Computational Design of Cyclic Peptide Inhibitors of a Bacterial Membrane Lipoprotein Peptidase.

There remains a critical need for new antibiotics against multi-drug-resistant Gram-negative bacteria, a major global threat that continues to impact mortality rates. Lipoprotein signal peptidase II is an essential enzyme in the lipoprotein biosynthetic pathway of Gram-negative bacteria, making it an attractive target for antibacterial drug discovery. Although natural inhibitors of LspA have been identified, such as the cyclic depsipeptide globomycin, poor stability and production difficulties limit their use in a clinical setting. We harness computational design to generate stable de novo cyclic peptide analogues of globomycin. Only 12 peptides needed to be synthesized and tested to yield potent inhibitors, avoiding costly preparation of large libraries and screening campaigns. The most potent analogues showed comparable or better antimicrobial activity than globomycin in microdilution assays against ESKAPE-E pathogens. This work highlights computational design as a general strategy to combat antibiotic resistance.

Comparison of Echocardiography and Multi-Planar Gated Acquisition Scans for Predicting Cancer-Treatment-Related Cardiovascular Dysfunction.

BACKGROUND: Current guidelines recommend using sequential cardiac imaging to monitor for cancer treatment-related cardiac dysfunction (CTRCD) in patients undergoing potentially cardiotoxic chemotherapy. Multiple different imaging cardiac modalities are available and there are few prospective head-to-head comparative studies to help guide treatment. OBJECTIVES: To perform an exploratory prospective cohort study of "real-world" CTRCD comparing multigated acquisition nuclear ventriculography (MUGA) at the referring cancer specialist's discretion with a novel echocardiographic strategy at an Australian tertiary hospital. METHOD: Patients were recruited from haematology and oncology outpatient clinics if they were scheduled for treatment with anthracyclines and/or trastuzumab. Patients underwent simultaneous MUGA-based cardiac imaging (conventional strategy) at a frequency according to evidenced-based guidelines in addition to researcher-conducted echocardiographic imaging. The echocardiographic imaging was performed in all patients at time points recommended by international society guidelines. Outcomes included adherence to guideline recommendations, concordance between MUGA and echocardiographic left ventricular ejection fraction (LVEF) measurements, and detection of cardiac dysfunction (defined as >5% LVEF decrement from baseline by three-dimensional [3D]-LVEF). A secondary end point was accuracy of global longitudinal strain in predicting cardiac dysfunction. RESULTS: In total, 35 patients were recruited, including 15 with breast cancer, 19 with haematological malignancy, and one with gastric cancer. MUGA and echocardiographic LVEF measurements correlated poorly with limits of agreement of 30% between 3D-LVEF and MUGA-LVEF and 37% for 3D-LVEF and MUGA-LVEF. Only one case (2.9%) of CTRCD was diagnosed by MUGA, compared with 12 (34.2%) cases by echocardiography. Four (4) patients had >10% decrement in 3D-LVEF that was not detected by MUGA. Global longitudinal strain at 2 months displayed significant ability to predict CTRCD (area under the curve, 0.75, 95% confidence interval, 0.55-0.94). CONCLUSIONS: The MUGA correlates poorly with echocardiographic assessment with substantial discrepancy between MUGA and echocardiography in CTRCD diagnosis. Echocardiographic and MUGA imaging strategies should not be considered equivalent for imaging cancer patients, and a single imaging modality should ideally be used per patient to prevent misdiagnosis by inter-modality variation These findings should be considered hypothesis-generating and require confirmation with larger studies.

Blood Pressure Lowering in Patients With Central Hypertension: A Randomized Clinical Trial.

