Innovation in Chemistry,Manufacturing, and Controls—A Regulatory Perspective From Industry

This review describes the landscape of novel modalities such as cell and gene therapies, viruses, other novel biologics, oligomers, and emerging technologies, including modern analytics. We summarize the regulatory history and recent landmark developments in some major markets and examine specific chemistry, manufacturing, and controls (CMC) challenges, including suggestions for exploration of potential science-based approaches in support of regulatory strategy development from an industry perspective. In addition, we evaluate the economic factors contributing to patient access to innovation and discuss the impact of regulation. There is a desperate need for a consistent form of regulation where global approaches to regulatory strategies can be harmonized, and specific CMC challenges can be dealt with using the appropriate science and risk-based tools. Although these tools are well described in current guidance documents, the specifics of applicability to complex novel modalities can still result in differing regulatory advice and outcomes. The future goals for efficiently regulating innovative modalities and technologies could be aided by more regulatory harmonization, regulatory education, and industry cooperation through consortia, enabling industry to supply key information to regulators in a transparent yet well-defined manner, and utilizing mutually understood risk-benefit analyses to produce drugs with appropriate safety, efficacy, and quality characteristics.     

Short-Term Left Ventricular Reverse Remodeling after Transcatheter Aortic Valve Replacement in Children

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Optimal dropout policies for networked control systems

By realizing the feedback paths over communication networks, we get a class of networked control systems (NCSs), where the network's quality‐of‐service (QoS) is commonly characterized by the average dropout rate of feedback data packets. The control performance of an NCS however, is determined not only by the average dropout rate but also by the dropout pattern of feedback data packets. This paper provides a systematic way to determine the optimal dropout pattern (policy) under a given average dropout rate, where the performance is measured by the output signal power under an exogenous white noise. By modeling the finite‐memory dropout policies with the general Markov chain, this paper formulates the optimal dropout policy design into the optimization of parameters of a dropout Markov chain. That optimization is first solved by an augmented Lagrangian gradient method, which may be stuck at local optima because of the problem's non‐convexity. To compensate this weakness, we apply the branch‐and‐bound method to the optimization whose constraints are bilinear. The branch‐and‐bound method can approach the global optimal solution with any desired tolerance in finite steps. The obtained optimal dropout policy may be interpreted as a network's QoS constraint whose enforcement provides a hard guarantee on the control system's performance. An example is used to illustrate the effectiveness of the achieved results. Copyright © 2012 John Wiley & Sons, Ltd.     

When narrow and wide complex tachycardia meet in one patient

Evaluation of arrhythmias, especially in the acute setting can be challenging. One of the most crucial steps is to accurately differentiate whether a tachyarrhythmia is of supraventricular (with aberrant conduction) or ventricular origin. A 12-lead electrocardiogram may be useful in some cases where specific morphology or features can be sought.     

Late arrhythmias in patients with new-onset persistent left bundle branch block after transcatheter aortic valve replacement using a balloon-expandable valve

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Left bundle branch–optimized cardiac resynchronization therapy (LOT-CRT): Results from an international LBBAP collaborative study group

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