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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.
Rare disease gene association discovery in the 100,000 Genomes Project.
Up to 80% of rare disease patients remain undiagnosed after genomic sequencing1, with many probably involving pathogenic variants in yet to be discovered disease-gene associations. To search for such associations, we developed a rare variant gene burden analytical framework for Mendelian diseases, and applied it to protein-coding variants from whole-genome sequencing of 34,851 cases and their family members recruited to the 100,000 Genomes Project2. A total of 141 new associations were identified, including five for which independent disease-gene evidence was recently published. Following in silico triaging and clinical expert review, 69 associations were prioritized, of which 30 could be linked to existing experimental evidence. The five associations with strongest overall genetic and experimental evidence were monogenic diabetes with the known β cell regulator3,4 UNC13A, schizophrenia with GPR17, epilepsy with RBFOX3, Charcot-Marie-Tooth disease with ARPC3 and anterior segment ocular abnormalities with POMK. Further confirmation of these and other associations could lead to numerous diagnoses, highlighting the clinical impact of large-scale statistical approaches to rare disease-gene association discovery.
Associations Between Lactate Thresholds and 2000 m Rowing Ergometer Performance: Implications for Prediction-A Systematic Review.
BACKGROUND: Various exercise thresholds have been evaluated to predict athlete performance. However, a systematic review of the literature assessing the association between lactate-based exercise thresholds and 2000 m rowing ergometer performance is still lacking. These may have utility in the prediction of 2000 m rowing ergometer performance due to the close relationship between metabolic parameters and development of endurance capacity. The aim of the present study is to review and assess the extent, quality, and reliability of lactate-based exercise testing and methodologies in their association with 2000 m rowing ergometer performance, and to discuss the potential implications for performance prediction. METHODS: The systematic review was performed following PRISMA 2020 guidelines. The databases searched were EMBASE, MEDLINE and SPORTDiscus. The initial search took place in July 2022, with an update search performed in September 2023, and again in August 2024. Studies which reported a lactate test and its correlation to 2000 m ergometer performance were included. No meta-analysis was performed. RESULTS: Twenty-four studies comprising 797 athletes (513 male, 257 female, 27 not stated) met the eligibility criteria for inclusion in the review. The most commonly used testing protocol involved the use of incremental step-tests. A range of exercise intensity parameters, lactate-based exercise thresholds and interpretation methodologies were employed. Of these, the power or velocity at a blood lactate concentration of 4 mmol l-1 was the most common test, with correlation coefficients ranging from 0.53 to 0.96 suggesting that 28-92% of the variance in rowing performance can be explained by this metric. Six studies that rated as GOOD on the risk of bias assessment found very strong correlations > 0.85 (p
Time to return of bowel function following perioperative probiotics in colorectal cancer surgery (PICCS-1): study protocol for a randomized controlled trial.
BACKGROUND: Postoperative ileus occurs in up to 30% of patients following major oncologic surgery for colorectal cancer, leading to significant morbidity, patient distress, as well as increased utilization of healthcare resources. Various modalities to reduce postoperative ileus rates have been explored. One such modality is the perioperative administration of probiotics which have hitherto achieved inconsistent success. Here, we design a trial to determine whether the perioperative administration with probiotics given together with nutritional supplementation can help to reduce postoperative ileus rates. METHODS: We propose a parallel three-arm randomized controlled trial. In Arm 1, no nutritional supplementation is provided to the patient. In Arm 2, Nestle Isocal is provided to the participant. Nestle Isocal provides nutritional supplementation but without any probiotic. In Arm 3, Nestle Boost Optimum is provided to the patient. Nestle Boost Optimum contains a similar nutritional profile to Isocal, but with the addition of Lactobacillus paracasei. The primary outcome is the time to first bowel movement in days from the day of surgery. Secondary outcomes are time to first flatus, infective complications, and adverse events related to the administration of nutritional supplementation. Statistical analysis will be conducted in an intention-to-treat approach. ANOVA with the Tukey test will be used to compare continuous variables, while the χ2 test will be used for categorical variables. DISCUSSION: Nutritional supplementation with probiotics is a convenient, non-pill alternative for patients. Furthermore, the interventions are commonly found in the formulary of many hospitals worldwide. If successful, probiotics in nutritional supplementation could be a cost-effective and simple way to reduce postoperative ileus. TRIAL REGISTRATION: ClinicalTrials.gov NCT06456229. This trial was registered on 11 June 2024. Thai Clinical Trials Registry TCTR20240706003. This trial was registered on 6 July 2024.
