Oxford University Hospitals NHS Foundation Trust is an English teaching hospital and part of the Shelford Group. It is one of the UK's largest teaching hospitals and one of the largest hospitals in Europe. The Trust is made up of four hospitals – the John Radcliffe Hospital (which includes the Children's Hospital, West Wing, Eye Hospital, Heart Centre and Women's Centre), the Churchill Hospital and the Nuffield Orthopaedic Centre, all located in Oxford, and the Horton General Hospital in Banbury, north Oxfordshire.As well as the four main hospitals, the trust also provides services in four community hospitals across Oxfordshire including Thame, Wallingford, Wantage and Witney. The services offered at these community hospitals are fairly basic and differ from hospital to hospital. Wantage community hospital is also accompanied by Wantage health centre whereby additional health services are provided by the trust. Other clinics and health centres serviced by the trust in Oxfordshire includes Bicester and Oxford with the trust also providing some services in clinics and hospitals in neighbouring counties.
BACKGROUND AND OBJECTIVE:BRCA1 and BRCA2 pathogenic germline variants (PGVs) are associated with higher risk of prostate cancer (PC). The IMPACT study evaluated the utility of targeted prostate-specific antigen (PSA) screening in BRCA1/BRCA2 PGV carriers. Here we report outcomes after five rounds of PSA screening in IMPACT. METHODS:Between 2005 and 2015, 3063 participants aged 40-69 yr (median 54 yr) were recruited from 65 centres in 20 countries in two cohorts: (1) BRCA1/BRCA2 PGV carriers (915 BRCA1, 901 BRCA2); and (2) age-matched noncarriers for a familial PGV (727 BRCA1 and 520 BRCA2 noncarriers). Annual PSA screening was performed, with PSA >3.0 ng/ml used as the indication for prostate biopsy. Our aim was to identify differences by PGV status in (1) the incidence of PC and of clinically significant PC (csPC; grade group ≥2) and (2) tumour stage and characteristics after five screening rounds. KEY FINDINGS AND LIMITATIONS:There was no statistically significant difference in PC incidence between BRCA1/BRCA2 PGV carriers and noncarriers. csPC incidence was significantly higher for BRCA2 PGV carriers than for noncarriers (3.1% vs 1.3%; p = 0.04). Among men with PC, the proportion of tumours with National Comprehensive Cancer Network intermediate unfavourable/high risk was higher in the BRCA1/BRCA2 PGV groups versus the corresponding group without PGVs (BRCA2: 65% vs 32%, p = 0.029; BRCA1: 56% vs 18%, p = 0.0017). There were no T4 or metastatic PC cases. Pathology after radical prostatectomy revealed tumour upgrading for 7/23 (26%) BRCA1 PGV carriers and 10/34 (26%) BRCA2 PGV carriers, with no tumour upgrading for men without PGVs. Study limitations include the biopsy compliance rate and changes in PC diagnostic pathways since 2005. CONCLUSIONS AND CLINICAL IMPLICATIONS:Annual PSA screening in BRCA2 PGV carriers confirmed a higher incidence of csPC and detection of clinically relevant tumours in comparison to noncarriers. For the first time, we confirm that PSA screening in BRCA1 PGV carriers results in early detection of NCCN IR-U/HR PC. Systematic PSA screening is recommended for BRCA2 PGV carriers and should be considered for BRCA1 PGV carriers.
Graphical Abstract: Abstract:Analysis of immunofluorescent images can be time-consuming and observer-dependant. We aimed to develop a standardised method for analysing immunofluorescent images of human and mouse testicular tissues using an existing software package. We used QuPath to train and apply an artificial neural network with multilayer perception (ANN-MLP) on images. We were able to automate the segmentation of cells in regions of interest (ROIs) using both StarDist (a convolution neural network) and Watershed image transformation. Segmented cells were classified using QuPath object classification system, which was successfully applied to a range of mouse and human interstitial, Sertoli and spermatogonial germ cell markers. We found that manual counting and classification of cells decoupled the relationship between tubular area and a number of SOX9+ (r 2 = 0.26, P = 0.35) and MAGE-A+ (r 2 = 0.26, P = 0.35) cells. However, automating the segmentation of ROIs and cell classification with simple macros yielded results that maintained the correlation between tubular area and number of SOX9+ (r 2 = 0.56, P = 0.03) and MAGE-A+ (r 2 = 0.93, P = 0.002) cells. In addition, we were able to export data into R/RStudio allowing for the analysis of classification-specific parameters such as mitotic index and cellular organisation in different regions of the tubule. Importantly, the time taken per image using the automated method was significantly faster (6,247 vs three seconds; P < 0.001) at segmenting tubules and quantifying cells than previous manual annotation methods. We propose the use of this method for analysis and cell quantification in testicular tissues. Lay summary:Machine learning (ML) is a type of algorithm that forms part of artificial intelligence (AI). ML is able to learn, detect and predict sequences and structures such as words in sentences or objects in images. ML combined with the ability of modern computers to process large quantities of data and perform repetitive tasks in an automated way makes it an attractive research tool. In particular, the analysis of images taken from a microscope of patient or experimental samples is one area in which ML can excel. We found that open-source software containing ML could be trained on as few as six images. Once trained, the machine learning algorithm could analyse an image in approximately one minute. The same image would take a skilled researcher nearly two hours to analyse. In addition to speed, ML was able to do this more accurately and consistently as well as being automated by a simple piece of code.
