionnaires were distributed to cancer patients and companions and 293 were returned. The type of information they obtained online, its usefulness, and its impact on the patient-physician relationship as well as other sources of searching were demanded. Student t-tests, chi-square tests, and multivariate regression logistic analysis were carried out. RESULTS: Internet use was low (27% patients, 58% relatives). Cancer-specific information was the principal research (41% and 70%). For 61% patients, the information had been useful. Information provided by clinicians was the primary reason to not use Internet (37% and 67%). Twenty-two percent patients discussed it with clinicians. Among other sources, health professional (62% and 51%) and printed materials (18% and 25%) were the most demanded. CONCLUSIONS: Cancer patients and carers reported a low use of the Internet for searching medical information, although it helps patients to better cope with cancer. To discuss this information may strengthen the patient-physician relationship. Physicians should ensure that their patients receive reliable online information.

Hypovitaminosis D as a risk factor of hip fracture severity.

SUMMARY: In a cross-sectional study including 324 patients older than 65 years admitted to our hospital for osteoporotic hip fracture, we found that those patients with a more severe vitamin D deficiency had more severe osteoporotic hip fractures (Garden grades III-IV and Kyle III-IV). INTRODUCTION: To identify possible differences in baseline characteristics of patients with different types of osteoporotic hip fracture. METHODS: Cross-sectional study including consecutive individuals over 65 admitted to our hospital for osteoporotic hip fracture over a year. Demographic data, fracture type, comorbidities, history of osteoporosis, functional capacity, nutritional status and vitamin D storage were evaluated. RESULTS: We included 324 patients (83 ± 7 years, 80% women). Two hundred sixteen patients (67%) had vitamin D deficiency (25OHD3 <25 ng/ml). In patients with severe femoral neck or intertrochanteric fractures (Garden III-IV and Kyle III-IV), vitamin D deficiency was more frequent (74%) and severe (25OHD3 20 ± 15 ng/ml) than in patients with less severe fractures (57%, 25OHD3 26 ± 21 ng/ml). Forty-three percent of patients had previous fractures. Only 15% of patients had been previously diagnosed with osteoporosis and 10% were receiving treatment. Patients receiving vitamin D supplements have higher 20OHD3 levels and less severe fractures. CONCLUSIONS: Although vitamin D levels are not different between patients with intracapsular or extracapsular hip fractures, a more severe vitamin D deficiency seems to be associated to more severe osteoporotic hip fractures. A prior vitamin D supplementation could avoid a higher severity of these fractures.

[Screening of patient manual handling risk using the MAPO method]. / Screening del rischio da movimentazione manuale pazienti con metodo MAPO.

BACKGROUND: International standards draw attention to the steps that risk assessment should follow to first identify hazards, then proceed to risk evaluation and lastly, if necessary, risk assessment. The same logic also applies to risk assessment of manual patient handling. OBJECTIVES: To check appropriateness of approach to "risk evaluation" of manual patient handling using MAPO, a cross sectional study was carried out aimed at checking the relationship between this new risk assessment model (MAPO screening) and occurrence of acute low back pain. METHODS: After proper training the MAPO screening method was used to assess risk of manual handling of patients in 31 wards, covering 411 exposed subjects employed in geriatric hospitals belonging to the UNEBA (National Union Institutions and Social Welfare Initiatives) of the Veneto Region. At the same time health data were collected on the occurrence of low back pain episodes during the last year both in the group of exposed subjects and in an external reference group (237 subjects). Risk and clinical assessment data were verified and checked by the EPM research unit. Logistic analysis was used as a method to evaluate the relationship between MAPO screening risk index and acute low back pain. RESULTS: Investigating the relationship between acute low back pain episodes and levels of MAPO screening index, carried out only on exposed subjects who reported working for at least 30 hours per week (N=178), showed definitely positive trends: for MAPO screening index of exposure levels between 1.51 and 5, OR were double (OR=2.22; IC 95% 0.88-5.63) whereas for index levels exceeding 5, OR were about 4 (OR=3.77; IC 95% 1.33-10.74). These results did not show significant differences when correcting the analysis for confounding factors such as gender and age classes. CONCLUSIONS: The results of the study indicate that the proposed method, "MAPO screening", can be a useful tool to estimate risk due to manual handling of patients and can also be used to test the efficacy of preventive measures.

Clinical activity of patupilone in patients with pretreated advanced/metastatic colon cancer: results of a phase I dose escalation trial.

