Efficacy of sacubitril/valsartan vs. enalapril at lower than target doses in heart failure with reduced ejection fraction: the PARADIGM-HF trial.

AimsIn this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril.Methods and resultsIn a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2-2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70-0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71-0.88, P < 0.001).ConclusionsIn PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices.

Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945-1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels

Instructional Systems Paradigm - Governors State University

The Instructional Systems Paradigm (ISP) was developed by a University-wide Task Force in response to a charge from the University Assembly to develop a paradigm that would, among other things, ••• provide some elaboration of the sequence of steps necessary for relating degree, program and module objectives and serve as the primary and substantive model and guide for curriculum development processes in each of the colleges, where the unique characteristics of collegial programs will be correlated with the University-wide mandates. Although the document is quite detailed and lengthy, its primary thrust can be summarized as follows: The Educational Planning Guidelines serve as a base for all subsequent activities. The College Guidelines evolve out of the Educational Planning Guidelines. The Instructional Program Guidelines, in turn, are based on the College Guidelines; the Area of Emphasis Guidelines are based on the Instructional Program Guidelines; and the Learning Modules are based on the Area of Emphasis Guidelines. The paradigm makes the above statement a policy position. Further, most of the material included in the ISP document can properly be viewed as supplementary in that it is presented solely as a means of accomplishing the task described above. A Glossary of terms is included for the purpose of reducing semantic confusion. The detailed approach was taken because curriculum development is a rigorous and complex endeavor. If the paradigm had been a global statement such as the summary paragraph above, then some faculty might legitimately have asked for more explicit directions. For many, the detailed directions will prove to be unnecessary. For others, the explicitness of the document serves as a reminder of the intellectual rigor involved and the true complexity of the task. The ISP will serve as a guide to all who are developing curriculum at the various levels within the University. The Instructional Systems Paradigm builds enough flexibility into the system to accommodate the variety of teaching and learning styles which exist at GSU. It is not intended to be a straitjacket for instructional development. It is, however, an approach to instructional development that will coordinate the efforts of the entire GSU Community toward the attainment of the University goal

The new paradigm of hepatitis C therapy: integration of oral therapies into best practices

SUMMARY. Emerging data indicate that all-oral antiviral treatments for chronic hepatitis C virus (HCV) will become a reality in the near future. In replacing interferon-based therapies, all-oral regimens are expected to be more tolerable, more effective, shorter in duration and simpler to administer. Coinciding with new treatment options are novel methodologies for disease screening and staging, which create the possibility of more timely care and treatment. Assessments of histologic damage typically are performed using liver biopsy, yet noninvasive assessments of histologic damage have become the norm in some European countries and are becoming more widespread in the United States. Also in place are new Centers for Disease Control and Prevention (CDC) initiatives to simplify testing, improve provider and patient awareness and expand recommendations for HCV screening beyond risk-based strategies. Issued in 2012, the CDC recommendations aim to increase HCV testing among those with the greatest HCV burden in the United States by recommending one-time testing for all persons born during 1945–1965. In 2013, the United States Preventive Services Task Force adopted similar recommendations for risk-based and birth-cohort-based testing. Taken together, the developments in screening, diagnosis and treatment will likely increase demand for therapy and stimulate a shift in delivery of care related to chronic HCV, with increased involvement of primary care and infectious disease specialists. Yet even in this new era of therapy, barriers to curing patients of HCV will exist. Overcoming such barriers will require novel, integrative strategies and investment of resources at local, regional and national levels

Report on Online Discussions on Promoting Internet Freedoms in Africa, November 11 – December 6, 2013

The popularity of social media, Wikileaks, and Arab Spring uprisings have led governments to recognise the power of online media. In a number of African countries, there are increasing legal and extra-legal curbs on internet rights. As shown in Google transparency reports, the number of governments requesting data about online users has doubled in the last three years (2010 - 2012). An online forum for internet freedom discussions was hosted on selected platforms in Uganda, Kenya and Nigeria. That some requests for content removal may be politically motivated, is cause for concern

Estimation of long-wavelength near-surface velocity and low-relief structural anomalies—Part I: A case history

Summary Undetected near-surface and subsurface velocity variations greater than an effective spread length produce false structures both in time and depth. The estimation of these variations rely on uphole measurements, high density shallow reflection data and sufficiently long offsets for subsurface reflectors. Despite inadequate near-surface velocity-depth measurements in the study area, we developed a strategy for the detection and estimation of both near-surface and subsurface long-wavelength velocity and low-relief structural variations. We chose two 2D seismic lines (dip and strike) over two existing low-relief fields in central Saudi Arabia, to demonstrate how the velocity-depth ambiguity problem is partially overcome by integrating the refraction delay time solutions derived from multiple refractors below the seismic reference datum with iterative pre-stack depth migration, residual analysis, and reflection tomography. We compare these results with the conventional isopach depthing method and discuss how this strategy improves the structural integrity of potential prospects. Even with the verification of the near-surface velocity and structural anomalies along the dip line and buried velocity anomaly along the strike line through forward modeling and flatness of depth image gathers, these models are non-unique. Based upon this case study, a new constrained tomographic algorithm has been developed which overcomes the above ambiguity and is discussed in Part II. Introduction In central Saudi Arabia, 2D seismic data is acquired along lines (greater than 70 km) over near-surface conditions which include different combinations of sand lenses, buried channels, leaching, outcropping formations, and in some areas the effects of a shallow unconfined aquifer. These variable near-surface conditions give rise to lateral velocity variations and thus to time anomalies of wavelengths of different scales, from as small as a cdp interval to much greater than a cable length. The base of weathering for short wavelength velocity variations is confined to several tens of meters below the surface and extends well below the seismic reference datum (SRD) for long wavelength lateral velocity variations. In the study area, the sparsely spaced and shallow uphole control points could not be used to generate a reliable 3D average velocity model because the base of weathering is well below the maximum uphole penetration depth and SRD

Angiotensin-neprilysin inhibition versus enalapril in heart failure

Background: we compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. Methods: in this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. Results: the trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. Conclusions: LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255)

Streamlining Digital Modeling and Building Information Modelling (BIM) Uses for the Oil and Gas Projects

The oil and gas industry is a technology-driven industry. Over the last two decades, it has heavily made use of digital modeling and associated technologies (DMAT) to enhance its commercial capability. Meanwhile, the Building Information Modelling (BIM) has grown at an exponential rate in the built environment sector. It is not only a digital representation of physical and functional characteristics of a facility, but it has also made an impact on the management processes of building project lifecycle. It is apparent that there are many similarities between BIM and DMAT usability in the aspect of physical modeling and functionality. The aim of this study is to streamline the usage of both DMAT and BIM whilst discovering valuable practices for performance improvement in the oil and gas projects. To achieve this, 28 BIM guidelines, 83 DMAT academic publications and 101 DMAT vendor case studies were selected for review. The findings uncover (a) 38 BIM uses; (b) 32 DMAT uses and; (c) 36 both DMAT and BIM uses. The synergy between DMAT and BIM uses would render insightful references into managing efficient oil and gas’s projects. It also helps project stakeholders to recognise future investment or potential development areas of BIM and DMAT uses in their projects