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RationaleMavacamten is a novel, FDA-approved, small molecule therapeutic designed to regulate cardiac function at the sarcomere level by selectively but reversibly inhibiting the enzymatic activity of myosin. It shifts myosin towards orderedoffstates close to the thick filament backbone.ObjectiveThe purpose of this study is to investigate whether mavacamten permanently sequester these myosin heads in theoffstate(s) and can these heads be recruited in response to physiological stimuli when required to boost cardiac output.Methods and ResultsWe show that cardiac myosins stabilized in theseoffstate(s) by mavacamten are recruitable by 1) Ca2+, 2) increased chronotropy (heart rate), 3) stretch, and 4) β-adrenergic (β-AR) stimulation, all known physiological inotropic effectors. At the molecular level, we show that Ca2+increases myosin ATPase activity by shifting mavacamten-stabilized myosin heads from the inactive super-relaxed (SRX) state to the active disordered relaxed (DRX) state. At the myofilament level, both Ca2+and passive lengthening can shift mavacamten-orderedoffmyosin heads from positions close to the thick filament backbone to disorderedonstates closer to the thin filaments. In isolated rat cardiomyocytes, increased stimulation rates enhanced shortening fraction in mavacamten-treated cells. This observation was confirmedin vivoin telemetered rats, where left-ventricular dP/dtmax,an index of inotropy, increased with heart rate in mavacamten treated animals. Finally, we show that β-AR stimulationin vivoincreases left-ventricular function and stroke volume in the setting of mavacamten.ConclusionsOur data demonstrate that the mavacamten-promotedoffstates of myosin in the thick filament are activable, thus leading to the preservation of the cardiac reserve. These results provide a potential mechanistic explanation, beyond mere LV outflow tract obstruction removal, for the clinical observation of increased peak oxygen uptake (pVO2) with exercise in HCM patients receiving mavacamten.

Hypertrophic cardiomyopathy (HCM) is a chronic, progressive disease of the cardiomyocyte with a diverse and heterogeneous clinical presentation and course. This diversity and heterogeneity have added to the complexity of modeling the pathophysiological pathways that contribute to the disease burden. The development of novel therapeutic approaches targeting precise mechanisms within the underlying biology of HCM provides a tool to model and test these pathways. Here, we integrate the results of clinical observations with mavacamten, an allosteric, selective, and reversible inhibitor of cardiac myosin, the motor unit of the sarcomere, to develop an integrated pathophysiological pathway model of HCM, confirming the key role of excess sarcomeric activity. This model may serve as a foundation to understand the role of HCM pathophysiological pathways in the clinical presentation of the disease, and how a targeted therapeutic intervention capable of normalizing sarcomeric activity and repopulating low-energy utilization states may reduce the impact of these pathways in HCM and potentially related disease states.

Green periurban residential areas in Mediterranean countries have flourished in the last decades and become foci for leishmaniasis. To remedy the absence of information on vector ecology in these environments, we examined phlebotomine sand fly distribution in 29 sites in Murcia City over a 3-year period, including the plots of 20 detached houses and nine non-urbanized sites nearby. We collected 5,066 specimens from five species using “sticky” interception and light attraction traps. The relative frequency of the main Leishmania infantum vector Phlebotomus perniciosus in these traps was 32% and 63%, respectively. Sand fly density was widely variable spatially and temporally and greatest in non-urbanized sites, particularly in caves and abandoned buildings close to domestic animal holdings. Phlebotomus perniciosus density in house plots was positively correlated with those in non-urbanized sites, greatest in larger properties with extensive vegetation and non-permanently lived, but not associated to dog presence or a history of canine leishmaniasis. Within house plots, sand fly density was highest in traps closest to walls. Furthermore, the study provides a guideline for insect density assessment and reporting and is envisioned as a building block towards the development of a pan-European database for robust investigation of environmental determinants of sand fly distribution.

Introduction: Left-atrial dilatation is thought to play a key pathological role in facilitating remodeling in both genetic and acquired cardiac myopathies, as well as enabling the onset and maintenance of atrial fibrillation. However, despite its likely role in disease, the structural responses of the atria to stretch remain understudied. The myofilament responses to stretch have been extensively studied in ventricular tissue, where strain-dependent recruitment of reserve, OFF-state, myosin heads from the thick-filament contribute to length dependent activation (LDA, i.e., greater forcer at longer sarcomere lengths). In these experiments, the effects of stretch in both atrial sarcomere and thick-filament structure were evaluated. Methods: Myofilament structure was evaluated via x-ray diffraction at two sarcomere lengths (SL, SHORT: 2.1 μm, and LONG: 2.3 μm) in relaxed left-atrial and left-ventricular myocardial skinned fibers from Yucatan mini-pigs. In these experiments, both equatorial and meridional reflections reflecting sarcomeric structure and ordering were evaluated. In addition, the biomechanical effects of stretch were also evaluated in both skinned porcine fibers and engineered heart tissues (EHT) from atrial and ventricular hIPSc-derived myocytes via a proprietary system (MyoPod; Propria Biosciences). Results: In both atrial skinned fibers and EHTs, stretch triggered moderate increases in force, demonstrating LDA. LA fibers, stretch decreased lattice spacing but failed to alter the I 11 /I 10 equatorial intensity ratio, suggesting negligible length-dependent recruitment of OFF-state myosin heads from the thick-filament. LA fibers, however, tended to have higher I 11 /I 10 values at short SL (vs. LV fibers) suggesting an intrinsically higher population of ON-state myosin heads. In addition, stretch triggered alterations in thick filament ordering in both LA and LV fibers, as reflected by changes in both the 3 rd and 6 th order meridional reflections (M3 and M6), suggesting effects in both myosin heads and thick-filament backbone. Conclusion: Atrial stretch results in marked sarcomere structural alterations, reducing both inter-filament spacing and thick-filament ordering that likely contribute to length dependent activation. The role of these alteration in atrial pathophysiology remains to be studied

VIII International Symposium on Marine Sciences, 6-8 July 2022, Las Palmas de Gran Canaria, España, "Centinelas de la Costa" aims, through a coordinated team of different entities and experts in coastal research, to promote the scientific culture of citizens, in terms of the changes that our coast shows as a consequence of different natural processes or of anthropic origin. It is articulated in two main actions with different spatial scope: (i) Action at the regional level: with the aim of implementing and promoting the means and resources already available within the international initiative of CoastSnap towards different sectors of society. Adding to existing resources, new functionalities have been implemented and a contest has been launched to encourage the use of the CoastSnap App and generate community. (ii) Action at the local level: a common space and format of a mobile application has been created, "Centinelas de la costa", that allows the different members of the project team to provide solutions according to the specific needs of each location. This action is complemented with training days for volunteers in data collection, in collaboration with local agents, Many thanks to FECYT funding, program of activities in the field of promoting Scientific, Technological and Innovation Culture, Ministry of Science and Innovation

In this paper an engine prototype of 2 degrees of freedom from a work still in progress that helps a solid fuel rocket to stay vertical during motor operation is presented. One of the philosophies of this paper consists in using cheap and accessible materials, as well as avoiding the use of industrial machinery for its manufacture. This paper describes the procedure to generate solid fuel from a mixture of sugar and potassium nitrate. Subsequently, the design of the engine and tests conserning reusability with the prototype are presented. The design is based solely on obtaining the torques required to keep the prototype rocket moving in a vertical direction. The corresponding equations are written and after linearization, the transfer function is presented and the system is simulated using a PID control. The electromechanical system (ES) as well as the solid fuel motor were manufactured, and even though the ES is not coupled to the motor so the control actions are not evaluated, the performance of the rocket motor is measured using different design options and the propulsion times were evaluated. To measure the orientation and position the BMP280 and MPU6050 sensors were selected, and their stabilization time after turning them on was evaluated. It was found that the materials can be reused at least once for tests up to 23 grams of solid fuel, and that the selected electronic devices must have a stabilization time before ignition.

