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Aim: Acyl ghrelin increases cardiac output (CO) in heart failure with reduced ejection fraction (HFrEF). This could impair the right ventricular‐pulmonary arterial coupling (RVPAC), both through an increased venous return and right ventricular afterload. We aim to investigate if acyl ghrelin increases CO with or without worsening the right‐sided haemodynamics in HFrEF assessed by RVPAC. Methods and results: The Karolinska Acyl ghrelin Trial was a randomized double‐blind placebo‐controlled trial of acyl ghrelin versus placebo (120‐min intravenous infusion) in HFrEF. RVPAC was assessed echocardiographically at baseline and 120 min. ANOVA was used for difference in change between acyl ghrelin versus placebo, adjusted for baseline values. Of the 30 randomized patients, 22 had available RVPAC (acyl ghrelin n = 12, placebo n = 10). Despite a 15% increase in CO in the acyl ghrelin group (from 4.0 (3.5–4.6) to 4.6 (3.9–6.1) L/min, P = 0.003), RVPAC remained unchanged; 5.9 (5.3–7.6) to 6.3 (4.8–7.5) mm·(m/s)−1, P = 0.372, while RVPAC was reduced in the placebo group, 5.2 (4.3–6.4) to 4.8 (4.2–5.8) mm·(m/s)−1, P = 0.035. Comparing change between groups, CO increased in the acyl ghrelin group versus placebo (P = 0.036) while RVPAC and the right ventricular pressure gradient remained unchanged. Conclusion: Treatment with acyl ghrelin increases CO while preserving or even improving RVPAC in HFrEF, possibly due to increased contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF with right ventricular failure. [ABSTRACT FROM AUTHOR]

A recent study published in the European Journal of Heart Failure investigated the effects of acyl ghrelin infusion on growth hormone (GH) release in patients with heart failure and reduced ejection fraction (HFrEF). The study found that acyl ghrelin significantly increased circulating GH levels in these patients. The researchers also observed a correlation between acyl ghrelin and GH concentrations. These findings suggest that treatment with acyl ghrelin may lead to an appropriate rapid GH response and increased cardiac output in patients with HFrEF. However, the study had a modest sample size, and further research is needed to confirm these results. [Extracted from the article]

Aims: Cardiac contractile dysfunction is prevalent in rheumatoid arthritis (RA), with an increased risk for heart failure. A hallmark of RA has increased levels of peptidyl arginine deaminases (PAD) that convert arginine to citrulline leading to ubiquitous citrullination, including in the heart. We aimed to investigate whether PAD‐dependent citrullination in the heart was linked to contractile function in a mouse model of RA during the acute inflammatory phase. Methods: We used hearts from the collagen‐induced arthritis (CIA) mice, with overt arthritis, and control mice to analyze cardiomyocyte Ca2+ handling and fractional shortening, the force‐Ca2+ relationship in isolated myofibrils, the levels of PAD, protein post‐translational modifications, and Ca2+ handling protein. Then, we used an in vitro model to investigate the role of TNF‐α in the PAD‐mediated citrullination of proteins in cardiomyocytes. Results: Cardiomyocytes from CIA mice displayed larger Ca2+ transients than controls, whereas cell shortening was similar in the two groups. Myofibrils from CIA hearts required higher [Ca2+] to reach 50% of maximum shortening, ie Ca2+ sensitivity was lower. This was associated with increased PAD2 expression and α‐actin citrullination. TNF‐α increased PAD‐mediated citrullination which was blocked by pre‐treatment with the PAD inhibitor 2‐chloroacetamide. Conclusion: Using a mouse RA model we found evidence of impaired cardiac contractile function linked to reduced Ca2+ sensitivity, increased expression of PAD2, and citrullination of α‐actin, which was triggered by TNF‐α. This provides molecular and physiological evidence for acquired cardiomyopathy and a potential mechanism for RA‐associated heart failure. [ABSTRACT FROM AUTHOR]

