Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction.

BACKGROUND: Whether revascularization by percutaneous coronary intervention (PCI) can improve event-free survival and left ventricular function in patients with severe ischemic left ventricular systolic dysfunction, as compared with optimal medical therapy (i.e., individually adjusted pharmacologic and device therapy for heart failure) alone, is unknown. METHODS: We randomly assigned patients with a left ventricular ejection fraction of 35% or less, extensive coronary artery disease amenable to PCI, and demonstrable myocardial viability to a strategy of either PCI plus optimal medical therapy (PCI group) or optimal medical therapy alone (optimal-medical-therapy group). The primary composite outcome was death from any cause or hospitalization for heart failure. Major secondary outcomes were left ventricular ejection fraction at 6 and 12 months and quality-of-life scores. RESULTS: A total of 700 patients underwent randomization - 347 were assigned to the PCI group and 353 to the optimal-medical-therapy group. Over a median of 41 months, a primary-outcome event occurred in 129 patients (37.2%) in the PCI group and in 134 patients (38.0%) in the optimal-medical-therapy group (hazard ratio, 0.99; 95% confidence interval [CI], 0.78 to 1.27; P = 0.96). The left ventricular ejection fraction was similar in the two groups at 6 months (mean difference, -1.6 percentage points; 95% CI, -3.7 to 0.5) and at 12 months (mean difference, 0.9 percentage points; 95% CI, -1.7 to 3.4). Quality-of-life scores at 6 and 12 months appeared to favor the PCI group, but the difference had diminished at 24 months. CONCLUSIONS: Among patients with severe ischemic left ventricular systolic dysfunction who received optimal medical therapy, revascularization by PCI did not result in a lower incidence of death from any cause or hospitalization for heart failure. (Funded by the National Institute for Health and Care Research Health Technology Assessment Program; REVIVED-BCIS2 ClinicalTrials.gov number, NCT01920048.).

Arrhythmia and Death Following Percutaneous Revascularization in Ischemic Left Ventricular Dysfunction: Prespecified Analyses From the REVIVED-BCIS2 Trial.

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82-1.30]; P=0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01920048.

Quantitative N- or C-Terminal Labelling of Proteins with Unactivated Peptides by Use of Sortases and a d-Aminopeptidase.

Quantitative and selective labelling of proteins is widely used in both academic and industrial laboratories, and catalytic labelling of proteins using transpeptidases, such as sortases, has proved to be a popular strategy for such selective modification. A major challenge for this class of enzymes is that the majority of procedures require an excess of the labelling reagent or, alternatively, activated substrates rather than simple commercially sourced peptides. We report the use of a coupled enzyme strategy which enables quantitative N- and C-terminal labelling of proteins using unactivated labelling peptides. The use of an aminopeptidase in conjunction with a transpeptidase allows sequence-specific degradation of the peptide by-product, shifting the equilibrium to favor product formation, which greatly enhances the reaction efficiency. Subsequent optimisation of the reaction allows N-terminal labelling of proteins using essentially equimolar ratios of peptide label to protein and C-terminal labelling with only a small excess. Minimizing the amount of substrate required for quantitative labelling has the potential to improve industrial processes and facilitate the use of transpeptidation as a method for protein labelling.

Molecular Detection of Candidatus Orientia chuto in Wildlife, Saudi Arabia.

Scrub typhus is a zoonosis caused by 3 species of Orientia bacteria, including Candidatus Orientia chuto. This species is known only from a human case in Dubai and infections in wildlife in Kenya. We report molecular detection of Candidatus O. chuto in 2 wild rodent species from Saudi Arabia.

Myocardial viability testing: all STICHed up, or about to be REVIVED?

