Hypoxia Sensitive Metal β-Ketoiminate Complexes Showing Induced Single Strand DNA Breaks and Cancer Cell Death by Apoptosis

A series of ruthenium and iridium complexes have been synthesised and characterised with 20 novel crystal structures discussed. The library of β-ketoiminate complexes has been shown to be active against MCF-7 (human breast carcino-ma), HT-29 (human colon carcinoma), A2780 (human ovarian carcinoma) and A2780cis (cisplatin resistant human ovarian carcinoma) cell lines, with selected complexes being more than three times as active as cisplatin against the A2780cis cell line. Complexes have also been shown to be highly active under hypoxic conditions, with the activities of some complexes increasing with a decrease in O2 concentration. The enzyme thioredoxin reductase is over-expressed in cancer cells and complexes reported herein have the advantage of inhibiting this enzyme, with IC50 values measured in the nanomolar range. The anti-cancer activity of these complexes was further investigated to determine whether activity is due to effects on cellular growth or cell survival. The complexes were found to induce significant cancer cell death by apoptosis with levels induced correlating closely with activity in chemosensitivity studies. As a possible cause of cell death, the ability of the complexes to induce damage to cellular DNA was also assessed. The complexes failed to induce double strand DNA break or DNA crosslinking but induced significant levels of single DNA strand breaks indi-cating a different mechanism of action to cisplatin

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

β-Ketoiminato Iridium(III) Organometallic Complexes: Selective Cytotoxicity towards Colorectal Cancer Cells HCT116 p53 -/-

This report presents a new library of organometallic iridium(III) compounds of the type [Cp*IrCl(L)] (Cp*=pentamethylcyclopentadienyl and L=a functionalized β‐ketoiminato ligand) showing moderate to high cytotoxicity against a range of cancer cell lines. All compounds show increased activity towards colorectal cancer, with preferential activity observed against the immortalized p53‐null colorectal cell line, HCT116 p53‐/‐, with sensitivity factors (SF) up to 26.7. Additionally, the compounds have excellent selectivity for cancerous cells when tested against normal cell types, with selectivity ratios (SR) up to 35.6, contrary to that of cisplatin, which is neither selective nor specific for cancerous cells (SF=0.43 and SR=0.7–2.3). This work provides a preliminary understanding of the cytotoxicity of iridium compounds in the absence of p53 and has potential applications in treatment of cancers for which the p53 gene is absent or mutant

Career intentions of medical students in the UK: a national, cross-sectional study (AIMS study)

Objective To determine current UK medical students’ career intentions after graduation and on completing the Foundation Programme (FP), and to ascertain the motivations behind these intentions.Design Cross-sectional, mixed-methods survey of UK medical students, using a non-random sampling method.Setting All 44 UK medical schools recognised by the General Medical Council.Participants All UK medical students were eligible to participate. The study sample consisted of 10 486 participants, approximately 25.50% of the medical student population.Outcome measures Career intentions of medical students postgraduation and post-FP, motivations behind these career intentions, characterising the medical student population and correlating demographic factors and propensity to leave the National Health Service (NHS).Results The majority of participating students (8806/10 486, 83.98%) planned to complete both years of the FP after graduation, with under half of these students (4294/8806, 48.76%) intending to pursue specialty training thereafter. A subanalysis of career intentions after the FP by year of study revealed a significant decrease in students’ intentions to enter specialty training as they advanced through medical school. Approximately a third of surveyed students (3392/10 486, 32.35%) intended to emigrate to practise medicine, with 42.57% (n=1444) of those students not planning to return. In total, 2.89% of students intended to leave medicine altogether (n=303). Remuneration, work-life balance and working conditions were identified as important factors in decision-making regarding emigration and leaving the profession. Subgroup analyses based on gender, type of schooling, fee type and educational background were performed. Only 17.26% of surveyed students were satisfied or very satisfied with the overall prospect of working in the NHS.Conclusions The Ascertaining the career Intentions of UK Medical Students study highlights UK students’ views and career intentions, revealing a concerning proportion of those surveyed considering alternative careers or emigration. Addressing factors such as remuneration, work-life balance and working conditions may increase retention of doctors and improve workforce planning efforts

The role of medical schools in UK students’ career intentions: findings from the AIMS study