BACKGROUND: Cuff blood pressure (BP) is recommended for guiding hypertension management. However, central BP has been proposed as a superior clinical measurement. This study aimed to determine whether controlling hypertension as measured by central BP was beneficial in reducing left ventricular mass index beyond control of standard cuff hypertension. METHODS: This multicenter, open-label, blinded-end point trial was conducted in individuals treated for uncomplicated hypertension with controlled cuff BP (<140/90 mm Hg) but elevated central BP (≥0.5 SD above age- and sex-specific normal values). Participants were randomized to 24-months intervention with spironolactone 25 mg/day (n=148) or usual care control (n=153). The primary outcome was change in left ventricular mass index measured by cardiac MRI. Cuff and central BPs were measured by clinic, 7-day home and 24-hour ambulatory BPs. RESULTS: At 24-months, there was a greater reduction in left ventricular mass index (-3.2 [95% CI, -5.0 to -1.3] g/m2; P=0.001) with intervention compared with control. Cuff and central BPs were lowered by a similar magnitude across all BP measurement modes (eg, clinic cuff systolic BP, -6.16 [-9.60 to -2.72] mm Hg and clinic central systolic BP, -4.96 [-8.06 to -1.86] mm Hg; P≥0.48 all). Secondary analyses found that changes in left ventricular mass index correlated to changes in BP, with the magnitude of effect nearly identical for BP measured by cuff (eg, 24-hour systolic BP, ß, 0.17 [0.02-0.31] g/m2) or centrally (24-hour systolic BP, ß, 0.16 [0.01-0.32] g/m2). CONCLUSIONS: Among individuals with central hypertension, spironolactone had beneficial effects in reducing LV mass. Secondary analyses showed that changes in LV mass were equally well associated with lower measured standard cuff BP and central BP. REGISTRATION: URL: https://www.anzctr.org.au/; Unique identifier: ACTRN12613000053729.

Cardiotoxicity of anti-cancer drugs: cellular mechanisms and clinical implications.

Cardio-oncology is an emerging field that seeks to enhance quality of life and longevity of cancer survivors. It is pertinent for clinicians to understand the cellular mechanisms of prescribed therapies, as this contributes to robust understanding of complex treatments and off-target effects, improved communication with patients, and guides long term care with the goal to minimise or prevent cardiovascular complications. Our aim is to review the cellular mechanisms of cardiotoxicity involved in commonly used anti-cancer treatments and identify gaps in literature and strategies to mitigate cardiotoxicity effects and guide future research endeavours.

Men placed on waiting lists for psychiatric admission from Irish Prisons over five years: Clinical outcomes during a forensic "bed crisis".

BACKGROUND: Ireland has low provision rates of general and forensic beds compared with other western countries. In recent years there have been difficulties and delays in accessing forensic beds for prisoners with severe mental illness. AIMS: We aimed to determine clinical outcomes for male prisoners assessed as requiring psychiatric admission over an extended period, with time frames for admission and other outcomes. We aimed to determine whether admissions to forensic and non-forensic locations were risk-appropriate. METHODS: Participants included all male prisoners placed on psychiatric admission waiting lists in Ireland over five years 2015-2019. We described demographic, clinical and offending variables. We measured clinical outcomes including forensic admission, other admission and recovery with voluntary treatment in prison. We also measured times to clinical outcomes. Security requirements and clinical urgency were assessed using the DUNDRUM Toolkit scales 1 and 2. RESULTS: 541 male prisoners were placed on admission waiting lists and spent an aggregate of over 114 years on admission waiting lists during 2015-2019. Almost one quarter improved with voluntary treatment allowing removal from waiting lists, while over 75% did not. Admission was achieved for a majority of cases, albeit after lengthy delays for some. The most frequent outcome was diversion from remand to non-forensic inpatient settings. Non-forensic admissions arranged by the Prison Inreach and Court Liaison Service (PICLS) at Ireland's main remand prison at Cloverhill contributed 54% (179/332) of all admissions achieved and 76% (179/235) of all non-forensic admissions from prison waiting list. Median delay to admission was 59 days for forensic admissions and 69 days for admissions to non-forensic hospitals from sentenced settings, compared with 16.5 days for admissions to non-forensic hospitals from remand. CONCLUSIONS: Long delays for forensic admission during a five-year period of limited access to such beds were partly mitigated by transfers to non-forensic hospitals, mainly diversion of minor offenders from remand settings.

At the heart of sentencing: exploring whether more compassionate delivery of sentencing remarks increases public concern for people who offend.

Compassion has the capacity to change how we think and feel about people who offend, enabling us to understand individual and systemic causes of criminality and whether, and in what circumstances, desistance is possible. Across two experiments, our research examined whether a more compassionate sentencing delivery, firstly, in written sentencing remarks and, secondly, in videoed sentencing remarks, stimulated more concern for sentenced offenders amongst members of the Australian public. Our results suggest that it is possible to alter the features of a written or orally-delivered sentence, so that it is recognisably more compassionate. Further, engagement with compassion-enhanced sentencing remarks altered criminal justice spending preferences, reducing the proportion of the criminal justice budget that the public believed should be spent on imprisonment and increasing that to be spent on rehabilitation.

