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The Nuffield Department of Surgical Sciences is the academic department of surgery at the University of Oxford, and hosts a multidisciplinary team of senior clinical academic surgeons, senior scientists, junior clinicians and scientists in training.
Prostate-Specific Antigen Screening and 15-Year Prostate Cancer Mortality: A Secondary Analysis of the CAP Randomized Clinical Trial.
IMPORTANCE: The Cluster Randomized Trial of PSA Testing for Prostate Cancer (CAP) reported no effect of prostate-specific antigen (PSA) screening on prostate cancer mortality at a median 10-year follow-up (primary outcome), but the long-term effects of PSA screening on prostate cancer mortality remain unclear. OBJECTIVE: To evaluate the effect of a single invitation for PSA screening on prostate cancer-specific mortality at a median 15-year follow-up compared with no invitation for screening. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of the CAP randomized clinical trial included men aged 50 to 69 years identified at 573 primary care practices in England and Wales. Primary care practices were randomized between September 25, 2001, and August 24, 2007, and men were enrolled between January 8, 2002, and January 20, 2009. Follow-up was completed on March 31, 2021. INTERVENTION: Men received a single invitation for a PSA screening test with subsequent diagnostic tests if the PSA level was 3.0 ng/mL or higher. The control group received standard practice (no invitation). MAIN OUTCOMES AND MEASURES: The primary outcome was reported previously. Of 8 prespecified secondary outcomes, results of 4 were reported previously. The 4 remaining prespecified secondary outcomes at 15-year follow-up were prostate cancer-specific mortality, all-cause mortality, and prostate cancer stage and Gleason grade at diagnosis. RESULTS: Of 415 357 eligible men (mean [SD] age, 59.0 [5.6] years), 98% were included in these analyses. Overall, 12 013 and 12 958 men with a prostate cancer diagnosis were in the intervention and control groups, respectively (15-year cumulative risk, 7.08% [95% CI, 6.95%-7.21%] and 6.94% [95% CI, 6.82%-7.06%], respectively). At a median 15-year follow-up, 1199 men in the intervention group (0.69% [95% CI, 0.65%-0.73%]) and 1451 men in the control group (0.78% [95% CI, 0.73%-0.82%]) died of prostate cancer (rate ratio [RR], 0.92 [95% CI, 0.85-0.99]; P = .03). Compared with the control, the PSA screening intervention increased detection of low-grade (Gleason score [GS] ≤6: 2.2% vs 1.6%; P
HIF prolyl hydroxylase inhibition prior to transient focal cerebral ischaemia is neuroprotective in mice
This study investigated the effects of 2-(1-chloro-4-hydroxyisoquinoline- 3-carboxamido) acetic acid (IOX3), a selective small molecule inhibitor of hypoxia-inducible factor (HIF) prolyl hydroxylases, on mouse brains subject to transient focal cerebral ischaemia. Male, 8- to 12-week-old C57/B6 mice were subjected to 45 min of middle cerebral artery occlusion (MCAO) either immediately or 24 h after receiving IOX3. Mice receiving IOX3 at 20 mg/kg 24 h prior to the MCAO had better neuroscores and smaller blood brain barrier (BBB) disruption and infarct volumes than mice receiving the vehicle, whereas those having IOX3 at 60 mg/kg showed no significant changes. IOX3 treatment immediately before MCAO was not neuroprotective. IOX3 up-regulated HIF-1a, and increased EPO expression in mouse brains. In an in vitro BBB model (RBE4 cell line), IOX3 up-regulated HIF-1α and delocalized ZO-1. Pre-treating IOX3 on RBE4 cells 24 h before oxygen glucose deprivation had a protective effect on endothelial barrier preservation with ZO-1 being better localized, while immediate IOX3 treatment did not. Our study suggests that HIF stabilization with IOX3 before cerebral ischaemia is neuroprotective partially because of BBB protection, while immediate application could be detrimental. These results provide information for studies aimed at the therapeutic activation of HIF pathway for neurovascular protection from cerebral ischaemia.