Ante-mortem diagnosis of caprine tuberculosis, as in other ruminant species, is a complex process. Therefore, it is sometimes necessary to apply a combination of methods that increases the sensitivity of diagnosis while maintaining adequate specificity. In the present study, we analysed the use of ELISA based on a double-recognition methodology for the diagnosis of goat tuberculosis. Serum samples from animals with tuberculosis, confirmed by histopathological studies and presence of Ziehl-Neelsen-positive bacteria in the lesions, were used to assess sensitivity. Sera from flocks without tuberculosis were used to assess diagnostic specificity. The relationship between ELISA results and the type of tuberculous lesions, both macroscopic and microscopic, was analysed. The sensitivity and specificity of ELISA test were 69.9% and 97.9%, respectively. Sensitivity was higher in animals with macroscopic lesions, indicating more advanced forms of the disease. Similarly, a higher sensitivity was found in animals with microscopic lesions associated with active tuberculosis, such as cavitary lesions.

Aims: Both left ventricular (LV) and left atrial (LA) dysfunction and remodelling contribute to adverse outcomes in heart failure with reduced ejection fraction (HFrEF). Danicamtiv is a novel, cardiac myosin activator that enhances cardiomyocyte contraction.Methods and results: We studied the effects of danicamtiv on LV and LA function in non-clinical studies (ex vivo: skinned muscle fibres and myofibrils; in vivo: dogs with heart failure) and in a randomized, double-blind, single- and multiple-dose phase 2a trial in patients with stable HFrEF (placebo, n = 10; danicamtiv, n = 30; 50–100 mg twice daily for 7 days). Danicamtiv increased ATPase activity and calcium sensitivity in LV and LA myofibrils/muscle fibres. In dogs with heart failure, danicamtiv improved LV stroke volume (+10.6 mL, P < 0.05) and LA emptying fraction (+10.7%, P < 0.05). In patients with HFrEF (mean age 60 years, 25% women, ischaemic heart disease 48%, mean LV ejection fraction 32%), treatment-emergent adverse events, mostly mild, were reported in 17 patients (57%) receiving danicamtiv and 4 patients (40%) receiving placebo. Danicamtiv (at plasma concentrations ≥2000 ng/mL) increased stroke volume (up to +7.8 mL, P < 0.01), improved global longitudinal (up to −1.0%, P < 0.05) and circumferential strain (up to −3.3%, P < 0.01), decreased LA minimal volume index (up to −2.4 mL/m2, P < 0.01) and increased LA function index (up to 6.1, P < 0.01), when compared with placebo.Conclusions: Danicamtiv was well tolerated and improved LV systolic function in patients with HFrEF. A marked improvement in LA volume and function was also observed in patients with HFrEF, consistent with pre-clinical findings of direct activation of LA contractility.

Background Promonitor Quick IFX and Promonitor Quick ADL are rapid point of care lateral flow tests (LFT) based on a sandwich immunoassay for the quantification of infliximab (IFX) and adalimumab (ADL), respectively, in human whole blood (finger prick or venous) or serum. These tests are to be used as an aid in Therapeutic Drug Monitoring (TDM) of inflammatory bowel disease (IBD) and rheumatic patients under anti-TNFα therapy. The international standards (IS) developed by World Health Organization (WHO) for IFX and ADL allow harmonization and comparability among different assays. The aim of this study, was to show that Promonitor Quick IFX and Promonitor Quick ADL can measure either reference or biosimilar drugs, as well as to evaluate the agreement of Promonitor Quick IFX and Promonitor Quick ADL tests and the WHO IS. Methods Clinical and Laboratory Standards Institute EP10-A3 guidelines were followed to estimate the bias of Promonitor Quick assays when used to quantify IFX or ADL in samples containing the reference drugs, biosimilars or the WHO IS. Briefly, whole blood was spiked with four known concentrations of IFX or ADL, including current clinical decision levels. Ten replicates were measured of each level along two days. Promonitor Quick IFX was evaluated using the reference drug, SB2 and CT-P13 biosimilars, and the WHO IS (NIBSC, 16/170). Promonitor Quick ADL was evaluated using the reference drug, ABP501 and SB5 biosimilars, and the WHO IS (NIBSC, 17/236). Results were obtained in combination with the automated portable reader PQreader. Results Bias was estimated by comparing the observed concentration of drug spiked whole blood samples. Each biosimilar was compared to the reference at the different drug levels tested. Results showed that Promonitor Quick IFX (Table, 1) and Promonitor Quick ADL (Table, 2) are able to measure equivalently any molecule. The accuracy or closeness of the agreement between the result provided by Promonitor Quick IFX and Promonitor Quick ADL and the true value of the measurand was assessed by measuring the IS developed by the WHO (Tables, 1 & 2). Similar results were obtained when serum matrix was used. Conclusion Promonitor Quick IFX and Promonitor Quick ADL allow monitoring of patients treated with IFX and ADL, respectively, with just a finger prick sample. Both tests can quantify reference and biosimilar drugs with equivalent results. Moreover, comparable results were obtained with the WHO IS, and thus, demonstrate that Promonitor Quick tests are suited to accurately determine drug levels at the clinical decision points in both whole blood and serum, proving to be an effective and valuable tool in TDM and immediate decision making in the doctor office or hospitals.

