Molecular mechanism of α-synuclein aggregation on lipid membranes revealed.

The central hallmark of Parkinson's disease pathology is the aggregation of the α-synuclein protein, which, in its healthy form, is associated with lipid membranes. Purified monomeric α-synuclein is relatively stable in vitro, but its aggregation can be triggered by the presence of lipid vesicles. Despite this central importance of lipids in the context of α-synuclein aggregation, their detailed mechanistic role in this process has not been established to date. Here, we use chemical kinetics to develop a mechanistic model that is able to globally describe the aggregation behaviour of α-synuclein in the presence of DMPS lipid vesicles, across a range of lipid and protein concentrations. Through the application of our kinetic model to experimental data, we find that the reaction is a co-aggregation process involving both protein and lipids and that lipids promote aggregation as much by enabling fibril elongation as by enabling their initial formation. Moreover, we find that the primary nucleation of lipid-protein co-aggregates takes place not on the surface of lipid vesicles in bulk solution but at the air-water and/or plate interfaces, where lipids and proteins are likely adsorbed. Our model forms the basis for mechanistic insights, also in other lipid-protein co-aggregation systems, which will be crucial in the rational design of drugs that inhibit aggregate formation and act at the key points in the α-synuclein aggregation cascade.

Pancreatic neuroendocrine tumour resection in circumportal pancreas: a rare anatomical anomaly with important surgical implications.

Various congenital anomalies of the pancreas have been reported due to its complex embryological development involving the fusion of two separate buds. Circumportal pancreas is a rare anatomical anomaly where the pancreatic head and uncinate process fuse abnormally with the pancreatic body, encasing the portal vein and/or superior mesenteric vein completely. This anomaly poses several challenges to hepatobiliary surgeons, as the encasement of the portal vein by the abnormal pancreatic tissue makes an additional parenchymal transection necessary. Vascular variants have also been reported with circumportal pancreas, which, if not recognised preoperatively, can be catastrophic. Therefore, careful preoperative evaluation and planning are essential, to ensure safe pancreatic resection and recovery in a patient with circumportal pancreas. We present a case of a successful subtotal pancreatectomy and splenectomy in a patient with circumportal pancreas, for a suspected pancreatic duct adenocarcinoma. The aim of this case report is to contribute valuable insights that can aid hepatobiliary surgeons in enhancing their preoperative planning when encountered with patients with similar anatomical variances.

Derivation, validation, and comparison of a new prognostic scoring system for acute lower gastrointestinal bleeding.

Objectives: Lower gastrointestinal bleeding is a common presentation with little data concerning risk factors for adverse outcomes. The aim was to derive and validate a scoring system to stratify risk in lower gastrointestinal bleeding and compare it to the Oakland score. Methods: A total of 2385 consecutive patients (mean age 65 years, 1140 males) were used to derive the score using multivariate logistic regression modeling then internally and externally validated. The Oakland score was applied and area under receiver operating characteristic (AUROC) curves were calculated and compared. A score of <1 was compared with an Oakland score of <9 to assess 30-day rebleeding and mortality rates. Results: Rebleeding was associated with age, inpatient bleeding, syncope, malignancy, tachycardia, hypotension, lower hemoglobin and mortality with age, inpatient bleeding, liver/gastrointestinal disease, tachycardia, and hypotension. The area under the receiver operating characteristic curves was 0.742 for rebleeding and 0.802 for mortality. A score <1 was associated with rebleeding (0.0%-2.2%) and mortality (0%). The Oakland score had a significantly lower area under the receiver operating characteristic curve for rebleeding of 0.687 but not for mortality; 0.757. A score <1 was associated with a lower 30-day rebleeding risk compared to an Oakland score <9 (4/379 vs. 15/355, p = 0.009) but not mortality (0/365 vs. 1/355, p = 0.493). Conclusions: Our score predicts 30-day rebleeding and mortality rate with low scores associated with very low risk. The Aberdeen score is superior to the Oakland score for predicting rebleeding. Prospective evaluation of both scores is required.