Traceless Thioacid-Mediated Radical Cyclization of 1,6-Dienes.

Five-membered ring systems are ubiquitous throughout natural products and synthetic therapeutics, and thus, efficient methods to access this essential scaffold are required. Herein, we report the thioacid-mediated, 5-exo-trig cyclization of various 1,6-dienes, with high yields of up to 98%. The labile thioester functionality can be exploited to generate a free thiol residue which can be used as a functional handle or removed entirely to provide the traceless cyclized product.

Screening for Coronary Artery Disease in Cancer Survivors: JACC: CardioOncology State-of-the-Art Review.

Coronary artery disease (CAD) is an important contributor to the cardiovascular burden in cancer survivors. This review identifies features that could help guide decisions about the benefit of screening to assess the risk or presence of subclinical CAD. Screening may be appropriate in selected survivors based on risk factors and inflammatory burden. In cancer survivors who have undergone genetic testing, polygenic risk scores and clonal hematopoiesis markers may become useful CAD risk prediction tools in the future. The type of cancer (especially breast, hematological, gastrointestinal, and genitourinary) and the nature of treatment (radiotherapy, platinum agents, fluorouracil, hormonal therapy, tyrosine kinase inhibitors, endothelial growth factor inhibitors, and immune checkpoint inhibitors) are also important in determining risk. Therapeutic implications of positive screening include lifestyle and atherosclerosis interventions, and in specific instances, revascularization may be indicated.

Cost-effectiveness of screening for paroxysmal atrial fibrillation in patients undergoing echocardiography.

BACKGROUND: Screening for atrial fibrillation is recommended for patients > 65 years on current guidelines. Targeted screening may be more efficient, however the appropriate location for screening programs has not been well defined. Our aim was to compare the cost-effectiveness of unselected electrocardiographic (ECG) screening for atrial fibrillation (AF), and selective screening based on an abnormal echocardiogram. METHODS: Two strategies of portable ECG screening for AF were compared in the base case of a hypothetical asymptomatic 65-year-old man (CHA2 DS2 -VASC = 3 based on hypertension and diabetes mellitus) with previous echocardiography but without a cause for AF (e.g. mitral valve disease, left ventricular (LV) dysfunction). With age-based screening (AgeScreen; 3% AF detection rate) all patients underwent ECG. With imaging-guided screening (ImagingScreen; 5% detection rate), only patients with left atrial (LA) volume ≥34 mL/m2 and LA reservoir strain <34% or LV global longitudinal strain > -18% underwent ECG screening. A Markov model was informed by published transition probabilities, costs and quality-adjusted life years (QALY). Costs, effects and incremental cost-effectiveness ratio were assessed for each screening strategy over a 20-year period. The willingness-to-pay threshold was $53 000/QALY. RESULTS: ImagingScreen dominated AgeScreen, with a lower cost ($54 823 vs $57842) and better outcome (11.56 vs 11.52 QALY over 20 years). Monte Carlo simulation demonstrated that 61% of observations were more efficacious with ImagingScreen, with cost below willingness to pay. The main cost determinants were annual costs of stroke or heart failure and AF detection rates. ImagingScreen was more cost-effective for AF detection rates up to 14%, and more cost-effective across a range of annual stroke ($24 000-$102 000) and heart failure ($4000-$12 000) costs. CONCLUSION: In patients with a previous echocardiogram, AF screening of those with baseline clinical and imaging risk parameters is more cost-effective than age-based screening.

Society for Cardiovascular Magnetic Resonance 2022 Cases of SCMR case series.

"Cases of SCMR" is a case series on the SCMR website (https://www.scmr.org) for the purpose of education. The cases reflect the clinical presentation, and the use of cardiovascular magnetic resonance (CMR) in the diagnosis and management of cardiovascular disease. The 2022 digital collection of cases are presented in this manuscript.

Thioether analogues of the pituitary neuropeptide oxytocin via thiol-ene macrocyclisation of unprotected peptides.