BackgroundPromonitor Quick IFX and Promonitor Quick ADL are rapid point of care lateral flow tests (LFT) based on a sandwich immunoassay for the quantification of infliximab (IFX) and adalimumab (ADL), respectively, in human whole blood (finger prick or venous) or serum. These tests are to be used as an aid in Therapeutic Drug Monitoring (TDM) of rheumatic and inflammatory bowel disease patients under anti-TNFα therapy. The international standards (IS) developed by World Health Organization (WHO) for IFX and ADL allow harmonization and comparability among different assays.ObjectivesThe aim of this study, was to show that Promonitor Quick IFX and Promonitor Quick ADL can measure either reference or biosimilar drugs, as well as to evaluate the agreement of Promonitor Quick IFX and Promonitor Quick ADL tests and the WHO IS.MethodsClinical and Laboratory Standards Institute EP10-A3 guidelines were followed to estimate the bias of Promonitor Quick assays when used to quantify IFX or ADL in samples containing the reference drugs, biosimilars or the WHO IS. Briefly, whole blood was spiked with four known concentrations of IFX or ADL, including current clinical decision levels. Ten replicates were measured of each level along two days.Promonitor Quick IFX was evaluated using the reference drug, SB2 and CT-P13 biosimilars, and the WHO IS (NIBSC 16/170).Promonitor Quick ADL was evaluated using the reference drug, ABP501 and SB5 biosimilars, and the WHO IS (NIBSC 17/236).Results were obtained in combination with the automated portable reader PQreader.ResultsBias was estimated by comparing the observed concentration of drug spiked whole blood samples. Each biosimilar was compared to the reference at the different drug levels tested. Results showed that Promonitor Quick IFX and Promonitor Quick ADL are able to measure equivalently any molecule (see Table 1).Table 1.Promonitor Quick IFX bias results in whole blood samples. Each molecule was compared to the reference drug.IFX concentration (μg/mL)Bias (%)CT-P13SB2GP1111WHO IS314%3%4%8%79%0%5%15%101%5%6%8%Promonitor Quick ADL bias results in whole blood samples.Each molecule was compared to the reference drug.ADL concentration (μg/mL)Bias (%)ABP501SB5WHO IS317%2%3%513%3%12%82%2%7%10517%2%Similar results were obtained when serum matrix was used.The accuracy or closeness of the agreement between the result provided by Promonitor Quick IFX and Promonitor Quick ADL and the true value of the measurand was assessed by measuring the IS developed by the WHO (see Table 1).ConclusionPromonitor Quick IFX and Promonitor Quick ADL allow monitoring of patients treated with IFX and ADL, respectively, with just a finger prick sample. Both tests can quantify reference and biosimilar drugs with equivalent results. Moreover, comparable results were obtained with the WHO IS, and thus, demonstrate that Promonitor Quick tests are suited to accurately determine drug levels at the clinical decision points in both whole blood and serum, proving to be an effective and valuable tool in TDM and immediate decision making in the doctor office or hospitals.Disclosure of InterestsAmagoia Ametzazurra Employee of: Employee of Progenika Biopharma - Grifols, Javier Pascual Employee of: Employee of Progenika Biopharma - Grifols, Lorena Del Rio Employee of: Employee of Progenika Biopharma - Grifols, Ane Urigoitia Employee of: Employee of Progenika Biopharma - Grifols, Daniel Nagore Employee of: Employee of Progenika Biopharma - Grifols, M. Begoña Ruiz-Argüello Employee of: Employee of Progenika Biopharma - Grifols

BackgroundCurrent techniques to monitor clinical response may require several days and centralised facilities, which may cause delays in effective therapeutic decisions. Therefore, the use of a rapid decentralized test will facilitate patient management and improve patient care.ObjectivesThe goal of this study was to validate the use of capillary blood in a real point-of-care (POC) setting for rheumatic patients under infliximab treatment by using Promonitor Quick lateral flow (LF) tests. Results were compared to the Promonitor ELISA reference technique in serum samples used by centralised laboratories.MethodsA prospective, observational study was designed to evaluate the performance of a rapid LF test (Promonitor Quick IFX, Progenika, Spain). 160 infliximab treated rheumatology consecutive patients (400 samples) were recruited in two hospitals in Galicia, Spain. Prior to the infusion, a finger prick sample was obtained and analysed. Anti-infliximab antibodies were also determined with Promonitor Quick ANTI-IFX1-4. Results were read with the automated portable PQreader instrument. Additionally, a serum sample was collected for subsequent comparative analysis with either LF or ELISA tests.Qualitative (positive (PPA) and negative (NPA) agreements) and quantitative (Pearson correlation and bias) performance of the LF test was compared to ELISA, as well as between different specimens following CLSI EP09-A3.ResultsOverall agreement between Promonitor Quick IFX finger prick and ELISA test was 91% (88% PPA; 100% NPA). The quantitative comparison showed a good correlation (Pearson correlation coefficient: 0.85 and observed bias: 25%) (Table 1).Table 1.Performance results: infliximab drugQualitative ComparisonN*PPANPAoverallPOC finger prick vs ELISA27488%100%91%POC serum vs ELISA28198%100%98%Quantitative ComparisonN*Pearson correlationBiasPOC finger prick vs ELISA1650.8525%POC serum vs ELISA1810.916%*Only samples in the common measurement range for both methods considered.Performance results: anti-infliximab anti-drug antibodiesQualitative ComparisonN*PPANPAoverallPOC finger prick visual vs. PQreader396100%99%99%POC serum visual vs PQreader398100%100%100%POC finger prick PQreader vs ELISA39390%99%98%POC serum PQreader vs ELISA39589%100%99%Similar results were also observed when serum was used with either the LF or the ELISA tests (98% overall agreement, 0.91 correlation coefficient; 6% bias) (Table 1).Overall agreements for visual and automated (PQreader) interpretations with Promonitor Quick ANTI-IFX were 99% and 100% for finger prick and serum specimens, respectively (Table 1).ConclusionPromonitor Quick can be used to reliably quantify infliximab in capillary blood samples and results are comparable to those obtained with the reference ELISA technique. The use of the rapid POC test with finger prick will allow clinicians to monitor their patients in a fully decentralized mode to aid in the decision making process. PQreader is a sensitive portable equipment to report drug as well as antibody levels in the patient samples.References[1]Atreya, R. et al. J Crohns Colitis. 2019;13:S391[2]Ametzazurra, A. et al. J Crohns Colitis. 2017;11:S335-S336[3]Fiorino, G. et al. J Crohns Colitis. 2017;11:S388[4]Facchin, A. et al. J Crohns Colitis. 2019;13:S349- S350Disclosure of InterestsM. Begoña Ruiz-Argüello Employee of: Employee of Progenika Biopharma - Grifols, Javier Pascual Employee of: Employee of Progenika Biopharma - Grifols, Lorena Del Rio Employee of: Employee of Progenika Biopharma - Grifols, Ane Urigoitia Employee of: Employee of Progenika Biopharma - Grifols, Cristina Balo-Farto: None declared, Carlos Fernández-López: None declared, ANTONIO MERA VARELA: None declared, Francisco Javier de-Toro-Santos: None declared, Daniel Nagore Employee of: Employee of Progenika Biopharma - Grifols, Amagoia Ametzazurra Employee of: Employee of Progenika Biopharma - Grifols

BackgroundPromonitor Quick IFX is a lateral flow test (LFT) for the quantification of infliximab (IFX) in human whole blood (finger prick or venous) or serum in 20 minutes. This LFT is based on a sandwich immunoassay to quantify either the reference IFX or biosimilars.ObjectivesThe objective of this study was to perform the required analytical studies to establish the specifications of the product.MethodsClinical and Laboratory Standards Institute (CLSI) guidelines were followed for the evaluation of the analytical specifications of the LFT in whole blood and serum matrices: Linearity (EP-06-A), Detection capability (EP17-A2), Interfering substances (EP07, 3rd Edition) and Intermediate precision (EP05-A3). Results were obtained in combination with the automated portable reader PQreader. A Datamatrix provided with each Promonitor Quick IFX kit contains the calibration information required for the PQreader to measure the Control and Test lines and report the IFX concentration.ResultsThe linear assay range was determined to be 1-58 µg/mL in whole-blood and 0.6-67 µg/mL in serum according to the processes indicated in the Package Insert. The Limit of Blank is 0.8 μg/mL, the Limit of Detection and Lower Limit of Quantification (LLoQ) are 1.1 μg/mL, and the Upper Limit of Quantification (ULoQ) is 15.4 μg/mL.There was no effect on assay performance when each of the following substances were added to samples with 0, 3, and 7 μg/mL of IFX: Haemoglobin (>1000 mg/dL), Bilirubin (>40 mg/dL), Triglycerides (>1500 mg/dL), HAMA (160 AU/mL), Rheumatoid factor (200 IU/mL), EDTA (5.4 mg/mL), Heparin (51 U/mL), Citrate (11.4%), Vedolizumab (60 μg/mL) and Adalimumab (20.25 μg/mL).Repeatability and within-device precision results obtained for the positive samples are shown in Table 1.Table 1.IFX theoretical concentration (μg/mL)Whole blood samplesSerum samplesMean observed IFX concentration (μg/mL)RepeatabilityWithin-device precisionMean observed IFX concentration (μg/mL)RepeatabilityWithin-device precisionSDCV%SDCV%SDCV%SDCV%33.20.6180.8253.60.5150.617771.3181.7248.31.4161.821109.81.8182.72810.91.8162.321The negative samples showed a negative result in all the measurements.ConclusionPromonitor Quick IFX is the first LFT available for true Point of Care testing of patients treated with IFX with just a finger prick sample. It provides quick turnaround time to facilitate therapeutic drug monitoring and aid immediate decision making in the doctor office or hospitals with an excellent analytical performance.Disclosure of InterestsAmagoia Ametzazurra Employee of: Employee of Progenika Biopharma - Grifols, Javier Pascual Employee of: Employee of Progenika Biopharma - Grifols, Lorena Del Rio Employee of: Employee of Progenika Biopharma - Grifols, Ainara Maguregui Employee of: Employee of Progenika Biopharma - Grifols, Daniel Nagore Employee of: Employee of Progenika Biopharma - Grifols, M. Begoña Ruiz-Argüello Employee of: Employee of Progenika Biopharma - Grifols