The interest in global multi‐tier sustainable supply chains is growing proportionally to its increase in developing countries. Developing countries are considered the new fertile territory for developing global chains for multinational enterprises (MNEs). Despite the positive outcomes derived from this global development, it also induces negative impacts in the domain of domestic firms' competition, education, welfare and infrastructure system. A way to overcome this pessimistic view has been found in corporate social responsibility (CSR) best practices. MNEs seek to involve local stakeholders in their social activities to show their commitment and generate innovations. It calls for a multi‐tier domestic involvement integrated into a global supply chain to create value. This study builds its empirical analysis exploring a range of 1547 Chinese manufacturing multinational enterprises listed in the Shanghai and Shenzhen stock exchanges between 2010 and 2018. The findings revealed that multi‐tier supply chain integration (SCI) practices positively moderate the relationship between CSR and MNE performance. In turn, it implies benefits for developing sustainable development goals, generating new job opportunities mostly in the developing countries guaranteeing wealth employment conditions. The sense of involvement and engagement towards their employees requires more development of CSR practices, which can be moderated by multi‐tier SCI, as shown in the present study. [ABSTRACT FROM AUTHOR]

B Discussion: b MRD analysis and PET scan are independent and complementary prognostic tools in FL: a MRD positivity in the two years after immuno-chemotherapy is predictive of POD24 and dismal PFS independently from the EoI PET result. This means that patients scoring PET- at EoI but showing a persistent or reappearing MRD+ signal during the following 24 months had a dismal PFS, superimposable to that of PET+ patients (Figure 1C). B Introduction: b In follicular lymphoma (FL), FDG-PET is routinely employed to evaluate response at the end of induction (EoI), while minimal residual disease (MRD) analysis is highly reliable in predicting relapse over the entire disease history. [Extracted from the article]

In this paper we deal with the mixed [ABSTRACT FROM AUTHOR]

In recent years, a number of papers have treated the problem of the finite-time stability and stabilization of impulsive (or, more in general, switching) dynamical linear systems. Generally, these works assume that the sequence of switching (in the following resetting) times is a priori known. In this paper, we remove such (strong) assumption, so making the technique more appealing from the practical control engineering point of view. A first result provided in this work is a sufficient condition for finite-time stability when the resetting times are known with a certain degree of uncertainty. Such condition requires the solution of a suitable feasibility problem based on coupled difference/differential LMIs. We show that as the uncertainty intervals reduce in size, our condition becomes less conservative, becoming necessary and sufficient in the certain case (i.e., the resetting instants are perfectly known). Eventually, we consider the conceptually different situation in which the resetting times are totally unknown, namely, the arbitrary switching case. The analysis results are then used to derive sufficient conditions for the existence of state-feedback controllers that finite time stabilizes the closed-loop system in the three cases mentioned earlier. A nontrivial example, considering the finite-time control of the liquid levels into three interconnected reservoirs, shows the effectiveness of the proposed approach. Copyright © 2014 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this study, the problem of input-output finite-time stabilisation of linear time-varying systems is dealt with. The classical definition of input-output finite-time stability (IO-FTS) is extended to that one of structured IO-FTS, which allows to incorporate, in the definition of the stabilisation problem, some amplitude constraints on the control input variables. A sufficient condition and a necessary and sufficient condition for structured IO finite-time stabilisation are provided in the case of L∞ and L2 inputs, respectively. Such conditions require the existence of a solution to a certain differential linear matrix inequality. The theory is applied to design the active suspension control system for a two-degree-of-freedom quarter-car model. [ABSTRACT FROM AUTHOR]

Background: Midday and evening twice-a-day quadruple therapy appears to be the most effective therapy for Helicobacter pylori infection in Northern Sardinia, a site where antibiotics resistance is common. Aim: The objective of our study was to estimate the efficacy, side-effects, and compliance of a quadruple therapy containing esomeprazole in a group of dyspeptic elderly patients. Patients and Methods: Consecutive elderly patients positive for H. pylori infection and not previously treated for eradication were enrolled. Therapy consisted of esomeprazole 20 mg, tetracycline 500 mg, metronidazole 500 mg, and bismuth subcitrate tablets 240 mg, all twice-a-day with the midday and evening meals, for 10 days. Efficacy was evaluated using 13C-urea breath testing. Compliance was assessed after completing treatment and at follow up. Side effects were graded based on daily activities. Results: Ninety-five dyspeptic patients (range 65–81 years), 52 men and 43 women, were enrolled. The intention-to-treat cure rate was 91% (81 of 89; 95% CI = 88–99%) and, 95% (81 of 85; 95% CI = 83–96%) per-protocol analysis. Compliance was excellent. Mild-moderate side effects occurred in 27 patients. Conclusions: Esomeprazole containing quadruple therapy was highly successful for initial eradication of H. pylori in elderly patients. [ABSTRACT FROM AUTHOR]

