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Background Acromegaly is produced by excess growth hormone secreted by a pituitary adenoma of somatotroph cells (ACRO). First-line therapy, surgery and adjuvant therapy with somatostatin analogs, fails in 25% of patients. There is no predictive factor of resistance to therapy. New therapies are investigated using few dispersed tumor cells in acute primary cultures in standard conditions where the cells do not grow, or using rat pituitary cell lines that do not maintain the full somatotroph phenotype. The RET/PIT1/p14ARF/p53 pathway regulates apoptosis in normal pituitary somatotrophs whereas the RET/GDNF pathway regulates survival, controlling PIT1 levels and blocking p14ARF (ARF) and p53 expression. Methods We investigated these two RET pathways in a prospective series of 32 ACRO and 63 non-functioning pituitary adenomas (NFPA), studying quantitative RNA and protein gene expression for molecular-clinical correlations and how the RET pathway might be implicated in therapeutic success. Clinical data was collected during post-surgical follow-up. We also established new'humanized’ pituitary cultures, allowing 20 repeated passages and maintaining the pituitary secretory phenotype, and tested five multikinase inhibitors (TKI: Vandetanib, Lenvatinib, Sunitinib, Cabozantinib and Sorafenib) potentially able to act on the GDNF-induced RET dimerization/survival pathway. Antibody arrays investigated intracellular molecular pathways. Findings In ACRO, there was specific enrichment of all genes in both RET pathways, especially GDNF. ARF and GFRA4 gene expression were found to be opposing predictors of response to first-line therapy. ARF cut-off levels, calculated categorizing by GNAS mutation, were predictive of good response (above) or resistance (below) to therapy months later. Sorafenib, through AMPK, blocked the GDNF/AKT survival action without altering the RET apoptotic pathway. Interpretation Tumor ARF mRNA expression measured at the time of the surgery is a prognosis factor in acromegaly. The RET inhibitor, Sorafenib, is proposed as a potential treatment for resistant ACRO. Fund This project was supported by national grants from Agencia Estatal de Investigacion (AEI) and Instituto Investigacion Carlos III, with participation of European FEDER funds, to IB (PI150056) and CVA (BFU2016-76973-R). It was also supported initially by a grant from the Investigator Initiated Research (IIR) Program (WI177773) and by a non-restricted Research Grant from Pfizer Foundation to IB. Some of the pituitary acromegaly samples were collected in the framework of the Spanish National Registry of Acromegaly (REMAH), partially supported by an unrestricted grant from Novartis to the Spanish Endocrine Association (SEEN). CVA is also supported from a grant of Medical Research Council UK MR/M018539/1.

Objectives This study sought to compare the in-hospital prognostic values of the original and updated GRACE (Global Registry of Acute Coronary Events) risk score (RS) and the AR-G (ACTION [Acute Coronary Treatment and Intervention Outcomes Network] Registry and the GWTG [Get With the Guidelines] Database) RS in acute coronary syndromes (ACS). To evaluate the utility of recalculating risk after percutaneous coronary intervention (PCI) with newer RS models (NCDR [National Cardiovascular Data Registry] and EHS [EuroHeart Score] RS). Background Defined in 2003, GRACE is among the most popular systems of risk stratification in ACS. An updated version of GRACE has since appeared and new RS have been developed, aiming to improve risk prediction. Methods From 2004 to 2010, 4,497 consecutive patients admitted to a single center in Spain with an ACS were included (32.1% ST-segment elevation myocardial infarction, 19.2% unstable angina). Discrimination (C-statistic) and calibration (Hosmer-Lemeshow [HL]) indexes were used to assess performance of each RS. A comparative analysis of RS designed to predict post-PCI mortality NCDR and EHS RS versus the GRACE and AR-G RS was performed in a subgroup of 1,113 consecutive patients included in the study. Results There were 265 in-hospital deaths (5.9%). Original and updated GRACE RS and the AR-G RS all demonstrated good discrimination for in-hospital death (C-statistics: 0.91, 0.90 and 0.90, respectively) with optimal calibration (HL p: 0.42, 0.50, and 0.47, respectively) in all spectra of ACS, according to different managements (PCI vs. conservative) and without significant differences between the 3 different RS. In patients undergoing PCI, EHS and NCDR RS (C-statistic = 0.80 and 0.84, respectively) were not superior to GRACE RS (C-statistic = 0.91), albeit in the subgroup of patients undergoing PCI who were categorized as high risk using the GRACE RS, both EHS and NCDR have contributed to decrease the false positive rate generated by using the GRACE RS. Conclusions Despite having been developed over 8 years ago, the GRACE RS still maintains its excellent performance for predicting in-hospital risk of death among ACS patients.

