Comparative effectiveness of revascularization strategies for early coronary artery disease: A multicenter analysis.

OBJECTIVES: The goal of this analysis was to examine the comparative effectiveness of coronary artery bypass grafting versus percutaneous coronary intervention among patients aged less than 60 years. METHODS: We performed a multicenter, retrospective analysis of all cardiac revascularization procedures from 2005 to 2015 among 7 medical centers. Inclusion criteria were age less than 60 years and 70% stenosis or greater in 1 or more major coronary artery distribution. Exclusion criteria were left main 50% or greater, ST-elevation myocardial infarction, emergency status, and prior revascularization procedure. After applying inclusion and exclusion criteria, the final study cohort included 1945 patients who underwent cardiac surgery and 2938 patients who underwent percutaneous coronary intervention. The primary end point was all-cause mortality stratified by revascularization strategy. Secondary end points included stroke, repeat revascularization, and 30-day mortality. We used inverse probability weighting to balance differences among the groups. RESULTS: After adjustment, there was no significant difference in 30-day mortality (surgery: 0.8%; percutaneous coronary intervention: 0.7%, P = .86) for patients with multivessel disease. Patients undergoing surgery had a higher risk of stroke (1.3% [n = 25] vs 0.07% [n = 2], P < .001). Overall, surgery was associated with superior 10-year survival compared with percutaneous coronary intervention (hazard ratio, 0.71; 95% confidence interval, 0.57-0.88; P = .002). Repeat procedures occurred in 13.4% (n = 270) of the surgery group and 36.4% (n = 1068) of the percutaneous coronary intervention group, with both groups mostly undergoing percutaneous coronary intervention as their second operation. Accounting for death as a competing risk, at 10 years, surgery resulted in a lower cumulative incidence of repeat revascularization compared with percutaneous coronary intervention (subdistribution hazard ratio, 0.34; 95% confidence interval, 0.28-0.40; P < .001). CONCLUSIONS: Among patients aged less than 60 years with 2-vessel disease that includes the left anterior descending or 3-vessel coronary artery disease, surgery was associated with greater long-term survival and decreased risk of repeat revascularization.

Reducing contrast-induced acute kidney injury using a regional multicenter quality improvement intervention.

BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is associated with increased morbidity and mortality after percutaneous coronary interventions and is a patient safety objective of the National Quality Forum. However, no formal quality improvement program to prevent CI-AKI has been conducted. Therefore, we sought to determine whether a 6-year regional multicenter quality improvement intervention could reduce CI-AKI after percutaneous coronary interventions. METHODS AND RESULTS: We conducted a prospective multicenter quality improvement study to prevent CI-AKI (serum creatinine increase ≥0.3 mg/dL within 48 hours or ≥50% during hospitalization) among 21 067 nonemergent patients undergoing percutaneous coronary interventions at 10 hospitals between 2007 and 2012. Six intervention hospitals participated in the quality improvement intervention. Two hospitals with significantly lower baseline rates of CI-AKI, which served as benchmark sites and were used to develop the intervention, and 2 hospitals not receiving the intervention were used as controls. Using time series analysis and multilevel poisson regression clustering to the hospital level, we calculated adjusted risk ratios for CI-AKI comparing the intervention period to baseline. Adjusted rates of CI-AKI were significantly reduced in hospitals receiving the intervention by 21% (risk ratio, 0.79; 95% confidence interval: 0.67-0.93; P=0.005) for all patients and by 28% in patients with baseline estimated glomerular filtration rate <60 mL/min per 1.73 m(2) (risk ratio, 0.72; 95% confidence interval: 0.56-0.91; P=0.007). Benchmark hospitals had no significant changes in CI-AKI. Key qualitative system factors associated with improvement included multidisciplinary teams, limiting contrast volume, standardized fluid orders, intravenous fluid bolus, and patient education about oral hydration. CONCLUSIONS: Simple cost-effective quality improvement interventions can prevent ≤1 in 5 CI-AKI events in patients with undergoing nonemergent percutaneous coronary interventions.

Breaking gridlock: the determinants of health policy change in Congress.

Prior to the 2010 health care reforms, scholars often commented that health policy making in Congress was mired in political gridlock, that reforms were far more likely to fail than to succeed, and that the path forward was unclear. In light of recent events, new narratives are being advanced. In formulating these assessments, scholars of health politics tend to analyze individual major reform proposals to determine why they succeeded or failed and what lessons could be drawn for the future. Taking a different approach, we examine all health policies proposed in the U.S. House of Representatives between 1973 and 2002. We analyze these bills' fates and the effectiveness of their sponsors in guiding these proposals through Congress. Setting these proposed policies against a baseline of policy advancements in other areas, we demonstrate that health policy making has indeed been far more gridlocked than policy making in most other areas. We then isolate some of the causes of this gridlock, as well as some of the conditions that have helped to bring about health policy change.