Patients with ischaemic left ventricular dysfunction frequently undergo myocardial viability testing. The historical model presumes that those who have extensive areas of dysfunctional-yet-viable myocardium derive particular benefit from revascularization, whilst those without extensive viability do not. These suppositions rely on the theory of hibernation and are based on data of low quality: taking a dogmatic approach may therefore lead to patients being refused appropriate, prognostically important treatment. Recent data from a sub-study of the randomized STICH trial challenges these historical concepts, as the volume of viable myocardium failed to predict the effectiveness of coronary artery bypass grafting. Should the Heart Team now abandon viability testing, or are new paradigms needed in the way we interpret viability? This state-of-the-art review critically examines the evidence base for viability testing, focusing in particular on the presumed interactions between viability, functional recovery, revascularization and prognosis which underly the traditional model. We consider whether viability should relate solely to dysfunctional myocardium or be considered more broadly and explore wider uses of viability testingoutside of revascularization decision-making. Finally, we look forward to ongoing and future randomized trials, which will shape evidence-based clinical practice in the future.

Challenges in the use of sortase and other peptide ligases for site-specific protein modification.

Site-specific protein modification is a widely-used biochemical tool. However, there are many challenges associated with the development of protein modification techniques, in particular, achieving site-specificity, reaction efficiency and versatility. The engineering of peptide ligases and their substrates has been used to address these challenges. This review will focus on sortase, peptidyl asparaginyl ligases (PALs) and variants of subtilisin; detailing how their inherent specificity has been utilised for site-specific protein modification. The review will explore how the engineering of these enzymes and substrates has led to increased reaction efficiency mainly due to enhanced catalytic activity and reduction of reversibility. It will also describe how engineering peptide ligases to broaden their substrate scope is opening up new opportunities to expand the biochemical toolkit, particularly through the development of techniques to conjugate multiple substrates site-specifically onto a protein using orthogonal peptide ligases.

Combined Application of Orthogonal Sortases and Depsipeptide Substrates for Dual Protein Labeling.

Staphylococcus aureus sortase A is a transpeptidase that has been extensively exploited for site-specific modification of proteins and was originally used to attach a labeling reagent containing an LPXTG recognition sequence to a protein or peptide with an N-terminal glycine. Sortase mutants with other recognition sequences have also been reported, but in all cases, the reversibility of the transpeptidation reaction limits the efficiency of sortase-mediated labeling reactions. For the wildtype sortase, depsipeptide substrates, in which the scissile peptide bond is replaced with an ester, allow effectively irreversible sortase-mediated labeling as the alcohol byproduct is a poor competing nucleophile. In this paper, the use of depsipeptide substrates for evolved sortase variants is reported. Substrate specificities of three sortases have been investigated allowing identification of an orthogonal pair of enzymes accepting LPEToG and LPESoG depsipeptides, which have been applied to dual N-terminal labeling of a model protein mutant containing a second, latent N-terminal glycine residue. The method provides an efficient orthogonal site-specific labeling technique that further expands the biochemical protein labeling toolkit.

Written in the stars: did your specialty choose you?

PURPOSE OF THE STUDY: Established over 2000 years ago, horoscopes remain a regular feature in contemporary society. We aimed to assess whether there could be a link between zodiac sign and medical occupation, asking the question-did your specialty choose you? STUDY DESIGN: A questionnaire-based study was distributed using an online survey tool. Questions explored the zodiac sign, specialty preferences and personality features of physicians. RESULTS: 1923 physicians responded between February and March 2020. Variations in personality types between different medical specialties were observed, introverts being highly represented in oncology (71.4%) and rheumatology (65.4%), and extroverts in sexual health (55%), gastroenterology (44.4%) and obstetrics and gynaecology (44.2%) (p<0.01). Proportions of zodiac signs in each specialty also varied; for example, cardiologists were more likely to be Leo compared with Aries (14.4% vs 3.9%, p=0.047), medical physicians more likely Capricorn than Aquarius (10.4% vs 6.7%, p=0.02) and obstetricians and gynaecologists more likely Pisces than Sagittarius (17.5% vs 0%, p=0.036). Intensive care was the most commonly reported second choice career, but this also varied between zodiac signs and specialties. Fountain pen use was associated with extroversion (p=0.049) and gastroenterology (p<0.01). CONCLUSIONS: Personality types vary in different specialties. There may be links to zodiac signs which warrant further investigation.

