Pharmacological strategies to reduce anthracycline-associated cardiotoxicity in cancer patients.

INTRODUCTION: Anthracycline chemotherapeutic agents are widely used in the treatment of hematological and solid tumors, working principally through DNA intercalation and topoisomerase II inhibition. However, they are also well known to have cardiotoxic sequelae, commonly denoted as a reduction in ejection fraction. Drug-associated cardiotoxicity remains a significant limiting factor in the use of anthracyclines. AREAS COVERED: In this review, we explore the potential mechanisms of anthracycline-associated cardiotoxicity, identifying high-risk cohorts and approaches to cardiovascular monitoring. The mechanisms through which cardiotoxicity occurs are complex and diverse, ultimately leading to increased oxidative stress, mitochondrial dysfunction, and subsequent cellular apoptosis. Many of the cardiotoxic effects of anthracyclines exhibit a dose-dependent cumulative relationship and are more apparent in patients with previously existing cardiovascular risk factors. Long-term cardiovascular monitoring and optimization of risk factors, prior to commencing treatment as well as beyond the time of treatment, is therefore essential. EXPERT OPINION: We discuss some of the pharmacological strategies proposed to mitigate anthracycline-associated cardiotoxicity as well as prevention strategies to reduce the burden of coexisting cardiovascular risk factors. We highlight methods of early detection of patient cohorts who are at increased risk of developing anthracycline-associated cardiotoxicity and identify potential avenues for further research

Single-dose administration and the influence of the timing of the booster dose on immunogenicity and efficacy of ChAdOx1 nCoV-19 (AZD1222) vaccine: a pooled analysis of four randomised trials.

BACKGROUND: The ChAdOx1 nCoV-19 (AZD1222) vaccine has been approved for emergency use by the UK regulatory authority, Medicines and Healthcare products Regulatory Agency, with a regimen of two standard doses given with an interval of 4-12 weeks. The planned roll-out in the UK will involve vaccinating people in high-risk categories with their first dose immediately, and delivering the second dose 12 weeks later. Here, we provide both a further prespecified pooled analysis of trials of ChAdOx1 nCoV-19 and exploratory analyses of the impact on immunogenicity and efficacy of extending the interval between priming and booster doses. In addition, we show the immunogenicity and protection afforded by the first dose, before a booster dose has been offered. METHODS: We present data from three single-blind randomised controlled trials-one phase 1/2 study in the UK (COV001), one phase 2/3 study in the UK (COV002), and a phase 3 study in Brazil (COV003)-and one double-blind phase 1/2 study in South Africa (COV005). As previously described, individuals 18 years and older were randomly assigned 1:1 to receive two standard doses of ChAdOx1 nCoV-19 (5 × 1010 viral particles) or a control vaccine or saline placebo. In the UK trial, a subset of participants received a lower dose (2·2 × 1010 viral particles) of the ChAdOx1 nCoV-19 for the first dose. The primary outcome was virologically confirmed symptomatic COVID-19 disease, defined as a nucleic acid amplification test (NAAT)-positive swab combined with at least one qualifying symptom (fever ≥37·8°C, cough, shortness of breath, or anosmia or ageusia) more than 14 days after the second dose. Secondary efficacy analyses included cases occuring at least 22 days after the first dose. Antibody responses measured by immunoassay and by pseudovirus neutralisation were exploratory outcomes. All cases of COVID-19 with a NAAT-positive swab were adjudicated for inclusion in the analysis by a masked independent endpoint review committee. The primary analysis included all participants who were SARS-CoV-2 N protein seronegative at baseline, had had at least 14 days of follow-up after the second dose, and had no evidence of previous SARS-CoV-2 infection from NAAT swabs. Safety was assessed in all participants who received at least one dose. The four trials are registered at ISRCTN89951424 (COV003) and ClinicalTrials.gov, NCT04324606 (COV001), NCT04400838 (COV002), and NCT04444674 (COV005). FINDINGS: Between April 23 and Dec 6, 2020, 24 422 participants were recruited and vaccinated across the four studies, of whom 17 178 were included in the primary analysis (8597 receiving ChAdOx1 nCoV-19 and 8581 receiving control vaccine). The data cutoff for these analyses was Dec 7, 2020. 332 NAAT-positive infections met the primary endpoint of symptomatic infection more than 14 days after the second dose. Overall vaccine efficacy more than 14 days after the second dose was 66·7% (95% CI 57·4-74·0), with 84 (1·0%) cases in the 8597 participants in the ChAdOx1 nCoV-19 group and 248 (2·9%) in the 8581 participants in the control group. There were no hospital admissions for COVID-19 in the ChAdOx1 nCoV-19 group after the initial 21-day exclusion period, and 15 in the control group. 108 (0·9%) of 12 282 participants in the ChAdOx1 nCoV-19 group and 127 (1·1%) of 11 962 participants in the control group had serious adverse events. There were seven deaths considered unrelated to vaccination (two in the ChAdOx1 nCov-19 group and five in the control group), including one COVID-19-related death in one participant in the control group. Exploratory analyses showed that vaccine efficacy after a single standard dose of vaccine from day 22 to day 90 after vaccination was 76·0% (59·3-85·9). Our modelling analysis indicated that protection did not wane during this initial 3-month period. Similarly, antibody levels were maintained during this period with minimal waning by day 90 (geometric mean ratio [GMR] 0·66 [95% CI 0·59-0·74]). In the participants who received two standard doses, after the second dose, efficacy was higher in those with a longer prime-boost interval (vaccine efficacy 81·3% [95% CI 60·3-91·2] at ≥12 weeks) than in those with a short interval (vaccine efficacy 55·1% [33·0-69·9] at <6 weeks). These observations are supported by immunogenicity data that showed binding antibody responses more than two-fold higher after an interval of 12 or more weeks compared with an interval of less than 6 weeks in those who were aged 18-55 years (GMR 2·32 [2·01-2·68]). INTERPRETATION: The results of this primary analysis of two doses of ChAdOx1 nCoV-19 were consistent with those seen in the interim analysis of the trials and confirm that the vaccine is efficacious, with results varying by dose interval in exploratory analyses. A 3-month dose interval might have advantages over a programme with a short dose interval for roll-out of a pandemic vaccine to protect the largest number of individuals in the population as early as possible when supplies are scarce, while also improving protection after receiving a second dose. FUNDING: UK Research and Innovation, National Institutes of Health Research (NIHR), The Coalition for Epidemic Preparedness Innovations, the Bill & Melinda Gates Foundation, the Lemann Foundation, Rede D'Or, the Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Microdissection testicular sperm extraction for men undergoing cancer treatment