Disulfide bonds are an essential feature of many bioactive peptides, however, they are labile to reducing conditions which can limit therapeutic application. Herein, we report an efficient methodology for peptide macrocyclisation, furnishing thioether mimetics of disulfide linkages via thiol-ene click chemistry. Furthermore, this methodology is applied to the efficient synthesis of analogues of the neuropeptide oxytocin and in a highly efficient route to the clinical therapeutic carbetocin.

Prognostic Value of Exercise Capacity in Kidney Transplant Candidates.

Background Exercise stress testing for cardiovascular assessment in kidney transplant candidates has been shown to be a feasible alternative to pharmacologic methods. Exercise stress testing allows the additional assessment of exercise capacity, which may have prognostic value for long-term cardiovascular outcomes in pre-transplant recipients. This study aimed to evaluate the prognostic value of exercise capacity on long-term cardiovascular outcomes in kidney transplant candidates. Methods and Results We retrospectively evaluated exercise capacity in 898 consecutive kidney transplant candidates between 2013 and 2020 who underwent symptom-limited exercise stress echocardiography for pre-transplant cardiovascular assessment. Exercise capacity was measured by age- and sex-predicted metabolic equivalents (METs). The primary outcome was incident major adverse cardiovascular events, defined as cardiac death, non-fatal myocardial infarction, and stroke. Cox proportional hazard multivariable modeling was performed to define major adverse cardiovascular events predictors with transplantation treated as a time-varying covariate. A total of 429 patients (48%) achieved predicted METs. During follow-up, 93 (10%) developed major adverse cardiovascular events and 525 (58%) underwent transplantation. Achievement of predicted METs was independently associated with reduced major adverse cardiovascular events (hazard ratio [HR] 0.49; [95% CI 0.29-0.82], P=0.007), as was transplantation (HR, 0.52; [95% CI 0.30-0.91], P=0.02). Patients achieving predicted METs on pre-transplant exercise stress echocardiography had favorable outcomes that were independent (HR, 0.78; [95% CI 0.32-1.92], P=0.59) and of similar magnitude to subsequent transplantation (HR, 0.97; [95% CI 0.42-2.25], P=0.95). Conclusions Achievement of predicted METs on pre-transplant exercise stress echocardiography confers excellent prognosis independent of and of similar magnitude to subsequent kidney transplantation. Future studies should assess the benefit on exercise training in this population.

The importance of calibration method in determining the association between central blood pressure with left ventricular and left atrial strain.

Afterload is an important determinant of left ventricular (LV) and atrial (LA) function, including myocardial strain. Central blood pressure (CBP) is the major component of cardiac afterload and independently associated with cardiovascular risk. However, the optimal means of calibrating CBP is unclear-standard CBP assessment uses systolic (SBP) and diastolic blood pressure (DBP) from brachial waveforms, but calibration with mean pressure (MAP) and DBP purports to be more accurate. Therefore, we sought to determine which CBP is best associated with LA and LV strain. CBP was measured using both standard and MAP based calibration methods in 546 participants (age 70.7 ± 4.7 years, 45% male) with risk factors for heart failure. Echocardiography was performed in all patients and strain analysis conducted to assess LA/LV function. The associations of CBP with LA and LV strain were assessed using linear regression. MAP-derived CSBP (150 ± 20 mmHg) was higher than standard CSBP (128 ± 15 mmHg) and brachial SBP (140 ± 17 mmHg, p < 0.001), whereas DBPs were similar (84 ± 10, 83 ± 10, and 82 ± 10 mmHg). MAP-derived CSBP was not independently associated with LV strain (p > 0.05), however was independently associated with LA reservoir strain (p < 0.05). Brachial and central DBP were more strongly associated with LA reservoir/conduit and LV strain than brachial and central SBP. LA pump strain was not independently associated with any SBP or DBP parameter (p > 0.05). MAP-derived CBP was more accurate in identifying patients with abnormal LA and LV strain than brachial SBP and standard CBP calibration. In conclusion, CBP calibrated using MAP and DBP may be more accurate in identifying patients with abnormal LA and LV function than standard brachial calibration methods.

Novel Non-pharmaceutical Advancements in Heart Failure Management: The Emerging Role of Technology.