Gene editing of CD3 epsilon gene to redirect regulatory T cells for adoptive T cell transfer.
Adoptive transfer of antigen-specific regulatory T cells (Tregs) is a promising strategy to combat immunopathologies in transplantation and autoimmune diseases. However, their low frequency in peripheral blood poses challenges for both manufacturing and clinical application. Chimeric antigen receptors (CARs) have been used to redirect the specificity of Tregs, employing retroviral vectors. However, retroviral gene transfer is costly, time consuming, and raises safety issues. Here, we explored non-viral CRISPR-Cas12a gene editing to redirect Tregs, using HLA-A2-specific constructs for proof-of-concept studies in transplantation models. Knock-in of an antigen-binding domain into the N terminus of CD3 epsilon (CD3ε) gene generates Tregs expressing a chimeric CD3ε-T cell receptor fusion construct (TRuC) protein which integrates into the endogenous TCR/CD3 complex. These CD3ε-TRuC Tregs exhibit potent antigen-dependent activation while maintaining responsiveness to TCR/CD3 stimulation. This enables preferential enrichment of TRuC-redirected Tregs over CD3ε KO Tregs via repetitive CD3/CD28-stimulation in a GMP-compatible expansion system. CD3ε-TRuC Tregs retained their phenotypic, epigenetic, and functional identity. In a humanized mouse model, HLA-A2-specific CD3ε-TRuC Tregs demonstrate superior protection of allogeneic HLA-A2+ skin grafts from rejection compared to polyclonal Tregs. This approach provides a pathway for developing clinical-grade CD3ε-TRuC-based Treg cell products for transplantation immunotherapy and other immunopathologies.
Safety of Nonsteroidal Anti-inflammatory Drugs in Major Gastrointestinal Surgery: A Prospective, Multicenter Cohort Study.
BACKGROUND: Significant safety concerns remain surrounding the use of nonsteroidal anti-inflammatory drugs (NSAIDs) following gastrointestinal surgery, leading to wide variation in their use. This study aimed to determine the safety profile of NSAIDs after major gastrointestinal surgery. METHODS: Consecutive patients undergoing elective or emergency abdominal surgery with a minimum one-night stay during a 3-month study period were eligible for inclusion. The administration of any NSAID within 3 days following surgery was the main independent variable. The primary outcome measure was the 30-day postoperative major complication rate, as defined by the Clavien-Dindo classification (Clavien-Dindo III-V). Propensity matching with multivariable logistic regression was used to produce odds ratios (OR) and 95 % confidence intervals. RESULTS: From 9264 patients, 23.9 % (n = 2212) received postoperative NSAIDs. The overall major complication rate was 11.5 % (n = 1067). Following propensity matching and adjustment, use of NSAIDs were not significantly associated with any increase in major complications (OR 0.90, 0.60-1.34, p = 0.560). CONCLUSIONS: Early use of postoperative NSAIDs was not associated with an increase in major complications following gastrointestinal surgery.
Multicentre prospective cohort study of body mass index and postoperative complications following gastrointestinal surgery.
