Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study

Background & Aims Use of dabigatran, an inhibitor of thrombin, increases the risk of gastrointestinal bleeding (GIB). However, it is not clear whether gastroprotective agents (GPAs) prevent GIB in dabigatran users. We investigated the risk of GIB and the role of gastroprotective agents (including proton pump inhibitors and histamine type-2-receptor antagonists) in patients using dabigatran. Methods We performed a retrospective cohort study using a population-wide database managed by the Hong Kong Hospital Authority. Patients newly prescribed dabigatran from 2010 through 2013 were included in the analysis. Poisson regression was used to assess the risk of GIB in dabigatran users by incidence rate ratio (IRR), adjusted for patient characteristics, comorbidities, and concurrent medications. Results Among the 5041 patients newly prescribed dabigatran, 124 (2.5%) developed GIB during follow-up evaluation (4.2/100 patient-years). The risk of GIB in this population increased among patients 75 years and older (IRR, 2.47; 95% confidence interval [CI], 1.66-3.68), patients with a history of peptic ulcers or GIB (IRR, 2.31; 95% CI, 1.54-3.46), and patients who used aspirin (IRR, 1.52; 95% CI, 1.03-2.24). Concomitant use of gastroprotective agents was associated with a reduced risk of GIB (IRR, 0.52; 95% CI, 0.35-0.77). Subcategory analysis showed that use of proton pump inhibitors (IRR, 0.53; 95% CI, 0.31-0.91) or histamine type-2-receptor antagonists (IRR, 0.61; 95% CI, 0.40-0.94) were associated with a lower risk of GIB. Further analysis showed that the risk reduction by gastroprotective agents was significant for only upper GIB (IRR, 0.29; 95% CI, 0.15-0.54), and only for patients with a prior history of peptic ulcers or GIB (IRR, 0.14; 95% CI, 0.06-0.30). Conclusions In the Hong Kong population, use of gastroprotective agents was associated with a reduced risk of GIB in patients taking dabigatran. The association was stronger for upper GIB than lower GIB, and in patients with a prior history of peptic ulcers or GIB.

Synthesis and evaluation of cationic norbornanes as peptidomimetic antibacterial agents

A series of structurally amphiphilic biscationic norbornanes have been synthesised as rigidified, low molecular weight peptidomimetics of cationic antimicrobial peptides. A variety of charged hydrophilic functionalities were attached to the norbornane scaffold including aminium, guanidinium, imidazolium and pyridinium moieties. Additionally, a range of hydrophobic groups of differing sizes were incorporated through an acetal linkage. The compounds were evaluated for antibacterial activity against both Gram-negative and Gram-positive bacteria. Activity was observed across the series; the most potent of which exhibited an MIC's ≤ 1 μg mL(-1) against Streptococcus pneumoniae, Enterococcus faecalis and several strains of Staphylococcus aureus, including multi-resistant methicillin resistant (mMRSA), glycopeptide-intermediate (GISA) and vancomycin-intermediate (VISA) S. aureus.

Synthesis and in vivo evaluation of [123I]melanin-targeted agents

This study reports the synthesis, [(123)I]radiolabeling, and biological profile of a new series of iodinated compounds for potential translation to the corresponding [(131)I]radiolabeled compounds for radionuclide therapy of melanoma. Radiolabeling was achieved via standard electrophilic iododestannylation in 60-90% radiochemical yield. Preliminary SPECT imaging demonstrated high and distinct tumor uptake of all compounds, as well as high tumor-to-background ratios compared to the literature compound [(123)I]4 (ICF01012). The most favorable compounds ([(123)I]20, [(123)I]23, [(123)I]41, and [(123)I]53) were selected for further biological investigation. Biodistribution studies indicated that all four compounds bound to melanin containing tissue with low in vivo deiodination; [(123)I]20 and [(123)I]53 in particular displayed high and prolonged tumor uptake (13% ID/g at 48 h). [(123)I]53 had the most favorable overall profile of the cumulative uptake over time of radiosensitive organs. Metabolite analysis of the four radiotracers found [(123)I]41 and [(123)I]53 to be the most favorable, displaying high and prolonged amounts of intact tracer in melanin containing tissues, suggesting melanin specific binding. Results herein suggest that compound [(123)I]53 displays favorable in vivo pharmacokinetics and stability and hence is an ideal candidate to proceed with further preclinical [(131)I] therapeutic evaluation.

