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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.

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

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

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.

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

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

Objectives Given the need for easily managed treatment of osteoporosis in HIV-infected patients, we evaluated the efficacy and tolerability of two doses of zoledronate, by comparing three groups of patients: those with annual administration, those with biennial administration (one dose in 2 years) and a control group with no administration of zoledronate. Methods We randomized (2:1) 31 patients on antiretroviral therapy with low bone mineral density (BMD) to zoledronate (5 mg administered intravenously; 21 patients) plus diet counselling and to a control group (diet counselling; 10 patients). At week 48, patients treated with zoledronate were randomized again to receive a second dose (two-dose group; n = 12) or to continue with diet counselling only (single-dose group; n = 9). Changes in lumbar spine and hip BMD and bone turnover markers were compared. Results The median percentage change from baseline to week 96 in L1−L4 BMD was −1.74% [interquartile range (IQR) −2.56, 3.60%], 7.90% (IQR 4.20, 16.57%) and 5.22% (IQR 2.02, 7.28%) in the control, two-dose and single-dose groups, respectively (P

Marked trabecular and cortical bone loss was observed at the proximal femur short-term after spinal cord injury (SCI). 3D-DXA provided measurement of vBMD evolution at both femoral compartments and cortical thinning, thereby suggesting that this technique could be useful for bone analysis in these patients. SCI is associated with a marked increase in bone loss and risk of osteoporosis development short-term after injury. 3D-DXA is a new imaging analysis technique providing 3D analysis of the cortical and trabecular bone from DXA scans. The aim of this study was to assess the evolution of trabecular macrostructure and cortical bone using 3D-DXA in patients with recent SCI followed over 12 months. Sixteen males with recent SCI (< 3 months since injury) and without antiosteoporotic treatment were included. Clinical assessment, bone mineral density (BMD) measurements by DXA, and 3D-DXA evaluation at proximal femur (analyzing the integral, trabecular and cortical volumetric BMD [vBMD] and cortical thickness) were performed at baseline and at 6 and 12 months of follow-up. vBMD significantly decreased at integral, trabecular, and cortical compartments at 6 months (- 8.8, - 11.6, and - 2.4%), with a further decrease at 12 months, resulting in an overall decrease of - 16.6, - 21.9, and - 5.0%, respectively. Cortical thickness also decreased at 6 and 12 months (- 8.0 and - 11.4%), with the maximal decrease being observed during the first 6 months. The mean BMD losses by DXA at femoral neck and total femur were - 17.7 and - 21.1%, at 12 months, respectively. Marked trabecular and cortical bone loss was observed at the proximal femur short-term after SCI. 3D-DXA measured vBMD evolution at both femoral compartments and cortical thinning, providing better knowledge of their differential contributory role to bone strength and probably of the effect of therapy in these patients.

Direct mechanical ventricular actuation (DMVA) exerts direct cardiac compression/decompression and does not require blood contact. The safety and effects of DMVA support in chronically dysfunctional beating hearts in vivo have not been established. This study evaluated hemodynamics and load-independent systolic/diastolic cardiac function before/after acute support (2 hours) using DMVA in small hearts with induced chronic failure. Chronic heart failure was created in seven small dogs (15 ± 2 kg) via either serial coronary microembolizations or right-ventricular overdrive pacing. Dogs were instrumented to measure cardiac output, hemodynamic pressures, left ventricular volumes for pressure-volume analysis via preload reduction. Temporary cardiac support using a DMVA device was instituted for 2 hours. Hemodynamic and mechanical assessments, including dobutamine dose-responses, were compared both before and after support. Hemodynamic indices were preserved with support. Both left-ventricular systolic and diastolic function were improved postsupport, as the slopes of the preload-recruitable stroke work (+29 ± 7%, p < 0.05) and the end-diastolic pressure-volume relationship (EDPVR: -28 ± 9%, p < 0.05) improved post-DMVA support. Diastolic/systolic myocardial reserve, as assessed by responsiveness to dobutamine challenges, was preserved after DMVA support. Short-term DMVA support can safely and effectively sustain hemodynamics, whereas triggering favorable effects on cardiac function in the setting of chronic heart failure. In particular, DMVA support preserved load-independent diastolic function and reserve.