BACKGROUND: There is currently conflicting evidence surrounding the effects of obesity on postoperative outcomes. Previous studies have found obesity to be associated with adverse events, but others have found no association. The aim of this study was to determine whether increasing body mass index (BMI) is an independent risk factor for development of major postoperative complications. METHODS: This was a multicentre prospective cohort study across the UK and Republic of Ireland. Consecutive patients undergoing elective or emergency gastrointestinal surgery over a 4-month interval (October-December 2014) were eligible for inclusion. The primary outcome was the 30-day major complication rate (Clavien-Dindo grade III-V). BMI was grouped according to the World Health Organization classification. Multilevel logistic regression models were used to adjust for patient, operative and hospital-level effects, creating odds ratios (ORs) and 95 per cent confidence intervals (c.i.). RESULTS: Of 7965 patients, 2545 (32·0 per cent) were of normal weight, 2673 (33·6 per cent) were overweight and 2747 (34·5 per cent) were obese. Overall, 4925 (61·8 per cent) underwent elective and 3038 (38·1 per cent) emergency operations. The 30-day major complication rate was 11·4 per cent (908 of 7965). In adjusted models, a significant interaction was found between BMI and diagnosis, with an association seen between BMI and major complications for patients with malignancy (overweight: OR 1·59, 95 per cent c.i. 1·12 to 2·29, P = 0·008; obese: OR 1·91, 1·31 to 2·83, P = 0·002; compared with normal weight) but not benign disease (overweight: OR 0·89, 0·71 to 1·12, P = 0·329; obese: OR 0·84, 0·66 to 1·06, P = 0·147). CONCLUSION: Overweight and obese patients undergoing surgery for gastrointestinal malignancy are at increased risk of major postoperative complications compared with those of normal weight.
High-resolution spatio-temporal bioactivity of a novel peptide revealed by optical imaging in rat orbitofrontal cortex in vitro: possible implications for neurodegenerative diseases.
Acetylcholinesterase (AChE) is now well known to have a secondary, non-enzymatic function independent of cholinergic transmission. In the last decade, the part of the molecule responsible for this action has been identified, i.e. a 14 amino acid peptide fragment ('T14'), deriving from the C-terminus of AChE: this peptide has been shown to be bioactive in a range of preparations and to act at an allosteric site on α₇ nicotinic acetylcholine receptors (α₇-nAChRs). Of particular significance is the finding that AChE-related peptides trigger calcium-induced neurotoxicity that may be pivotal in the process of neurodegenerative diseases, such as Alzheimer's. However to date all studies have been performed on isolated cell preparations. The aim of this study was therefore to characterise the bioactivity of T14 on meso-scale in vitro cortical networks ('neuronal assemblies') from rat brain slices containing orbitofrontal cortex. Local field potential (LFP) recordings showed that the T14 peptide has a selective, holistic action on cortical networks in a modulatory biphasic manner i.e. predisposing excitation at concentrations of up to 1 μM, after which the trend is reversed in favour of inhibition at higher doses (>1 μM). By contrast, a scrambled variant of the T14 peptide sequence (S14), showed no significant changes in neuronal activation. Optical imaging using voltage-sensitive dyes (VSDI) corroborated the electrophysiological findings and also provided further insight into the spatial dynamics of the effects of the peptide: T14 application had a facilitatory effect i.e. increased the time-course of activation at sub-micromolar concentrations only (700 nM) without significantly affecting the spread of evoked assemblies. Moreover: co-applying T14 with the α₇-nAChR competitive antagonist methyllycaconitine (MLA) produced inhibition in activation synchrony not seen with either agent on their own, suggesting an additive inhibitory effect. In conclusion, the T14 peptide derived from AChE produced a dose-dependent biphasic modulation of cortical networks activity dependent on the α₇-nAChR: these findings should thus provide a more comprehensive insight into the immediate actions of a novel bioactive agent of high potential relevance to neurodegenerative disorders such as Alzheimer's disease.
Deep Brain Stimulation of the Nucleus Accumbens in Severe Enduring Anorexia Nervosa: A Pilot Study.
