Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy : a randomised, open-label, phase 3 trial

Background: Previous bisphosphonate treatment attenuates the bone-forming effect of teriparatide. We compared the effects of 12 months of romosozumab (AMG 785), a sclerostin monoclonal antibody, versus teriparatide on bone mineral density (BMD) in women with postmenopausal osteoporosis transitioning from bisphosphonate therapy. Methods: This randomised, phase 3, open-label, active-controlled study was done at 46 sites in North America, Latin America, and Europe. We enrolled women (aged >= 55 to <= 90 years) with postmenopausal osteoporosis who had taken an oral bisphosphonate for at least 3 years before screening and alendronate the year before screening; an areal BMD T score of -2.5 or lower at the total hip, femoral neck, or lumbar spine; and a history of fracture. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous romosozumab (210 mg once monthly) or subcutaneous teriparatide (20 mu g once daily). The primary endpoint was percentage change from baseline in areal BMD by dual-energy x-ray absorptiometry at the total hip through month 12 (mean of months 6 and 12), which used a linear mixed effects model for repeated measures and represented the mean treatment effect at months 6 and 12. All randomised patients with a baseline measurement and at least one post-baseline measurement were included in the efficacy analysis. This trial is registered with ClinicalTrials.gov, number NCT01796301. Findings: Between Jan 31, 2013, and April 29, 2014, 436 patients were randomly assigned to romosozumab (n=218) or teriparatide (n=218). 206 patients in the romosozumab group and 209 in the teriparatide group were included in the primary efficacy analysis. Through 12 months, the mean percentage change from baseline in total hip areal BMD was 2.6% (95% CI 2.2 to 3.0) in the romosozumab group and -0.6% (-1.0 to -0.2) in the teriparatide group; difference 3.2% (95% CI 2.7 to 3.8; p<0.0001). The frequency of adverse events was generally balanced between treatment groups. The most frequently reported adverse events were nasopharyngitis (28 [13%] of 218 in the romosozumab group vs 22 [10%] of 214 in the teriparatide group), hypercalcaemia (two [<1%] vs 22 [10%]), and arthralgia (22 [10%] vs 13 [6%]). Serious adverse events were reported in 17 (8%) patients on romosozumab and in 23 (11%) on teriparatide; none were judged treatment related. There were six (3%) patients in the romosozumab group compared with 12 (6%) in the teriparatide group with adverse events leading to investigational product withdrawal. Interpretation: Transition to a bone-forming agent is common practice in patients treated with bisphosphonates, such as those who fracture while on therapy. In such patients, romosozumab led to gains in hip BMD that were not observed with teriparatide. These data could inform clinical decisions for patients at high risk of fracture

Functional connectivity between prefrontal and parietal cortex drives visuospatial attention shifts

It is well established that the frontal eye-fields (FEF) in the dorsal attention network (DAN) guide top-down selective attention. In addition, converging evidence implies a causal role for the FEF in attention shifting, which is also known to recruit the ventral attention network (VAN) and fronto-striatal regions. To investigatethe causal influence of the FEF as (part of) a central hub between these networks, we applied thetaburst transcranial magnetic stimulation (TBS) off-line, combined with functional magnetic resonance (fMRI) during a cued visuo-spatial attention shifting paradigm. We found that TBS over the right FEF impaired performance on a visual discrimination task in both hemifields following attention shifts, while only left hemifield performance was affected when participants were cued to maintain the focus of attention. These effects recovered ca. 20 min post stimulation. Furthermore, particularly following attention shifts, TBS suppressed the neural signal in bilateral FEF, right inferior and superior parietal lobule (IPL/SPL) and bilateral supramarginal gyri (SMG). Immediately post stimulation, functional connectivity was impaired between right FEF and right SMG as well as right putamen. Importantly, the extent of decreased connectivity between right FEF and right SMG correlated with behavioural impairment following attention shifts. The main finding of this study demonstrates that influences from right FEF on SMG in the ventral attention network causally underly attention shifts, presumably by enabling disengagement from the current focus of attention

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation

Platelet indices and platelet-to-lymphocyte ratio predict coronary chronic total occlusion in patients with acute ST-elevation myocardial infarction