2-Acetyl-pyridinium bromanilate.

In the crystal of the title mol-ecular salt (systematic name: 2-acetyl-pyridinium 2,5-dibromo-4-hydr-oxy-3,6-dioxocyclo-hexa-1,4-dienolate), C(7)H(8)NO(+)·C(6)HBr(2)O(4) (-), centrosymmetric rings consisting of two cations and two anions are formed, with the components linked by alternating O-H⋯O and N-H⋯O hydrogen bonds. Short O⋯Br contacts [3.243 (2) and 3.359 (2) Å] may help to consolidate the packing.

p53 protein or BID protein select the route to either apoptosis (programmed cell death) or to cell cycle arrest opposing carcinogenesis after DNA damage by ROS.

p53 is a tumour-suppressor protein of human cells that prevents their entry into the route to carcinogenesis. Furthermore, p53 protein acts at the p53-response loci in genomic DNA to facilitate the switch-on of genes that can be expressed by the biosynthesis of routing-proteins for apoptosis or stalling of cellular proliferation (via cell cycle progression checkpoint arrests). Moreover, oxidative stress by reactive oxygen species (ROS) such as the hydroxyl radical (*OH) produced by ionizing radiation (carcinogenic) triggers p53 activation in response to the damage of DNA (followed by initiation of DNA-repair mechanisms). Phosphorylation of the BID protein may lead to the recovery from DNA-damage by ROS.

Crohn's disease leading to bowel cancer may be avoided by consumption of soya isoflavones: adjunct-chemotherapy with oxaliplatin.

Crohn's disease (inflammatory bowel syndrome) is caused by gut exposure to harmful reactive oxygen species (ROS) derived from oxygen, such as the superoxide anion ((.)O(2)'), the hydroxyl radical ((.)OH) or the peroxide anion (O(2)''): the superoxide anion is generated by breakdown of oxygen-peroxidised phospholipids membranes. Crohn's disease predisposes to bowel cancer in susceptible human sub-populations. It may be preventable in these as yet unpredictable sub-populations by dietary-based intervention strategies, such as the daily consumption of appropriate quantities of soya isoflavones. These isoflavonoids are ROS-directed antioxidants, and they include the phytoestrogens, daidzin and genistin present in soya foods (consumed also in dietary supplements). Oxaliplatin is a platinum-containing Pt(II) organometallic therapeutic agent that binds to tumour DNA. Oxaliplatin may provide, therefore, a form of chemotherapy for some bowel cancers especially when administered in adjunct-chemotherapies that employ inhibitors of proliferation of the tumour cell. Such inhibitors include 5-fluorouracil, which prevents the correct replication of tumour cell DNA that is an essential prerequisite for bowel tumour growth. Furthermore, the therapeutic index for adjunct-chemotherapy with toxic inhibitors of DNA replication and expression could potentially be raised significantly by an associated dietary regime. This should include supplementation daily, per or, with antioxidant isoflavones (or other bioflavonoids) in selected cases of unresponsive cancer of the bowel, to possibly seek to trigger the pathway of apoptosis (programmed cell death) in the tumour cells preferentially.

Oxygen-induced reperfusion-injury is caused by ROS: Amelioration is possible by recombinant-DNA antioxidant enzymes and mimics in selected tissues.

Billions of years of photolytic cleavage of the water molecule has led to a build-up at sea-level of a "toxic" oxygen concentration in the atmosphere (to 20%). Unfortunately, this dioxygen is likely to be converted in the mitochondria (cell organelles) during cellular respiration to generate reactive oxygen species (ROS); including free-radicals such as superoxide anion (.O2') and hydroxyl radical (.OH) (peroxide O2") a ROS is not a free radical because its electrons are paired). Development of recombinant-DNA improved isoenzyme forms (or mimics) of antioxidant enzymes such as superoxide dismutases is predicted in this hypothesis to be utilised to ameliorate reperfusion-injury (and other oxygen-induced molecular pathology). Introduction into the human genome of the genes for expression of antioxidant enzymes, to order in particular tissues, is imminent. Furthermore, O2 itself will be recognised universally as a harmful gas that can subject the cell to oxidative stress; because it produces ROS, such as the superoxide anion when it acts as the terminal electron acceptor in cellular respiration in the production of water from hydrogen ions in mitochondria. In conclusion, therefore, oxygen-induced injury in humans can no longer be accepted during medical techniques such as reperfusion procedures, because this is associated with reperfusion-injury that can be the cause of several serious medical conditions arising from biomolecular pathology. Some of this is caused by isoforms of cytochromes P450 (CYP; EC 1.14.14.1) such as 3A4, 2D6 and 2C19. These can generate ROS in the liver at low substrate concentrations by futile recycling of oxygen.

