Royal College of Surgeons of England

Aging can prolong the wound healing and is associated with decline in stem cells, delays in cellular migration, and lower vascularization. Tissue engineering has largely evolved to incorporate advanced three-dimensional wound dressings, scaffolds, and hydrogels that may be seeded with mesenchymal stromal cells (MSCs) to foster an environment conducive to regeneration and enhance the healing process. The effectiveness of stem cell-seeded scaffolds can be improved by incorporating activating agents such as nucleic acids resulting in gene-activated scaffolds (GAS), thereby facilitating targeted wound healing in aged patients. In this study, we assess the in vivo wound healing potential of a promising MSC seeded gene-activated collagen scaffold, containing the anti-fibrotic agent β-klotho and pro-angiogenic stromal derived factor (SDF-1α) in aged male Sprague Dawley rats (20–24 month old). A MSC cell loaded split skin model compared MSC only with the clinical standard dressing +Jelonet, MSCs +gene-free collagen scaffold, and MSCs +SDF-1α/β-klotho dual gene-activated collagen scaffold up to 21 days. Our results showed wound healing in all groups except in MSC +Jelonet which showed scab formation with exudate. MSC only group healed primarily via fibrotic contraction. In contrast, the scaffold groups showed host tissue integration and a redistribution of extracellular matrix proteins, less contraction, and complete re-epithelized wounds at day 21. The dual GAS displayed programmed wound healing with the greatest neo-vascularization CD31 expression. In conclusion, wound healing in aged rats can be effectively modulated when MSCs are loaded on biocompatible collagen scaffolds, particularly when these scaffolds are loaded with anti-fibrotic and pro-angiogenic factors. This approach enhances blood vessel formation while reducing fibrosis, suggesting a promising potential for programmed wound healing strategies in aged chronic wounds.

Blood coagulation is essential for stopping bleeding but also drives thromboembolic disorders. Factor XII (FXII)–triggered coagulation promotes thrombosis while being dispensable for hemostasis, making it a potential anticoagulant target. However, its physiological role remains unclear. Here, we demonstrate that FXII-driven coagulation enhances innate immunity by trapping pathogens and restricting bacterial infection in mice. Streptococcus pneumoniae infection was more severe in FXII-deficient (F12−/−) mice, with increased pulmonary bacterial burden, systemic spread, and mortality. Similarly, Staphylococcus aureus skin infections and systemic dissemination were exacerbated in F12−/− mice. Reconstitution with human FXII restored bacterial containment. Plasma kallikrein amplifies FXII activation, and its deficiency aggravated S. aureus skin infections, similarly to F12−/− mice. FXII deficiency impaired fibrin deposition in abscess walls, leading to leaky capsules and bacterial escape. Bacterial long-chain polyphosphate activated FXII, triggering fibrin formation. Deficiency in FXII substrate factor XI or FXII/factor XI co-deficiency similarly exacerbated S. aureus infection. The data reveal a protective role for FXII-driven coagulation in host defense, urging caution in developing therapeutic strategies targeting this pathway.

Purpose The SMART Stone Multidisciplinary Team (MDT) recommendations aim to provide guidance on the role of the MDT in the early identification, referral and assessment of adult high-risk recurrent kidney stone formers to advance patient care. Methods Recommendations were developed by the expert Steering Committee (SC) comprising of three Urologists, one Nephrologist, and two Biochemists/Geneticists from the UK, Spain, Germany, and Italy. These recommendations were voted on by invited specialists via an online survey to determine their level of agreement, from ‘strongly agree’ to ‘strongly disagree’. With an agreement threshold set at ≥ 70%, the SC reviewed the survey results, additional comments, and any areas of disagreement before finalizing the recommendations. Results A total of 44 recommendations were developed by the SC designed to support the set-up of an ideal MDT. Thirteen core recommendations were chosen as being highest priority and were voted on by 29 invited specialists from 19 countries across Europe, Canada, East Asia, South/Southeast Asia, and the Middle East. All 13 core recommendations reached the ≥ 70% agreement threshold. The remaining 31 recommendations were voted on by those specialists who opted-in to partake in the extended questionnaire. Fifteen specialists provided their responses from 14 different countries. All 31 recommendations reached the ≥ 70% agreement threshold. Conclusions An ideal MDT process can achieve comprehensive, high-quality, and coordinated patient care, which is especially useful for patients with complex stone diseases. A high level of agreement was reached in areas relating to the implementation of an ideal MDT in identifying high-risk stone formers.