INTRODUCTION: Anorexia nervosa (AN) is one of the most debilitating psychiatric disorders, becoming severe and enduring in a third of cases; with few effective treatments. Deep brain stimulation is a reversible, adjustable neurosurgical procedure that has been gaining ground in psychiatry as a treatment for depression and obsessive-compulsive disorder, yet few studies have investigated AN. Abnormal eating behavior and the compulsive pursuit of thinness in AN is, in part, a consequence of dysfunction in reward circuitry and the nucleus accumbens (NAcc) is central to reward processing. METHODS: Phase 1 prospective open-label pilot study of seven individuals with severe enduring AN. Electrodes were implanted bilaterally into the NAcc with stimulation at the anterior limb of the internal capsule using rechargeable implantable pulse generators. The protocol of 15 months included 12 months of deep brain stimulation incorporating two consecutive, randomized blind on-off fortnights 9 months after stimulation onset. The primary objectives were to investigate safety and feasibility, together with changes in eating disorder psychopathology. RESULTS: Feasibility and safety was demonstrated with no serious adverse events due to deep brain stimulation. Three patients responded to treatment [defined as > 35% reduction in Eating Disorders Examination (EDE) score at 12 months] and four patients were non-responders. Responders had a statistically significant mean reduction in EDE scores (50.3% reduction; 95% CI 2.6-98.2%), Clinical Impairment Assessment (45.6% reduction; 95% CI 7.4-83.7%). Responders also had a statistically significant mean reduction in Hamilton Depression Scale, Hamilton Anxiety Scale and Snaith-Hamilton pleasure scale. There were no statistically significant changes in Body Mass Index, Yale-Brown-Cornell Eating Disorder Scale, Yale-Brown Obsessive-Compulsive Scale and World Health Organization Quality of Life Psychological subscale. CONCLUSION: This study provides some preliminary indication that deep brain stimulation to the NAcc. Might potentially improve some key features of enduring AN. In this small study, the three responders had comorbid obsessive-compulsive disorder which predated AN diagnosis. Future studies should aim to further elucidate predictors of outcome. CLINICAL TRIAL REGISTRATION: [www.ClinicalTrials.gov], identifier [Project ID 128658].
Deep Brain Stimulation (DBS) and Motor Cortex Stimulation (MCS) for Central Post-Stroke Pain: A Systematic Review And Meta-Analysis.
INTRODUCTION: Deep Brain Stimulation (DBS) and Motor Cortex stimulation (MCS) are invasive interventions in order to treat various neuropathic pain syndromes such as Central Post-Stroke Pain. While each treatment has varying degree of success, comparative analysis has not yet been performed, and the success rates of these techniques using validated, objective pain scores have not been synthesised. METHODS: A systematic review and meta-analysis was conducted in accordance with PRISMA guidelines. Three databases were searched, and articles published from January 2000 October 2024 were included (last search date 25 October 2024). Meta-Analysis was performed using random effects models. We evaluated the performance of DBS or MCS by assessing studies that reported pain relief using Visual Analogue Scale (VAS) or Numerical Rating Scale (NRS) scores. RESULTS: Of the 478 articles identified, 32 were included in the analysis (330 patients- 139 DBS, & 191 MCS). The improvement in mean VAS score for patients that underwent DBS post-surgery was 48.6% compared to a score of 53.1% for patients that had MCS. The pooled number of patients who improved after DBS was 0.62 (95% CI, 0.51-0.71, I2=16%). The pooled number of patients who improved after MCS was 0.64 (95% CI, 0.53-0.74, I2=40%). CONCLUSION: The use of neurosurgical interventions such as DBS and MCS are last-resort treatments for Central Post-Stroke Pain, with limited studies exploring and comparing these two techniques. While our study shows that MCS might be a slightly better treatment option, further research would need to be done to determine the appropriate surgical intervention in the treatment of Central Post-Stroke Pain.
Pallido-putaminal connectivity predicts outcomes of deep brain stimulation for cervical dystonia.
