Impact of Renal Impairment on Beta-Blocker Efficacy in Patients With Heart Failure.

BACKGROUND: Moderate and moderately severe renal impairment are common in patients with heart failure and reduced ejection fraction, but whether beta-blockers are effective is unclear, leading to underuse of life-saving therapy. OBJECTIVES: This study sought to investigate patient prognosis and the efficacy of beta-blockers according to renal function using estimated glomerular filtration rate (eGFR). METHODS: Analysis of 16,740 individual patients with left ventricular ejection fraction <50% from 10 double-blind, placebo-controlled trials was performed. The authors report all-cause mortality on an intention-to-treat basis, adjusted for baseline covariates and stratified by heart rhythm. RESULTS: Median eGFR at baseline was 63 (interquartile range: 50 to 77) ml/min/1.73 m2; 4,584 patients (27.4%) had eGFR 45 to 59 ml/min/1.73 m2, and 2,286 (13.7%) 30 to 44 ml/min/1.73 m2. Over a median follow-up of 1.3 years, eGFR was independently associated with mortality, with a 12% higher risk of death for every 10 ml/min/1.73 m2 lower eGFR (95% confidence interval [CI]: 10% to 15%; p < 0.001). In 13,861 patients in sinus rhythm, beta-blockers reduced mortality versus placebo; adjusted hazard ratio (HR): 0.73 for eGFR 45 to 59 ml/min/1.73 m2 (95% CI: 0.62 to 0.86; p < 0.001) and 0.71 for eGFR 30 to 44 ml/min/1.73 m2 (95% CI: 0.58 to 0.87; p = 0.001). The authors observed no deterioration in renal function over time in patients with moderate or moderately severe renal impairment, no difference in adverse events comparing beta-blockers with placebo, and higher mortality in patients with worsening renal function on follow-up. Due to exclusion criteria, there were insufficient patients with severe renal dysfunction (eGFR <30 ml/min/1.73 m2) to draw conclusions. In 2,879 patients with atrial fibrillation, there was no reduction in mortality with beta-blockers at any level of eGFR. CONCLUSIONS: Patients with heart failure, left ventricular ejection fraction <50% and sinus rhythm should receive beta-blocker therapy even with moderate or moderately severe renal dysfunction

A FAIR guide for data providers to maximise sharing of human genomic data

It is generally acknowledged that, for reproducibility and progress of human genomic research, data sharing is critical. For every sharing transaction, a successful data exchange is produced between a data consumer and a data provider. Providers of human genomic data (e.g., publicly or privately funded repositories and data archives) fulfil their social contract with data donors when their shareable data conforms to FAIR (findable, accessible, interoperable, reusable) principles. Based on our experiences via Repositive (https://repositive.io), a leading discovery platform cataloguing all shared human genomic datasets, we propose guidelines for data providers wishing to maximise their shared data’s FAIRness. Citation: Corpas M, Kovalevskaya NV, McMurray A, Niel

Systems biology approaches applied to regenerative medicine

Systems biology is the creation of theoretical and mathematical models for the study of biological systems, as an engine for hypothesis generation and to provide context to experimental data. It is underpinned by the collection and analysis of complex datasets from different biological systems, including global gene, RNA, protein and metabolite profiles. Regenerative medicine seeks to replace or repair tissues with compromised function (for example, through injury, deficiency or pathology), in order to improve their functionality. In this paper, we will address the application of systems biology approaches to the study of regenerative medicine, with a particular focus on approaches to study modifications to the genome, transcripts and small RNAs, proteins and metabolites

Physician and Patient Predictors of Evidence-Based Prescribing in Heart Failure: A Multilevel Study

