Peer Review Certifies Quality and Innovation in Clinical Pharmacology & Therapeutics.

Clinical Pharmacology & Therapeutics (CPT) is an established voice of the discipline, a trusted source of new knowledge showcasing discovery, translation, and application of novel therapeutic paradigms to advance the management of patients and populations. Identifying, evaluating, prioritizing, and disseminating the best science along the discovery-development-regulatory-utilization continuum are responsibilities shared through peer review. To enhance the uniformity of this essential component of quality assurance and innovation, and maximize the value of the journal and its contents to authors, reviewers, and the readership, we review key concepts concerning peer review as it specifically relates to CPT.

Affairs of the Heart: Innovation in Cardiovascular Research and Development.

Cardiovascular disease represents the single largest contributor to morbidity and mortality, yet the flow of therapeutic innovation is lagging. Globally, academia, industry, and regulatory agencies must work together to address this gap, and ensure new disruptive therapeutic modalities to address growing needs of patients and society.

Clinical Pharmacology & Therapeutics: Past, Present, and Future.

Clinical Pharmacology & Therapeutics (CPT), the definitive and timely source for advances in human therapeutics, transcends the drug discovery, development, regulation, and utilization continuum to catalyze, evolve, and disseminate discipline-transformative knowledge. Prioritized themes and multidisciplinary content drive the science and practice of clinical pharmacology, offering a trusted point of reference. An authoritative herald across global communities, CPT is a timeless information vehicle at the vanguard of discovery, translation, and application ushering therapeutic innovation into modern healthcare.

Managing Innovation to Maximize Value Along the Discovery-Translation-Application Continuum.

Success in pharmaceutical development led to a record 51 drugs approved in the past year, surpassing every previous year since 1950. Technology innovation enabled identification and exploitation of increasingly precise disease targets ensuring next generation diagnostic and therapeutic products for patient management. The expanding biopharmaceutical portfolio stands, however, in contradistinction to the unsustainable costs that reflect remarkable challenges of clinical development programs. This annual Therapeutic Innovations issue juxtaposes advances in translating molecular breakthroughs into transformative therapies with essential considerations for lowering attrition and improving the cost-effectiveness of the drug-development paradigm. Realizing the discovery-translation-application continuum mandates a congruent approval, adoption, and access triad.

Pharmacological Modulation of Calcium Homeostasis in Familial Dilated Cardiomyopathy: An In Vitro Analysis From an RBM20 Patient-Derived iPSC Model.

For inherited cardiomyopathies, abnormal sensitivity to intracellular calcium (Ca(2+) ), incurred from genetic mutations, initiates subsequent molecular events leading to pathological remodeling. Here, we characterized the effect of ß-adrenergic stress in familial dilated cardiomyopathy (DCM) using human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes (CMs) from a patient with RBM20 DCM. Our findings suggest that ß-adrenergic stimulation accelerated defective Ca(2+) homeostasis, apoptotic changes, and sarcomeric disarray in familial DCM hiPSC-CMs. Furthermore, pharmacological modulation of abnormal Ca(2+) handling by pretreatment with ß-blocker, carvedilol, or Ca(2+) -channel blocker, verapamil, significantly decreased the area under curve, reduced percentage of disorganized cells, and decreased terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive apoptotic loci in familial DCM hiPSC-CMs after ß-adrenergic stimulation. These translational data provide patient-based in vitro analysis of ß-adrenergic stress in RBM20-deficient familial DCM hiPSC-CMs and evaluation of therapeutic interventions to modify heart disease progression, which may be personalized, but more importantly generalized in the clinic.

Big Data Transforms Discovery-Utilization Therapeutics Continuum.

Enabling omic technologies adopt a holistic view to produce unprecedented insights into the molecular underpinnings of health and disease, in part, by generating massive high-dimensional biological data. Leveraging these systems-level insights as an engine driving the healthcare evolution is maximized through integration with medical, demographic, and environmental datasets from individuals to populations. Big data analytics has accordingly emerged to add value to the technical aspects of storage, transfer, and analysis required for merging vast arrays of omic-, clinical-, and eco-datasets. In turn, this new field at the interface of biology, medicine, and information science is systematically transforming modern therapeutics across discovery, development, regulation, and utilization.

