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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.
Fluid mechanical modeling of the upper urinary tract.
The upper urinary tract (UUT) consists of kidneys and ureters, and is an integral part of the human urogenital system. Yet malfunctioning and complications of the UUT can happen at all stages of life, attributed to reasons such as congenital anomalies, urinary tract infections, urolithiasis and urothelial cancers, all of which require urological interventions and significantly compromise patients' quality of life. Therefore, many models have been developed to address the relevant scientific and clinical challenges of the UUT. Of all approaches, fluid mechanical modeling serves a pivotal role and various methods have been employed to develop physiologically meaningful models. In this article, we provide an overview on the historical evolution of fluid mechanical models of UUT that utilize theoretical, computational, and experimental approaches. Descriptions of the physiological functionality of each component are also given and the mechanical characterizations associated with the UUT are provided. As such, it is our aim to offer a brief summary of the current knowledge of the subject, and provide a comprehensive introduction for engineers, scientists, and clinicians who are interested in the field of fluid mechanical modeling of UUT. This article is categorized under: Cancer > Biomedical Engineering Infectious Diseases > Biomedical Engineering Reproductive System Diseases > Biomedical Engineering.
The utility of automated volume analysis of renal stones before and after shockwave lithotripsy treatment.
This study aimed to evaluate the additional utility of an automated method of estimating volume for stones being treated with shockwave lithotripsy (SWL) using computed tomography (CT) images compared to manual measurement. Utility was assessed as the ability to accurately measure stone burden before and after SWL treatment, and whether stone volume is a better predictor of SWL outcome than stone diameter. 72 patients treated with SWL for a renal stone with available CT scans before and after treatment were included. Stone axes measurement and volume estimation using ellipsoid equations were compared to volume estimation using software using CT textural analysis (CTTA) of stone images. There was strong correlation (r > 0.8) between manual and CTTA estimated stone volume. CTTA measured stone volume showed the highest predictive value (r2 = 0.217) for successful SWL outcome on binary logistic regression analysis. Three cases that were originally classified as 'stone-free with clinically insignificant residual fragments' based on manual axis measurements actually had a larger stone volume based on CTTA estimation than the smallest fragments remaining for cases with an outcome of 'not stone-free'. This study suggests objective measurement of total stone volume could improve estimation of stone burden before and after treatment. Current definitions of stone-free status based on manual measurements of residual fragment sizes are not accurate and may underestimate remaining stone burden after treatment. Future studies reporting on the efficacy of different stone treatments should consider using objective stone volume measurements based on CT image analysis as an outcome measure of stone-free state.
Association between circulating inflammatory markers and adult cancer risk: a Mendelian randomization analysis.
BACKGROUND: Tumour-promoting inflammation is a "hallmark" of cancer and conventional epidemiological studies have reported links between various inflammatory markers and cancer risk. The causal nature of these relationships and, thus, the suitability of these markers as intervention targets for cancer prevention is unclear. METHODS: We meta-analysed 6 genome-wide association studies of circulating inflammatory markers comprising 59,969 participants of European ancestry. We then used combined cis-Mendelian randomization and colocalisation analysis to evaluate the causal role of 66 circulating inflammatory markers in risk of 30 adult cancers in 338,294 cancer cases and up to 1,238,345 controls. Genetic instruments for inflammatory markers were constructed using genome-wide significant (P 70% was employed to indicate support for shared causal variants across inflammatory markers and cancer outcomes. Findings were replicated in the FinnGen study and then pooled using meta-analysis. FINDINGS: We found strong evidence to support an association of genetically-proxied circulating pro-adrenomedullin concentrations with increased breast cancer risk (OR: 1.19, 95% CI: 1.10-1.29, q-value = 0.033, PPH4 = 84.3%) and suggestive evidence to support associations of interleukin-23 receptor concentrations with increased pancreatic cancer risk (OR: 1.42, 95% CI: 1.20-1.69, q-value = 0.055, PPH4 = 73.9%), prothrombin concentrations with decreased basal cell carcinoma risk (OR: 0.66, 95% CI: 0.53-0.81, q-value = 0.067, PPH4 = 81.8%), and interleukin-1 receptor-like 1 concentrations with decreased triple-negative breast cancer risk (OR: 0.92, 95% CI: 0.88-0.97, q-value = 0.15, PPH4 = 85.6%). These findings were replicated in pooled analyses with the FinnGen study. Though suggestive evidence was found to support an association of macrophage migration inhibitory factor concentrations with increased bladder cancer risk (OR: 2.46, 95% CI: 1.48-4.10, q-value = 0.072, PPH4 = 76.1%), this finding was not replicated when pooled with the FinnGen study. For 22 of 30 cancer outcomes examined, there was little evidence (q-value ≥0.20) that any of the 66 circulating inflammatory markers examined were associated with cancer risk. INTERPRETATION: Our comprehensive joint Mendelian randomization and colocalisation analysis of the role of circulating inflammatory markers in cancer risk identified potential roles for 4 circulating inflammatory markers in risk of 4 site-specific cancers. Contrary to reports from some prior conventional epidemiological studies, we found little evidence of association of circulating inflammatory markers with the majority of site-specific cancers evaluated. FUNDING: Cancer Research UK (C68933/A28534, C18281/A29019, PPRCPJT∖100005), World Cancer Research Fund (IIG_FULL_2020_022), National Institute for Health Research (NIHR202411, BRC-1215-20011), Medical Research Council (MC_UU_00011/1, MC_UU_00011/3, MC_UU_00011/6, and MC_UU_00011/4), Academy of Finland Project 326291, European Union's Horizon 2020 grant agreement no. 848158 (EarlyCause), French National Cancer Institute (INCa SHSESP20, 2020-076), Versus Arthritis (21173, 21754, 21755), National Institutes of Health (U19 CA203654), National Cancer Institute (U19CA203654).
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.