BACKGROUND: The management of patients with heart failure (HF) needs to account for changeable and complex individual clinical characteristics. The use of renin angiotensin system inhibitors (RAAS-I) to target doses is recommended by guidelines. But physicians seemingly do not sufficiently follow this recommendation, while little is known about the physician and patient predictors of adherence. METHODS: To examine the coherence of primary care (PC) physicians' knowledge and self-perceived competencies regarding RAAS-I with their respective prescribing behavior being related to patient-associated barriers. Cross-sectional follow-up study after a randomized medical educational intervention trial with a seven month observation period. PC physicians (n = 37) and patients with systolic HF (n = 168) from practices in Baden-Wuerttemberg. Measurements were knowledge (blueprint-based multiple choice test), self-perceived competencies (questionnaire on global confidence in the therapy and on frequency of use of RAAS-I), and patient variables (age, gender, NYHA functional status, blood pressure, potassium level, renal function). Prescribing was collected from the trials' documentation. The target variable consisted of ≥50% of recommended RAAS-I dosage being investigated by two-level logistic regression models. RESULTS: Patients (69% male, mean age 68.8 years) showed symptomatic and objectified left ventricular (NYHA II vs. III/IV: 51% vs. 49% and mean LVEF 33.3%) and renal (GFR<50%: 22%) impairment. Mean percentage of RAAS-I target dose was 47%, 59% of patients receiving ≥50%. Determinants of improved prescribing of RAAS-I were patient age (OR 0.95, CI 0.92-0.99, p = 0.01), physician's global self-confidence at follow-up (OR 1.09, CI 1.02-1.05, p = 0.01) and NYHA class (II vs. III/IV) (OR 0.63, CI 0.38-1.05, p = 0.08). CONCLUSIONS: A change in physician's confidence as a predictor of RAAS-I dose increase is a new finding that might reflect an intervention effect of improved physicians' intention and that might foster novel strategies to improve safe evidence-based prescribing. These should include targeting knowledge, attitudes and skills

Summary of data reported to CDC's national automated biosurveillance system, 2008

<p>Abstract</p> <p>Background</p> <p>BioSense is the US national automated biosurveillance system. Data regarding chief complaints and diagnoses are automatically pre-processed into 11 broader syndromes (e.g., respiratory) and 78 narrower sub-syndromes (e.g., asthma). The objectives of this report are to present the types of illness and injury that can be studied using these data and the frequency of visits for the syndromes and sub-syndromes in the various data types; this information will facilitate use of the system and comparison with other systems.</p> <p>Methods</p> <p>For each major data source, we summarized information on the facilities, timeliness, patient demographics, and rates of visits for each syndrome and sub-syndrome.</p> <p>Results</p> <p>In 2008, the primary data sources were the 333 US Department of Defense, 770 US Veterans Affairs, and 532 civilian hospital emergency department facilities. Median times from patient visit to record receipt at CDC were 2.2 days, 2.0 days, and 4 hours for these sources respectively. Among sub-syndromes, we summarize mean 2008 visit rates in 45 infectious disease categories, 11 injury categories, 7 chronic disease categories, and 15 other categories.</p> <p>Conclusions</p> <p>We present a systematic summary of data that is automatically available to public health departments for monitoring and responding to emergencies.</p

The 3' region of Human Papillomavirus type 16 early mRNAs decrease expression

BACKGROUND: High risk human papillomavirus (HR-HPV) infects mucosal surfaces and HR-HPV infection is required for development of cervical cancer. Accordingly, enforced expression of the early HR-HPV proteins can induce immortalisation of human cells. In most cervical cancers and cervical cancer cell lines the HR-HPV double stranded DNA genome has been integrated into the host cell genome. METHODS: We have used a retroviral GUS reporter system to generate pools of stably transfected HaCaT and SiHa cells. The HPV-16 early sequences that are deleted upon integration of the HPV-16 genome was inserted into the 3' UTR of the reporter mRNA. Pools containing thousands of independent integrations were tested for the steady state levels of the reporter mRNA by Real Time PCR and reporter protein by a GUS enzymatic activity assays. In addition, we tested the cellular distribution and half lives of the reporter mRNAs. The integrity of the reporter mRNAs were tested by northern blotting. RESULTS: We show that the 3' region of the HPV-16 early mRNAs (HPV-16 nucleotide (nt.) 2582–4214) act in cis to decrease both mRNA and protein levels. This region seems to affect transcription from the exogenous minimal CMV promoter or processing of the reporter mRNA. The observed repression was most pronounced at the protein level, suggesting that this sequence may also affect translation. For the HPV types: 2, 6, 11, 13, 18, 30, 31, and 35 we have investigated the regulatory effect of the regions corresponding to the HPV-16 nt. 3358–4214. For all types, except HPV-18, the region was found to repress expression by posttranscriptional mechanisms. CONCLUSION: We find that the 3' region of HPV-16 early mRNAs interfere with gene expression. It is therefore possible that the deletion of the 3' part of early HPV-16 mRNAs occurring during cervical oncogenesis could contribute to transformation of cells through deregulation of the viral oncogene synthesis. Moreover, we find that the corresponding region from several other HPV types also repress expression, suggesting that the repression by this region may be a general feature of the HPV life cycle