Temporal differences of neurodevelopmental milestones' achievement are commonly taken into account in preterm infant assessment during the first year of life, especially when minor or none neurological signs arise from clinical examination. The influence of gender on neurodevelopment in preterm infants was examined by a milestones‐based neurological approach. Two‐hundred twenty‐seven moderate and late preterm and full‐term infants (51.9% male), without evidence of severe white matter insults, were early assessed by classic neurological examination. Griffiths Mental Developmental Scale was used at long‐term observation. Children were sorted into three gestational age groups (Group 1: 32–33 weeks, Group 2: 34–36 weeks, and Group 3: ≥37 weeks) and compared according to their neurodevelopmental pathways and gender. The achievement of head control was slightly earlier in females. The pointing, one of the main communicative hand gesture, appeared significantly earlier in females across all the groups. At the Griffiths Scale, the majority of gender‐related differences emerged in personal–social and eye and hand coordination subscale. An independent role of male gender was evidenced in personal–social, language, and eye and hand coordination subscales. Gender and gestational age likely addressed different temporal profiles of neurodevelopment in early and late assessments in preterm and full‐term infants. The role of gender and gestational age on these findings has been discussed. Highlights: A classic, milestones‐based neurological evaluation disclosed different developmental profiles in males versus females preterm infants.Moderate preterm and full‐term infants showed similar developmental profiles.Gender and gestational age may influence neurodevelopment. [ABSTRACT FROM AUTHOR]

Introduction Rules-based HIV-1 drug-resistance interpretation (DRI) systems disregard many amino-acid positions of the drug's target protein. The aims of this study are (1) the development of a drug-resistance interpretation system that is based on HIV-1 sequences from clinical practice rather than hard-to-get phenotypes, and (2) the assessment of the benefit of taking all available amino-acid positions into account for DRI. Materials and Methods A dataset containing 34,934 therapy-naïve and 30,520 drug-exposed HIV-1 pol sequences with treatment history was extracted from the EuResist database and the Los Alamos National Laboratory database. 2,550 therapy-change-episode baseline sequences (TCEB) were assigned to test set A. Test set B contains 1,084 TCEB from the HIVdb TCE repository. Sequences from patients absent in the test sets were used to train three linear support vector machines to produce scores that predict drug exposure pertaining to each of 20 antiretrovirals: the first one uses the full amino-acid sequences (DEfull), the second one only considers IAS drug-resistance positions (DEonlyIAS), and the third one disregards IAS drug-resistance positions (DEnoIAS). For performance comparison, test sets A and B were evaluated with DEfull, DEnoIAS, DEonlyIAS, geno2pheno[resistance], HIVdb, ANRS, HIV-GRADE, and REGA. Clinically-validated cut-offs were used to convert the continuous output of the first four methods into susceptible-intermediate-resistant (SIR) predictions. With each method, a genetic susceptibility score (GSS) was calculated for each therapy episode in each test set by converting the SIR prediction for its compounds to integer: S=2, I=1, and R=0. The GSS were used to predict therapy success as defined by the EuResist standard datum definition. Statistical significance was assessed using a Wilcoxon signed-rank test. Results A comparison of the therapy-success prediction performances among the different interpretation systems for test set A can be found in Table 1, while those for test set B are found in Figure 1. Therapy-success prediction of first-line therapies with DEnoIAS performed better than DEonlyIAS (p<10-16). Conclusions Therapy success prediction benefits from the consideration of all available mutations. The increase in performance was largest in first-line therapies with transmitted drug-resistance mutations. [ABSTRACT FROM AUTHOR]

7-11 November 2010, Tenth International Congress on Drug Therapy in HIV Infection, Glasgow, UK [ABSTRACT FROM AUTHOR]

An abstract of the research paper "The EuResist Expert model for Customised HAART Optimisation: 2010 Update and Extension to Newest Compounds," by A. Pironti and colleagues which was presented at the Tenth International Congress on Drug Therapy in HIV Infection held at Glasgow, Scotland from November 7-11, 2010 is presented.