Foundation rotations in medical training: is it love at first sight?

PURPOSE OF STUDY: Factors influencing physician specialty choice is a prominent topic given the recruitment challenges faced by various specialties. We aimed to assess whether specialty exposure in the first foundation year was a positive predictive factor for permanent career choice. STUDY DESIGN: A questionnaire-based study was distributed online using a survey tool. Questions recorded the foundation rotations of participants as well as their chosen medical specialty. RESULTS: 1181 responses were included in the analysis. 23% of respondents had undertaken a Foundation Year 1 (F1) rotation in their career specialty. Having undertaken a foundation rotation in anaesthetics, cardiology, emergency medicine, endocrinology, gastroenterology, genito-urinary medicine, intensive care, obstetrics and gynaecology, oncology, paediatrics, palliative care, psychiatry, radiology, respiratory and rheumatology was found to be statistically significantly linked to choosing that specialty as a career (p<0.01). There was a significant correlation between the second foundation rotation and career choice (p=0.02). CONCLUSIONS: For many specialties, direct experience within foundation training has a positive effect on later career choice.

Sodium-glucose co-transporter 2 inhibitors and heart failure-the present and the future.

Type 2 diabetes mellitus is associated with an increased risk of heart failure. The prevalence of type 2 diabetes mellitus is on an upward trend. Heart failure represents one of the major causes for hospitalisation and mortality despite advances in management. Recent cardiovascular outcome trials have demonstrated that sodium-glucose co-transporter 2 inhibitors, which were introduced to the market in 2013, can incur a clinically significant risk reduction in heart failure outcomes in such patients. In this review, we discuss the epidemiology and pathophysiology of heart failure in diabetes and explore the landmark trials, the potential mechanisms of benefit of SGLT-2 inhibitors in heart failure, how the trials have led to major changes in treatment guidelines, and future potential directions for use of these drugs, including in those without diabetes.

Antiplatelet therapy in pregnancy: A systematic review.

OBJECTIVE: To systematically review contemporary data on the safety of clopidogrel and newer antiplatelet agents in pregnant women, with particular attention to maternal and neonatal complications. METHODS: The review protocol was published via PROSPERO (ID 42020165235) and conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). Databases were searched using MeSH and free text terms encompassing the included antiplatelets, relevant indications, and pregnancy. Included studies reported the drug dose, the stage of pregnancy at which it was administered, and at least one primary or secondary outcome relating to pregnancy. The primary outcome was reporting of complications associated with antiplatelet use in pregnancy. RESULTS: The search yielded 5271 results. 39 publications were included, incorporating 42 live births. The mean age of women was 34.6 years. Seven different antiplatelet agents were described, clopidogrel being most frequent (n = 37). 14 women received antiplatelet therapy in the first trimester. 14 women had regional anaesthesia (12 while taking clopidogrel), all without complication. Two women developed bleeding post caesarean section. There were no recorded neonatal delivery complications. Two neonates had congenital anomalies not felt to be related to maternal antiplatelet use. CONCLUSIONS: This systematic review describes outcomes for both mothers and neonates when exposed to clopidogrel at varying durations throughout gestation, and does not suggest higher than acceptable risk, with a congenital anomaly rate comparable to background risk. Evidence for other antiplatelet agents remains limited. Regional anaesthesia should be offered, with recommendation to stop prior to delivery in line with national guidance and in the context of individualised decision making.

Deception of Ambient Temperature Does Not Elicit Performance Benefits During a 5 km Run in Hot, Humid Conditions.

