Despite improvements in pharmacological therapy and pacing, prognosis in advanced heart failure (HF) remains poor, with a 1‐year mortality of 25–50%. While heart transplantation provides excellent ...survival and quality of life for eligible patients, only a few can be offered this treatment due to shortage of donor organs. Implantable left ventricular assist device (LVAD) technology has improved considerably, and the currently used continuous flow devices may last >10 years in a patient. LVADs are being used increasingly both as bridge‐to‐transplantation and as destination therapy. Current studies report 1‐ and 2‐year survival after LVAD implantation of 80% and 70%, respectively. Outcome after LVAD implantation in stable patients is superior to that of ‘crash and burn’ patients or patients sliding on inotropes, favouring early referral and implantation. This review summarizes factors to consider when deciding on LVAD implantation such as age, co‐morbidity, and cardiac pathophysiology. Complications to LVAD therapy are reviewed. It is concluded that while complications with LVAD therapy are not uncommon, most are manageable, and current outcomes clearly justify use of LVADs in advanced HF.
In broad terms, "advanced" heart failure describes a clinical syndrome characterized by persistent or progressive symptoms and ventricular dysfunction despite guideline-directed medical therapy. ...Clinically the definition is often dependent upon iterative and integrated clinical assessments to identify patients with worsening status and reliance on specific therapies. This review examines current consensus definitions, highlights strategies for risk stratification and prognostication, and examines short- and long-term treatment strategies. Lastly, this paper explores future directions of research and development for the field.
Over the last 2 decades, numerous innate inflammatory mediators have been reported to be upregulated in pathologically vulnerable regions of the brain in Alzheimer's disease (AD). These data have led ...to a reexamination of the dogma of brain immunologic privilege and to new studies that examine the role of the innate inflammatory response in a number of other neurologic disorders, particularly Parkinson's disease and human immunodeficiency virus dementia. In addition, basic science discoveries about neuroinflammation are now beginning to move to the clinic. More than 20 epidemiologic surveys have consistently demonstrated that common non‐steroidal anti‐inflammatory drugs may protect against the development of AD. By contrast, anti‐inflammatory treatment trials for existing AD have typically shown little to no effect on halting or reversing the disorder, although the agents tested have often been at odds with those suggested by the epidemiologic and basic science results. The extensive literature on innate inflammation and neurologic disease notwithstanding, three fundamental questions still remain to be answered fully. First, are innate inflammatory responses a cause of neurologic disease or merely a more sophisticated means than previously imagined for removing the detritus left by more primary pathogenic mechanisms? Second, can anti‐inflammatory agents effectively treat existing neurologic disease, or is a protective strategy in high‐risk patients the only reasonable option? Third, whether for protection or treatment, what is the best choice of anti‐inflammatory agent given the basic science mechanisms and epidemiologic results that have been reported?
High-resolution structure–activity analysis of polypeptides requires amino acid structures that are not present in the universal genetic code. Examination of peptide and protein interactions with ...this resolution has been limited by the need to individually synthesize and test peptides containing nonproteinogenic amino acids. We describe a method to scan entire peptide sequences with multiple nonproteinogenic amino acids and, in parallel, determine the thermodynamics of binding to a partner protein. By coupling genetic code reprogramming to deep mutational scanning, any number of amino acids can be exhaustively substituted into peptides, and single experiments can return all free energy changes of binding. We validate this approach by scanning two model protein-binding peptides with 21 diverse nonproteinogenic amino acids. Dense structure–activity maps were produced at the resolution of single aliphatic atom insertions and deletions. This permits rapid interrogation of interaction interfaces, as well as optimization of affinity, fine-tuning of physical properties, and systematic assessment of nonproteinogenic amino acids in binding and folding.
Coupled folding and binding of intrinsically disordered proteins (IDPs) is prevalent in biology. As the first step toward understanding the mechanism of binding, it is important to know if a reaction ...is ‘diffusion-limited’ as, if this speed limit is reached, the association must proceed through an induced fit mechanism. Here, we use a model system where the ‘BH3 region’ of PUMA, an IDP, forms a single, contiguous α-helix upon binding the folded protein Mcl-1. Using stopped-flow techniques, we systematically compare the rate constant for association (k +) under a number of solvent conditions and temperatures. We show that our system is not ‘diffusion-limited’, despite having a k + in the often-quoted ‘diffusion-limited’ regime (105–106 M–1 s–1 at high ionic strength) and displaying an inverse dependence on solvent viscosity. These standard tests, developed for folded protein–protein interactions, are not appropriate for reactions where one protein is disordered.