The effect of ascites on bone densitometry has been assessed in 25 patients with advanced cirrhosis, and it was concluded that ascites over 4 l causes inaccuracy of BMD measurements, particularly at the lumbar spine. This fact must be considered when assessing bone mass in patients with decompensated cirrhosis. Bone mineral density (BMD) measured by dual-energy x-ray absorptiometry (DXA) is the best procedure for assessment of osteoporosis and fracture risk, but BMD values at the central skeleton may be influenced by changes in soft tissues. Therefore, we have studied the effect of ascites on BMD. BMD was measured by DXA at the lumbar spine, femoral neck and total hip, just before and shortly after therapeutic paracentesis in 25 patients with advanced liver cirrhosis. Changes in BMD, lean and fat mass, abdominal diameter and weight, as well as the amount of removed ascites were measured. The amount of drained ascites was 6.6 ± 0.5 l (range: 3.0 to 12.7 l). After paracentesis, BMD increased at the lumbar spine (from 0.944 ± 0.035 to 0.997 ± 0.038 g/cm2, p

Objective To assess whether changes in antiretroviral drugs other than thymidine nucleoside reverse transcriptase inhibitors (NRTI) may have a body fat impact in HIV-infected patients with lipoatrophy. Methods Ninety-six-week phase IV, open-label, multicentre, pilot randomized trial. HIV-infected patients with moderate/severe lipoatrophy at one or more body sites despite long-term thymidine NRTI-free therapy were randomized to continue their efavirenz (EFV)-based antiretroviral regimen or to switch from EFV to lopinavir/ritonavir (LPV/r). The primary endpoint was the absolute change in limb fat mass measured by dual X-ray absorptiometry from baseline to 96 weeks. Changes in other body fat measurements, subjective perception of lipoatrophy, subcutaneous fat gene expression and plasma lipids were also assessed. Results Thirty-three patients (73% men, median age 52 years) were recruited. At 96 weeks, absolute limb fat mass increased in the LPV/r arm vs. the EFV arm (estimated difference +1082.1 g; 95% CI +63.7 to +2103.5; P = 0.04); this difference remained significant after adjustment by gender, age, fat mass, body mass index and CD4 cell count at baseline. Subjective lipoatrophy perception scores also improved in the LPV/r arm relative to the EFV arm. Adipogenesis, glucose and lipid metabolism, and mitochondrial gene expression increased in the LPV/r arm compared with the EFV arm at 96 weeks. HDL cholesterol decreased in the LPV/r arm relative to the EFV arm. Conclusions Switching from EFV to LPV/r in HIV-infected patients with lipoatrophy may offer further limb fat gain beyond thymidine NRTI discontinuation, although this strategy decreased plasma HDL cholesterol and caused changes in subcutaneous fat gene expression that may be associated with increased insulin resistance.

Vasomera™ is a first-in-class stable long-acting vasoactive intestinal peptide (VIP) agonist, with preferential actions on the G-protein-coupled VPAC2-receptors; VIP mediates cardiopulmonary regulation and has been proposed as a therapeutic target for both hypertension and systolic dysfunction. Here, the acute effects of Vasomera in load-independent function and ventriculo-arterial coupling were in evaluated in a rats with chronic diastolic dysfunction, mimicking heart failure with preserved ejection fraction (HFpEF). Diastolic dysfunction, as demonstrated by altered E/A ratios via echocardiography, was induced by renoprival hypertension secondary to renal wrapping (RW). Conditioned rats (n = 5) were instrumented for the determination of left-ventricular (LV) hemodynamics as well as load-independent fnction and ventriculo-arterial coupling (via pressure-volume relationships); data were evaluated before/after a single-dose continuous IV infusion of Vasomera (7.5 μg/kg/min IV). Vasomera decreased the estimated arterial elastance (Ea: -20 ± 5%, P < 0.05) with negligible changes in heart rate (-4 ± 2%). Improved inotropy (Ees: +28 ± 8% and PRSW: +22 ± 3%, P < 0.05) was observed post-treatment, suggesting improved ventriculo-arterial coupling (Ea/Ees: -37 ± 5%, P < 0.05). Concomitantly, Vasomera reduced filling pressures (EDP: -30 ± 8%, P < 0.05), accelerated the time-constant of relaxation (tau: -24 ± 3%, P < 0.05) and improved compliance (EDPVR: -26 ± 5%, P < 0.05). Vasomera, a novel VPAC2 agonist, improved arterial elastance and ventriculo-arterial coupling, while improving indices of diastolic function (i.e., lusitropy) in animals with chronic renoprival hypertension mimicking HFpEF.