Making evaluations useful for healthcare leadership development programmes
Background: Effective healthcare leadership has been linked to improved individual and organisational outcomes globally. However, evaluations of healthcare leadership development programmes have often been of low quality. This study investigates the evaluation and decision-making needs of stakeholders for the Oxford Emerging Leaders Programme and aims to redesign its evaluation approach. Methods: Drawing from Michael Quinn Patton’s utilisation-focused evaluation approach, semistructured interviews were conducted with 12 key programme stakeholders. Interviews were thematically analysed to identify key areas for useful and impactful evaluation. Results: Three main themes were identified: impact on patients, impact on healthcare organisations and individual outcomes. Individual outcomes were further divided into skills and qualities. Stakeholders emphasised the importance of measuring improvements in organisational culture, as well as from the perspectives of patients and individual leaders. The need for a multifaceted and longitudinal evaluation approach was highlighted. Conclusions: The study underscores the importance of aligning evaluation methods with stakeholder needs. Tailoring evaluations to specific programme aims and incorporating both qualitative and quantitative measures can enhance their utility. These insights contribute to the broader literature on healthcare leadership development and programme evaluation.
Simultaneous versus delayed resection of synchronous colorectal liver metastases: A systematic review and meta-analysis.
Colorectal cancer is a leading malignancy, with synchronous colorectal liver metastases (CRLM) presenting in 20 % of patients. Resection remains the gold standard treatment for CRLMs, significantly improving survival outcomes. However, the optimal timing of resection of these synchronous lesions - simultaneous versus staged - remains controversial. This systematic review and meta-analysis synthesises data exclusively from propensity-score-matched and prospective studies. A comprehensive search of five databases identified 11 eligible studies, encompassing 2884 patients. Of these, 1453 underwent simultaneous resection, and 1431 underwent staged procedures. The primary outcome was 5-year overall survival (OS), with secondary outcomes including disease-free survival (DFS), surgical morbidity, operating time, and length of hospital stay. Meta-analysis demonstrated no significant difference in 5-year OS between simultaneous and staged resection groups (odds ratio [OR] 1.10, 95 % CI 0.75-1.61; p = 0.83). However, simultaneous resection was associated with significantly higher 3-year DFS (OR 1.67, 95 % CI 1.28-2.17; p = 0.0001) but also increased major surgical complications (Clavien-Dindo ≥ III: OR 1.32, 95 % CI 1.03-1.68; p = 0.03). This review highlights a lack of oncological advantage for simultaneous resection, coupled with higher morbidity, suggesting its use should be limited to select patients with low surgical risk. The findings underscore the need for well-powered, randomised trials to confirm these conclusions, as well as assess quality of life and economic outcomes, however delivering such trials in this patient cohort brings unique challenges. Until such data are available, clinical decision-making should remain individualised, guided by multidisciplinary discussion and available local expertise.
Global, regional, and national burden of epilepsy, 1990-2021: a systematic analysis for the Global Burden of Disease Study 2021.
BACKGROUND: Epilepsy is one of the most common serious neurological disorders and affects individuals of all ages across the globe. The aim of this study is to provide estimates of the epilepsy burden on the global, regional, and national levels for 1990-2021. METHODS: Using well established Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) methodology, we quantified the prevalence of active idiopathic (epilepsy of genetic or unknown origin) and secondary epilepsy (epilepsy due to an underlying abnormality of the brain structure or chemistry), as well as incidence, death, and disability-adjusted life-years (DALYs) by age, sex, and location (globally, 21 GBD regions and seven super-regions, World Bank country income levels, Socio-demographic Index [SDI], and 204 countries) and their trends from 1990 to 2021. Vital registrations and verbal autopsies provided information about deaths, and data on the prevalence and severity of epilepsy, largely came from population representative surveys. All estimates were calculated with 95% uncertainty intervals (UIs). FINDINGS: In 2021, there were 51·7 million (95% UI 44·9-58·9) people with epilepsy (idiopathic and secondary combined) globally, with an age-standardised prevalence of 658 per 100 000 (569-748). Idiopathic epilepsy had an age-standardised prevalence of 307 per 100 000 (235-389) globally, with 