In 2018, the Organ Procurement and Transplantation Network (OPTN) modified adult heart allocation to better stratify candidates and provide broader access to the most medically urgent candidates. We ...analyzed OPTN data that included waiting list and transplant characteristics, geographical distribution, and early outcomes 1 year before (pre: October 18, 2017‐October 17, 2018) and following (post: October 18, 2018‐October 17, 2019) implementation. The number of adult heart transplants increased from 2954 pre‐ to 3032 postimplementation. Seventy‐eight percent of transplants in the post era were for the most medically urgent (statuses 1‐3) compared to 68% for status 1A in the pre era. The median distance between the donor hospital and transplant center increased from 83 to 216 nautical miles, with an increase in total ischemic time from 3 to 3.4 hours (all P < .001). Waiting list mortality was not different across eras (14.8 vs 14.9 deaths per 100 patient‐years pre vs post respectively). Posttransplant patient survival was not different, 93.6% pre and 92.8% post. There is early evidence that the heart allocation policy has enhanced stratification of candidates by their medical urgency and broader distribution for the most medically urgent candidates with minimal impact on overall waiting list mortality and posttransplant outcomes.
This article compares timeframes before and after implementation of a revised heart allocation policy, showing increased travel distance, more transplants for the most medically urgent, and similar waitlist and posttransplant mortality rates.
Changes in United States heart allocation: A community energized to improve policy Rogers, Joseph G.
Journal of thoracic and cardiovascular surgery/The Journal of thoracic and cardiovascular surgery/The journal of thoracic and cardiovascular surgery,
December 2016, 2016-12-00, 20161201, Letnik:
152, Številka:
6
Journal Article
Recenzirano
Odprti dostop
Donor heart allocation in the United States has not evolved in concert with changes in the characteristics of patients on the waiting list or evolution in technology. Data showing the growing ...population of patients with advanced heart failure coupled with the relatively fixed number of cardiac donors and regional access disparities motivated the United Network for Organ Sharing (UNOS) Thoracic Committee to reexamine candidate prioritization and broader organ sharing. The resultant proposed policy change stratifies patients in a more granular manner based primarily on wait-list mortality and is designed to expand the geographic boundaries to permit greater access to donor hearts for the most critically ill patients awaiting transplant.
Ribosomal peptide synthesis begins almost exclusively with the amino acid methionine, across all domains of life. The ubiquity of methionine initiation raises the question; to what extent could ...polypeptide synthesis be realized with other amino acids, proteinogenic or otherwise? This highlight describes the breadth of building blocks now known to be accepted by the ribosome initiation machinery, from subtle methionine analogues to large exotic non-proteinogenic structures. We outline the key methodological developments that have enabled these discoveries, including the exploitation of methionyl-tRNA synthetase promiscuity, synthetase and tRNA engineering, and the utilization of artificial tRNA-loading ribozymes, flexizymes. Using these methods, the number and diversity of validated initiation building blocks is rapidly expanding permitting the use of the ribosome to synthesize ever more artificial polymers in search of new functional molecules.
This highlight describes the breadth of building blocks now known to be accepted by the ribosome initiation machinery, from subtle methionine analogues to large exotic non-proteinogenic structures.
We describe a procedure for designing proteins with backbones produced by varying the parameters in the Crick coiled coil–generating equations. Combinatorial design calculations identify low-energy ...sequences for alternative helix supercoil arrangements, and the helices in the lowest-energy arrangements are connected by loop building. We design an antiparallel monomeric untwisted three-helix bundle with 80-residue helices, an antiparallel monomeric right-handed four-helix bundle, and a pentameric parallel left-handed five-helix bundle. The designed proteins are extremely stable (extrapolated ΔGfold > 60 kilocalories per mole), and their crystal structures are close to those of the design models with nearly identical core packing between the helices. The approach enables the custom design of hyperstable proteins with fine-tuned geometries for a wide range of applications.
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