Migrated Laparoscopic Surgical Clips Causing Acute Cholangitis 32 Years After Laparoscopic Cholecystectomy.

Surgical clip migration post-laparoscopic cholecystectomy is a rare but important complication to consider in patients presenting with biliary obstruction. Titanium surgical clips are widely used in laparoscopic surgery to ligate vessels and ducts and are particularly important in laparoscopic cholecystectomy to ligate the cystic duct. More common complications associated with clips involve dislodgement, however, there are reported cases of migration into visceral structures causing an obstruction. We describe a case that demonstrated an acute migration of surgical clips into the common bile duct (CBD) within a three-week period, which occurred 32 years after laparoscopic cholecystectomy, likely attributed to erosion. On the patient's first presentation, she had acute pancreatitis with a CT demonstrating clips in the correct position. Three weeks later, the patient presented a second time with acute cholangitis and the repeat CT demonstrated the clips in the CBD. We hypothesize that the erosion of the bile duct is due to the pressure effects from either intra-abdominal organ movements or subtle clip movements, and eventually, persistent erosion leading to intra-ductal migration of the clips with the passage of the clips along the path of least resistance into the CBD, resulting in biliary obstruction. Management included standard treatment for biliary obstruction with intravenous broad-spectrum antibiotics and endoscopic retrograde cholangiopancreatography with excellent outcomes.

A novel device for atrial septal defect occlusion (GORE CARDIOFORM).

The GORE CARDIOFORM atrial septal defect (ASD) Occluder (GCA) is composed of a platinum-filled nitinol wire frame covered with expanded polytetrafluoroethylene, making it softer and more conformable compared with nitinol mesh devices. After the ASSURED clinical study confirmed the efficacy and safety of the device, it received U.S. Food and Drug Administration approval and a European conformity mark. Our aim was to understand the learning curve implicated in using the GCA for ASD closure in paediatric and adult patients as well as to study the early outcomes. To this end, a review of ASD device closures with GCA in 4 UK centres was conducted between January 2020 and January 2023. Implantation success was the primary outcome; the secondary outcomes were serious adverse events, including new onset arrhythmia. In all, 135 patients were included, and 128 (95%) had successful ASD device closure with GCA. The median patient age was 49 years, the median defect size was 18 mm, and the median device size was 37 mm. The median follow-up time was 6 months (interquartile range 1-14). One device embolisation occurred, and 15 patients (12% of GCA implantations) developed new onset arrhythmia - this was not related to patient age, defect diameter or device oversizing but was positively associated with device size. With growing experience using GCA, the device can be applied to a wide variety of ASD sizes and morphologies. Given the number of successful implantations with an absence of aortic erosion, as well as the ability to perforate through the device should procedures be required in the left atrium, the GCA device is an important addition for interventionists who close atrial septal defects.

Atrial Fibrillation Ablation in a Patient With SV ASD and PAPVR Preceding Transcatheter Septal Closure.

Atrial fibrillation (AF) is common in adults with unrepaired atrial septal defects (ASDs). Sinus venosus (SV) ASDs associated with partial anomalous pulmonary venous return (PAPVR) are traditionally managed surgically. We report the first AF catheter ablation in a patient with SV ASD and PAPVR preceding transcatheter ASD repair with a covered stent. (Level of Difficulty: Advanced.).

Whole exome sequencing of low grade serous ovarian carcinoma identifies genomic events associated with clinical outcome.