Available evidence suggests that fracture prediction with bone densitometry may improve when used on people at high risk of osteoporotic fractures. The objectives of this literature review were: (1) to identify risk factors for fracture that are associated with the development of a low bone mass for both men and women; (2) to describe and assess the relationship between these factors and the risk of fracture; and (3) to classify them according to the strength of their association with fracture incidence. Studies were identified from MEDLINE (1982-1997), HealthSTAR (1975-1997) and The Cochrane Library (1997) databases. Pre-stated inclusion criteria (original analytic studies assessing risk factors for osteoporotic fractures in men and women) and methodologic quality were assessed by two independent investigators. Information on the study design and analysis, characteristics of participants, exposure (risk factor) and outcome measures (relative risk and odds ratios for fracture incidence), control for potential confounding factors and risk estimates was extracted using a standardized protocol. Qualitative and meta-analytic techniques were used for data synthesis. As a result, risk factors were classified into three groups according to their strength of association with fracture: high risk (RRor = 2), moderate risk (1RR2) and no risk or protective (RRor = 1). Of approximately 80 risk factors identified from 94 cohort and 72 case-control studies, 15% were classified in the high-risk group, including low body weight, loss of weight, physical inactivity, the consumption of corticosteroids or anticonvulsants, primary hyperparathyroidism, diabetes mellitus type 1, anorexia nervosa, gastrectomy, pernicious anemia, and aging (70-80 years). Eighteen percent and 8% of risk factors were classified in the moderate and no risk group respectively, whereas 60% showed either a lack of scientific evidence confirming their association with fracture or contradictory results. An efficient strategy for bone densitometry provision may thus be its selective use in those individuals who present with several strong or moderate risk factors for fracture related to bone mass loss.

Recent studies suggest that inhaled corticosteroids can adversely affect bone metabolism. The objective of this study was to evaluate the importance of these adverse effects in a case-control study. Bone mineral density (BMD) was measured in 48 asthmatic adults (15 males and 33 females) treated with inhaled steroids (beclomethasone or budesonide) and in 48 gender and age-matched healthy subjects at baseline and at 2 yrs. Vertebral BMD was measured by dual energy X-ray densitometry. Patients had been treated with a dose of 662 +/- 278 micrograms (range 300-1,000 micrograms) of beclomethasone dipropionate or budesonide for more than 1 yr (mean duration of treatment 10.6 yrs, range 1-16 yrs). Twenty four patients had needed 1-6 short courses of oral steroids and seven had received oral corticosteroids (mean daily dose 6.2 mg prednisone) for 2-15 yrs more than 4 yrs prior to the BMD measurements. During the follow-up, 14 patients required 1-3 short courses of oral steroids. There was no correlation either between inhaled corticosteroid doses or duration of treatment and BMD values. There were no significant differences in BMD baseline values between patients and healthy controls. BMD significantly decreased in both groups at 2 yrs, from 1.08 +/- 0.19 to 1.05 +/- 0.19 g.cm-2 (p = 0.002) in asthmatics versus 1.12 +/- 0.17 to 1.09 +/- 0.18 g.cm-2 (p = 0.008) in controls. There were no significant differences in BMD loss between patients and healthy controls. Furthermore, no differences were found in bone loss when pre- and postmenopausal women were compared with their healthy control counterparts. No differences in baseline BMD were found between patients who had received regular oral corticosteroid therapy or booster courses of oral corticosteroids and those who had not. Inhaled corticosteroid treatment at a mean dose of 662 micrograms.day-1 and sporadic booster courses of oral corticosteroids do not further increase bone mass loss with respect to that expected from natural bone mass loss.