Objective Following emerging evidence of autoimmune‐associated seizures in medication‐refractory epilepsy, we began offering a trial of immunotherapy to selected patients. Here, we review this approach's treatment response, predictive clinical features, and utility. Methods This was a retrospective single‐center cohort study (2018–2022) of empiric, palliative immunotherapy in 31 adults with highly refractory, highly active epilepsy. Since 2018, in line with the International League Against Epilepsy's addition of “immune” as an etiology in the Classification of Epilepsy, we initiated immunotherapy after comprehensive antiseizure medication failures while at the same time screening for an autoimmune origin. The workup included assessing clinical features, serum autoantibody testing, cerebrospinal fluid testing (where feasible), magnetic resonance imaging (MRI), and electroencephalography. All patients received intravenous methylprednisolone or IV immunoglobulin according to previously published protocols, and follow‐up was for at least 12 months. Results Nine patients (29%) in this highly refractory cohort demonstrated a sustained treatment response, measured as a greater than 50% improvement in seizure frequency for at least 12 months. Three patients (10%) became seizure‐free. Six patients (20%) were classified as partial responders and experienced an initial response that was not sustained. Apart from a trend toward a diagnosis of focal epilepsy, we did not identify any specific serological, clinical, electrodiagnostic, or imaging features with statistical significance that were predictive of treatment response. Significance This patient group demonstrated a reasonable response rate to an immunotherapy trial. These findings are surprising but support the consideration of an immunotherapy trial in patients with refractory epilepsy. Requirements for repeated courses of immunotherapy differed significantly between patients, and this is an area of interest for further research. The basis for response in this cohort remains unclear; in some cases, antiseizure medication changes may have contributed; however, without any apparent autoimmune features, we consider potential blood–brain barrier repair or a placebo effect as hypothetical alternative mechanisms of action for the response to immunotherapy.

Background The role of the placenta in the development of hypoxic ischaemic encephalopathy (HIE) remains undefined. There is limited research comparing placental histology for infants with HIE and healthy controls. This is limiting our ability to understand its role in HIE. This study hypothesised that placental pathology is more common in infants with HIE compared with healthy infants and aimed to report the differences in placental histology between infants with HIE and healthy controls. Methods A case-control study of infants with moderate andsevere HIE and healthy controls at a single tertiary Neonatal Intensive Care Unit. Placental histology was reviewed by one perinatal histopathologist using consensus guidelines. Results Seventy-four cases and 98 controls were included. Cases had a higher incidence of pathology, including fetal vascular malperfusion, histological chorioamnionitis and delayed villous maturation. Conclusion This study demonstrates a higher incidence of placental pathology for infants born with HIE suggesting that the placenta is an important factor in the pathogenesis of HIE. Further research is required to delineate this relationship.

Objectives Perineal assessment and repair are fundamental to providing quality obstetric and midwifery care to women. Up to 80% of women sustain perineal trauma during vaginal delivery, and 70% require repair. This study aimed to establish baseline perineal anatomy knowledge, training exposure, and experience, and to assess whether ongoing training is needed to strengthen perineal repair education and skills. Methods This is a prospective multicenter observational study. Obstetricians and midwives actively involved in perineal repair were recruited in three maternity units between April and July 2024. A pre‐survey was completed. A teaching intervention was delivered to participants. After the teaching intervention, a post‐survey was completed. The sample size was appropriately powered and the data were analyzed accordingly. Results During the study period, 89 clinicians completed the pre‐survey, and 72 attended the training initiative and completed the post‐survey. A total of 84.3% of clinicians had prior training in assessing perineal injury, and 83.1% had some form of practical training in perineal repair. Only 75.3% had received training on assessing for obstetric anal sphincter injury. A total of 88.8% of clinicians felt confident performing an episiotomy, and only 69.7% felt confident in repairing an episiotomy. After the teaching intervention, the post‐survey responses highlighted significant improvement in anatomical knowledge among clinicians conducting perineal repair (P = 0.0078). Conclusions Ongoing learning is necessary for clinicians who are actively completing perineal repair. It results in increased knowledge, which should impact the quality of care for women requiring perineal repair.