BACKGROUND: New agents that are active in patients with metastatic colorectal cancer are needed. Patupilone (EPO906; epothilone B) is a novel microtubule-stabilising agent. METHODS: Patients with advanced colon cancer who progressed after prior treatment regimens received intravenous patupilone (6.5-10.0 mg m(-2)) once every 3 weeks by a 20-min infusion (20MI), 24-h continuous infusion (CI-1D) or 5-day intermittent 16-h infusion (16HI-5D). Adverse events (AEs), dose-limiting toxicities (DLTs), pharmacokinetics and anti-tumour activity were assessed. RESULTS: Sixty patients were enrolled. The maximum tolerated dose (MTD) was not reached in the 20MI arm (n=31), as no DLTs were observed. Three patients in the CI-1D arm (n=26) experienced 1 DLT each at 7.5, 8.0 and 9.0 mg m(-2), but MTD was not reached. However, the prolonged 16HI-5D arm was terminated at 6.5 mg m(-2) after two of the three patients developed a DLT. Diarrhoea was the most common AE and DLT, with increased severity at the higher doses (9.0 and 10.0 mg m(-2)). Grade 3 or 4 diarrhoea was observed in 11 (35%) of the patients in the 20MI arm, 4 (15%) of the patients in the CI-1D arm and 2 (67%) of the patients in the 16HI-5D arm. Patupilone activity was observed in the 20MI arm with a disease control rate of 58%, including four confirmed partial responses. The disease control rate in CI-1D arm was 39%. CONCLUSION: Patupilone given once every 3 weeks as a 20-min infusion had promising anti-tumour activity and manageable safety profile at doses that demonstrated therapeutic efficacy.

Insect larvae biofactories as a platform for influenza vaccine production.

Increased production capacity is one of the most important priorities for seasonal and pandemic influenza vaccines. In the present study, we used a baculovirus-insect larvae system (considered small, living biofactories) to improve the production of recombinant influenza virus H1N1 hemagglutinin (HA). Insect larvae produced four-fold more HA protein than insect cells per biomass unit (1 g of fresh larvae weight). A single infected Trichoplusia ni larva produced up to 113 µg of soluble and easily purified recombinant HA, an amount similar to that produced by 1.2×10(8) Sf21 insect cells infected by the same baculovirus. The use of the KDEL endoplasmic reticulum retention signal fused to the HA protein further increased recombinant protein production. Larvae-derived HA was immunogenically functional in vaccinated mice, inducing the generation of hemagglutination inhibition antibodies and a protective immune response against a lethal challenge with a highly virulent virus. The productivity, scalability and cost efficiency of small, living biofactories based on insect larvae suggest a broad-based strategy for the production of recombinant subunit vaccines against seasonal or pandemic influenza as an alternative to fermentation technologies.

Rainbow trout surviving infections of viral haemorrhagic septicemia virus (VHSV) show lasting antibodies to recombinant G protein fragments.

Rainbow trout antibodies (Abs) binding to recombinant fragments (frgs) derived from the protein G of the viral haemorrhagic septicemia virus (VHSV)-07.71 strain, could be detected by ELISA (frg-ELISA) in sera from trout surviving laboratory-controlled infections. Abs were detected not only by using sera from trout infected with the homologous VHSV isolate but also with the VHSV-DK-201433 heterologous isolate, which had 13 amino acid changes. Sera from healthy trout and/or from trout surviving infectious haematopoietic necrosis virus (IHNV) infection, were used to calculate cut-off absorbances to differentiate negative from positive sera. Specific anti-VHSV Abs could then be detected by using any of the following frgs: frg11 (56-110), frg15 (65-250), frg16 (252-450) or G21-465. While high correlations were found among the ELISA values obtained with the different frgs, no correlations between any frg-ELISA and complement-dependent 50% plaque neutralization test (PNT) titres could be demonstrated. Between 4 and 10 weeks after VHSV infection, more trout sera were detected as positives by using heterologous frg-ELISA rather than homologous PNT. Furthermore, the percentage of positive sera detected by frg11-ELISA increased with time after infection to reach 100%, while those detected by complement-dependent PNT decreased to 29.4%, thus confirming that the lack of neutralizing Abs does not mean the lack of any anti-VHSV Abs in survivor trout sera. Preliminary results with sera from field samples suggest that further refinements of the frg-ELISA could allow detection of anti-VHSV trout Abs in natural outbreaks caused by different heterologous VHSV isolates. The homologous frg-ELISA method could be useful to follow G immunization attempts during vaccine development and/or to best understand the fish Ab response during VHSV infections. The viral frgs approach might also be used with other fish species and/or viruses.