Steady improvements in the long term outlook for adolescents and young adults with cancer require a shift in focus towards ensuring quality of life after cancer treatment as well as quantity. An important component of quality of life for many men is the ability to father a biological child. However, direct effects of malignancy, as well as potentially gonadotoxic cancer treatments, render many men azoospermic. Where cryopreservation of a good quality semen sample is not possible or was not offered prior to initiation of treatment, microdissection testicular sperm extraction (mTESE) offers a potential route to biological fatherhood. This review explores current evidence supporting the use of mTESE in patients treated for cancer, as well as some of the barriers and questions that still remain before this technique can form part of routine practice

Anomalies in the gravitational recoil of eccentric black-hole mergers with unequal mass ratios

The radiation of linear momentum imparts a recoil (or "kick") to the center of mass of a merging black hole binary system. Recent numerical relativity calculations have shown that eccentricity can lead to an approximate 25% increase in recoil velocities for equal-mass, spinning binaries with spins lying in the orbital plane ("superkick" configurations) [U Sperhake et al. Phys. Rev. D 101 (2020) 024044 (arXiv:1910.01598)]. Here we investigate the impact of nonzero eccentricity on the kick magnitude and gravitational-wave emission of nonspinning, unequal-mass black hole binaries. We confirm that nonzero eccentricities at merger can lead to kicks which are larger by up to ~25% relative to the quasicircular case. We also find that the kick velocity $v$ has an oscillatory dependence on eccentricity, that we interpret as a consequence of changes in the angle between the infall direction at merger and the apoapsis (or periapsis) direction

Analisis Pengaruh NPF dan FDR terhadap Profitabilitas dengan CAR sebagai Variabel Intervening

The background of this research is due to unstable fluctuations in ROA, which shows that Islamic banks have not been able to maintain their stability, so research on profitability is needed. This study aims to determine the effect of NPF, FDR, on profitability with CAR as the Intervening variable for the case study of Islamic Commercial Banks for the period 2011-2020. The data collection method is by accessing data on financial ratios of each bank through the OJK website with purposive sampling as the sample used. The research method is quantitative research and uses WarpPLS 8.0 software. The findings of this study are to contribute to BUS regarding the factors that affect the profitability of Islamic Commercial Banks. From this study, it was found that the NPF and FDR variables had a significant negative effect on profitability, while the CAR had a significant positive effect. The NPF variable has a significant negative effect on CAR and the FDR variable has a significant positive effect. Based on the results of the path analysis test, CAR is able to mediate the effect of NPF on profitability, while for FDR, CAR is not able to mediate the relationship of FDR to profitability

The difficulty of managing recurrent sigmoid volvulus in a frail patient

Abdominal pain is a common cause for presentation of the older patient to healthcare services. Sigmoid volvulus is one of the leading causes of acute large bowel obstruction in adults. It affects older, comorbid, frailer and institutionalized patients. In this report, we highlight some of the clinical and ethical dilemmas clinicians face when caring for patients with recurrent sigmoid volvulus. We endorse early involvement of geriatricians and palliative care services in these individuals to ensure maximum patient comfort, quality of life and dignity

Unequal-mass boson-star binaries: initial data and merger dynamics

Funder: Centre for Doctoral Training (CDT) at the University of CambridgeAbstractWe present a generalisation of the curative initial data construction derived for equal-mass compact binaries in Helferet al(2019Phys. Rev.D99044046; 2022Class. Quantum Grav.39074001) to arbitrary mass ratios. We demonstrate how these improved initial data avoid substantial spurious artifacts in the collision dynamics of unequal-mass boson-star binaries in the same way as has previously been achieved with the simpler method restricted to the equal-mass case. We employ the improved initial data to explore in detail the impact of phase offsets in the coalescence of equal- and unequal-mass boson star binaries.</jats:p

Lessons for adaptive mesh refinement in numerical relativity

Funder: Queen’s College, University of Oxford; doi: https://doi.org/10.13039/100010356Funder: Homerton College, University of Cambridge; doi: https://doi.org/10.13039/501100008420We demonstrate the flexibility and utility of the Berger-Rigoutsos Adaptive Mesh Refinement (AMR) algorithm used in the open-source numerical relativity code GRChombo for generating gravitational waveforms from binary black-hole inspirals, and for studying other problems involving non-trivial matter configurations. We show that GRChombo can produce high quality binary black-hole waveforms through a code comparison with the established numerical relativity code Lean. We also discuss some of the technical challenges involved in making use of full AMR (as opposed to, e.g. moving box mesh refinement), including the numerical effects caused by using various refinement criteria when regridding. We suggest several "rules of thumb" for when to use different tagging criteria for simulating a variety of physical phenomena. We demonstrate the use of these different criteria through example evolutions of a scalar field theory. Finally, we also review the current status and general capabilities of GRChombo