Nurse-led titration of angiotensin converting enzyme inhibitors, beta-adrenergic blocking agents, and angiotensin receptor blockers for people with heart failure with reduced ejection fraction

BACKGROUND: Heart failure is associated with high mortality and hospital readmissions. Beta-adrenergic blocking agents, angiotensin converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) can improve survival and reduce hospital readmissions and are recommended as first-line therapy in the treatment of heart failure. Evidence has also shown that there is a dose-dependent relationship of these medications with patient outcomes. Despite this evidence, primary care physicians are reluctant to up-titrate these medications. New strategies aimed at facilitating this up-titration are warranted. Nurse-led titration (NLT) is one such strategy. OBJECTIVES: To assess the effects of NLT of beta-adrenergic blocking agents, ACEIs, and ARBs in patients with heart failure with reduced ejection fraction (HFrEF) in terms of safety and patient outcomes. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials in the Cochrane Library (CENTRAL Issue 11 of 12, 19/12/2014), MEDLINE OVID (1946 to November week 3 2014), and EMBASE Classic and EMBASE OVID (1947 to 2014 week 50). We also searched reference lists of relevant primary studies, systematic reviews, clinical trial registries, and unpublished theses sources. We used no language restrictions. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing NLT of beta-adrenergic blocking agents, ACEIs, and/or ARBs comparing the optimisation of these medications by a nurse to optimisation by another health professional in patients with HFrEF. DATA COLLECTION AND ANALYSIS: Two review authors (AD & JC) independently assessed studies for eligibility and risk of bias. We contacted primary authors if we required additional information. We examined quality of evidence using the GRADE rating tool for RCTs. We analysed extracted data by risk ratio (RR) with 95% confidence interval (CI) for dichotomous data to measure effect sizes of intervention group compared with usual-care group. Meta-analyses used the fixed-effect Mantel-Haenszel method. We assessed heterogeneity between studies by Chi(2) and I(2). MAIN RESULTS: We included seven studies (1684 participants) in the review. One study enrolled participants from a residential care facility, and the other six studies from primary care and outpatient clinics. All-cause hospital admission data was available in four studies (556 participants). Participants in the NLT group experienced a lower rate of all-cause hospital admissions (RR 0.80, 95% CI 0.72 to 0.88, high-quality evidence) and fewer hospital admissions related to heart failure (RR 0.51, 95% CI 0.36 to 0.72, moderate-quality evidence) compared to the usual-care group. Six studies (902 participants) examined all-cause mortality. All-cause mortality was also lower in the NLT group (RR 0.66, 95% CI 0.48 to 0.92, moderate-quality evidence) compared to usual care. Approximately 27 deaths could be avoided for every 1000 people receiving NLT of beta-adrenergic blocking agents, ACEIs, and ARBs. Only three studies (370 participants) reported outcomes on all-cause and heart failure-related event-free survival. Participants in the NLT group were more likely to remain event free compared to participants in the usual-care group (RR 0.60, 95% CI 0.46 to 0.77, moderate-quality evidence). Five studies (966 participants) reported on the number of participants reaching target dose of beta-adrenergic blocking agents. This was also higher in the NLT group compared to usual care (RR 1.99, 95% CI 1.61 to 2.47, low-quality evidence). However, there was a substantial degree of heterogeneity in this pooled analysis. We rated the risk of bias in these studies as high mainly due to a lack of clarity regarding incomplete outcome data, lack of reporting on adverse events associated with the intervention, and the inability to blind participants and personnel. Participants in the NLT group reached maximal dose of beta-adrenergic blocking agents in half the time compared with participants in usual care. Two studies reported on adverse events; one of these studies stated there were no adverse events, and the other study found one adverse event but did not specify the type or severity of the adverse event. AUTHORS' CONCLUSIONS: Participants in the NLT group experienced fewer hospital admissions for any cause and an increase in survival and number of participants reaching target dose within a shorter time period. However, the quality of evidence regarding the proportion of participants reaching target dose was low and should be interpreted with caution. We found high-quality evidence supporting NLT as one strategy that may improve the optimisation of beta-adrenergic blocking agents resulting in a reduction in hospital admissions. Despite evidence of a dose-dependent relationship of beta-adrenergic blocking agents, ACEIs, and ARBs with improving outcomes in patients with HFrEF, the translation of this evidence into clinical practice is poor. NLT is one strategy that facilitates the implementation of this evidence into practice.

Norbornane-based peptidomimetics as antibacterial agents

 A library of norbornane-based peptide mimetics have been synthesised and shown to exhibit antibacterial activity against a range of troublesome Gram-positive and Gram-negative bacterial pathogens.

Equilibria in security markets with a continuum of agents

We prove the existence of a competitive equilibrium for exchange economies with a measure space of agents and for which the commodity space is ` p, 1 < p < +∞. A vector x = (xn) in ` p may be interpreted as a security which promises to deliver xn units of numeraire at state (or date) n. Under assumptions imposing uniform bounds on marginal rates of substitution, positive results on core-Walras equivalence were established in Rustichini–Yannelis [21] and Podczeck [20]. In this paper we prove that under similar assumptions on marginal rates of substitution, the set of competitive equilibria (and thus the core) is non-empty.