Background Patients with chronic obstructive pulmonary disease (COPD) have a high risk of osteoporosis and fractures. We reported 27% of vertebral fractures in COPD male patients with normal bone mineral density (BMD) 1 . TBS has been described as an index of bone microarquitecture, and could be a new assessment tool to detect bone quality impairment. Objectives Analysis of TBS in a sub-cohort of male patients with COPD and its possible association with BMD,corticoid use, COPD severity or vertebral fractures. Methods Male patients, older than 50 years, with COPD were included.Exclusion criteria: Other concomitant pulmonary disease, rheumatologic and/or vertebral disease that may lead to missinterpretation of BMD by DXA. Exclusion criteria: Other concomitant pulmonary disease,rheumatologic and/or vertebral disease that may lead to missinterpretation of BMD by DXA. BMD wasdetermined by dual-energy X-ray absorptiometry (DXA) at lumbar spine and proximal femur. Vertebralfractures were assessed by thoracic and lumbar X-ray. Corticosteroid use in the previous five years andnumber of hospitalizations were recorded in all patients. Results We included 98 patients. Mean age 67.8±7.5 years. 38% patients had a mild pulmonar disease, 39% moderate and 23% had a severe disease ((FEV1/FVC 98 patients were included. Mean age 67.8±7.5 years. 41% of patients had mild lung disease and 22% had severe disease (FEV1/FVC Conclusions TBS is severely impaired in male patients with chronic obstructive pulmonary disease, especially in patients with moderate and severe pulmonary disease and those who have received corticosteroids. Although patients with vertebral fractures have a lower value of TBS, this technique does not detect many cases with fracture. References Casado E, et al. JBMR 2007; 22 (S1): S202 Disclosure of Interest None declared

The aim of this study was to identify and describe possible alterations of bone histomorphometry in patients with human immunodeficiency virus (HIV-1) infection and to assess the relation between these alterations and disease severity. Forty-four HIV-1-infected patients seen successively at our hospital were evaluated for the study. In an attempt to avoid confounding factors as far as possible, we excluded patients who fulfilled any of the following criteria: age less than 18 or greater than 40 years; recent history of extended bed rest; previous diagnosis of metabolic bone disease, renal insufficiency, or hepatic failure; clinical or echographic signs of liver cirrhosis; diabetes mellitus or previous diagnosis of other endocrine diseases; drug therapy that could act on bone metabolism; and/or moderate to severe nutritional alteration. Twenty-two patients (13 men, 9 women; age: 27.9 ± 4.1 years, mean ± standard deviation) were included in the study. Plasma and urine biochemistry and calcium-regulating hormones were determined. Bone mineral content was measured on vertebrae L2 to L4 and on the neck and intertrochanteric areas of the femur by dual-photon absorptiometry. A transiliac bone biopsy was performed after double-tetracycline labelling, with histomorphometric study of undecalcified bone. Serum osteocalcin was found to be lower in patients who, according to the Centers for Disease Control (CDC) classification, had greater disease severity, and showed a positive correlation with the number of CD4 + T lymphocytes. No alterations in bone densitometry were observed. Several histomorphometric parameters of bone formation and turnover and the number of osteoclasts were significantly lower in the patients than in the healthy controls (surface-based bone formation rate: 0.01 ± 0.01 μm 3 /μm 2 / day versus 0.04 ± 0.02 μm 3 /μm 2 /day, p = 0.05; activation frequency: 0.02 ± 0.03 year −1 versus 0.25 ± 0.13 year −1 , p = 0.004; osteoclast index: 0.02 ± 0.08 mm −2 versus 0.03 ± 0.04 mm −2 , p = 0.005). Several parameters of formation, such as surface-based bone formation rate, or of turnover, such as activation frequency, were lower in patients with greater disease severity according to the CDC classification and presented a positive correlation with the number of CD4 + T lymphocytes. No biochemical parameter of mineral metabolism or hormones, except osteocalcin, showed a correlation with disease severity. We conclude that HIV-1-infected patients in our series presented a notable decrease in bone formation and turnover. These changes appeared to be more marked in patients with more severe disease.