Introduction Hypertrophic cardiomyopathy (HCM) is a progressive disease characterized by cardiac remodeling, hyperdynamic contraction, and impaired ventricular filling that can lead to dynamic left-ventricular outflow-track (LVOT) obstruction and exertional intolerance. Direct myosin-inhibition with mavacamten can normalize contractility and improve exercise capacity in patients with oHCM, providing sustained symptomatic relief. However, mavacamten can also improve ventricular filling by limiting residual cross-bridges during diastole, and therefore, may offer cardiac benefits beyond obstruction reprieve. This study leveraged a feline model of oHCM, cats with the A31P MYBPC3 variant, to study the acute in vivo effects of MYK-581, a mavacamten surrogate, on cardiac hemodynamics and filling. Methods A31P-homozygous cats with HCM (A31P, n=10) and wild-type healthy controls (CTRL, n=9) were anesthetized and instrumented for invasive pressure-volume (PV) measurements as well as trans-thoracic echocardiographic recording. A subset of cats were assigned to receive either vehicle (VEH, n=7) or MYK-581 (MYK, n=8) with a short IV infusion. Cardiac hemodynamics, function, and geometry were assessed at steady state before and during dobutamine challenges (2.5 μg/kg/min IV). Results A31P cats had thicker ventricular walls (6.4±0.1 vs. 5.2±0.2 mm, P Conclusions Bred cats, homozygous for the A31P MYBPC3 variant, presented a cardiac phenotype that models multiple characteristics of the human oHCM phenotype including dynamic LVOT obstruction. Acute treatment with the mavacamten surrogate, MYK-581, not only alleviated hypercontractility and LVOT obstruction, but improved ventricular filling and end-diastolic pressures. Taken together, these pre-clinical observations show potential salutary effects beyond obstruction relief in patients with HCM. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): MyoKardia

B: Alterations in the length dependent activation (LDA) of left ventricular (LV) muscle fibres, the mechanistic driver of the Frank-Starling Law of the heart, are thought to mediate impaired LV function in heart failure (HF). However, little is known about LDA's role in the left atria (LA). Given the concomitant presence of LA dysfunction in HF, the purpose of this study was to compare/assess LDA on LA and LV muscle, as well to evaluate the effects of a novel small-molecule acto-myosin activator, danicamtiv (formerly known as MYK-491). M: LA and LV myofibrils from healthy Yucatan mini-pigs were used to determine biomechanical function with ATPase assays, with and without danicamtiv. Skinned LA and LV muscle fibres from these same animals were prepared to study contractile force, Ca2+ sensitivity, active/passive stiffness, and responsiveness to increasing sarcomere length (2.0 and 2.3). These parameters were also evaluated in the presence of danicamtiv. R: LA myofibrils had significantly faster ATPase and Pi release rates compared to LV, consistent with their respective alpha/beta myosin-isoform content. Despite increased metabolic rate, LA fibres generated less maximum isometric tension (12.3±1.96 vs 35.2±3.07 mN/mm2) and had a lower pCa50 than LV fibres (5.66±0.02 vs 5.82±0.02), demonstrating reduced force-generating capability and Ca2+ sensitivity. Stretch of LV fibres resulted in a gain in tension over a range of pCas (pCa6.4, 6.2, 6.0, and 5.8, all p0.05). Stretch had no effect on active stiffness, but increased passive stiffness in both muscle types. Stretched LA fibres showed grater passive stiffness compared to LV (196.7±21.5 vs. 138.5±22.3 kN/m3). A stiffer myofilament would in part explain the blunted ability of the LA to generate force in response to stretch. Danicamtiv activated both LA and LV myofibrils, increasing ATPase and Pi release rates, and increased Ca2+ sensitivity in fibres (ΔpCa; LV, 0.320±0.032; LA, 0.149±0.028, p C: These data confirm the functional differences between LA and LV muscle fibres and demonstrate a blunted ability of LA tissue to recruit force when stretched. The acto-myosin activator danicamtiv increased biochemical activity, Ca2+ sensitivity, and the active S/T relationship in LA and LV fibres without altering passive strain. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): MyoKardia Inc.

Rheumatoid arthritis (RA) patients had a higher risk of developing low bone mineral density (BMD) or osteoporosis. RA patients on classic disease-modifying antirheumatic drug (c-DMARD) therapy showed significantly lower BMD than controls, while no significant differences in most parameters were found between RA patients receiving biological disease-modifying antirheumatic drugs (b-DMARDs) and controls. The 3D analysis allowed us to find changes in the trabecular and cortical compartments.To evaluate cortical and trabecular bone involvement of the hip in RA patients by dual-energy X-ray absorptiometry (DXA) and 3D analysis. The secondary end-point was to evaluate bone involvement in patients treated with classic (c-DMARD) or biological (b-DMARD) disease-modifying antirheumatic drug therapies and the effect of the duration of the disease and corticosteroid therapy on 3D parameters.A cross-sectional study of 105 RA patients and 100 subjects as a control group (CG) matched by age, sex, and BMI was carried out. BMD was measured by DXA of the bilateral femoral neck (FN) and total hip (TH). The 3D analyses including trabecular and cortical BMD were performed on hip scans with the 3D-Shaper software.FN and TH BMD and trabecular and cortical vBMD were significantly lower in RA patients. The c-DMARD (n = 75) group showed significantly lower trabecular and cortical vBMD than the CG. Despite the lower values, the b-DMARD group (n = 30) showed no significant differences in most parameters compared with the CG. The trabecular and cortical 3D parameters were significantly lower in the group with an RA disease duration of 1 to 5 years than in the CG, and the trabecular vBMD was significantly lower in the group with a duration of corticosteroid therapy of 1 to 5 years than in the CG, while no significant differences were found by standard DXA in the same period.RA patients had a higher risk of developing low BMD or osteoporosis than controls. RA patients receiving c-DMARD therapy showed significantly lower BMD than controls, while no significant differences in most parameters were found between RA patients receiving b-DMARDs and controls. 3D-DXA allowed us to find changes in trabecular and cortical bone compartments in RA patients.