OBJECTIVES: Low-grade serous ovarian carcinoma (LGSOC) is a distinct, rare, ovarian cancer type characterised by younger patient age and intrinsic chemoresistance. Understanding the molecular landscape is crucial for optimising targeted therapy. METHODS: Genomic data from whole exome sequencing of tumour tissue was analysed in a LGSOC cohort with detailed clinical annotation. RESULTS: 63 cases were analysed and three subgroups identified based on single nucleotide variants: canonical MAPK mutant (cMAPKm: 52%, KRAS/BRAF/NRAS), MAPK-associated gene mutation (MAPK-assoc: 27%) and MAPK wild-type (MAPKwt: 21%). NOTCH pathway disruption occurred across all subgroups. Tumour mutational burden (TMB), mutational signatures and recurrent copy number (CN) changes varied across the cohort with co-occurrence of chromosome 1p loss and 1q gain (CN Chr1pq) a recurrent feature. Low TMB and CN Chr1pq were associated with inferior disease-specific survival (HR 6.43; p < 0.001 and HR 3.29, p = 0.011 respectively). Stepwise genomic classification in relation to outcome resulted in four groups (TMB low; CN Chr1pq; MAPKwt/MAPKassoc; cMAPKm). 5 year disease-specific survival was 46%, 55%, 79% and 100% respectively for these groups. The two most favourable genomic subgroups were enriched for the SBS10b mutational signature, particularly the cMAPKm subgroup. CONCLUSIONS: LGSOC comprises multiple genomic subgroups with distinct clinical and molecular features. Chr1pq CN arm disruption and TMB represent promising methods to identify individuals with poorer prognosis. Further investigation of the molecular basis for these observations is required. MAPKwt cases represent around a fifth of patients. NOTCH inhibitors represent a candidate therapeutic strategy worthy of exploration across these cases.

AEPC recommendations for training in interventional catheterisation for CHD.

To reflect new developments in imaging, indications, and techniques in catheterisation of patients with CHD, the training recommendations of the Association for European Paediatric and Congenital Cardiology (AEPC) for the training in interventional catheterisation for CHD have been reviewed and updated after more than 7 years. They include detailed information about knowledge, skills, and approach to clinical practice expected from trainees at basic, intermediate, and advanced level.

Distinct histopathological features are associated with molecular subtypes and outcome in low grade serous ovarian carcinoma.

Low grade serous ovarian carcinoma (LGSOC) demonstrates unique clinical and molecular features compared to other ovarian cancer types. The relationship between common histological features of LGSOC and molecular events, such as hormone receptor expression patterns and MAPK gene mutation status, remains poorly understood. Recent data suggest some of these molecular features may be biomarkers of response to recently introduced biologically-targeted therapies, namely endocrine therapy and MEK inhibitors. We utilize a cohort of 63 pathologically-confirmed LGSOC cases with whole exome sequencing and hormone receptor expression data to investigate these relationships. LGSOC cases demonstrated uniformly high oestrogen receptor (ER) expression, but variable progesterone receptor (PR) expression intensity. 60% and 37% of cases demonstrated micropapillary and macropapillary patterns of stromal invasion, respectively. 63% of cases demonstrated desmoplasia, which was significantly associated with advanced disease stage and visible residual disease after cytoreductive surgery. MAPK-mutant cases (KRAS, BRAF, NRAS) more frequently demonstrated macropapillary stromal invasion, while Chr1p loss was associated with desmoplasia and low PR expression. Presence of micropapillary stromal invasion and low PR expression were associated with significantly poorer survival after accounting for stage and residual disease status. Together, these data identify novel relationships between histopathological features and molecularly-defined subgroups in LGSOC.

The Scottish COVID Cancer Immunity Prevalence Study: A Longitudinal Study of SARS-CoV-2 Immune Response in Patients Receiving Anti-Cancer Treatment.