Cervical dystonia is a non-degenerative movement disorder characterized by dysfunction of both motor and sensory cortico-basal ganglia networks. Deep brain stimulation targeted to the internal pallidum is an established treatment, but its specific mechanisms remain elusive, and response to therapy is highly variable. Modulation of key dysfunctional networks via axonal connections is likely important. Fifteen patients underwent preoperative diffusion-MRI acquisitions and then progressed to bilateral deep brain stimulation targeting the posterior internal pallidum. Severity of disease was assessed preoperatively and later at follow-up. Scans were used to generate tractography-derived connectivity estimates between the bilateral regions of stimulation and relevant structures. Connectivity to the putamen correlated with clinical improvement, and a series of cortical connectivity-based putaminal parcellations identified the primary motor putamen as the key node (r = 0.70, P = 0.004). A regression model with this connectivity and electrode coordinates explained 68% of the variance in outcomes (r = 0.83, P = 0.001), with both as significant explanatory variables. We conclude that modulation of the primary motor putamen-posterior internal pallidum limb of the cortico-basal ganglia loop is characteristic of successful deep brain stimulation treatment of cervical dystonia. Preoperative diffusion imaging contains additional information that predicts outcomes, implying utility for patient selection and/or individualized targeting.
Modulation of limbic resting-state networks by subthalamic nucleus deep brain stimulation.
Beyond the established effects of subthalamic nucleus deep brain stimulation (STN-DBS) in reducing motor symptoms in Parkinson's disease, recent evidence has highlighted the effect on non-motor symptoms. However, the impact of STN-DBS on disseminated networks remains unclear. This study aimed to perform a quantitative evaluation of network-specific modulation induced by STN-DBS using Leading Eigenvector Dynamics Analysis (LEiDA). We calculated the occupancy of resting-state networks (RSNs) in functional MRI data from 10 patients with Parkinson's disease implanted with STN-DBS and statistically compared between ON and OFF conditions. STN-DBS was found to specifically modulate the occupancy of networks overlapping with limbic RSNs. STN-DBS significantly increased the occupancy of an orbitofrontal limbic subsystem with respect to both DBS OFF (p = 0.0057) and 49 age-matched healthy controls (p = 0.0033). Occupancy of a diffuse limbic RSN was increased with STN-DBS OFF when compared with healthy controls (p = 0.021), but not when STN-DBS was ON, which indicates rebalancing of this network. These results highlight the modulatory effect of STN-DBS on components of the limbic system, particularly within the orbitofrontal cortex, a structure associated with reward processing. These results reinforce the value of quantitative biomarkers of RSN activity in evaluating the disseminated impact of brain stimulation techniques and the personalization of therapeutic strategies.
Early and ultra-early surgical decompression for acute spinal cord injury: bracing for the winds of change.
PURPOSE: Until recently, there has been no consensus on the optimal operative window for decompressive surgery in acute spinal cord injury (aSCI). However, recent evidence is now supporting a role for early intervention in improving outcomes in this type of patients. The purpose of this letter is to discuss the implications for clinical practice within the European community. METHODS: Critical appraisal and interpretation of these results for clinical implementation. RESULTS: Leveraging on the evidence that early (
Safety of Endoscopic Transsphenoidal Pituitary Surgery during the COVID-19 Pandemic and Comparison to the Pre-Pandemic Era.