Introduction The aim of the study is to describe the natural history of an unselected population of patients with atrial fibrillation (AF) currently attending primary care services in a single health-service area in Galicia, north-western Spain. Methods AFBAR is a transverse prospective study in which 35 general practitioners within one health-service area have enrolled patients diagnosed with AF who presented at their clinics during a three-month recruiting period. Primary endpoints are mortality or hospital admission. Here we report the results of the first 7-month follow-up period. Results 798 patients (421 male) were recruited; mean age of cohort was 75years old. Hypertension was the most prevalent risk factor (77%). 87% of the patients were both overweight and obese. Permanent AF was diagnosed in 549 patients (69%). In the follow-up period, 16.4% of the patients underwent a primary endpoint and the overall survival was 98%. The following independent determinants of primary endpoint were identified: change in AF status (Hazard Ratio (HR) 2.89 (95% confidence interval (CI) 1.28–6.55); p=0.011); ischemic heart disease (IHD) (HR 2.78 (95% CI 1.51–5.13); p=0.001); pre-recruitment hospital admission (HR 2.22 (95% CI 1.18–4.19); p=0.013); left ventricular systolic dysfunction (HR 2.19 (95% CI 1.11–4.32); p=0.023); or AF-related complications (HR 1.98 (95% CI 1.10–3.56); p=0.022). Conclusions In the first 7-month follow-up period of patients with AF in a primary care setting the study identified several independent risk factors for mortality or hospital admission, i.e. change in AF status, ischemic heart disease, left ventricular systolic dysfunction, previous AF-related complications and hospital admission.

Krüppel-like factor 4 (KLF4) is a zinc-finger-type transcription factor expressed in a range of tissues that plays multiple functions. We report that hypothalamic KLF4 represents a new transcription factor specifically modulating agouti-related protein (AgRP) expression in vivo. Hypothalamic KLF4 colocalizes with AgRP neurons and is modulated by nutritional status and leptin. Over-expression of KLF4 in the hypothalamic arcuate nucleus (ARC) induces food intake and increases body weight through the specific stimulation of AgRP, as well as blunting leptin sensitivity in lean rats independent of forkhead box protein 01 (FoxO1). Down-regulation of KLF4 in the ARC inhibits fasting-induced food intake in both lean and diet-induced obese (DIO) rats. Silencing KLF4, however, does not, on its own, enhance peripheral leptin sensitivity in DIO rats., Graphical abstract

Haemorrhagic complications are strongly linked with adverse outcomes in acute coronary syndrome (ACS) patients. Various risk scores (RS) are available to predict bleeding risk in these patients. We compared the performance of three contemporary bleeding RS in ACS.We studied 4500 consecutive patients with ACS. We calculated the ACTION, CRUSADE, and Mehran et al. (2010) bleeding RS, and evaluated their performance for predicting their own major bleeding events and TIMI serious (major or minor) bleeding episodes, in patients with either non-ST-elevation ACS (NSTEACS) or ST-elevation myocardial infarction (STEMI). Calibration (Hosmer-Lemeshow test, HL) and discrimination (c-statistic) for the three RS were computed and compared.For RS-specific major bleeding, ACTION and CRUSADE showed the best prognostic discrimination in STEMI (c=0.734 and 0.791, respectively; p=0.04), and in NSTEACS (c=0.791 and 0.810; p=0.4); being CRUSADE significantly superior to Mehran et al. in both ACS types (p0.05). All RS performed well in patients undergoing coronary arteriography using either a radial or femoral approach (all c≥0.718); however, their discriminative capacity was modest in patients not undergoing coronary arteriography and in those previously on oral anticoagulant (all c0.70). For TIMI serious bleeding, ACTION and CRUSADE displayed the highest c-index values in both STEMI (0.724 and 0.703, respectively; p=0.3) and NSTEACS (c=0.733 and 0.744, respectively; p=0.6); however, calibration of ACTION was poor in both ACS types (HL p0.05).Of contemporary bleeding RS, the CRUSADE score was found to be the most accurate quantitative tool for NSTEACS and STEMI patients undergoing coronary arteriography.

To determine the prognostic value of pro B-type natriuretic peptide (pro-BNP) to predict mortality after transcatheter aortic valve implantation (TAVI). Logistic EuroSCORE (LES) overestimates observed mortality after TAVI. A new risk score specific to TAVI is needed to accurately assess mortality and outcome.Eighty-five patients were included. Indications for TAVI were nonoperable or surgically high-risk patients (LES20%). Pro-BNP was measured 24h before the procedure. Cox proportional hazards model was used to evaluate clinical factors. The predictive accuracy of these Cox models was determined by using time-dependent receiver operating characteristic (ROC) curves.Pro-BNP levels (log-transformed) were significantly higher in non-survivors than in survivors at 30 days (3.36 ± 0.43 vs. 3.81 ± 0.43, p0.004) and at the end of follow-up (3.34 ± 0.42 vs. 3.63 ± 0.48, p0.011). Multivariate analysis revealed that only increased log pro-BNP levels were associated with higher mortality rate at short [hazard ratio (HR) (95% confidence intervals (CI)]=5.35 (1.74-16.5), p=0.003] and long-term follow-ups [HR=11 (CI: 1.51-81.3), p=0.018]. LES was not associated with increased mortality at either time point [HR=1.03 (CI: 0.95-1.10), p=0.483 and HR=1.03 (CI: 0.98-1.07), p=0.230, respectively]. At 30, 90, 180, and 365 days, the c-index was 0.72 for log pro-BNP and 0.63 for LES (p=0.044).Pre-procedure log transform of plasma pro-BNP levels are an independent and strong predictor of short- and long-term outcomes after TAVI and are more discriminatory than LES.