Immunohistochemical analysis of tumour regression grade for rectal cancer after neoadjuvant chemoradiotherapy.

AIM: Tumour regression grade (TRG) as defined by Rödel et al. has been used as an independent prognostic factor for rectal carcinoma after preoperative treatment by chemoradiotherapy (CRT). Determination of TRG 2 and 3, semiquantitatively defined as more or less than 50% tumour regression, respectively, does not appear to correlate with prognosis. The purpose of this study was to find an immunohistochemical pattern to permit improved stratification of intermediate responders defined by disease free (DFS) and overall survival (OS). METHOD: Immunohistochemistry of EGFR (epidermal growth factor receptor), VEGF (vascular endothelial growth factor), CD133 antibody, p53 antibody and Ki67 antibody was evaluated using tissue microarrays (TMA) on post-treatment surgical specimens from 88 patients. CD133 expression was confirmed in the whole section when available. RESULTS: At a median follow-up of 40 months, TRG was found to be an independent predictor of DFS (P = 0.05) and OS (P = 0.001) but no differences were found between TRG 2 and 3 in terms of DFS (P = 0.74) or OS (P = 0.41). The results of TMA showed an immunohistochemically poor prognostic profile for intermediate responders configured by negativity of CD133 expression. However, when examining CD133 expression in the whole section, there was an intermediate correlation with TMA and the prognostic significance was lost. CONCLUSION: The results did not confirm the value of immunohistochemistry in predicting the prognosis of patients with rectal cancer following neoadjuvant chemoradiotherapy. This questions the accuracy of TMA in detecting CD133 expression in this setting.

Multidisciplinary expert consensus on secondary fracture prevention in Spain.

The study aimed to achieve expert consensus to optimize secondary fracture prevention in Spain. Relevant gaps in current patient management were identified. However, some aspects were considered difficult to apply. Future efforts should focus on those items with greatest divergences between importance and feasibility. PURPOSE: To establish a Spanish multidisciplinary expert consensus on secondary fracture prevention. METHODS: A two-round Delphi consensus was conducted, guided by a Scientific Committee. The 43-item study questionnaire was designed from a literature review and a subsequent multidisciplinary expert group (n = 12) discussion. The first-round questionnaire, using a 7-point Likert scale, assessed the experts' opinion of the current situation, their wish for items to happen, and their prognosis that items would be implemented within 5 years. Items for which consensus was not achieved were included in the second round. Consensus was defined as ≥ 75% agreement or ≥ 75% disagreement. A total of 102 experts from 14 scientific societies were invited to participate. RESULTS: A total of 75 (response rate 73.5%) and 69 (92.0%) experts answered the first and second Delphi rounds, respectively. Participants mean age was 51.8 years [standard deviation (SD): 10.1 years]; being 24.0% rheumatologists, 21.3% primary care physicians, 14.7% geriatricians, 8.0% internal medicine specialists, 8.0% rehabilitation physicians, and 8.0% gynecologists. Consensus was achieved for 79.1% of items (wish, 100%; prognosis, 58.1%). Effective secondary prevention strategies identified as requiring improvement included: clinical report standardization, effective hospital primary care communication (telephone/mail and case managers), health-related quality of life (HRQoL) questionnaires use, and treatment compliance monitoring (prognosis agreement 33.3%, 47.8%, 18.8%, and 55.1%, respectively). CONCLUSION: A consensus was reached by health professionals in their wish to implement strategies to optimize secondary fracture prevention; however, they considered some difficult to apply. Efforts should focus on those items with currently low application and those with greatest divergence between wish and prognosis.

Quality of care in psychiatry is related to research activity.

BACKGROUND: The top biomedical research institutions have traditionally been assumed to provide better medical treatment for their patients. However, this may not necessarily be the case. Low-to-moderate negative associations between research activity and the quality-of-care provided by clinical departments have been described. We aimed to examine this relationship in the psychiatric units of the largest hospitals in Spain. METHODS: Scientific publications for 50 hospitals were retrieved from the Web of Science (2006-2015), and quality of mental healthcare data were gathered from Spanish National Health System records (2008-2014). Spearman-rank correlation analyses (adjusting for number of beds and population) were used to examine the associations between research data and quality-of-care outcomes in psychiatry. Stepwise regression models were built in order to determine the predictive value of research productivity for healthcare outcomes. RESULTS: We found a positive association between research activity indicators (i.e., number of publications, number of citations, cumulative impact factor, and institutional H-index) and better quality-of-care outcomes in psychiatry (i.e., number of readmissions, transfers, and discharges from hospital). In particular, a higher research activity predicted a lower level of readmissions for individuals with psychoses (p = 0.025; R = 0.317), explaining 8.2% of the variance when other factors were accounted for. CONCLUSIONS: Higher research activity is associated with better quality of mental healthcare in psychiatry. Our results can inform decision-making in clinical and research management settings in order to determine the most appropriate quality measures of the impact of research on the prognosis of individuals with psychiatric conditions.