The natural vasoactive intestinal peptide (VIP) triggers potent pulmonary vasodilatation by activating the G-protein-coupled VAPC receptors, and has been suggested as a therapeutic target in pulmonary artery hypertension (PAH); however, VIP’s clinical utility is limited due to its short half-life. A novel ELP fusion technology (PhaseBio’s) permits the creation of long-acting protein-fusion biopolymer-based VPAC-receptor agonists. Here, the pulmonary/systemic hemodynamic effects of two novel ELP-enhanced VIP analogues (ELP-VIP) were evaluated in anesthetized rats with hypoxia-induced PAH. Sprague-Dawley rats (259 ± 5 g, n = 25) were anesthetized (propofol), intubated, mechanically-ventilated (95% FiO2), and instrumented for systemic (arterial) and mean pulmonary-artery pressure monitoring. Following instrumentation PAH was induced by acutely decreasing the inspired FiO2 (to ∼10-11%). Subsequently, the animals were assigned to receive either a novel VPAC agonist (VIP-ELP, n = 18: 3-6 mg/kg) or placebo (VEH, n = 11: 0.9% NaCl). Treatments were delivered as acute single-dose boluses given either intravenously (IV) or intratracheally (IT) at a fixed volume. Reductions in the inspired FiO2 resulted in sustained pulmonary artery pressure increases (+45 ± 3%, 28 ± 1 to 41 ± 1 mmHg; P < 0.05), consistent with hypoxic PAH. Induced-PAH was preserved in the absence of active treatment, as pulmonary pressures remained elevated following placebo administration (VEH: -1 ± 2%, from 40 ± 2 to 40 ± 2 mmHg; n = 11, N.S.). Acute administration of the VIP-ELP analogues resulted in rapid pulmonary artery pressure reductions (-24 ± 3%, from 41 ± 1 to 31 ± 1 mmHg, P < 0.05) with moderate/negligible changes in systemic pressures (MAP: -12 ± 6%) and heart rate (-4 ± 3%). Notably, the pulmonary vaso-relaxation triggered by VIP-ELP agonists was sustained and independent of the route of administration (IV: -17 ± 4%, n = 8; IT: -28 ± 4%, n = 10). The novel ELP-enhanced VIP analogues triggered rapid and sustained reductions in pulmonary-artery pressures in the setting of induced (hypoxic) pulmonary hypertension (PAH). These effects were independent of the route of administration, as both intravenous/intra-tracheal administrations were efficacious.

Introduction Several methods are used to measure infliximab (IFX), adalimumab (ADL), antibodies to IFX (ATI) and antibodies to ADL (ATA). These agents elicit an unwanted immune response leading to loss of response. Measurement of drug levels (DL) and anti-drug antibodies (ADA) are often required for routine patient monitoring. The aim of this study was to compare different commercially available ELISA tests for the measurement of DL and ADA for IFX and ADL. Method A total of 109 samples (69 IFX and 40 ADL) from 71 patients with IBD were included in the study. DL and ADA trough levels were measured with Promonitor kits (Progenika, Spain) and LISA-TRACKER (LT) Duo IFX and ADL kits (Theradiag, France). In addition, drug-spiked samples were analysed to ascertain trueness. Pearson and Bland-Altman analysis was used to study the association and agreement between DL methods. Cohen´s kappa was used to study agreement of ADA assays. Results Correlation coefficients between each Promonitor test and the corresponding LT assay were 0.99 and 0.83 (p Conclusion Performances of both assays were comparable for all measurements. However, the systematic differences in the magnitude of DL and limited measurement ranges observed for LT tests should be taken with caution since this could impact patient management. Disclosure of interest D. Nagore Employee of: Progenika, A. Ruiz del Agua Employee of: Progenika, J. Pascual Employee of: Progenika, F. Llinares-Tello: None Declared, B. Herreros: None Declared, A. Martinez Employee of: Progenika, S. Martin Grant/ Research Support from: Progenika, R. Navarro: None Declared, L. del Rio Employee of: Progenika.

Colles’ fracture (CF) in postmenopausal women has been linked to low bone mass at the lumbar spine and hip. However, the diverse methodological approaches of previous studies make the results difficult to compare and thus the implications of CF in osteoporosis daily clinical practice are not clear. We explored the association between CF and low bone mineral density (BMD) in an incident case-control study in 58 postmenopausal Spanish women aged 45–80 years with recent CF and in 83 population-based controls of the same age range. The BMD of ultradistal distal forearm, lumbar spine and hip was measured by dual-energy X-ray absorptiometry (DXA) and WHO criteria were used to define osteoporosis and osteopenia. BMD was significantly lower in cases for all three areas (p