Bioinnovation Enterprise: An engine driving breakthrough therapies.

Biological advances have radically expanded our insights into the underpinnings of health and disease. New knowledge has formed the substrate for translation-expedited in turn by the biotechnology and pharmaceutical industry into novel therapeutic solutions impacting the management of patients and populations. Indeed, this Bioinnovation Enterprise has become the dominant growth sector in drug development and the engine driving the translation of breakthrough therapies worldwide. This annual Therapeutic Innovations issue highlights recent exceptional advances by the Bioinnovation Enterprise in translating molecular insights in pathobiology into transformative therapies.

Clinical Pharmacology & Therapeutics: the next five years.

It has been nearly ten years since we joined the editorial organization of Clinical Pharmacology & Therapeutics (CPT), as part of the American Society for Clinical Pharmacology and Therapeutics (ASCPT) family. During that tenure, the primary mandate has been the growth of CPT, recognized as one of the key voices of the discipline and the Society. Set goals were realized in concert with a strong editorial team, a diverse editorial board, a dedicated editorial staff, and outstanding authors, leveraging a leading publishing infrastructure and responding to the needs of a global readership, expanding membership, and the discipline as a whole. The impending decade anniversary, and the transition to a new publisher, offers a natural juncture to reflect on progress, and chart plans for the future of the Journal.

Managing the innovation supply chain to maximize personalized medicine.

Personalized medicine epitomizes an evolving model of care tailored to the individual patient. This emerging paradigm harnesses radical technological advances to define each patient's molecular characteristics and decipher his or her unique pathophysiological processes. Translated into individualized algorithms, personalized medicine aims to predict, prevent, and cure disease without producing therapeutic adverse events. Although the transformative power of personalized medicine is generally recognized by physicians, patients, and payers, the complexity of translating discoveries into new modalities that transform health care is less appreciated. We often consider the flow of innovation and technology along a continuum of discovery, development, regulation, and application bridging the bench with the bedside. However, this process also can be viewed through a complementary prism, as a necessary supply chain of services and providers, each making essential contributions to the development of the final product to maximize value to consumers. Considering personalized medicine in this context of supply chain management highlights essential points of vulnerability and/or scalability that can ultimately constrain translation of the biological revolution or potentiate it into individualized diagnostics and therapeutics for optimized value creation and delivery.

Molecular insights provide the critical path to disease mitigation.

The revolution in scientific innovation, driven by the engines of enabling technologies, is increasingly capable of deconstructing complex disease processes for the express purpose of reconstructing patient-specific solutions. These revelations in biological mechanisms provide the pressure points of opportunity for radical discovery and development to advance modern health care. Principles of mechanism-based discovery and their translation into therapeutic algorithms will, however, be challenged in the near term by emerging global public health crises that currently have no immediate solutions: chronic diseases, obesity, antibiotic-resistant infections, dementia, depression. The threat of these pandemics (multiplied in an increasingly aging population), the global burden of disease they represent, and their worldwide assault on human capital underscore the importance of continued and accelerated investments in science-propelled practice advancement, converting new knowledge into delivery of tangible health solutions. In that context, this annual issue of CPT on therapeutics innovations highlights remarkable recent successes in the discovery-development paradigm translating molecular innovations into diagnostic and therapeutic realities that transform the management of disease, impacting global health.

[Accuracy of morphological simulation for orthognatic surgery. Assessment of a 3D image fusion software]. / Précision des prédictions morphologiques en chirurgie orthognathique. Évaluation d'un procédé de fusion d'images 3D.