24·2 million (18·5-30·7) prevalent cases, and secondary epilepsy had a global age-standardised prevalence of 350 per 100 000 (322-380). In 2021, 0·7% of the population had active epilepsy (0·3% attributed to idiopathic epilepsy and 0·4% to secondary epilepsy), and the age-standardised global prevalence of epilepsy from idiopathic and secondary epilepsy combined increased from 1990 to 2021 by 10·8% (1·1-21·3), mainly due to corresponding changes in secondary epilepsy. However, age-standardised death and DALY rates of idiopathic epilepsy reduced from 1990 to 2021 (decline of 15·8% [8·8-22·8] and 14·5% [4·2-24·2], respectively). There were three-fold to four-fold geographical differences in the burden of active idiopathic epilepsy, with the bulk of the burden residing in low-income to middle-income countries: 82·1% (81·1-83·4) of incident, 80·4% prevalent (79·7-82·7), 84·7% (83·7-85·1) fatal epilepsy, and 87·9% (86·2-89·2) epilepsy DALYs. INTERPRETATION: Although the global trends in idiopathic epilepsy deaths and DALY rates have improved in the preceding decades, in 2021 there were almost 52 million people with active epilepsy (24 million from idiopathic epilepsy and 28 million from secondary epilepsy), with the bulk of the burden (>80%) residing in low-income to middle-income countries. Better treatment and prevention of epilepsy are required, along with further research on risk factors of idiopathic epilepsy, good-quality long-term epilepsy surveillance studies, and exploration of the possible effect of stigma and cultural differences in seeking medical attention for epilepsy. FUNDING: Bill and Melinda Gates Foundation.
Multicentre, multi-arm, double-blind randomised placebo-controlled dose-finding trial investigating the safety and Efficacy of MirococePt (APT070) In Reducing delayed graft function In the Kidney ALlograft (EMPIRIKAL-2): study protocol for a randomised controlled trial.
BACKGROUND: Up to 50% of kidney transplant patients are diagnosed with delayed graft function (DGF) following transplantation-the majority being linked to ischaemia reperfusion injury (IRI). DGF is traditionally defined as the requirement for dialysis during the first week after transplantation and is associated with inferior graft and patient outcomes. Local synthesis of complement components, largely by the renal tubule, plays a critical role in IRI. We have developed Mirococept, a membrane-targeted complement inhibitor, that can be administered to the donor kidney ex vivo prior to transplantation. After administration, Mirococept is retained in the donor organ, thereby minimising the risk of systemic side effects. We previously launched the EMPIRIKAL study aiming to evaluate the efficacy of Mirococept in reducing DGF in deceased-donor kidney transplantation (KT). The funding body recommended termination of the study to allow a dose-saturating study before the next stage of clinical evaluation. This was carried out in a porcine kidney model and led to a revised dosing regimen for EMPIRIKAL-2 (60-180 mg compared with 5-25 mg in the initial trial). The EMPIRIKAL-2 trial (REC 24/NE/0071) aims to identify the most safe and efficacious dose of Mirococept to reduce DGF rate in deceased-donor KT. METHODS AND ANALYSIS: EMPIRIKAL-2 is a Phase IIa multicentre double-blind randomised controlled trial (RCT) with an initial safety run. Participants will be recruited from renal departments at National Health Service tertiary hospital sites in the UK. The purpose of the safety run is to assess the tolerance of each of the three proposed Mirococept doses (60, 120 or 180 mg), before the RCT begins. Three patients will be assigned to each treatment dose, starting from the lower dose. The safety run will be considered successful if at least one dose can be taken forward to the RCT for comparison to placebo.If safety is met, 144 participants (36 per arm excluding drop-outs) will be randomised to all doses meeting the safety criteria or placebo on a 1:1:1:1 basis. The primary endpoint is DGF, defined as the requirement for dialysis during the first week after transplantation. Safety evaluation will include the monitoring of laboratory data and the recording of all adverse events. Immunosuppression therapy, antibiotic and antiviral prophylaxis will be administered as per local centre protocols. Enrolment in the RCT is anticipated to take approximately 12 months, and patients will be followed-up for 12 months. ETHICS AND DISSEMINATION: The study has been approved by the Northeast - Newcastle and North Tyneside 2 Research Ethics Service Committee, REC reference 24/NE/0071. The results of the study will be reported and disseminated at international conferences and in peer-reviewed scientific journals. Once published, a lay summary of the results will be made available to participants who request this information. TRIAL REGISTRATION NUMBER: ISRCTN14279222. Registered on 4 July 2024. PROTOCOL VERSION: 2.0 dated 9 May 2024.