Abstract Objectives To investigate differences in students’ career intentions between UK medical schools. Design Cross-sectional, mixed-methods online survey. Setting The primary study included all 44 UK medical schools, with this analysis comprising 42 medical schools. Participants Ten thousand four hundred eighty-six UK medical students. Main outcome measures Career intentions of medical students, focusing on differences between medical schools. Secondary outcomes included variation in medical students’ satisfaction with a prospective career in the NHS, by medical school. Results 2.89% of students intended to leave medicine altogether, with Cambridge Medical School having the highest proportion of such respondents. 32.35% of respondents planned to emigrate for practice, with Ulster medical students being the most likely. Of those intending to emigrate, the University of Central Lancashire saw the highest proportion stating no intentions to return. Cardiff Medical School had the greatest percentage of students intending to assume non-training clinical posts after completing FY2. 35.23% of participating medical students intended to leave the NHS within 2 years of graduating, with Brighton and Sussex holding the highest proportion of these respondents. Only 17.26% were satisfied with the prospect of working in the NHS, with considerable variation nationally; Barts and the London medical students had the highest rates of dissatisfaction. Conclusions This study reveals variability in students’ career sentiment across UK medical schools, emphasising the need for attention to factors influencing these trends. A concerning proportion of students intend to exit the NHS within 2 years of graduating, with substantial variation between institutions. Students’ intentions may be shaped by various factors, including curriculum focus and recruitment practices. It is imperative to re-evaluate these aspects within medical schools, whilst considering the wider national context, to improve student perceptions towards an NHS career. Future research should target underlying causes for these disparities to facilitate improvements to career satisfaction and retention. </jats:sec

Identification of seven new prostate cancer susceptibility loci through a genome-wide association study

Prostate cancer (PrCa) is the most frequently diagnosed male cancer in developed countries. To identify common PrCa susceptibility alleles, we have previously conducted a genome-wide association study in which 541, 129 SNPs were genotyped in 1,854 PrCa cases with clinically detected disease and 1,894 controls. We have now evaluated promising associations in a second stage, in which we genotyped 43,671 SNPs in 3,650 PrCa cases and 3,940 controls, and a third stage, involving an additional 16,229 cases and 14,821 controls from 21 studies. In addition to previously identified loci, we identified a further seven new prostate cancer susceptibility loci on chromosomes 2, 4, 8, 11, and 22 (P=1.6×10−8 to P=2.7×10−33)

Risdiplam in Patients Previously Treated with Other Therapies for Spinal Muscular Atrophy: An Interim Analysis from the JEWELFISH Study

Introduction: Risdiplam is a survival of motor neuron 2 (SMN2) splicing modifier for the treatment of patients with spinal muscular atrophy (SMA). The JEWELFISH study (NCT03032172) was designed to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of risdiplam in previously treated pediatric and adult patients with types&nbsp;1–3 SMA. Here, an analysis was performed after all patients had received at least 1&nbsp;year of treatment with risdiplam. Methods: Patients with a confirmed diagnosis of 5q-autosomal recessive SMA between the ages of 6&nbsp;months and 60&nbsp;years were eligible for enrollment. Patients were previously enrolled in the MOONFISH study (NCT02240355) with splicing modifier RG7800 or treated with olesoxime, nusinersen, or onasemnogene abeparvovec. The primary objectives of the JEWELFISH study were to evaluate the safety and tolerability of risdiplam and investigate the PK after 2&nbsp;years of treatment. Results: A total of 174 patients enrolled: MOONFISH study (n = 13), olesoxime (n = 71 patients), nusinersen (n = 76), onasemnogene abeparvovec (n = 14). Most patients (78%) had three SMN2 copies. The median age and weight of patients at enrollment was 14.0&nbsp;years (1–60&nbsp;years) and 39.1&nbsp;kg (9.2–108.9&nbsp;kg), respectively. About 63% of patients aged 2–60&nbsp;years had a baseline total score of less than 10 on the Hammersmith Functional Motor Scale–Expanded and 83% had scoliosis. The most common adverse event (AE) was upper respiratory tract infection and pyrexia (30 patients each; 17%). Pneumonia (four patients; 2%) was the most frequently reported serious AE (SAE). The rates of AEs and SAEs per 100 patient-years were lower in the second 6-month period compared with the first. An increase in SMN protein was observed in blood after risdiplam treatment and was comparable across all ages and body weight quartiles. Conclusions: The safety and PD of risdiplam in patients who were previously treated were consistent with those of treatment-naïve patients