Objetivo: El diagnóstico de osteoporosis se ha fundamentado en la medición de la densidad mineral ósea, si bien esta variable tiene una capacidad limitada en la discriminación de pacientes con o sin fracturas. La aplicación del análisis de elementos finitos (FE) sobre imágenes volumétricas de tomografía computarizada ha mejorado la clasificación de sujetos hasta 90%, aunque la dosis de radiación, complejidad y coste no aconsejan su práctica regular. Nuestro objetivo es aplicar el análisis FE a modelos tridimensionales con absorciometría radiológica dual (3DDXA), para clasificar pacientes con fractura osteoporótica de fémur proximal y sin fractura. Material y métodos: Se selecciónó una cohorte de 111 pacientes con osteoporosis densitométrica: 62 con fractura y 49 sin ella. Se utilizaron modelos FE sujetoespecíficos para el impacto, como la simulación estática de la caída lateral. Las simulaciónes de impacto permiten identificar la región crítica en el 95% de los casos, y la respuesta mecánica a una fuerza lateral máxima. Se realizó un análisis mediante un clasificador discriminativo (Support Vector Machine) por tipo de fractura, tejido y género, utilizando las mediciónes DXA y parámetros biomecánicos. Resultados: Los resultados mostraron una sensibilidad de clasificación del 100%, y una tasa de falsos negativos de 0% para los casos de fractura de cuello para el hueso trabecular en las mujeres. Se identifica la variable tensión principal mayor (MPS) como el mejor parámetro para la clasificación. Conclusión: Los resultados sugieren que el uso de modelos 3DDXA podría ayudar a discriminar mejor a los pacientes con elevado riesgo de fracturarse. Objetive: The diagnosis of osteoporosis has been based on the measurement of bone mineral density, although this variable has a limited capacity in discriminating patients with or without fractures. The application of finite element analysis (FE) on computed tomography volumetric images has improved the classification of subjects by up to 90%, although the radiation dose, complexity, and cost do not favor their regular practice. Our objective is to apply FE analysis to threedimensional models with dualenergy xray absorptiometry (3DDXA), to classify patients who present osteoporotic fracture of the proximal femur and those without fracture. Material and methods: A cohort of 111 patients with densitometric osteoporosis was selected: 62 with fracture and 49 without it. Subjectspecific FE models for impact were used, such as static simulation of lateral fall. Impact simulations allow identifying the critical region in 95% of cases, and the mechanical response to maximum lateral force. An analysis was performed using a discriminative classifier (Support Vector Machine) by fracture type, tissue and gender, using DXA measurements and biomechanical parameters. Results: The results showed a classification sensitivity of 100%, and a false negative rate of 0% for cases of neck fracture for trabecular bone in women. The variable major main stress (MPS) is identified as the best parameter for the classification. Conclusion: The results suggest that using 3DDXA models help in order to better discriminate patients with raised fracture risk. Este estudio ha sido posible gracias al soporte a la investigación que ha supuesto la beca FEIOMM y ayuda financiera del MINECO (RYC-2015-18888).

Background Promonitor Quick IFX is a lateral flow test (LFT) for the quantification of infliximab (IFX) in human whole blood (finger prick or venous) or serum in 20 minutes. This LFT is based on a sandwich immunoassay to quantify either the reference IFX or biosimilars. This abstract describes the studies performed to establish the analytical specifications of the product. Methods Clinical and Laboratory Standards Institute (CLSI) guidelines were followed for the evaluation of the analytical specifications of the LFT in whole blood and serum matrices: Linearity (EP-06-A), Detection capability (EP17-A2), Interfering substances (EP07, 3rd Edition), Intermediate precision (EP05-A3) and Bias evaluation study for Biosimilars (EP10-A3). Results were obtained in combination with the automated portable reader PQreader. A Datamatrix provided with each Promonitor Quick IFX kit contains the calibration information required for the PQreader to measure the Control and Test lines and report the IFX concentration. Results The linear assay range was determined to be 1-58 µg/mL in whole-blood and 0.6-67 µg/mL in serum according to the processes indicated in the Package Insert. The Limit of Blank is 0.8 μg/mL, the Limit of Detection and Lower Limit of Quantification (LLoQ) are 1.1 μg/mL, and the Upper Limit of Quantification (ULoQ) is 15.4 μg/mL. There was no effect on assay performance when each of the following substances were added to samples with 0, 3, and 7 μg/mL of IFX: Haemoglobin (>1000 mg/dL), Bilirubin (>40 mg/dL), Triglycerides (>1500 mg/dL), HAMA (160 AU/mL), Rheumatoid factor (200 IU/mL), EDTA (5.4 mg/mL), Heparin (51 U/mL), Citrate (11.4%), Vedolizumab (60 μg/mL) and Adalimumab (20.25 μg/mL). Repeatability and within-device precision results obtained for the positive samples are shown in the table below. The negative samples showed a negative result in all the measurements. A bias study showed that Promonitor Quick IFX can quantify CT-P13, SB2 and GP1111 biosimilars throughout the measurement range with a maximum bias of 14%. Conclusion Promonitor Quick IFX is the first LFT available for true Point of Care testing of patients treated with IFX with just a finger prick sample. It provides quick turnaround time to facilitate therapeutic drug monitoring and aid immediate decision making in the doctor office or hospitals with an excellent analytical performance.

Background Hypertrophic cardiomyopathy (HCM) is a heritable cardiac disease characterized by hyper-contractility, hindered relaxation, and impaired exercise capacity. Conventional negative inotropes can alleviate enhanced inotropy in HCM, but do not improve ventricular filling and have the potential to further decrease exercise capacity due to their off/on-target systemic effects. Recently, a novel small molecule cardiac-myosin attenuator, Mavacamten, has been shown to normalize hyper-contractility in the setting of HCM. This study evaluated and compared the in vivo functional selectivity of MYK-581, a mavacamten analog, with those of disopyramide (DISO), a commonly-used negative inotrope. Methods In vivo, the acute cardiac (left ventricular pressures) and neuro-muscular (force of diaphragmatic and skeletal muscle contractions) responses to MYK-581 (up to 0.5 mg/kg IV) and DISO (up to 10 mg/kg IV) were simultaneously evaluated using anesthetized and mechanically-ventilated Sprague-Dawley rats; diaphragmatic (both intrinsic and phrenic nerve stimulated) and skeletal contractions (stimulated quadriceps) were measured via strain gauges. Results MYK-581 decreased indices of systolic function (dP/dtmax: −32±2% and vmax: −14±2%, P Conclusions Direct myosin modulation with MYK-581, a mavacamten analog, is characterized in vivo by reductions in systolic function with preserved filling pressures and improved LV compliance. Moreover, this cardiovascular profile was devoid in vivo of diaphragmatic/skeletal off-target effects that could further hinder exercise capacity in patients with HCM.