Objective This study investigates incidence, outcomes and echocardiographic characteristics of preterm infants with early pulmonary hypertension (PH) compared to those without. Study design A prospective observational study of infants born <29 weeks gestation between July 2021–March 2024. Echocardiograms were performed at 24–48 h and 36 weeks postmenstrual age (PMA). Early PH was defined as bidirectional or right-to-left shunt across the ductus. Result Early PH was identified in 20/166 (12%) infants. These infants had higher mortality than controls (55% vs 11%; P < 0.01). Initial echocardiogram revealed differences in twist(°) (5.1 vs 7.9; P = 0.03), torsion(°/mm) (0.29 vs 0.41; P = 0.04), systolic time(ms) (146 vs 162; P < 0.01) and isovolumic relaxation time(ms) (58 vs 46; P < 0.01), with several persistent abnormalities at 36 weeks PMA. Conclusion Preterm infants with early PH have higher mortality and distinct echocardiographic profiles, with functional alterations persisting to 36 weeks PMA in survivors. Early identification and targeted management may improve outcomes.

Background Targeting RAS mutant (MT) colorectal cancer (CRC) remains a difficult challenge, mainly due to the pervasiveness of RAS/MEK-mediated feedback loops. Preclinical studies identified MET/STAT3 as an important mediator of resistance to KRAS-MEK1/2 blockade in RASMT CRC. This dose escalation/expansion study assessed safety and initial efficacy of the MEK1/2 inhibitor binimetinib with MET inhibitor crizotinib in RASMT advanced CRC patients. Methods In the dose escalation phase, patients with advanced solid tumours received binimetinib with crizotinib, using a rolling- 6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. A subsequent dose expansion in RASMT CRC patients assessed treatment response. Blood samples for pharmacokinetics, MET biomarker and ctDNA analyses, and skin/tumour biopsies for pharmacodynamics, c-MET immunohistochemistry (IHC), MET in situ hybridisation (ISH) and MET DNA-ISH analyses were collected. Results Twenty patients were recruited in 3 cohorts in the dose escalation. The MTD was binimetinib 30 mg B.D, days 1–21 every 28 days, with crizotinib 250 mg O.D continuously. Dose-limiting toxicities included grade ≥ 3 transaminitis, creatinine phosphokinase increases and fatigue. Thirty-six RASMT metastatic CRC patients were enrolled in the dose expansion. Pharmacokinetic and pharmacodynamic parameters showed evidence of target engagement. Across the entire study, the most frequent treatment-related adverse events (TR-AE) were rash (80.4%), fatigue (53.4%) and diarrhoea (51.8%) with grade ≥ 3 TR-AE occurring in 44.6%. Best clinical response within the RASMT CRC cohort was stable disease in seven patients (24%). Tumour MET super-expression (IHC H-score > 180 and MET ISH + 3) was observed in 7 patients (24.1%), with MET-amplification only present in 1 of these patients. This patient discontinued treatment early during cycle 1 due to toxicity. Patients with high baseline RASMT allele frequency had a significant shorter median overall survival compared with that seen for patients with low baseline KRASMT allele frequency. Conclusions Combination binimetinib/crizotinib showed a poor tolerability with no objective responses observed in RASMT advanced CRC patients. EudraCT-Number: 2014–000463 - 40 (20/06/2014: A Sequential Phase I study of MEK1/2 inhibitors PD- 0325901 or Binimetinib combined with cMET inhibitor Crizotinib in RAS Mutant and RAS Wild Type with aberrant c-MET).