BACKGROUND: Cancer and anti-cancer treatment (ACT) may be risk factors for severe SARS-CoV-2 infection and limited vaccine efficacy. Long-term longitudinal studies are needed to evaluate these risks. The Scottish COVID cancer immunity prevalence (SCCAMP) study characterizes the incidence and outcomes of SARS-CoV-2 infection and vaccination in patients with solid tumors undergoing ACT. This preliminary analysis includes 766 patients recruited since May 2020. METHODS: Patients with solid-organ cancers attending secondary care for active ACT consented to the collection of routine electronic health record data and serial blood samples over 12 months. Blood samples were tested for total SARS-CoV-2 antibody. RESULTS: A total of 766 participants were recruited between May 28, 2020 and October 31, 2021. Most received cytotoxic chemotherapy (79%). Among the participants, 48 (6.3%) were tested positive for SARS-CoV-2 by PCR. Infection rates were unaffected by ACT, largely aligning with the local population. Mortality proportion was not higher with a recent positive SARS-CoV-2 PCR (10.4% vs 10.6%). Multivariate analysis revealed lower infection rates in vaccinated patients regardless of chemotherapy (HR 0.307 [95% CI, 0.144-0.6548]) or immunotherapy (HR 0.314 [95% CI, 0.041-2.367]) treatment. A total of 96.3% of patients successfully raised SARS-CoV-2 antibodies after >2 vaccines. This was independent of the treatment type. CONCLUSION: This is the largest on-going longitudinal real-world dataset of patients undergoing ACT during the early stages of the COVID-19 pandemic. This preliminary analysis demonstrates that patients with solid tumors undergoing ACT have high protection from SARS-CoV-2 infection following COVID-19 vaccination. The SCCAMP study will evaluate long-term COVID-19 antibody trends, focusing on specific ACTs and patient subgroups.

The role of liquid biopsy in management of the neck with indeterminate response on post-treatment imaging following non-surgical management of oropharyngeal cancer.

INTRODUCTION: This study aimed to determine if post-treatment HPV cell-free DNA (cfDNA) can assist in the decision-making process for salvage neck dissection in patients following non-surgical treatment of oropharyngeal squamous cell carcinoma (OPSCC) with a partial response in the neck on imaging at 12 weeks post-treatment. METHODS: 86 patients who completed treatment were prospectively recruited through the regional multidisciplinary team (MDT). Treatment response was categorised as complete response (CR), partial response (PR) or progressive disease on 12-week post-treatment imaging. Pre- and post-treatment blood samples were assessed for HPV cfDNA through droplet digital PCR (ddPCR). RESULTS: Eight patients had an isolated partial response in the neck. One (12.5%) had detectable HPV cfDNA (22.96 copies/ml) at ∼12 weeks post-treatment with positive disease on subsequent neck dissection (positive predictive value; PPV = 100%). Of the seven patients with undetectable HPV cfDNA, two patients had evidence of regional disease recurrence at 23.9 and 27.4 months respectively (negative predictive value; NPV = 71%). CONCLUSION: The detection of HPV cfDNA may help target salvage therapy in patients with a partial response in the neck. Follow-up studies in larger cohorts would be required to further validate the use of post-treatment HPV cfDNA in the management of OPSCC.

Guidelines for Perioperative Care for Liver Surgery: Enhanced Recovery After Surgery (ERAS) Society Recommendations 2022.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) has been widely applied in liver surgery since the publication of the first ERAS guidelines in 2016. The aim of the present article was to update the ERAS guidelines in liver surgery using a modified Delphi method based on a systematic review of the literature. METHODS: A systematic literature review was performed using MEDLINE/PubMed, Embase, and the Cochrane Library. A modified Delphi method including 15 international experts was used. Consensus was judged to be reached when >80% of the experts agreed on the recommended items. Recommendations were based on the Grading of Recommendations, Assessment, Development and Evaluations system. RESULTS: A total of 7541 manuscripts were screened, and 240 articles were finally included. Twenty-five recommendation items were elaborated. All of them obtained consensus (>80% agreement) after 3 Delphi rounds. Nine items (36%) had a high level of evidence and 16 (64%) a strong recommendation grade. Compared to the first ERAS guidelines published, 3 novel items were introduced: prehabilitation in high-risk patients, preoperative biliary drainage in cholestatic liver, and preoperative smoking and alcohol cessation at least 4 weeks before hepatectomy. CONCLUSIONS: These guidelines based on the best available evidence allow standardization of the perioperative management of patients undergoing liver surgery. Specific studies on hepatectomy in cirrhotic patients following an ERAS program are still needed.