Objective The COVID-19 pandemic has caused significant disruption to the surgical care of patients with pituitary tumors. Guidance issued early during the pandemic suggested avoiding transnasal approaches to minimize risks of transmitting COVID-19 to health care professionals involved in these procedures. Methods This observational, single-center study compares results of endoscopic transsphenoidal approach (TSA) for pituitary tumors since the start of the pandemic to a pre-pandemic period. Anesthetic time, surgical time, and complication rates were compared. Newly acquired COVID-19 infections and transmission rates to patients and staff were reviewed. Data were analyzed by using the independent t -test, Mann-Whitney U test, and Pearson Chi-square test, significance set at p <0.05. Results Over a 12-month period, a total of 50 and 69 patients underwent endoscopic TSA for pituitary tumor during and before the pandemic, respectively. All patients tested negative for COVID-19 preoperatively. Median duration of anesthesia was 35 minutes (interquartile range [IQR]: 22) during the pandemic and 25 minutes (IQR: 8, p = 0.0002) pre-pandemic. Median duration of surgery was 70 minutes (IQR: 28) during the pandemic and 79 minutes (IQR: 33.75, p = 0.126) pre-pandemic. There were no statistically significant differences between intraoperative CSF leaks and complication rates. No staff members tested positive for COVID-19. Three patients tested positive for COVID-19 postdischarge, but the infections were community acquired. Conclusion In contrast to published guidelines, adequate preoperative testing, a multidisciplinary approach and the implementation of standardized protocols and vaccination against COVID-19 allow for endoscopic transsphenoidal surgery to be performed safely in patients with pituitary pathology during the pandemic.
Critical care usage after major gastrointestinal and liver surgery: a prospective, multicentre observational study.
BACKGROUND: Patient selection for critical care admission must balance patient safety with optimal resource allocation. This study aimed to determine the relationship between critical care admission, and postoperative mortality after abdominal surgery. METHODS: This prespecified secondary analysis of a multicentre, prospective, observational study included consecutive patients enrolled in the DISCOVER study from UK and Republic of Ireland undergoing major gastrointestinal and liver surgery between October and December 2014. The primary outcome was 30-day mortality. Multivariate logistic regression was used to explore associations between critical care admission (planned and unplanned) and mortality, and inter-centre variation in critical care admission after emergency laparotomy. RESULTS: Of 4529 patients included, 37.8% (n=1713) underwent planned critical care admissions from theatre. Some 3.1% (n=86/2816) admitted to ward-level care subsequently underwent unplanned critical care admission. Overall 30-day mortality was 2.9% (n=133/4519), and the risk-adjusted association between 30-day mortality and critical care admission was higher in unplanned [odds ratio (OR): 8.65, 95% confidence interval (CI): 3.51-19.97) than planned admissions (OR: 2.32, 95% CI: 1.43-3.85). Some 26.7% of patients (n=1210/4529) underwent emergency laparotomies. After adjustment, 49.3% (95% CI: 46.8-51.9%, P<0.001) were predicted to have planned critical care admissions, with 7% (n=10/145) of centres outside the 95% CI. CONCLUSIONS: After risk adjustment, no 30-day survival benefit was identified for either planned or unplanned postoperative admissions to critical care within this cohort. This likely represents appropriate admission of the highest-risk patients. Planned admissions in selected, intermediate-risk patients may present a strategy to mitigate the risk of unplanned admission. Substantial inter-centre variation exists in planned critical care admissions after emergency laparotomies.
Lymph node yield as a surrogate marker for tumour biology and prognosis in colon cancer
Abstract Background We interrogated two large national databases to explore the underlying mechanisms and institutional effects of the known association of enhanced survival with a higher lymph node yield (LNY) in non-metastatic colon cancer. Method Clinical and pathological data for stage I-III colon adenocarcinomas were extracted from the CORECT-R (England, 2010–2020) and SEER database (USA, 2000–2020). A lymph node (LN) cut-off for the lack of clinically significant increase in nodal positivity was identified. A multivariable Cox-regression model was developed to study the effect of LNY on overall survival. Furthermore, institutional variations in LNY and their impact on survival were explored. Results Patients were retrospectively included from the CORECT-R (n = 84,116) and SEER (n = 287,974) databases. No significant increase in nodal positivity was noted after a LN cut-off of 9. However, improved survival was noted in node-negative and node-positive cancers beyond this cut-off. A 1% risk-reduction concerning overall survival was reported for every node counted. We identified ten outlying institutions across England with an observed LNY greater or less than the expected, with no impact on overall survival. Discussions We advocate incorporating LNY into patient and clinician discussions as a surrogate marker of tumour biology and prognosis rather than using LNY as a quality indicator.