Hanson, NJ, Carriveau, DM, Morgan, HE, Smith, AR, Michael, TJ, and Miller, MG. Deception of ambient temperature does not elicit performance benefits during a 5 km run in hot, humid conditions. J Strength Cond Res 32(8): 2250-2257, 2018-The purpose of this study was to investigate the effect of deception of ambient temperature on 5 km performance in recreational runners. Eleven participants (6 men, 5 women) each performed three 5 km runs in a random order consisting of a control trial (CON) in temperate conditions (21° C, 43% RH), a hot humid trial (HOT; 31° C, 65% RH) and a deception trial (DEC; 31° C, 65% RH), where participants were told it was 5° C lower than it actually was. Overall completion time was recorded at the end of trials; thermal sensation (TS), rating of perceived exertion (RPE), and core temperature (TC) were recorded each kilometer. Participants completed the 5 km run faster in the CON condition (23:18 ± 2:05; mean ± SD) compared with DEC (p = 0.005) and HOT (p = 0.014). There was no difference in completion time (p = 0.554) between DEC (25:11 ± 2:41) and HOT (24:25 ± 2:47). Similarly, TS was lower in the CON condition (5.7 ± 0.2) compared with DEC and HOT (p < 0.001 and p = 0.016, respectively) and no differences were seen between the DEC (6.4 ± 0.2) and HOT (6.5 ± 0.2) conditions. No differences in RPE (p = 0.115) or rise in TC (p = 0.289) were seen between the 3 conditions. Deception of the environmental conditions did not positively affect 5 km running performance, and no differences were seen in physiological or psychological variables.

The Mechanism of Regulation of Pantothenate Biosynthesis by the PanD-PanZ·AcCoA Complex Reveals an Additional Mode of Action for the Antimetabolite N-Pentyl Pantothenamide (N5-Pan).

The antimetabolite pentyl pantothenamide has broad spectrum antibiotic activity but exhibits enhanced activity against Escherichia coli. The PanDZ complex has been proposed to regulate the pantothenate biosynthetic pathway in E. coli by limiting the supply of ß-alanine in response to coenzyme A concentration. We show that formation of such a complex between activated aspartate decarboxylase (PanD) and PanZ leads to sequestration of the pyruvoyl cofactor as a ketone hydrate and demonstrate that both PanZ overexpression-linked ß-alanine auxotrophy and pentyl pantothenamide toxicity are due to formation of this complex. This both demonstrates that the PanDZ complex regulates pantothenate biosynthesis in a cellular context and validates the complex as a target for antibiotic development.

Right Coronary Dissection and Left Anterior Descending Thrombus: Dual Dilemma in a Young Cardiac Arrest Survivor.

BACKGROUND: ST-elevation myocardial infarction (STEMI) leading to cardiac arrest is an exceptionally rare occurrence in young adults. Those affected tend to abuse sympathomimetic drugs, have strong family histories, or have a significant burden of cardiac risk factors. Another uncommon cause of STEMI is coronary artery dissection, which overwhelmingly affects middle- and older-aged women with few cardiac risk factors. CASE REPORT: A 22-year-old athlete with no medical history was admitted to our institution post-cardiac arrest with an anterior STEMI and concomitant right coronary dissection. To our knowledge, this represents the first documented case of these simultaneous pathologies in a young cardiac arrest survivor. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Myocardial infarction is rare in young adults, and a diverse range of etiologies must be considered promptly to prevent delays in time-sensitive therapies, such as antiplatelet agents and revascularization. The emergency physician is most often the first point of contact in patients with acute coronary syndromes, and the failure to recognize it in young adults threatens them with premature death and potentially life-long disability.

Hospital doctors' Opinions regarding educational Utility, public Sentiment and career Effects of Medical television Dramas: the HOUSE MD study.