Bone mineral content was measured by dual-energy x-ray absorptiometry in the lumbar spine at the L2-L4 level with a Lunar DPX densitometer model in 471 healthy white Mediterranean Spanish children and adolescents (256 boys and 215 girls) randomly selected from the urban area of Barcelona. Ages ranged from 3 mo to 21 y. Weight, height, and pubertal development were in the normal age distribution. Bone mineral content values were corrected by the vertebral surface area scanned and expressed as bone mineral density (BMD) values. BMD increased progressively from infancy to adulthood, and values were similar in both sexes, with the only differences related to the earlier onset of puberty in girls. A statistically significant correlation (p < 0.001) was found between BMD values and age, height, and weight. BMD values increased annually, but the periods of higher increase were observed during the first 3 y of life and late puberty. A significant (p < 0.001) increase in BMD was observed between Tanner pubertal stages III and IV and between Tanner stage IV and adult values. Lumbar BMD values peaked in a similar way to growth height velocity during pubertal development. However, the BMD peak seemed to occur somewhat later than height velocity peak, particularly in girls. In conclusion, we report normative data for BMD values at the lumbar level in our normally growing pediatric population and show that the first 3 y of life and adolescence are critical periods for bone mineralization. These data provide a tool for the investigation and follow-up of pediatric populations at risk for low bone mineralization.

e18144 Background: Patients (Pts) with SCLC progressing after first-line chemotherapy (FL) have a poor prognosis and evidence of a benefit of SL is still limited. This retrospective analysis evalua...

Low-bone-turnover osteoporosis is a common complication of primary biliary cirrhosis (PBC). Since sodium fluoride stimulates bone formation we assessed the effect of this drug on bone mass in a 2-year, prospective, double-blind trial including 22 women with PBC who were randomly assigned to receive sodium fluoride (50 mg/day) or placebo. All received calcium supplements and low doses of vitamin D. Bone mineral density of the lumbar spine was measured by dual-photon absorptiometry initially and every 6 months. Vertebral fractures were evaluated in thoracic and lumbar spine initially, and after 1 and 2 years. Seven patients in the fluoride group and eight in the placebo group completed the trial. In the fluoride group, bone mineral density did not change after 2 years (initial 1.05 +/- 0.07, final 1.07 +/- 0.06 g/cm2; p = n.s.). In the placebo group, however, bone mineral density decreased significantly (initial 1.00 +/- 0.07, final 0.93 +/- 0.06 g/cm2; p = 0.03). Moreover, in the fluoride group bone mineral density increased by 2.9 +/- 3.6%, and in the placebo group decreased by 6.6 +/- 2.6% (p = 0.04). None of the patients developed new vertebral or non-vertebral fractures. Treatment with sodium fluoride did not impair liver function or cholestasis in PBC. These results indicate that sodium fluoride prevents bone loss in PBC and therefore might be considered as a possible therapeutic agent for osteoporosis associated with this liver disease. Since a small number of patients completed the trial, further studies are required.

6068 Background: Standard treatment for advanced HNSCC is concurrent chemoradiation. Erlotinib (e) is an oral tyrosine-kinase inhibitor of EGFR, which has activity in HNSCC. The Spanish Group of Cl...

16544 Background: Concurrent chemoradiation is considered the optimal treatment for advanced HNSCC, including post-resected status. Erlotinib is an oral EGFR TKI, with activity in recurrent and metastatic HNSCC.The Spanish Group of Clinical Research in Radiation Oncology (GICOR) leads a phase I/II study to determine the maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of adding erlotinib (e) to chemoradiation to patients (p) with surgically resected locally advanced HNSCC Methods: p had surgically resected advanced HNSCC, with a least one of the following criteria: T3 or T4 primary lesion (except T3N0 with negative resection margins), pathologic N2-N3 disease, and poor prognostic findings (i.e. extranodal spread, positive resection margins, perineural or perivascular involvement). Additional eligibility criteria included: age 18–70 y; life expectancy = 12 w; PS 0–1; no evidence of metastasis; adequate organic function; and written informed consent. Dose-escalating phase I study consisted on 3 cohorts of 3–6 p each, with increasing doses of erlotinib (100–150 mg po qd) and cisplatin (30–40 mg/m2, iv, d 1) for 7 w. Radiotherapy was delivered as a fixed standard regimen of daily 1.8 Gy (5 fractions/w) to a total dose of 63 Gy in high risk areas along 7 w. Results: By the time of this analysis, 7 p have entered the phase I component of the study. Median age: 52 y; male 100%. Complete data for 4 pats included in cohort 1 (e 100 mg/d, c 30 mg/m2) are available. One p withdrew prematurely the study due to a grade 2 toxicity (not considered DLT) and was considered unevaluable by the Scientific Committee. Among evaluable p, 2 developed mucositis (1g.3), vomiting (g.1) and nausea (g.1). All p developed skin rash (mild in all the cases). Haematological toxicities were single cases of anaemia, leukopenia and thrombocytopenia (g.1). All 3 p completed 7 weeks of treatment and no dose reduction was required. No DLT as per protocol has been described and study went subsequently further to cohort 2. Conclusions: This study demonstrates the safe addition of erlotinib to chemoradiotherapy in the treatment of this p population. Full data from the phase I study will be presented. No significant financial relationships to disclose.