INTRODUCTION: The CT/CBCT data allows for 3D reconstruction of skeletal and untextured soft tissue volume. 3D stereophotogrammetry technology has strongly improved the quality of facial soft tissue surface texture. The combination of these two technologies allows for an accurate and complete reconstruction. The 3D virtual head may be used for orthognatic surgical planning, virtual surgery, and morphological simulation obtained with a software dedicated to the fusion of 3D photogrammetric and radiological images. TECHNICAL NOTE: The imaging material include: a multi-slice CT scan or broad field CBCT scan, a 3D photogrammetric camera. The operative image processing protocol includes the following steps: 1) pre- and postoperative CT/CBCT scan and 3D photogrammetric image acquisition; 2) 3D image segmentation and fusion of untextured CT/CBCT skin with the preoperative textured facial soft tissue surface of the 3D photogrammetric scan; 3) image fusion of the pre- and postoperative CT/CBCT data set virtual osteotomies, and 3D photogrammetric soft tissue virtual simulation; 4) fusion of virtual simulated 3D photogrammetric and real postoperative images, and assessment of accuracy using a color-coded scale to measure the differences between the two surfaces.

Interpreting networks in systems biology.

Implementation of network systems biology principles offers unparalleled opportunity to synthesize and integrate inherently complex high-throughput data for meaningful interpretation. Nonstochastic network templates constructed from extant knowledge facilitate large data set prioritization and prognostication, identifying context-dependent candidates for follow-up functional validation and interpretation. In conjunction, enrichment and representation assessment refines comprehension of network-associated molecular functions and biological processes. Together, exploiting intrinsic network properties provides a value-added decision-support instrument for data deconvolution in systems biomedicine.

Systems-based discovery advances drug development.

Drug development expenditures continue to escalate, in part reflecting inefficiencies in current drug discovery paradigms. Traditional drug discovery has been dichotomous, focusing either on phenotypic effects of distinct agents in biological systems, without knowledge of respective targets, or on target-based activities of specific molecules in cell-free assays. Driven by advances in biology, engineering, and informatics, new paradigms integrate phenotypic with target-based algorithms into comprehensive, systems-level approaches offering value-added strategies for optimized drug discovery.

Information hierarchies optimize patient-centered solutions.

Enabling science and information technologies has catalyzed a surge of biological, clinical, demographic, health services, and comparative-effectiveness data. While accelerating the deconvolution of complex pathophysiological, medical, social, and environmental networks and systems, these platforms have produced informational quanta devoid of contextualization. Therapeutic innovation is thus now challenged with moving beyond knowledge generation and curation to integrated solution-seeking paradigms that organize functionally related information, producing system-level insights into health and disease for optimized patient-centered outcomes. This annual issue on therapeutics innovations highlights emerging considerations for the generation and hierarchical organization of scientific and clinical information and its translation to advancing next-generation disease management.

Advancing pharmacometrics and systems pharmacology.

Pharmacometrics and systems pharmacology are emerging as principal quantitative sciences within drug development and experimental therapeutics. In recognition of the importance of pharmacometrics and systems pharmacology to the discipline of clinical pharmacology, the American Society for Clinical Pharmacology and Therapeutics (ASCPT), in collaboration with Nature Publishing Group and Clinical Pharmacology & Therapeutics, has established CPT: Pharmacometrics & Systems Pharmacology to inform the field and shape the discipline.

Computer assisted maxillofacial surgery.

Technical developments strongly influence modern medicine. This is especially obvious in imaging technology. Today, one of the most difficult tasks for surgeons is transferring all the available imaging information for their patients into one "complete picture". In the operation theatre, this picture then has to be applied to the patient. Computer-assisted surgery (CAS) promises to help in fulfilling this task and, thereby, to fully utilize the possibilities offered by modern imaging techniques. Today's standard procedures for CAS in the maxillofacial region are described in technical principles and clinical applications. They are evaluated and discussed based on the available literature and in light of practical experience of more than ten years in the field of CAS. In addition, an outlook is given into developments of the near future that have appeared in the current literature. While technical development is leading toward a complete integration of all processes surrounding the patient and his or her surgery, basic CAS has moved from research to clinical care. Before it is routinely used, more investigation about its effectiveness and benefits has to be done, especially since increasing medical care costs are an issue in all countries.