Treatment of proteinuria with lercanidipine associated with renin-angiotensin axis-blocking drugs.

OBJECTIVE: Most calcium antagonists do not seem to reduce microalbuminuria or proteinuria. We have tried to assess the antiproteinuric effect of a calcium channel blocker, lercanidipine, in patients previously treated with ACE inhibitors or angiotensin receptor blockers. DESIGN AND METHODS: The study included 68 proteinuric (> 500 mg/day) patients (age 63.1 +/- 12.9 years, 69.1% males and 30.9 females). All patients were receiving ACE inhibitors (51.4%) or angiotensin II receptor blockers (48.6%) therapy but had higher blood pressure than recommended for proteinuric patients (<130/80 mmHg). Patients were clinically evaluated one, three, and six months after starting treatment with lercanidipine (20 mg/day). Samples for urine and blood examination were taken during the examination. When needed, a third drug was added to treatment. Creatinine clearance was measured using 24 h urine collection. RESULTS: BP significantly decreases from 152 +/- 15/86 +/- 11 mmHg to 135 +/- 12/77 +/- 10 mmHg at six months of follow-up (p < 0.001). After six months of treatment, the percentage of normalized patients (BP < 130/80 mmHg) was 42.5%, and the proportion of patients whose BP was below 140/90 mmHg was 58.8%. Plasmatic creatinine did not change nor did creatinine clearance. Plasmatic cholesterol also decreased from 210 +/- 48 to 192 +/- 34 mg/dL (p < 0.001), as did plasma triglycerides (from 151 +/- 77 to 134 +/- 72 mg/dL, p = 0.022). Basal proteinuria was 1.63 +/- 1.34 g/day; it was significantly (p < 0.001) reduced by 23% at the first month, 37% at three months, and 33% at the last visit. CONCLUSIONS: Lercanidipine at 20 mg dose, associated to renin-angiotensin axis-blocking drugs, showed a high antihypertensive and antiproteinuric effect. This antiproteinuric effect seems to be dose-dependent as compared with previous reports and proportionally higher than blood pressure reduction.

[Hypertensive vascular disease: evolution of its incidence in the period 1991-2007 and survival prior to end-stage renal disease]. / Enfermedad vascular hipertensiva: evolución de la incidencia en el período 1991-2007 y supervivencia antes de la enfermedad renal terminal.

OBJECTIVE: Hypertensive nephropathy is the second most common cause for starting renal replacement therapy in Spain with a steady incidence since 1997. Data on incidence of hypertensive nephropathy previously to dialysis are scanty because there are not registries similar to those used for renal replacement therapy. DESIGN AND METHODS: Retrospectively we studied the records of our hospital Nephrology outpatients clinic from January, 1991 to December, 2007. Diagnosis was commonly made using clinical criteria in most of cases. There were 60 cases with proteinuria higher than 1 g/day and so that renal biopsies were performed. RESULTS: During this time 479 (44.0 pmp) patients were diagnosed of hypertensive nephropathy (mean age 66.6 +/- 12.1 years and 43.0% were women). Incidence increased from 33.3 pmp (1991) to 76.2 pmp (2006). There was a steady trend to increase incidence since 16.7 pmp in 1991 up to 89.5 pmp in 2007. Mean incidence was 31.8 pmp between 1991 and 1995, 32.1 pmp in the period 1996-2000; and 54.4 pmp from 2001 to 2006. The mean age of incident patients showed a J curve. 53 subjects (11.6%) have started renal replacement therapy. Survival before starting renal replacement therapy was 96.0 at first year, 85.9% at five years and 81.6% after seven years of follow-up. CONCLUSIONS: Incidence of hypertensive nephropathy seems to have increased last years specially in spite of therapeutic improvements the prognosis is still unfavourable. Less restricted age criteria for submitting patients may have influenced these results.