Background The goal of this study was to validate the use of capillary blood in a real point-of-care (POC) setting for patients under infliximab treatment by using Promonitor Quick lateral flow (LF) tests. Results were compared to the Promonitor ELISA reference technique in serum samples used by centralised laboratories. Methods A prospective, observational study was designed to evaluate the performance of a rapid LF test (Promonitor Quick IFX, Progenika, Spain). 160 infliximab treated rheumatology consecutive patients (400 samples) were recruited in two hospitals in Galicia, Spain. Prior to the infusion, a finger prick sample was obtained and analysed. Anti-infliximab antibodies were also determined with Promonitor Quick ANTI-IFX1-4. Results were read with the automated portable PQreader instrument. Additionally, a serum sample was collected for subsequent comparative analysis with either LF or ELISA tests. Qualitative (positive (PPA) and negative (NPA) agreements) and quantitative (Pearson correlation and bias) performance of the LF test was compared to ELISA, as well as between different specimens following CLSI EP09-A3. Results Overall agreement between Promonitor Quick IFX finger prick and ELISA test was 91% (88% PPA; 100% NPA). The quantitative comparison showed a good correlation (Pearson correlation coefficient: 0.85 and observed bias: 25%) (Table 1). Similar results were also observed when serum was used with either the LF or the ELISA tests (98% overall agreement, 0.91 correlation coefficient; 6% bias) (Table 1). Overall agreements for visual and automated (PQreader) interpretations with Promonitor Quick ANTI-IFX were 99% and 100% for finger prick and serum specimens, respectively (Table 2). Conclusion Promonitor Quick can be used to reliably quantify infliximab in capillary blood samples and results are comparable to those obtained with the reference ELISA technique. The use of the rapid POC test with finger prick will allow clinicians to monitor their patients in a fully decentralized mode to aid in the decision making process. PQreader is a sensitive portable equipment to report drug as well as antibody levels in the patient samples. References

Explanations for the industrial epoch warming are polarized around the hypotheses of anthropogenic warming (AW) and giant natural fluctuations (GNFs). While climate sceptics have systematically attacked AW, up until now they have only invoked GNFs. This has now changed with the publication by D. Keenan of a sample of 1000 series from stochastic processes purporting to emulate the global annual temperature since 1880. While Keenan's objective was to criticize the International Panel on Climate Change's trend uncertainty analysis (their assumption that residuals are only weakly correlated), for the first time it is possible to compare a stochastic GNF model with real data. Using Haar fluctuations, probability distributions, and other techniques of time series analysis, we show that his model has unrealistically strong low-frequency variability so that even mild extrapolations imply ice ages every ≈1000 years. Helped by statistics, the GNF model can easily be scientifically rejected.

Background. After decades of obscurity, Zika virus (ZIKV) has spread through the Americas since 2015 accompanied by congenital microcephaly and Guillain-Barre syndrome. Although these epidemics presumably involve transmission by Aedes aegypti, no direct evidence of vector involvement has been reported, prompting speculation that other mosquitoes such as Culex quinquefasciatus could be involved. Methods. We detected an outbreak of ZIKV infection in southern Mexico in late 2015. Sera from suspected ZIKV-infected patients were analyzed for viral RNA and antibodies. Mosquitoes were collected in and around patient homes and tested for ZIKV. Results. Of 119 suspected ZIKV-infected patients, 25 (21%) were confirmed by RT-PCR of serum collected 1–8 days after the onset of signs and symptoms including rash, arthralgia, headache, pruritus, myalgia, and fever. Of 796 mosquitoes collected, A. aegypti yielded ZIKV detection by RT-PCR in 15 of 55 pools (27.3%). No ZIKV was detected in C. quinquefasciatus. ZIKV sequences derived from sera and mosquitoes showed a monophyletic relationship suggestive of a point source introduction from Guatemala. Conclusions. These results demonstrate the continued, rapid northward progression of ZIKV into North America with typically mild disease manifestations, and implicate A. aegypti for the first time as a principal vector in North America.

Access-induced ischemia is an uncommon but devastating complication for patients maintained on hemodialysis. The construction of an arteriovenous access results in a predictable decrease in the perfusion pressure distal to the anastomosis, which can result in ischemia if the compensatory mechanisms are inadequate. Because many of the signs and symptoms are nonspecific, the diagnosis can be aided in equivocal cases with non-invasive vascular laboratory studies. A digital/brachial index < 0.45 is suggestive of severe ischemic syndrome, and is usually associated with pain at rest and/or trophic lesions on the fingers. The aims of the treatments are to reverse the hand ischemia and to preserve the access. There are a variety of treatments, including correction of the inflow lesion, access ligation, limiting the flow through the access (banding), distal revascularization with interval ligation (DRIL), revision using distal inflow (RUDI), or proximalization of arterial inflow (PAI). The optimal choice should be based on hemodynamic mechanisms and severity of symptoms, in conjunction with the access type and patient comorbidities. A review of the underlying pathophysiology and treatment options will be presented. To date, the DRIL procedure has been the most consistently successful strategy. However, the particular circumstances of each case demand an individualization of treatment.

We examined the susceptibility to temephos and spinosad (Natular EC) of eight Aedes aegypti (L.) populations from Puerto Rico, following WHO method (WHO 2005). Enzyme activity was measured for alpha- and beta-esterases, multiple function oxidases, glutathione-s-transferases, and insensitive acetylcholinesterase and was tested for correlation with the susceptibility level. The results showed that larval populations from Puerto Rico obtained during 2014 were found to be susceptible to both larvicides, with low (resistance factor) RRLC50 values (

Background:Androgen deprivation therapy (ADT), by inducing severe hypogonadism, leads to a loss of bone mineral density (BMD) and an increased risk of fragility fractures after 6 months of treatment in men with prostate cancer1. However, its effect on bone quality has not been described.Objectives:To evaluate the changes on bone microarchitecture (bone quality) assessed by TBS (trabecular Bone Score) in male patients with prostate cancer after one year of treatment with ADT.Methods:All patients diagnosed with prostate cancer candidates for long-term ADT admitted to Urology department of Hospital Universitari Parc Tauli (reference population of 450,000 inhabitants) between April 2017 and December 2019 were included. Patients who received chemotherapy, previous hormonal therapy or specific treatment for osteoporosis in the last year or those who had a very impaired functional capacity (Barthel index Demographic, clinical and analytical data (testosterone, calcium, phosphorous, alkaline phosphatase, 25-hidroxyvitamin D, PTH) were collected in all patients. A bone densitometry (GE-Lunar Prodigy) including the measurement of lumbar spine TBS (L1-L4) using Medimaps Software was performed at baseline and at 12 months of treatment with ADT.Results:78 patients were included. Mean age 77,9±8,3 years. The median Gleason score was 7,88±1,05. 3 patients had previous fragility fracture (one sacral fracture, one fibula and one multiple vertebral fracture). Baseline analytical values in patients were the following: testosterone11,6±74,9 nmol/L.; 25-hidroxyvitamin D 20,8±10,4 ng/ml; PTH 51,8±23,0 pg/ml; CTX 0,58±0,66. The daily calcium intake was 573±207 mg/day.According to BMD, 17 patients (21,8%) had osteoporosis before starting ADT, with the following average T-score values: lumbar spine +0,15±1,85, femoral neck -1,75±1,00, and total hip -1,19±1,16. Mean baseline TBS value of the entire cohort was 1,279±0,122. 30,5% of the patients showed very degraded microarchitecture (TBS1,310).After one year of ADT treatment, TBS mildly worsened in this cohort, with a median value of 1,256±0,131 (p = NS). However up to 43% of patients reached highly degraded microarchitecture, 27% partially degraded and only 29,5% had a normal TBS (p = NS).Conclusion:Most patients with prostate cancer have an altered bone quality before starting ADT. After 12 months of treatment, the percentage of patients with highly degraded bone microarchitecture increases, although not significantly. More studies are needed to confirm this trend and to evaluate if these patients present more long-term fractures.References:[1]Lee R, et al. Bone 2011; 48 (1): 88-95Disclosure of Interests:Silvia Garcia-Cirera: None declared, Enrique Casado Speakers bureau: UCB, Lilly, Amgen, Theramex, Gebro, Gedeon-Richter, Stada, Jesús Muñoz: None declared, Luis Del Río: None declared, Marta Arévalo: None declared, Menna Rusiñol: None declared, Noemí Navarro: None declared, Víctor Parejo: None declared, Jordi Gratacos-Masmitja Grant/research support from: a grant from Pfizzer to study implementation of multidisciplinary units to manage PSA in SPAIN, Consultant of: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly, Speakers bureau: Pfizzer, MSD, ABBVIE, Janssen, Amgen, BMS, Novartis, Lilly