7334 Purpose: To evaluate the efficacy and safety of biweekly docetaxel and vinorelbine in previously treated patients with advanced NSCLC. Patients and Methods: Patients with stage IIIB and IV NSC...

Bone mineral density, gr/cm2, (BMD) of the lumbar spine, L2-L4, was measured by dual energy X-ray absorptiometry (Lunar DPX) in 10 prepubertal GH-deficient children (8 boys and 2 girls, chronological age 7 to 12 years) and compared with that of 471 normal controls (256 boys, 215 girls, age range: 1-20 years). GH deficiency was established on the basis of: height < 3rd percentile, growth velocity < 5 cm/y, GH response < 10 ng/ml in two provocative tests, and bone age delayed of two or more years.

Infection with human immunodeficiency virus (HIV) causes a progressive immunodeficiency, often manifested in adults by the development of infections with relatively rare, opportunistic organisms. However, in HIV-infected children, recurrent serious infections with common encapsulated bacteria, as well as recurrent minor bacterial and viral infections, may be early and frequent manifestations of HIV disease. The use of i.v. immune globulin (IVIG) has been shown to prevent infections in patients with primary immunodeficiency and in uncontrolled studies of HIV-infected children. This article reviews the problem of and immunologic predisposition for recurrent infections in pediatric HIV infection and reports on the use of IVIG for prophylaxis. Updated analysis from the National Institute of Child Health and Human Development IVIG Clinical Trial, a multicenter, double-blind, placebo-controlled trial of the safety and efficacy of IVIG for the prevention of infections in children with symptomatic HIV infection, is presented. Between March 1988 and January 1991, 376 children with clinical or immunologic evidence of HIV disease who were randomized to receive IVIG or albumin placebo were enrolled in this trial. In children with an entry CD4+ count of 200/mm3 or higher, IVIG significantly increased the time free from serious bacterial infections and significantly decreased the rates of minor bacterial infections and viral infections. (Pediatr Res 33 (Suppl): S80-S89, 1993)

Sixty-two steroid-dependent asthmatics who had not received any form of treatment to prevent bone loss were studied during a 12-month period. Patients were randomly divided into two groups. Thirty-one patients were treated with 1 g of elemental calcium taken daily plus 100 IU of salmon calcitonin every other day, administered subcutaneously; the remaining 31 patients received only calcium supplementation. In the calcitonin group, 11 patients dropped out of the study because of severe side effects (seven patients), lack of compliance (three patients), and exacerbation of asthma (one patient). The 20 patients who completed the 12-month follow-up period were analyzed and compared with 20 sex-matched patients from the control group. At one year, bone mineral density (BMD) had increased in the calcitonin group by a mean of 4% (p less than or equal to 0.001), whereas in the control group BMD had decreased by 2.5% (p less than or equal to 0.05). Parameters of bone remodeling (alkaline phosphatase and osteocalcin) decreased significantly in the calcitonin-treated group but not in the control group. Our findings show that calcitonin 100 IU, given three times/wk, is an effective drug in the treatment of steroid-induced osteopenia. Side effects, however, are frequent and cause a high degree of dropout from therapy. These findings suggest that further studies should be carried out with lower doses of calcitonin or by other better tolerated forms of delivery such as in a nasal spray.