Various items are complicating the treatment of HIV-2 infected patients. Compared to HIV-1 there is much less treatment experience, no evidence from randomized control trials, a reduced number of effective drugs and no broadly available test for viral load monitoring. In case of treatment failure there is only limited guidance and presently no easy accessible tool for nucleic acid sequence interpretation available. To solve this problem, we initiated an expert workshop to address some of these problems. A panel of experts from four different European countries voted on a rule set for interpretation of mutations in the HIV-2 protease, reverse transcriptase and integrase. Rules were proposed by each member and were then modified during discussion by considering data gained from HIV-1 and accumulated experience of the follow up of HIV-2-infected patients. Based on the HIV-GRADE internet-tool an online tool was developed to make the rule set easily accessible and usable. Rules were laid down for the interpretation of HIV-2 drug resistance to NRTIs, PIs and INIs (integrase inhibitors). Due to natural resistance of HIV-2, usage of NNRTIs and T-20 was not recommended as part of an antiretroviral regimen for HIV-2. These rules were then translated in a machine interpretable format (algorithm specification interface, ASI) and the HIV-GRADE tool was extended for usage of HIV-2 sequences. Further consensus sequences were generated from the reference sequence data set provided by Los Alamos National Laboratories. In contrast to HIV-1, mutations were compared to a group specific consensus sequence (Group A or Group B) and not to a consensus sequence from the most predominant HIV-2 Group A. This change was necessary due to significant differences between the various HIV-2 strains. We developed a rule set and an automated tool for HIV-2 drug resistance analyses. This tool and the rules will be freely available on the internet. Access to the pre-publication versions can be granted by each of the group members. To keep the algorithm rules up-to-date it will be actualized on a yearly basis. [ABSTRACT FROM AUTHOR]

Different diagnostic parameters may affect the tropism prediction reliability. The impact of usage of FPR cut-offs<20%, use of viral RNA versus proviral DNA samples, single versus triple amplification, and presence of MVC resistance mutations on tropism prediction at baseline were analysed on 101 patients receiving maraviroc (MVC) and correlated with their clinical outcome. This was a non-interventional, retrospective study. 82 RNA and 54 DNA samples from the 101 patients receiving MVC were obtained. The V3 region was sequenced and the tropism predicted using the geno2pheno[coreceptor] and T-CUP tools with FPR cut-offs of 5%, 7.5%, 10%, 15% and 20%. Additionally, 27/82 RNA and 28/54 DNA samples were analysed in triplicate and 34/82 samples with the ESTA assay. The influence of 16 MVC resistance mutations on clinical outcome was studied. The genotypic susceptibility score (GSS) of the concomitant drugs was mapped to numerical values: susceptible to 1 (or 0.5 for NRTIs), intermediate to 0.5 (0.25 for NRTIs) and resistant to 0. Detection of baseline R5 viruses in RNA (by geno2pheno[coreceptor] and T-CUP) or DNA (by T-CUP) samples correlated with MVC-treatment success. Both tools performed very similarly, with PPVs close to 90%, even with FPR cut-offs as low as 5%. The use of triple amplification did not improve the prediction value but reduced the number of patients elegible for MVC treatment. No influence of the GSS or MVC resistance mutations on the clinical outcome was detected. Genotypic tropism testing from viral RNA and proviral DNA using the geno2pheno[coreceptor] and T-CUP systems is valid to select candidates for MVC treatment. Our data suggest that the use of FPR cut-offs of 5-7.5% and single amplification from RNA or DNA would assure a safe administration of MVC without excluding many patients who could benefit from this potent antiretroviral drug. [ABSTRACT FROM AUTHOR]

Etravirine (ETR) is a next generation non-nucleoside reverse transcriptase inhibitor (NNRTI). The studies for ETR EMA approval were almost exclusively performed together with the protease inhibitor (PI) darunavir. However the fact that ETR can be active against NNRTI-pretreated HIV variants and that it is well tolerated suggests its application in PI-free antiretroviral combination therapies. Although approved only for PI-containing therapies, a number of ETR treatments without PIs are performed currently. To evaluate the performance of ETR in PI-free regimens, we analyzed the EURESIST database. We observed a total of 70 therapy switches to a PI-free, ETR containing antiretroviral combination with detectable baseline viral load. 50/70 switches were in male patients and 20/70 in females. The median of previous treatments was 10. The following combinations were detected in the EURESIST database: ETR+MVC+RAL (20.0%); ETR+FTC+TDF (18.6%); 3TC+ETR+RAL (7.1%); 3TC+ABC+ETR (5.7%); other combinations (31.4%). A switch was defined as successful when either ≤50 copies/mL or a decline of the viral load of 2 log10, both at week 24 (range 18-30) were achieved. The overall success rate (SR) was 77% (54/70), and for the different combinations: ETR+MVC+RAL=78.6% (11/14); ETR+FTC+TDF=92.3% (12/13); 3TC+ETR+RAL =80.0% (4/5), 3TC+ABC+ETR=100% (SR 4/4); and for other combinations=67.6% (23/34). These SR values are comparable to those for other therapy combinations in such pretreated patients. [ABSTRACT FROM AUTHOR]