The influence of the supply chain agents on the new product development's performance: an analysis based on the multi-group moderation

Este estudo buscou verificar a influencia dos agentes da cadeia de suprimentos no desempenho do desenvolvimento de novos produtos quando os agentes são analisados em conjunto. A motivação desta pesquisa veio de estudos que alertaram para a consideração da integração da cadeia de suprimentos como um constructo multidimensional, englobando o envolvimento da manufatura, fornecedores e clientes no desenvolvimento de novos produtos; e devido à falta de informação sobre as influencias individuais destes agentes no desenvolvimento de novos produtos. Sob essas considerações, buscou-se construir um modelo analítico baseado na Teoria do Capital Social e Capacidade Absortiva, construir hipóteses a partir da revisão da literatura e conectar constructos como cooperação, envolvimento do fornecedor no desenvolvimento de novos produtos (DNP), envolvimento do cliente no DNP, envolvimento da manufatura no DNP, antecipação de novas tecnologias, melhoria contínua, desempenho operacional do DNP, desempenho de mercado do NPD e desempenho de negócio do DNP. Para testar as hipóteses foram consideradas três variáveis moderadoras, tais como turbulência ambiental (baixa, média e alta), indústria (eletrônicos, maquinários e equipamentos de transporte) e localização (América, Europa e Ásia). Para testar o modelo foram usados dados do projeto High Performance Manufacturing que contém 339 empresas das indústrias de eletrônicos, maquinários e equipamentos de transporte, localizadas em onze países. As hipóteses foram testadas por meio da Análise Fatorial Confirmatória (AFC) incluindo a moderação muti-grupo para as três variáveis moderadoras mencionadas anteriormente. Os principais resultados apontaram que as hipóteses relacionadas com cooperação foram confirmadas em ambientes de média turbulência, enquanto as hipóteses relacionadas ao desempenho no DNP foram confirmadas em ambientes de baixa turbulência ambiental e em países asiáticos. Adicionalmente, sob as mesmas condições, fornecedores, clientes e manufatura influenciam diferentemente no desempenho de novos produtos. Assim, o envolvimento de fornecedores influencia diretamente no desempenho operacional e indiretamente no desempenho de mercado e de negócio em baixos níveis de turbulência ambiental, na indústria de equipamentos de transporte em países da Americanos e Europeus. De igual forma, o envolvimento do cliente influenciou diretamente no desempenho operacional e indiretamente no desempenho de mercado e do negócio em médio nível de turbulência ambiental, na indústria de maquinários e em países Asiáticos. Fornecedores e clientes não influenciam diretamente no desempenho de mercado e do negócio e não influenciam indiretamente no desempenho operacional. O envolvimento da manufatura não influenciou nenhum tipo de desempenho do desenvolvimento de novos produtos em todos os cenários testados.

On the optimality of the Friedman Rule with heterogeneous agents and non-linear income taxation

We study the optimal “inflation tax” in an environment with heterogeneous agents and non-linear income taxes. We first derive the general conditions needed for the optimality of the Friedman rule in this setup. These general conditions are distinct in nature and more easily interpretable than those obtained in the literature with a representative agent and linear taxation. We then study two standard monetary specifications and derive their implications for the optimality of the Friedman rule. For the shopping-time model the Friedman rule is optimal with essentially no restrictions on preferences or transaction technologies. For the cash-credit model the Friedman rule is optimal if preferences are separable between the consumption goods and leisure, or if leisure shifts consumption towards the credit good. We also study a generalized model which nests both models as special cases.

Dynamic coordination among heterogeneous agents

We study a dynamic model of coordination with timing frictions and payoff heterogeneity. There is a unique equilibrium, characterized by thresholds that determine the choices of each type of agent. We characterize equilibrium for the limiting cases of vanishing timing frictions and vanishing shocks to fundamentals. A lot of conformity emerges: despite payoff heterogeneity, agents’ equilibrium thresholds partially coincide as long as there exists a set of beliefs that would make this coincidence possible – though they never fully coincide. In case of vanishing frictions, the economy behaves almost as if all agents were equal to an average type. Conformity is not inefficient. The efficient solution would have agents following others even more often and giving less importance to the fundamental

Molecular detection of tick-borne bacterial agents in Brazilian and exotic captive carnivores

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Use of Cassava Wastewater Treated Anaerobically with Alkaline Agents as Fertilizer for Maize (Zea mays L.)

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Topliss method in the optimization of salicylic acid derivatives as potential antimycobacterial agents

The Topliss method was used to guide a synthetic path in support of drug discovery efforts toward the identification of potent antimycobacterial agents. Salicylic acid and its derivatives, p-chloro, p-methoxy, and m-chlorosalicylic acid, exemplify a series of synthetic compounds whose minimum inhibitory concentrations for a strain of Mycobacterium were determined and compared to those of the reference drug, p-aminosalicylic acid. Several physicochemical descriptors (including Hammett's sigma constant, ionization constant, dipole moment, Hansch constant, calculated partition coefficient, Sterimol-L and -B-4 and molecular volume) were considered to elucidate structure-activity relationships. Molecular electrostatic potential and molecular dipole moment maps were also calculated using the AM1 semi-empirical method. Among the new derivatives, m-chlorosalicylic acid showed the lowest minimum inhibitory concentration. The overall results suggest that both physicochemical properties and electronic features may influence the biological activity of this series of antimycobacterial agents and thus should be considered in designing new p-aminosalicylic acid analogs.

Ruthenium (II) phosphine/picolinate complexes as antimycobacterial agents

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Synthesis of 4-aminoquinoline analogues and their platinum(II) complexes as new antileishmanial and antitubercular agents

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)