Therapeutic-antagonists of oestrogens can be produced for cancer and other therapies using cytochromes P450 (CYP).

Oestrogens such as 17beta-oestradiol initiates nuclear-gene transcription in gender-specified tissues such as the ovaries and mammaries; and unfortunately too in cancer cells derived from target tissues. Consequently, there has been the development of novel agents for particular cancer therapies that are antagonists of oestrogens for oestrogen-receptor (ER) binding and of drugs with ER-specific interference RNA (RNAi) abilities. Therapeutic-antagonists of oestrogens will be re-designed and biosynthesised and deployed to circumvent the gene DNA-transcription abilities of oestrogens and mimics: and their metabolites in oestrogen-target tissues (see above). Furthermore, opportunities will emerge for adjunct-chemotherapy of particular tissue cancers: and in the prevention of recurrence outcomes. Cytochromes P450 can play an important part in these developments especially for the production of novel metabolites of oestrogens as therapeutic-antagonists of oestrogen-stimulated cancers.

Oestrogen-receptors (ER) are likely to be promiscuous: wider role for oestrogens and mimics.

The anti-breast cancer drug tamoxifen that binds to ER is metabolised in human liver by CYP2D6 isoenzyme, whilst the metabolism of 17beta-oestradiol (by hydroxylation) is by phase I biotransformation in the liver to 2-hydroxyoestradiol and to 4-hydroxyoestradiol respectively by two isoenzymes of this mixed function oxidase CYP cytochromes P450 (EC 1.14.14.1); CYP1A2 and by CYP1B1. Nevertheless, it appears that the receptor (AhR) itself causes the expression of oestrogen-regulated target genes (studied by binding of dioxin). This is the result of an unknown signalling mechanism at the genome that is triggered directly by this receptor by binding promiscuously to ER (alpha or beta) sites. This has been observed even in the absence of oestrogens or mimics therefore in genome-binding investigations of target tissues such as uterus: oestrogen-receptor (ER) is likely to be promiscuous therefore. Furthermore, AhR (polycyclic aromatic hydrocarbon receptor), when activated by the binding of aromatic hydrocarbons (Ah) forms a complex with the aryl hydrocarbon nuclear-translocator chaperone protein (Arnt). It is this binding to xenobiotic response elements in DNA that initiates expression of the appropriate oestrogen-regulated target-genes in the uterus and other target tissues (including mammary, ovaries, and brain). The likely promiscuity of oestrogen receptors is proposed to be the cause of numerous side effects when oestrogen is involved in therapy, these can be manifest in hormone replacement therapy (HRT) and in the incorporation of synthetic oestrogens in the wide varieties of oral contraceptives now available.

p53 Protein is activated by Pin1: and also by Cu-SOD prion-like enzyme.

Peptidyl-proline isomerase (Pin1) is able to trigger some conformationally important change in the p53 protein: there is notable protection by p53 (tumour suppressor protein) of human cells that prevents their entry into the carcinogenesis-committed routeway. Pin1 controls the ready (low energy change) equilibrium between the cis and trans distinctive folding configurations differentially at a proline residue: this amino acid residue in proteins is unique in bending sharply its peptide chain (to 90 degrees change): in the cis rather than trans orientation with respect to the peptide bond to residue X "upstream" linked as XCONHR. Moreover p53 protein can arrest a cell cycle progression (or trigger apoptosis) by acting as a transcription factor to nuclear DNA acting at p53 nuclear responsive element controlling a larger number of genes that produce proteins that stop cell growth or stimulate apoptosis, in stressed cells. Oxidative stress by reactive oxygen species (ROS) is carcinogenic but also stops cell growth and triggers apoptosis, Cu-SOD removes ROS (see figure). Could superoxide dismutase (Cu-SOD), therefore, provide the DNA-damage direct second route (first route is binding of Pin1) in DNA-damaged cells to p53 activation? The p53 protein that prevents carcinogenesis is activated by Pin1. In addition, this p53 tumour suppressor protein is activated by Cu-SOD.

Elimination of major side effects due to ROS of therapeuticals through biotransformation control of the 57 cytochromes P450 isoenzymes.