First-in-man study of the PSMA Minibody IR800-IAB2M for molecularly targeted intraoperative fluorescence guidance during radical prostatectomy.
PURPOSE: Prostate-specific membrane antigen (PSMA) is increasingly used to image prostate cancer in clinical practice. We sought to develop and test a humanised PSMA minibody IAB2M conjugated to the fluorophore IRDye 800CW-NHS ester in men undergoing robot-assisted laparoscopic radical prostatectomy (RARP) to image prostate cancer cells during surgery. METHODS: The minibody was evaluated pre-clinically using PSMA positive/negative xenograft models, following which 23 men undergoing RARP between 2018 and 2020 received between 2.5 mg and 20 mg of IR800-IAB2M intravenously, at intervals between 24 h and 17 days prior to surgery. At every step of the procedure, the prostate, pelvic lymph node chains and extra-prostatic surrounding tissue were imaged with a dual Near-infrared (NIR) and white light optical platform for fluorescence in vivo and ex vivo. Histopathological evaluation of intraoperative and postoperative microscopic fluorescence imaging was undertaken for verification. RESULTS: Twenty-three patients were evaluated to optimise both the dose of the reagent and the interval between injection and surgery and secure the best possible specificity of fluorescence images. Six cases are presented in detail as exemplars. Overall sensitivity and specificity in detecting non-lymph-node extra-prostatic cancer tissue were 100% and 65%, and 64% and 64% respectively for lymph node positivity. There were no side-effects associated with administration of the reagent. CONCLUSION: Intraoperative imaging of prostate cancer tissue is feasible and safe using IR800-IAB2M. Further evaluation is underway to assess the benefit of using the technique in improving completion of surgical excision during RARP. REGISTRATION: ISCRCTN10046036: https://www.isrctn.com/ISRCTN10046036 .
External validity of randomized clinical trials in vascular surgery: systematic review of demographic factors of patients recruited to randomized clinical trials with comparison to the National Vascular Registry
Background: Evidence-based medicine relies on randomized clinical trials, which should represent the patients encountered in clinical practice. Characteristics of patients recruited to randomized clinical trials involving vascular index operations (carotid endarterectomy, abdominal aortic aneurysm repair, infrainguinal bypass and major lower limb amputations) were compared with those recorded in the National Vascular Registry across England and Wales. Methods: MEDLINE, Embase, Web of Science, CENTRAL, clinicaltrials.gov and World Health Organization International Trials Registry Platform (CRD42021247905) were searched for randomized clinical trials involving the index operations. Demographic (age, sex, ethnicity) and clinical (co-morbidities, medications, body mass index, smoking, alcohol, cognition) data were extracted, by operation. Characteristics of operated on patients were extracted from publicly available National Vascular Registry reports (2014–2020). All findings are reported according to PRISMA guidelines. Rayyan.AI, Excel and GraphPad Prism were used for screening and analysis. Results: A total of 307 randomized clinical trials (66 449 patients) were included and compared with National Vascular Registry data for 119 019 patients. Randomized clinical trial patients were younger across all operations; for carotid endarterectomy, bypass and major lower limb amputation randomized clinical trials, there were differences in female patient representation. Further comparisons were limited by the insufficient baseline data reporting across randomized clinical trials, though reporting improved over decades. National Vascular Registry reports lacked information on patient factors such as patient ethnicity or body mass index. Conclusions: There are significant differences in demographic and clinical factors between patients recruited to vascular surgery randomized clinical trials and the real-world National Vascular Registry vascular surgery patient population. Minimum reporting standards for baseline data should be defined to allow future randomized clinical trials to represent real-world patient populations and ensure the external validity of their results.