PURPOSE OF REVIEW: To summarise and discuss the implications of recent technological advances in heart failure care. RECENT FINDINGS: Heart failure remains a significant source of morbidity and mortality in the US population despite multiple classes of approved pharmacological treatments. Novel cardiac devices and technologies may offer an opportunity to improve outcomes. Baroreflex Activation Therapy and Cardiac Contractility Remodelling may improve myocardial contractility by altering neurohormonal stimulation of the heart. Implantable Pulmonary Artery Monitors and Biatrial Shunts may prevent heart failure admissions by altering the trajectory of progressive congestion. Phrenic Nerve Stimulation offers potentially effective treatment for comorbid conditions. Smartphone applications offer an intriguing strategy for improving medication adherence. SUMMARY: Novel heart failure technologies offer promise for reducing this public health burden. Randomized controlled studies are indicated for assessing the future role of these novel therapies.

Cysteinyl radicals in chemical synthesis and in nature.

Nature harnesses the unique properties of cysteinyl radical intermediates for a diverse range of essential biological transformations including DNA biosynthesis and repair, metabolism, and biological photochemistry. In parallel, the synthetic accessibility and redox chemistry of cysteinyl radicals renders them versatile reactive intermediates for use in a vast array of synthetic applications such as lipidation, glycosylation and fluorescent labelling of proteins, peptide macrocyclization and stapling, desulfurisation of peptides and proteins, and development of novel therapeutics. This review provides the reader with an overview of the role of cysteinyl radical intermediates in both chemical synthesis and biological systems, with a critical focus on mechanistic details. Direct insights from biological systems, where applied to chemical synthesis, are highlighted and potential avenues from nature which are yet to be explored synthetically are presented.

Site- and Enantioselective Iridium-Catalyzed Desymmetric Mono-Hydrogenation of 1,4-Dienes.

The control of site selectivity in asymmetric mono-hydrogenation of dienes or polyenes remains largely underdeveloped. Herein, we present a highly efficient desymmetrization of 1,4-dienes via iridium-catalyzed site- and enantioselective hydrogenation. This methodology demonstrates the first iridium-catalyzed hydrogenative desymmetriation of meso dienes and provides a concise approach to the installation of two vicinal stereogenic centers adjacent to an alkene. High isolated yields (up to 96 %) and excellent diastereo- and enantioselectivities (up to 99:1 d.r. and 99 % ee) were obtained for a series of divinyl carbinol and divinyl carbinamide substrates. DFT calculations reveal that an interaction between the hydroxy oxygen and the reacting hydride is responsible for the stereoselectivity of the desymmetrization of the divinyl carbinol. Based on the calculated energy profiles, a model that simulates product distribution over time was applied to show an intuitive kinetics of this process. The usefulness of the methodology was demonstrated by the synthesis of the key intermediates of natural products zaragozic acid A and (+)-invictolide.

Role of microvascular dysfunction in left ventricular dysfunction in type 2 diabetes mellitus.

BACKGROUND: Although microvascular disease (mVD) has been linked to poor cardiovascular outcomes in diabetes mellitus, the contribution of mVD to diabetic cardiomyopathy (DC) is unexplored. We investigated whether LV systolic and diastolic dysfunction is associated with mVD in T2DM. METHODS: We recruited 32 asymptomatic patients with T2DM (age 71 ±â€¯4 years, 31% females) from a community-based population. All underwent a comprehensive echocardiogram at baseline including assessment of global longitudinal strain (GLS) and diastolic function. Adenosine stress perfusion on cardiac magnetic resonance imaging (CMR) was performed in all patients. Coronary sinus flow (CSF) was measured offline at rest and peak stress with coronary flow reserve (CFR) calculated as the ratio of global stress and rest CSF. RESULTS: Resting CSF was reduced in 15 (47%) compared to 4 (13%) with adenosine-stress (p = 0.023). Overall, CFR was observed to be reduced in the cohort (2.38 [IQR 2.20]). Abnormal CFR was not associated with diabetes duration of ≥10 years or poor glycaemic control. CFR was not associated with abnormal GLS (OR 1.04 [95% CI 0.49, 2.20], p = 0.93). However, a modest negative correlation was observed with e' and CFR (r = -0.49, p = 0.004). CONCLUSION: This pilot study did not show correlation between subclinical systolic dysfunction and a novel MRI biomarker of microvascular disease. However, there was a weak correlation with myocardial relaxation. Confirmation of these findings in larger studies is indicated.