Analysis of high-resolution multi-beam bathymetry, 2D multi-channel seismic, and high-resolution seismic sub-bottom profiles revealed the presence of widespread fluid escape features in the middle slope of the Patagonian Continental Margin. On the sea-bottom, these features correspond to pockmarks and mud volcanoes, whereas in the sub-surface they are represented in the seismic records by several acoustic anomalies such as chimneys, acoustic blanking, enhanced reflectors, and reverse-phase enhanced reflectors among others. Some of these acoustic signatures can be traced to syn-rift deposits that fill a deep re-activated and inverted graben. Analysis of pockmarks elongation and pockmarks alignments show a good correlation with inverted normal faults, suggesting that faults and fractures have influenced the pockmark's shape and might have acted as pathways for upward fluid migration. Some of the acoustic anomalies associated with pockmarks are interpreted as evidence of gas. The gas observed in the seismic data seems to be thermogenic, and the seismic data suggests a deep origin associated with over-pressured syn-rift deposits. Two morphometrically different sets of pockmarks were identified: an older set hosted by Miocene aged rocks, and a younger set hosted by Quaternary deposits. Different potential triggers are discussed for the genesis of the Miocene pockmarks in relation to the seismostratigraphy, structural geology and regional tectonics. It is concluded that, tectonic activity associated with the Neogene inversion of the graben faults, due to Andean compression, is the most likely cause for the formation these pockmarks. The presence of gas charged sediment and young pockmarks also suggest that after the Middle Miocene tectonic climax, a more recent pulse of release of fluids occurred., Sí

Chlamydia abortus produces ovine enzootic abortion (OEA). Symptoms are not observed until the organism colonises the placenta, eventually causing abortion. Infected animals become carriers and will shed the organism in the following oestruses. This process suggests that sex hormones might play an important role in the physiopathology of OEA, affecting the success of chlamydial clearance and also jeopardising the effectiveness of vaccination. However, the mechanisms through which sex hormones are involved in chlamydial pathogenicity remain unclear. The aim of this study, therefore, was to determine the effect of progesterone on the immune response against C. abortus and on the protection conferred by an experimental inactivated vaccine in sheep. Eighteen sheep were ovariectomised and divided into four groups: vaccinated and progesterone-treated (V-PG), vaccinated and non-treated (V-NT), non-vaccinated and non-treated (NV-NT) and non-vaccinated and progesterone-treated sheep (NV-PG). Animals from both PG groups were treated with commercial medroxyprogesterone acetate impregnated intravaginal sponges before and during the vaccination (V-PG) or just before challenge (NV-PG). The animals from both V groups were subcutaneously immunised with an experimental inactivated vaccine, which was seen to confer high protection in previous studies. All sheep were challenged intratracheally with C. abortus strain AB7 and were sacrificed on day 8 post-infection. Morbidity was measured as the variation in rectal temperature and samples of sera were collected for antibody and cytokine (IFN-γ and IL-10) analysis by commercial ELISA. In addition, lung and lymph node samples were collected for chlamydial detection by qPCR and for histopathological and immunohistochemical analyses. Sheep from the V-PG group showed less severe or no lesions and lower morbidity than the other groups. They also had the highest abundance of regulatory T-cells. The sheep from V-NT also manifested high antibody levels against C. abortus and less severe lesions than those observed in non-vaccinated sheep, which showed high morbidity, low antibody levels and severe lesions, especially in NV-NT. These results confirm the effectiveness of the experimental vaccine employed and suggest that progesterone could enhance the effect.

Background Osteoporotic fractures are a serious complication in patients with cirrhosis. In addition to the high morbidity and mortality of the patients who suffer them, fragility fractures represent a high cost for Healthcare systems. However, there are very few studies that evaluate the prevalence of osteoporosis and fractures in patients with liver cirrhosis different than primary biliary cirrhosis (non-PBC cirrhosis). There are also no clinical guidelines with recommendations for osteoporosis screening in these patients. Objectives To assess the prevalence of osteoporosis and fragility fractures in patients with non-PBC cirrhosis in our environment, and the associated risk factors. To analyse if the FRAX tool can be useful in the diagnostic screening of these patients. Methods From November 2015 to September 2017, outpatients older than 40 years diagnosed with non-PBC cirrhosis (any Child stage) were randomly included. Demographic, clinical and analytical data (calcium, phosphorus, 25-hydroxyvitamin D and PTH) were collected from all patients. A bone densitometry, GE, Lunar Prodigy (DXA) and vertebral fracture assessment (VFA) were also performed, for the diagnosis of osteoporosis (T-score ≤−2.5), and vertebral fracture. The 10 year absolute fracture risk was calculated using FRAX (https://www.sheffield.ac.uk/FRAX/tool.aspx?country=4). A descriptive statistic of the main variables was carried out, with univariate and multivariate analysis to assess which predictive factors could be related to the presence of osteoporosis and/or fragility fractures. Results Ninety-two patients were included (71% male and 29% female). Age 63±11 years. The etiology of cirrhosis was: alcohol (52%), hepatitis C virus (27%) and alcohol +hepatitis C virus (9%). Stage: Child A (80.4%), B (17.4%) and C (2.2%). Mean 25-hydroxyvitamin D was 18.5±9.8 ng/ml and PTH 51.8±23.0 pg/ml. 16 patients (17%) had osteoporosis by DXA, 54 patients (59%) osteopenia and 22 (24%) had a normal bone mineral density (BMD). 8 patients (9%) had suffered some fragility fracture (vertebral fracture in 6 cases). The 10 year absolute risk for major fracture (vertebra, humerus, femur or radius) by FRAX without BMD was 5.7±4.5; and with BMD 4.7±4.9. Age and female sex were associated with the presence of osteoporosis, and a BMI higher than 30 was found to be a protective factor. A BMD in the range of osteoporosis was the only factor associated with fracture. FRAX for major fracture without BMD higher than 6.6% in this population had a high sensitivity (69%) and specificity (85%) for the diagnosis of osteoporosis, which implies a negative predictive value of 93%. Using this FRAX cut-off for indicating DXA in cirrhotic patients could expect a saving of 76% of DXA scans. Conclusions The prevalence of osteoporosis and fractures in patients with non-PBC cirrhosis, even in mild stages, is higher than in the healthy population, being more frequent in women and older patients. The FRAX tool can be useful in the selection of patients with cirrhosis to be assessed by a bone densitometry. Disclosure of Interest None declared