Background Pseudomonas aeruginosa can proliferate in immunocompromised individuals, forming biofilms that increase antibiotic resistance. This bacterium poses a significant global health risk due to its resistance to human defenses, antibiotics, and various environmental stresses. The objective of this study was to evaluate the antibacterial, anti-biofilm, and anti-quorum sensing activities of galloylquinic acid compounds (GQAs) extracted from Copaifera lucens leaves against clinical isolates of multidrug-resistant (MDR) P. aeruginosa. We have investigated the optimal concentration of GQAs needed to eradicate preexisting biofilms and manage wound infections caused by P. aeruginosa, in vitro and in vivo. Results Our results revealed that GQAs exhibited 25–40 mm inhibition zone diameters, with 1–4 µg/mL MIC and 2–16 µg/mL MBC values. GQAs interfered with the planktonic mode of P. aeruginosa isolates, and significantly inhibited their growth in the pre-formed biofilm architecture, with MBIC80 and MBEC80 values of 64 µg/mL and 128 µg/mL, respectively. The anti-biofilm effect was confirmed by fluorescence staining and confocal microscopy which showed a dramatic reduction in the cell viability and the biofilm thickness (62.5%), after exposure to 128 µg/mL of GQAs in particular. The scanning electron micrographs showed that GQAs impaired biofilm and bacterial structures by interfering with the biomass and the exopolysaccharides forming the matrix. GQAs also interfered with virulence factors and bacterial motility, where 128 µg/mL of GQAs significantly (p < 0.05) reduced rhamnolipid, pyocyanin, and the swarming motility of the organism which play a vital role in the biofilm formation. GQAs downregulated 89% of the quorum-sensing genes (lasI and lasR, pqsA and pqsR) involved in the biofilm formation. Conclusion GQAs demonstrate significant promise as novel and potent antibiofilm and antivirulence agents against clinical isolates of MDR P. aeruginosa, with substantial potential to enhance wound healing in biofilm-associated infections. This promising antibacterial action positions GQAs as a superior alternative for the treatment of biofilm-associated wound infections, with substantial potential to improve wound healing and mitigate the impact of persistent bacterial infections. Clinical trial number not applicable.

The synthetically convenient strain promoted double azide cycloaddition of the Sondheimer‐Wong diyne produces resolvable chiral dibenzo‐cycloocta‐bis‐triazoles whose stereogenicity, to date, has gone unrecognised. Enantiomers were separable by chiral HPLC and showed no racemization at 100 °C. This unique method to produce chiral substrates was exploited for the synthesis and resolution of a chiral fluorescent BF2‐azadipyrromethene, with absorption and emission spanning the important spectral range of 600 to 700 nm. The fluorophore properties were studied utilising X‐ray structural analysis, electronic circular dichroism spectra and DFT calculations.

Background Transperineal prostate biopsy (TPPB) under local anaesthesia is a widely employed biopsy method, and is currently endorsed by the European Association of Urology (EAU). This review aimed to assess the pooled detection rates of clinically significant prostate cancer using TPPB under local anaesthetic. Additionally, pain scores and complications were also reported. Methods Our search was conducted in line with the most recent Preferred Reporting Items for Systematic reviews and Meta‐Analyses (PRISMA) recommendations up to August 2024. The study was registered on PROSPERO under the ID: CRD42024588824. An electronic search was conducted of the PubMed, Embase and Cochrane Central Register of Controlled Trials databases along with grey literature using the Google search engine. Results In total, there were 2881 patients included in this review. Biopsy histology results were reported in 11 studies comprising 2781 cases. We observed a clinically significant prostate cancer rate of 52% (95% CI 44%–60%) for studies that employed both a mix of systematic and targeted biopsies and 26% (95% CI 23%–30%) when systematic biopsies alone were taken. The pooled rate was 48% (95% CI 37%–59%), overall. Complications after prostate biopsies were reported by 9 studies with a combined 2688 patients. There were 61 patients (2.3%) who had Clavien–Dindo (CD) 1–2 complications and three patients (0.1%) who had CD 3–5 complications. The pooled rate of CD 1 and 2 complications was 2% (95% CI 1%–4%). Conclusions TPPB under local anaesthetic is a safe, efficacious and well‐tolerated method of prostate biopsy when compared with other methods. Undertaking the procedure under local anaesthesia does not seem to lower cancer detection rates.