Post-infarction ventricular septal defect: percutaneous or surgical management in the UK national registry.

AIMS: Post-infarction ventricular septal defect (PIVSD) is a mechanical complication of acute myocardial infarction (AMI) with a poor prognosis. Surgical repair is the mainstay of treatment, although percutaneous closure is increasingly undertaken. METHODS AND RESUTS: Patients treated with surgical or percutaneous repair of PIVSD (2010-2021) were identified at 16 UK centres. Case note review was undertaken. The primary outcome was long-term mortality. Patient groups were allocated based upon initial management (percutaneous or surgical). Three-hundred sixty-two patients received 416 procedures (131 percutaneous, 231 surgery). 16.1% of percutaneous patients subsequently had surgery. 7.8% of surgical patients subsequently had percutaneous treatment. Times from AMI to treatment were similar [percutaneous 9 (6-14) vs. surgical 9 (4-22) days, P = 0.18]. Surgical patients were more likely to have cardiogenic shock (62.8% vs. 51.9%, P = 0.044). Percutaneous patients were substantially older [72 (64-77) vs. 67 (61-73) years, P < 0.001] and more likely to be discussed in a heart team setting. There was no difference in long-term mortality between patients (61.1% vs. 53.7%, P = 0.17). In-hospital mortality was lower in the surgical group (55.0% vs. 44.2%, P = 0.048) with no difference in mortality after hospital discharge (P = 0.65). Cardiogenic shock [adjusted hazard ratio (aHR) 1.97 (95% confidence interval 1.37-2.84), P < 0.001), percutaneous approach [aHR 1.44 (1.01-2.05), P = 0.042], and number of vessels with coronary artery disease [aHR 1.22 (1.01-1.47), P = 0.043] were independently associated with long-term mortality. CONCLUSION: Surgical and percutaneous repair are viable options for management of PIVSD. There was no difference in post-discharge long-term mortality between patients, although in-hospital mortality was lower for surgery.

Longitudinal measurement of HPV copy number in cell-free DNA is associated with patient outcomes in HPV-positive oropharyngeal cancer.

INTRODUCTION: Oropharyngeal squamous cell carcinoma (OPSCC) is increasing in global prevalence and is divided into two types dependent on association with human papillomavirus (HPV). Assay of HPV copy number in plasma cell-free DNA (cfDNA) provides a minimally invasive method for detecting and monitoring tumour-derived HPV, with potential for enhancing clinical care. MATERIALS AND METHODS: In a prospectively recruited cohort of 104 OPSCC patients, we evaluate the utility of cfDNA droplet digital PCR (ddPCR) as a method for characterisation and longitudinal monitoring of patients with OPSCC. RESULTS: ddPCR assay of pre-treatment plasma cfDNA for five HPV types showed overall 95% concordance with p16 immunohistochemistry and PCR analysis of tumour tissue. Longitudinal sampling in 48 HPV+ve patients, with median follow-up of 20 months, was strongly associated with patient outcomes. Persistently elevated cfDNA-HPV post-treatment was associated with treatment failure (2/2 patients) and an increase of cfDNA-HPV in patients whose HPV levels were initially undetectable post-treatment was associated with disease recurrence (5/6 patients). No recurrence was observed in patients in whom cfDNA-HPV was undetectable in all post-treatment samples. In two patients, sequential HPV measurement could have avoided surgical intervention which did not confirm recurrence. CONCLUSION: The high concordance of pre-treatment plasma cfDNA-HPV analysis with tissue-based assays, together with the clinical associations of sequentially measured post-treatment cfDNA-HPV copy number add to a growing body of evidence that suggest utility of cfDNA-HPV ddPCR in management of OPSCC. Standardised clinical trials based on these data are now needed to assess the impact of such testing on overall patient outcomes.

Human biliary epithelial cells from discarded donor livers rescue bile duct structure and function in a mouse model of biliary disease.