Multicenter double blind trial of autologous bone marrow mononuclear cell transplantation through intracoronary injection post acute myocardium infarction – MiHeart/AMI study

Background: Myocardial infarction remains as a major cause of mortality worldwide and a high rate of survivors develop heart failure as a sequel, resulting in a high morbidity and elevated expenditures for health system resources. We have designed a multicenter trial to test for the efficacy of autologous bone marrow (ABM) mononuclear cell (MC) transplantation in this subgroup of patients. The main hypothesis to be tested is that treated patients will have a significantly higher ejection fraction (EF) improvement after 6 months than controls. Methods: A sample of 300 patients admitted with ST elevation acute myocardial infarction (STEMI) and left ventricle (LV) systolic dysfunction, and submitted to successful mechanical or chemical recanalization of the infarct-related coronary artery will be selected for inclusion and randomized to either treated or control group in a double blind manner. The former group will receive 100 x 106 MC suspended in saline with 5% autologous serum in the culprit vessel, while the latter will receive placebo (saline with 5% autologous serum). Implications: Many phase I/II clinical trials using cell therapy for STEMI have been reported, demonstrating that cell transplantation is safe and may lead to better preserved LV function. Patients with high risk to develop systolic dysfunction have the potential to benefit more. Larger randomized, double blind and controlled trials to test for the efficacy of cell therapies in patients with high risk for developing heart failure are required.Brazilian Ministry of Science and Technology (MCT)/The Financing Agency for Studies and Projects (FINEP

Interference between Sentence Processing and Probabilistic Implicit Sequence Learning

During sentence processing we decode the sequential combination of words, phrases or sentences according to previously learned rules. The computational mechanisms and neural correlates of these rules are still much debated. Other key issue is whether sentence processing solely relies on language-specific mechanisms or is it also governed by domain-general principles.In the present study, we investigated the relationship between sentence processing and implicit sequence learning in a dual-task paradigm in which the primary task was a non-linguistic task (Alternating Serial Reaction Time Task for measuring probabilistic implicit sequence learning), while the secondary task were a sentence comprehension task relying on syntactic processing. We used two control conditions: a non-linguistic one (math condition) and a linguistic task (word processing task). Here we show that the sentence processing interfered with the probabilistic implicit sequence learning task, while the other two tasks did not produce a similar effect.Our findings suggest that operations during sentence processing utilize resources underlying non-domain-specific probabilistic procedural learning. Furthermore, it provides a bridge between two competitive frameworks of language processing. It appears that procedural and statistical models of language are not mutually exclusive, particularly for sentence processing. These results show that the implicit procedural system is engaged in sentence processing, but on a mechanism level, language might still be based on statistical computations

Uptake and Accumulation of Oxidized Low-Density Lipoprotein during Mycobacterium tuberculosis Infection in Guinea Pigs

The typical host response to infection of humans and some animals by M. tuberculosis is the accumulation of reactive oxygen species generating inflammatory cells into discrete granulomas, which frequently develop central caseous necrosis. In previous studies we showed that infection of immunologically naïve guinea pigs with M. tuberculosis leads to localized and systemic oxidative stress that results in a significant depletion of serum total antioxidant capacity and the accumulation of malondialdehyde, a bi-product of lipid peroxidation. Here we show that in addition, the generation of excessive reactive oxygen species in vivo resulted in the accumulation of oxidized low density lipoproteins (OxLDL) in pulmonary and extrapulmonary granulomas, serum and lung macrophages collected by bronchoalveolar lavage. Macrophages from immunologically naïve guinea pigs infected with M. tuberculosis also had increased surface expression of the type 1 scavenger receptors CD36 and LOX1, which facilitate the uptake of oxidized host macromolecules including OxLDL. Vaccination of guinea pigs with Bacillus Calmette Guerin (BCG) prior to aerosol challenge reduced the bacterial burden as well as the intracellular accumulation of OxLDL and the expression of macrophage CD36 and LOX1. In vitro loading of guinea pig lung macrophages with OxLDL resulted in enhanced replication of bacilli compared to macrophages loaded with non-oxidized LDL. Overall, this study provides additional evidence of oxidative stress in M. tuberculosis infected guinea pigs and the potential role OxLDL laden macrophages have in supporting intracellular bacilli survival and persistence