There is growing interest in the role of extracellular vesicles (EVs) in neonatal pathology. This study aimed to characterise circulating EVs following preterm birth. This single‐centre prospective observational study included cord and postnatal plasma from preterm (n = 101) and full‐term infants (n = 66). EVs were analysed using nanoparticle tracking analysis, flow cytometry, proteomics and procoagulant activity assay. We found changes in the concentration, size, cellular origin and proteomic content of circulating EVs in preterm infants during perinatal adaptation. To understand if these changes were related to prematurity or normal adaptation to extrauterine life, they were also investigated in term infants. There was a dramatic increase in the concentration of small and large EVs on Day 3 in the preterm group; specific subsets of platelet (CD42b⁺ and CD62P⁺), endothelial (VEGFR2) and tissue factor EVs were elevated. Differentially expressed proteins relating to haemostasis, pulmonary physiology and immunity were identified between Day 1 and 3 in preterm infants. These changes have never previously been described in a large cohort of preterm infants and differ from healthy term infants. These findings have major implications for future neonatal EV studies, particularly the timing of sample collection. Further work is required to understand the clinical implications of this unique EV profile following preterm birth.

Young people who self-harm are at an increased risk of suicide. Furthering our understanding of the risk factors for self-harm is essential for identifying high-risk groups, which can be used to inform the design of preventative interventions. This study used the Avon Longitudinal Study of Parents and Children (ALSPAC) and applied latent class analysis to the risk factors for self-harm at ages 13 and 17. Longitudinal associations between the latent classes and self-harm at ages 17 and 20 were examined. Cross-cohort comparisons were conducted between this study and a previous study using Irish data. At age 13 there was a low risk group, a peer problems group, and substance use group, similar for the two cohort studies, and a family conflict group, which was the least similar group to its matching group in the Irish study. All of these age 13 high-risk groups had approximately twice the relative risk (between 1.3 and 2.5) for self-harm at age 17 compared to the low risk group. The age 17 models were very similar across the two cohorts, each with a low risk group, a depression and high substance use group, a depression and low substance use group, and a substance use group. The relative risk of self-harm at age 20 for these high-risk groups compared the low risk group ranged from 3.6 to 8.0. These groups could help identify those at risk of self-harm and inform the design of prevention programmes to reduce self-harm behaviour in young people.

Pericallosal artery aneurysms (PCAA) are relatively rare intracranial aneurysms that present unique challenges in diagnosis and management. This study provides a comprehensive review of the literature to assess demographic patterns, risk factors, treatment approaches, and complications associated with PCAA. Data from 23 studies were analyzed using Python with libraries such as Pandas and Matplotlib. Descriptive statistics and crosstabulations explored the relationships between treatment modalities (microsurgical, endovascular, combined) and complications, including hydrocephalus, vasospasms, and intraprocedural ruptures. Visualizations were employed to depict the prevalence and impact of various outcomes. Analysis revealed a notable gender disparity, with females constituting 70.47% of the study population. The average age was 49.93 years, and the average aneurysm size was 6.34 mm. A majority of aneurysms were ruptured (542 ruptured vs. 251 unruptured). Risk factors like smoking were prevalent, and radiological features such as subarachnoid hemorrhage (SAH) were commonly reported. Endovascular treatment was slightly more frequent (86.96%) than microsurgical treatment (73.91%). Vasospasm was the most reported complication (56.5%), followed by hydrocephalus and intraprocedural rupture. The analysis of the distribution of studies reporting complication for each treatment modality showed that endovascular treatment studies reported higher rates of vasospasms, hydrocephalus and intraprocedural rupture. The mortality rate was 6.52%, with a mean follow-up duration of 20.77 months. This review reveals that PCAAs predominantly affect females, with an average patient age of 49.93 years. Aneurysms averaged 6.34 mm and often caused SAH. Endovascular treatments were more common but had higher complication rates than microsurgical methods, which also carried risks. The mortality rate was 6.52%. Supplementary Information The online version contains supplementary material available at 10.1007/s10143-025-03500-6.

Purpose of Review to explore a paradigm shift in the definition of opioid-responsive cancer pain in this hypothesis-driven review. Opioid-responsive cancer pain may be misplaced within the definition of chronic pain, chronic pain takes three months to establish, early effective control is worthwhile to achieve. Recent findings, from a bench-to-bed perspective, debates the interpretation of results supporting the hypothesis that opioid-responsive cancer pain could remain ‘constant acute pain’, with explanations, best solutions, for tolerance and/or addiction, in cancer patients compared to those with chronic pain from other conditions. Summary Unraveling the unique apparent properties of opioid-responsive cancer pain empowers knowledge of the process by which acute pain may have the potential to remain acute in nature and not transition into chronic pain. Findings outlined defend the hypothesis of probable sustained acute nature of opioid-responsive cancer pain, importance of early, sustained pain control, opioid reduction and further exploration of this hypothesis in clinical practice.