OBJECTIVES: To evaluate the opinions of practicing clinicians on medical television dramas and the effects these series have on society as well as their own practice. DESIGN, SETTING AND PARTICIPANTS: Observational study using a structured questionnaire disseminated among doctors of all grades and specialties at one tertiary centre and two large secondary care district general hospitals in Wales, United Kingdom. Three hundred and seventy-two questionnaires were distributed over a 3-month period, with 200 completed questionnaires received (response rate, 54%). MAIN OUTCOME MEASURES: Frequency and reasons for watching these programs, and opinions regarding realism, educational value and public perception, evaluated by doctors' grades and specialties. Identification of work practice with any observed traits in fictional doctors was also analysed. RESULTS: 65% of doctors surveyed admitted to watching these programs on more than one occasion. Junior doctors (interns and resident medical officers) were more regular viewers. Most doctors who admitted to watching medical dramas did so for entertainment purposes (69%); 8% watched for educational purposes and, of these, 100% watched House MD, 82% felt that these dramas were unrepresentative of daily practice, and 10% thought that they accurately portrayed reality. Most of the positive responses were from junior doctors. 61% of doctors identified some aspect of their clinical practice with another doctor (fictional or non-fictional; most junior doctors identified with a fictional doctor, compared with non-fictional role models for more senior practicing clinicians. CONCLUSIONS: This survey shows that a large body of the medical workforce watches medical television dramas and that such programs exercise a growing influence on the practice of junior doctors, particularly those in physicianly specialties. The reasons for certain role model selections remain unknown and may require further evaluation.

Percutaneous Revascularization for Ischemic Left Ventricular Dysfunction: Cost-Effectiveness Analysis of the REVIVED-BCIS2 Trial.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. METHODS: REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. RESULTS: Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: -0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. CONCLUSIONS: A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920048.

Characterizing Mechanisms of Ischemia in Patients With Myocardial Bridges.

BACKGROUND: Myocardial bridges (MBs) are prevalent and can be associated with acute and chronic ischemic syndromes. We sought to determine the substrates for ischemia in patients with angina with nonobstructive coronary arteries and a MB in the left anterior descending artery. METHODS: Patients with angina with nonobstructive coronary arteries underwent the acquisition of intracoronary pressure and flow during rest, supine bicycle exercise, and adenosine infusion. Coronary wave intensity analysis was performed, with perfusion efficiency defined as accelerating wave energy/total wave energy (%). Epicardial endothelial dysfunction was defined as a reduction in epicardial vessel diameter ≥20% in response to intracoronary acetylcholine infusion. Patients with angina with nonobstructive coronary arteries and a MB were compared with 2 angina with nonobstructive coronary arteries groups with no MB: 1 with coronary microvascular disease (CMD: coronary flow reserve, <2.5) and 1 with normal coronary flow reserve (reference: coronary flow reserve, ≥2.5). RESULTS: Ninety-two patients were enrolled in the study (30 MB, 33 CMD, and 29 reference). Fractional flow reserve in these 3 groups was 0.86±0.05, 0.92±0.04, and 0.94±0.05; coronary flow reserve was 2.5±0.5, 2.0±0.3, and 3.2±0.6. Perfusion efficiency increased numerically during exercise in the reference group (65±9%-69±13%; P=0.063) but decreased in the CMD (68±10%-50±10%; P<0.001) and MB (66±9%-55±9%; P<0.001) groups. The reduction in perfusion efficiency had distinct causes: in CMD, this was driven by microcirculation-derived energy in early diastole, whereas in MB, this was driven by diminished accelerating wave energy, due to the upstream bridge, in early systole. Epicardial endothelial dysfunction was more common in the MB group (54% versus 29% reference and 38% CMD). Overall, 93% of patients with a MB had an identifiable ischemic substrate. CONCLUSIONS: MBs led to impaired coronary perfusion efficiency during exercise, which was due to diminished accelerating wave energy in early systole compared with the reference group. Additionally, there was a high prevalence of endothelial and microvascular dysfunction. These ischemic mechanisms may represent distinct treatment targets.