Coronary chronic total occlusion (CTO) is caused by organized thrombi or atherosclerotic plaque progression. The presence of a CTO is an independent predictor of mortality in patients presenting with ST-segment elevation myocardial infarction (STEMI). Platelets have a crucial role in the pathophysiology of atherosclerosis. The aim of this retrospective study was to investigate platelet indices as predictors of CTO in patients with STEMI treated with primary percutaneous coronary intervention (pPCI). A total number of 334 patients admitted for STEMI between January 2011 and December 2013 were included and divided in two groups based on the presence of CTO (48 patients in CTO+ group, 286 patients in CTO-group). Platelet count, mean platelet volume (MPV), platelet distribution width (PDW), platelet-large cell ratio (P-LCR), lymphocyte and neutrophil count determined on admission were analyzed. MPV was larger in patients with CTO compared with patients without CTO (p=0.02), as were PDW (p=0.03) and P-LCR (p=0.01). Platelet-to-lymphocyte ratio (PLT/LYM) was lower in patients with CTO: 105.2 (75.86-159.1) compared to 137 (97-188.1), p<0.01. Receiver-operator characteristic curve analysis identified an area under the curve of 0.61 (95%CI=0.57-0.67, p< 0.01) for PLT/LYM in predicting the presence of a CTO, with a cut-off value at 97.73. Lower values than this were independent predictors of a CTO in multivariate logistic regression analysis, with an Odds Ratio of 2.2 (95%CI=1.15-4.20, p=0.02). Our results support the use of platelet indices and PLT/LYM as predictors of CTO in patients presenting with STEMI

The CHA2DS2-VASc Score Predicts New-Onset Atrial Fibrillation and Hemodynamic Complications in Patients with ST-Segment Elevation Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention

Arrhythmic and hemodynamic complications related to ST-segment elevation myocardial infarction (STEMI) represent a major clinical challenge. Several scores have been developed to predict mortality in STEMI. However, those scores almost exclusively include factors related to the acute phase of STEMI, and no score has been evaluated to date for its ability to specifically predict arrhythmic and hemodynamic complications. We, thus, aimed to assess the ability of chronic risk factors burden, as expressed by the CHA2DS2-VASc score, to predict STEMI-related arrhythmic and hemodynamic complications. Data were collected from 839 consecutive STEMI patients treated by primary percutaneous coronary interventions (pPCI). CHA2DS2-VASc and GRACE scores were calculated for all patients, and their ability to predict STEMI-related arrhythmic (i.e., new-onset atrial fibrillation (AF), ventricular tachycardia/fibrillation) and hemodynamic (i.e., cardiogenic shock, asystole) complications was assessed in univariate and multiple regression analysis. Arrhythmic and hemodynamic complications occurred in 14.8% and 10.2% of patients, respectively. Although the GRACE score outweighed the CHA2DS2-VASc score in the ability to predict STEMI-related hemodynamic complications (p &lt; 0.0001), both scores had a similar predictive value for STEMI-related new-onset AF (p = 0.20), and both remained independent predictors of new-onset AF and of hemodynamic complications in the multiple regression analyses. A CHA2DS2-VASc score &gt; 2 points independently predicted new-onset AF (p &lt; 0.01) and hemodynamic complications (p = 0.04). Alongside the GRACE score, the CHA2DS2-VASc score independently predicted new-onset AF and hemodynamic complications in STEMI patients treated by pPCI. These data suggest that a combination of acute and chronic risk factors could provide additional benefit in identifying patients at risk of STEMI-related complications, who could benefit from closer follow-up and more intensive prophylactic and therapeutic strategies

Avaliação Institucional em Polos do Sistema Universidade Aberta do Brasil

The study wanted to know the institutional evaluation in poles of distance education, of the Open University of Brazil (UAB) system, analyzing the poles of the State of Ceará. The UAB system of the Brazilian Ministry of Education makes it possible to offer courses of higher level agreements with public universities. Ceará counts on UAB poles, since 2006, that form teachers and other professionals, even in regions lacking public higher education. The objective of this study was to discuss the importance of the institutional evaluation in the poles of the Open University of Brazil program through an exploratory and descriptive field research, showing that the institutional evaluation at the poles is minimal and out of line with the legislation in force. Suggestions on how to develop the evaluative practice.O estudo quis conhecer a avaliação institucional em polos de educação a distância, do sistema Universidade Aberta do Brasil (UAB), analisando os polos do estado do Ceará. O sistema UAB do Ministério da Educação do Brasil possibilita a oferta de cursos de nível superior conveniados com universidades públicas. O Ceará conta com polos UAB desde 2006, que formam professores e outros profissionais, inclusive em regiões desprovidas de ensino superior público. Objetivou-se discutir a importância da avaliação institucional nos polos do programa Universidade Aberta do Brasil por meio de uma pesquisa de campo de caráter exploratório e descritivo. Evidenciou-se que a avaliação institucional nos polos é ínfima e desalinhada com a legislação em vigor e, em razão disso, foram elencadas sugestões de como desenvolver a prática avaliativa