The incidence of anterior cruciate ligament (ACL) injuries is increasing in the UK, with a particularly sharp increase among young female athletes participating in sport. ACL injuries result in significant morbidity, with a profound impact on the physical, mental and social health of individuals, alongside lengthy rehabilitation. Therefore, primary prevention of ACL injuries is desirable. The intrinsic and extrinsic risk factors associated with ACL injury, such as deficits in neuromuscular control, impaired movement quality, fatigue, strength imbalances, and suboptimal load management, are shared with a spectrum of other lower-limb musculoskeletal injuries. This overlap supports the concept that ACL injury prevention may not be best considered a condition-specific endeavour, but rather as a component of a comprehensive lower-limb injury prevention strategy. ACL prevention interventions typically include multi-component training methods designed to improve neuromuscular control, functional performance, balance, strength and power. while often framed around ACL injury reduction, their effects extend beyond the knee, conveying protection against other lower-limb injuries and improving overall performance. Despite a growing body of evidence demonstrating the efficacy of neuromuscular injury prevention programmes, their translation into routine practice has been inconsistent. This annotation outlines the current best evidence relating to ACL injury epidemiology and the effectiveness of injury prevention strategies, supporting a transition to integrate ACL injury prevention into wider, sport-specific lower-limb injury prevention programmes. In doing so, it highlights key stakeholders and barriers relevant to large-scale implementation of injury prevention programmes.
In these two cases, we highlight the concept of pregnancy-associated thrombotic microangiopathy (TMA) overlap syndrome, where two different TMAs occur together, likely one driving another. Thrombotic microangiopathies occurring in pregnancy threaten the lives of both mother and fetus, and yet precise diagnosis may be difficult because of overlapping clinical and laboratory features. The three main syndromes to be considered are thrombotic thrombocytopenic purpura (TTP) - an acute disorder caused by severe ADAMTS13 deficiency; preeclampsia/HELLP syndrome - characterised by haemolysis, elevated liver enzymes, and low platelets; and atypical haemolytic uremic syndrome (aHUS)- most commonly caused by mutations in the complement regulatory genes. We present two cases where the combination of two TMAs (one most likely driving the other) led to difficult management dilemmas.
Background: There are multiple effective treatment options for patients diagnosed with chronic lymphocytic leukemia and small lymphocytic lymphoma (hereafter, simply CLL). In 2025, two phase 3 randomized clinical trials of pirtobrutinib, a non-covalent BTK inhibitor, were reported, demonstrating improved outcomes versus comparator therapies in the treatment-naïve setting (NCT05254743 and NCT05023980). Methods: A systematic literature review was conducted to identify RCTs in the first-line setting for CLL. A Bayesian NMA was performed to compare overall response rate (ORR) and progression-free survival (PFS) of pirtobrutinib versus treatments recommended by the National Comprehensive Cancer Network in the first-line setting, with a focus on BTKi monotherapy. Results: Eight unique trials were identified for comparison versus pirtobrutinib. Eligible RCTs formed two disconnected networks (pirtobrutinib, ibrutinib and zanubrutinib were in Network 1; acalabrutinib was in Network 2). Results from Network 1 for ORR showed an odds ratio (OR) = 0.56 (95% credible interval [CrI], 0.28, 1.12) for ibrutinib versus pirtobrutinib and OR = 0.50 (95% CrI, 0.20, 1.27) for zanubrutinib versus pirtobrutinib. The PFS of ibrutinib was inferior to pirtobrutinib (hazard ratio (HR) = 1.89, 95% CrI, 1.13, 3.19); the PFS HR comparing zanubrutinib with pirtobrutinib was 1.51 (95% CrI, 0.84, 2.72). Conclusions: This NMA shows that pirtobrutinib has better PFS outcomes than ibrutinib. While PFS outcomes suggest that pirtobrutinib is comparable to second-generation covalent BTKi monotherapies, uncertainty exists in the interpretation of the treatment effect, as evidenced by wide credible intervals. These findings suggest the value of pirtobrutinib as a future treatment option for patients in the first-line setting.