Background Lifestyle measures in addition to pharmacotherapy are recommended to optimise stroke secondary prevention. Adopting and sustaining good health behaviours after stroke necessitates ongoing motivation, influenced by complex social and cultural factors. This study analysed stroke survivors’ experiences of addressing their lifestyle-related risks through a comprehensive theoretical lens addressing cognitive, affective, social, and environmental influences. Patient and public involvement (PPI) enhanced the research quality and transparency. Methods Eight focus group discussions (N = 35 stroke participants; N = 3 family members/informal carers) were facilitated using semi-structured questions co-developed with a PPI panel. Purposive sampling ensured adequate representation (e.g. urban/rural location and stroke-related disabilities). Data were first coded and categorised inductively and mapped to the Theoretical Domains Framework (TDF) deductively to identify relevant constructs and theories of behaviour-change. Results Participants reported risk reducing lifestyle changes as largely self-directed activities they figured out themselves. Their experiences mapped to 10 of the 14 theoretical domains of the TDF. The most reported behaviour-change mediators discussed were in the domains of Knowledge and Social Influences, seen as encouraging change and supporting emotional reactions. Goals were discussed in a limited way indicating underutilisation. Reminders, reinforcements, and rules to observe for maintaining healthy behaviours, mapping to the Reinforcement and Behavioural Regulation domains, were valued constructs. Psychosocial challenges, emotional responses and cognitive difficulties (Memory, Attention & Decision Processes and Emotions domains) were strongly evident, resonating with the experiences of our PPI contributor and interfacing with behaviour change processes and knowledge uptake. Health-beliefs, self-identity and perceived ability to change behaviour were considered to assert both positive and negative influences on behaviours, mapping to Social/Professional Role & Identity, Beliefs about Consequences and Beliefs about Capabilities domains. ‘Know how’ was highlighted as largely lacking for behaviour change, with the associated theoretical domains Intentions, Skills, Environmental context & resources to encourage skills development and Optimism about change notably absent from discussions. Conclusions The TDF proved a valuable tool to link stroke survivors’ secondary prevention experiences and unmet needs with recognised constructs for behaviour-change. Results have important theory-driven implications to guide future interventions designed to support individuals in risk reducing behaviours following stroke.

Objective To evaluate the area-based incidence of metastatic prostate cancer at diagnosis, reflecting the risk of late-stage diagnosis, and overall prostate cancer incidence, reflecting the risk of over-diagnosis, in a country without a formal screening programme. Methods and analysis National study of annual prostate cancer incidence between 2015 and 2019. Mixed-effects regression estimated area-based incidence, adjusted for age, ethnicity and socioeconomic deprivation. Linear regression assessed the association between metastatic and overall cancer incidence. Results National annual incidence of metastatic prostate cancer was 5.7 per 10 000 men and overall incidence was 43.9. Higher incidence of both metastatic and overall cancer were observed in areas with older populations and with more men with black ethnicity (both p<0.0001). Greater socioeconomic deprivation was linked to higher metastatic but lower overall cancer incidence (p<0.0001). Metastatic incidence varied across the country from 4.0 to 6.8, and prostate cancer overall from 37.9 to 50.1 per 10 000 men. Areas with higher metastatic cancer incidence had lower overall cancer incidence (p<0.0001). Conclusions There is significant geographic variation in metastatic prostate cancer incidence at diagnosis, with a higher incidence of metastatic cancer observed in areas with a lower overall prostate cancer incidence and in more socioeconomically deprived neighbourhoods, which likely contributes to poorer long-term outcomes. The findings highlight the need for a targeted, risk-based diagnostic approach as well as improved diagnostic facilities and referral pathways. Further research is needed to understand the factors driving this variation in order to reduce metastatic presentations and tackle inequalities in prostate cancer outcomes.