Effects of osteoporosis drugs on proximal femur cortical and trabecular bone were studied using dual-energy x-ray absorptiometry (DXA)-based 3D modeling method. Changes observed in this head-to-head study were consistent with those obtained using computed tomography in the literature. The aim of the present study was to assess the effects of osteoporosis drugs on cortical and trabecular bone at the proximal femur using DXA-based 3D modeling. We retrospectively analyzed 155 patients stratified by treatments: naive of treatment (NAIVE), alendronate (AL), denosumab (DMAB), and teriparatide (TPTD). DXA scans were performed at baseline and after treatment, and areal bone mineral density at spine and femur were measured. A software algorithm (3D-SHAPER) was used to derive 3D models from hip DXA scans and compute: trabecular and cortical volumetric BMD (vBMD), cortical thickness (Cth), and cortical surface BMD (cortical sBMD). Changes from baseline were normalized at 24 months and evaluated in terms or percentage. After 24 months, a non-significant decrease was observed for trabecular vBMD, Cortical sBMD, Cth, and cortical vBMD (− 2.3, − 0.8, − 0.3, and − 0.5%) in the NAIVE group. Under AL and DMAB, significant increases were observed in trabecular vBMD (3.8 and 7.3%), cortical vBMD (1.4 and 2.0%), and cortical sBMD (1.5 and 3.6%). An increase in Cth was observed in patients under DMAB (1.8%). Under TPTD, a significant increase in Trabecular vBMD was observed (5.9%) associated with a non-significant increase of Cth (+ 1%) concomitant with a decrease in cortical vBMD (− 1.1%). Results obtained in this head-to-head study are consistent with those obtained using computed tomography in the literature. DXA-based modeling techniques could complement standard DXA examination to monitor treatment effects on trabecular and cortical compartments.

Fishing activity in waters beyond national jurisdiction generates multiple management issues, such as data poor fisheries, management of straddling fish stocks and lack of impact assessments on deep-sea Vulnerable Marine Ecosystems (VMEs). Fishing strategy is the key to understanding and managing high seas fisheries, targeting highly migratory resources that are widely distributed. An international fleet, including Spanish flag bottom trawlers, operates along the Patagonian shelf in Southwest Atlantic waters, which includes an unregulated strip of continental shelf beyond national jurisdiction. The Spanish fleet’s fishing strategy was analyzed, and based on on-board observer data collected from 1989 to 2015, three main fishing seasons were identified: a first season mainly targeting Argentinean squid (Illex argentinus) from January to March, a second season targeting hake (Merluccius hubbsi) from April to August, and a third season from September to December showing an opportunistic and heterogeneous behavior. Findings were framed within current knowledge on resource distribution. A preliminary observation of the inter-annual CPUE rates of target species during their respective fishing seasons highlights the possible existence of species linkages and bioclimatic cycles which may affect species distribution and abundance in the area and might require future research. Even if current fishing activity from the Spanish fleet does not overlap deep-water VMEs, any slight change in the fishing strategy to deeper waters (i.e. the fleet targeting high density I. argentinus areas below 300 m, or a change in the target species) would be critical for the conservation of VMEs in these waters., Sí

On scales of ≈ 10 days (the lifetime of planetary-scale structures), there is a drastic transition from high-frequency weather to low-frequency macroweather. This scale is close to the predictability limits of deterministic atmospheric models; thus, in GCM (general circulation model) macroweather forecasts, the weather is a high-frequency noise. However, neither the GCM noise nor the GCM climate is fully realistic. In this paper we show how simple stochastic models can be developed that use empirical data to force the statistics and climate to be realistic so that even a two-parameter model can perform as well as GCMs for annual global temperature forecasts. The key is to exploit the scaling of the dynamics and the large stochastic memories that we quantify. Since macroweather temporal (but not spatial) intermittency is low, we propose using the simplest model based on fractional Gaussian noise (fGn): the ScaLIng Macroweather Model (SLIMM). SLIMM is based on a stochastic ordinary differential equation, differing from usual linear stochastic models (such as the linear inverse modelling – LIM) in that it is of fractional rather than integer order. Whereas LIM implicitly assumes that there is no low-frequency memory, SLIMM has a huge memory that can be exploited. Although the basic mathematical forecast problem for fGn has been solved, we approach the problem in an original manner, notably using the method of innovations to obtain simpler results on forecast skill and on the size of the effective system memory. A key to successful stochastic forecasts of natural macroweather variability is to first remove the low-frequency anthropogenic component. A previous attempt to use fGn for forecasts had disappointing results because this was not done. We validate our theory using hindcasts of global and Northern Hemisphere temperatures at monthly and annual resolutions. Several nondimensional measures of forecast skill – with no adjustable parameters – show excellent agreement with hindcasts, and these show some skill even on decadal scales. We also compare our forecast errors with those of several GCM experiments (with and without initialization) and with other stochastic forecasts, showing that even this simplest two parameter SLIMM is somewhat superior. In future, using a space–time (regionalized) generalization of SLIMM, we expect to be able to exploit the system memory more extensively and obtain even more realistic forecasts.

Pregnant ewes have been widely used to test vaccines against Chlamydia abortus . However, this model entails many disadvantages such as high economic costs and long periods of pregnancy. The murine model is very useful for specific studies but cannot replace the natural host for the later stages of vaccine evaluation. Therefore, a non-pregnant model of the natural host might be useful for a vaccine trial to select the best vaccine candidates prior to use of the pregnant model. With this aim, two routes of infection were assessed in young non-pregnant sheep, namely, intranasal (IN) and intratracheal (IT). In addition, groups of non-vaccinated sheep and sheep immunised with an inactivated vaccine were established to investigate the suitability of the model for testing vaccines. After the experimental infection, isolation of the microorganism in several organs, with pathological and immunohistochemical analyses, antibody production assessment and investigation by PCR of the presence of chlamydia in the vagina or rectum were carried out. Experimental IT inoculation of C. abortus induced pneumonia in sheep during the first few days post-infection, confirming the suitability of the IT route for testing vaccines in the natural host. The course of infection and the resulting pathological signs were less severe in vaccinated sheep compared with non-vaccinated animals, demonstrating the success of vaccination. IN infection did not produce evident lesions or demonstrate the presence of chlamydial antigen in the lungs and cannot be considered an appropriate model for testing vaccines.

The objective of the study was to assess longitudinal effects of different osteoporosis treatments on TBS and aBMD at lumbar spine.We analyzed 390 patients (men: 72; women: 318; age40 years; mean follow-up of 20 months and BMI37 kg/m(2)). We stratified the cohort by treatments: Naive of treatment (Naive, n=67), Calcium and Vitamin D (CaVitD, n=87), Testosterone (Te, n=36), Alendronate (AL, n=88), Risedronate (Ri, n=39), Denosumab (Dmb, n=43) and Teriparatide (PTH, n=30). The follow-up changes from baseline were normalized at 24 months.After 24 months, Naive group TBS decreased by 3.1% (p0.05) whereas a non-significant increase was observed for spine aBMD (Δ=+0.5%). Compared to the Naive group, significant improvement (p0.05) was observed in both TBS and aBMD for Te, AL, Ri, Dmb and PTH groups and in the CaVitD group for TBS. At the end of the follow-up, significant improvement have been observed for aBMD in Te (+4.4%), AL (+4.1%), Ri (+4.8), D (+8.8%) and PTH (+8.8%) groups. Significant improvement was observed only in the AL (+1.4%), Dmb (+2.8%) and PTH (+3.6%) groups for TBS.As expected, TBS of Naive subjects decreased with age. As expected a TBS preservation has been observed under AL and Ri. Te and CaVitD effects on TBS were evaluated for the first time: a similar preservation effect has been observed. A significant TBS increase was observed under Denosumab and PTH. TBS could be a useful tool to monitor treatment effects.