Drug biotransformations are controlled in the body by tissue-differentiated choice of a selection of the induced and constitutive 57 isoforms of the human cytochromes P450 (CYP). CYP are the mixed function oxidase enzyme family (EC 1.14.14.1: mono-oxygenases that contain iron-dependent protohaematin IX). Many of the major side effects of clinical therapeutical agents have been attributed to the generation of highly toxic "reactive oxygen species" (ROS). Such ROS generation can be circumvented however by the ability to exert control over which forms of CYP are present: and as to which are bioactive in tissues other than the drug-target ones. Up to 57 isoenzymes of human cytochromes P450 are likely to be present: generation of a variety of species of ROS can be anticipated therefore with outcomes that include cancer, premature ageing, heart (arterial) damage and osteoporosis (in association with oestrogen/testosterone imbalance). Moreover, therapeutic vaccines could be constructed to remove the most harmful forms of cytochromes P450. Designer CYP protein enzymes can now be readily constructed by genetic engineering techniques: these include site-directed mutagenesis to place the modified cyp gene in suitable enzyme expression location in particular tissues only. Furthermore, gene therapy could be arranged to augment (or replace activities lost) for example the production of insulin in the Islets of Langerhans of the pancreas by production of the appropriate form of human insulin in the liver.

Gene therapy for the circumvention of inborn errors of metabolism (IEM) caused by single-nucleotide-polymorphisms (SNPs).

Single nucleotide polymorphisms (SNPs) are the result of point mutations in nuclear (and mitochondrial) DNA. Such localised damage to DNA (and its replicative mechanisms) may not be excised fully by the DNA repair mechanism in the genome: and therefore can become inheritable; subsequently to manifest later as an inborn error of metabolism (IEM). Causes of mutagenic damage to the DNA can include background radiation (such as emitted by radon gas), and by reactive oxygen species (ROS): and also by mutagenic chemicals that occur naturally (inter alia in the diet). Other causes of DNA damage are variable environmental hazards such as solar-derived short wave ultraviolet light A. Gene therapy involves the placement of missing genes into particular tissues by the harnessing of suitable vectors (originally these were animal viruses such as SV40). For example, gene therapy in the rat for diabetes has succeeded by liver-production of insulin (using genes obtained from pancreatic Islets of Langerhans cells). Many inborn errors of metabolism could be treated in this way: examples may include 100 haemoglobinopathies (such as sickle cell anaemia), phenylketonuria; and other diseases caused by lack of tissue-production of a particular enzyme (in its catalytically-active conformation).

Dietary alkyl thiol free radicals (RSS) can be as toxic as reactive oxygen species (ROS).

Harmful free-radicals, such as superoxide anion (a reactive oxygen species: ROS) are produced during aerobic respiration in all tissues because of only partial reduction of some oxygen molecules in mitochondria: this is due to one-electron reduction of each atom of oxygen, instead of four-electron reduction per molecule of oxygen to form water. Similarly, in liver, and many other tissues such as lung and brain, an electron transfer chain from NADPH to water occurs (with insertion of one oxygen atom into xenobiotic substrates) that uses cytochromes P450 (EC 1.14.14.1) as the electron acceptor. Here, futile recycling of electrons, in the absence of substrate produces the superoxide anion (*O2')--see above. Reactive oxygen species (ROS) and reactive sulfur species (RSS) may act in unison to damage biomolecules. For example, damage to biomolecules can occur by attack on phospholipid membranes, and also the targeting of DNA results in mutagenicity and associated carcinogenicity-related mutagenic damage. Free radical injury to low density lipoprotein (LDL) has been identified in the causation of atherosclerosis implicated in arterial disease, which can lead to heart attack and strokes.

A genomewide scan for early-onset coronary artery disease in 438 families: the GENECARD Study.

A family history of coronary artery disease (CAD), especially when the disease occurs at a young age, is a potent risk factor for CAD. DNA collection in families in which two or more siblings are affected at an early age allows identification of genetic factors for CAD by linkage analysis. We performed a genomewide scan in 1,168 individuals from 438 families, including 493 affected sibling pairs with documented onset of CAD before 51 years of age in men and before 56 years of age in women. We prospectively defined three phenotypic subsets of families: (1) acute coronary syndrome in two or more siblings; (2) absence of type 2 diabetes in all affected siblings; and (3) atherogenic dyslipidemia in any one sibling. Genotypes were analyzed for 395 microsatellite markers. Regions were defined as providing evidence for linkage if they provided parametric two-point LOD scores >1.5, together with nonparametric multipoint LOD scores >1.0. Regions on chromosomes 3q13 (multipoint LOD = 3.3; empirical P value <.001) and 5q31 (multipoint LOD = 1.4; empirical P value <.081) met these criteria in the entire data set, and regions on chromosomes 1q25, 3q13, 7p14, and 19p13 met these criteria in one or more of the subsets. Two regions, 3q13 and 1q25, met the criteria for genomewide significance. We have identified a region on chromosome 3q13 that is linked to early-onset CAD, as well as additional regions of interest that will require further analysis. These data provide initial areas of the human genome where further investigation may reveal susceptibility genes for early-onset CAD.