Biliary diseases can cause inflammation, fibrosis, bile duct destruction, and eventually liver failure. There are no curative treatments for biliary disease except for liver transplantation. New therapies are urgently required. We have therefore purified human biliary epithelial cells (hBECs) from human livers that were not used for liver transplantation. hBECs were tested as a cell therapy in a mouse model of biliary disease in which the conditional deletion of Mdm2 in cholangiocytes causes senescence, biliary strictures, and fibrosis. hBECs are expandable and phenotypically stable and help restore biliary structure and function, highlighting their regenerative capacity and a potential alternative to liver transplantation for biliary disease.

Surgical versus transcatheter palliation for insufficient pulmonary blood supply in infants with cyanotic CHD.

Infants with complex cyanotic CHD can become symptomatic from insufficient pulmonary blood supply following either ductal closure or due to outflow tract obstruction. Blalock-Taussig shunt mortality remains significant and recent studies have highlighted the advantages of using transcatheter alternatives. We present here our experience in changing our primary choice of palliation from the Blalock-Taussig shunt to transcatheter palliation with either a ductal stent or, if antegrade flow is present, a right ventricular outflow tract stent.This is a retrospective, single-unit cohort study. Eighty-seven infants underwent palliation for insufficient pulmonary blood flow at under 3 months of age between 2012 and 2019. On an intention-to-treat basis, 29 underwent insertion of a Blalock-Taussig shunt, 36 duct stents, and 22 right ventricular outflow tract stents at median ages of 15, 9, and 32 days, respectively, and median weights of 3.3, 3.1, and 3.1 kg, respectively. No primary Blalock-Taussig shunts have been performed in our institution since 2017.At 30-days there had been one death in each group (univariable p = 0.93) and deaths prior to repair totalled three in the shunt group, four in the ductal stent group, and two in the right ventricular outflow tract stent group (univariable p = 0.93). Reintervention on the pulmonary circuit prior to next stage of surgery was more frequent in those undergoing transcatheter intervention, reaching statistical significance by logrank (p = 0.012).In conclusion, within this work we provide further evidence of the safety and efficacy of transition from a primary surgical to primary transcatheter palliation pathway in infants with insufficient pulmonary blood supply.

Comparative analysis of surgical and percutaneous pulmonary valve implants over a 20-year period.

OBJECTIVES: Since percutaneous pulmonary valve implantation (PPVI) was introduced to prolong the lifetime of surgically placed right ventricular to pulmonary artery conduits, valve technology has evolved and the indications for PPVI expanded to native and larger right ventricular outflow tracts. We explore how indications, patient populations and outcomes compare to surgical pulmonary valve replacement (PVR). METHODS: This is a retrospective cohort study of PPVI and PVR procedures between 1998 and 2020 at a single UK centre. One hundred and twenty-eight patients underwent PPVI and 365 patients PVR. Primary outcome measures were survival, infective endocarditis and reintervention. RESULTS: The most common indication for PVR was replacement of the native pulmonary valve for pulmonary regurgitation whereas PPVI was more commonly used to treat pulmonary stenosis in a previously placed bioprosthetic conduit or valve. Treatment indications for PPVI expanded over the study to include the native right ventricular outflow tract. Survival was similar for PPVI and PVR (92% PPVI and 96.8% PVR at 5 years; 85.8% PPVI and 95.1% PVR at 10 years). Preprocedural New York Heart Association class 3 and 4 was the most important predictor of poor outcome. Annualized infective endocarditis rate was significantly higher for the Melody PPVI (0.024 vs 0.0024/person/year for PVR, P < 0.05). Both groups showed significant symptomatic improvement postprocedure with remodelling of ventricular volumes and improvement in cardiac output. Long-term follow-up for PVR showed half of patients will need replacement at 10-15 years post-index procedure. CONCLUSIONS: An increasing number of patients requiring PVR can now be treated percutaneously. A lifetime strategy for re-valving should be considered at the first valve implant.