bluuebunny/crossref_metadata_2025_split huggingface dataset:
O3 Ex vivo normothermic machine perfusion facilitates gymnotic delivery of RNA interference therapeutics in donor kidneys
Authors: Thompson E R , Sewpaul A , Figuereido R , Bates L , Ferdinand J R , Connelly C M , Hosgood S A , Nicholson M L , Clatworthy M R , Ali S , Wilson C H , Sheerin N S 
Published: July 2021

Abstract

Introduction
Normothermic machine perfusion (NMP) of donor kidneys prior to transplantation provides a platform for delivery of novel therapeutics to optimize organ quality. This includes RNA interference (RNAi) therapeutics e.g. antisense oligonucleotides (ASO) that block detrimental microRNAs. The intracellular kinetics of RNAi therapeutics are crucial for their pharmacological effect, however, it remains poorly understood. NMP provides an ideal platform to investigate this further.

Method
During NMP, human kidneys (n = 12) were treated for 6 hours with a fluorescently-labelled ASO designed to block microRNA-24-3p activity. Biopsies were taken at 0, 2, 4, and 6 hours. Kidney sections were stained with antibodies against early endosomes (Rab5), late endosomes (Rab7), RNA-induced silencing complexes (GW182) and lysosomes (LAMP2). Confocal microscopy images were obtained and co-localisation quantified using Hugyens™ software following batch deconvolution. The global transcriptomic impact of ASO therapy was also assessed using RNA sequencing.

Result
Following 2 hours of NMP, ASO was primarily found in tubular epithelial cells. Co-localisation studies revealed ASO uptake via endocytosis and endosomal sorting occurring during NMP. This was followed by cytoplasmic escape and co-localisation of ASO with GW182 proteins. This pattern of co-localisation was not seen in scrambled sequence or cold perfusion controls. RNAseq analysis revealed a decrease in inflammatory pathways and upregulation of microRNA-24-3p targets.

Discussion
This is the first study to demonstrate NMP facilitates gymnotic ASO delivery directly into the RISC, whereby, it blocks microRNA-mediated mRNA silencing and increases bioavailability of protective targets. This study highlights the capacity of NMP to re-programme gene expression in donor kidneys using RNAi therapeutics.

Take-home Message
Ex vivo normothermic machine perfusion of donor kidneys provides a unique window of opportunity prior to transplantation when we can deliver therapies to improve the quality of the organ. Novel genetic therapies designed to protect kidneys against ischemia reperfusion injury could potentially increase organ utilisation and improve post-transplant outcomes for the many patients on the kidney transplant waiting list.
O10 Myocardial tolerance to exsanguination and retrieval using whole blood-selective aortic arch perfusion
Authors: Madurska M J , Elansary N N , Pate N , Edwards J , Richmond M J , Scalea T M , Rasmussen T E , Morrison J J 
Published: July 2021

Abstract

Introduction
Exsanguination cardiac arrest is the leading preventable cause of death in trauma. Treatment modalities are limited, and prognosis remains dismal. Selective aortic arch perfusion (SAAP) is an emerging endovascular resuscitation technique consisting of aortic occlusion and perfusion of coronary and cerebral circulation with oxygenated resuscitation fluid. Translational research has demonstrated promising outcomes; however, little is known about the duration of cardiac arrest beyond which the myocardium cannot be resuscitated. The aims of this study are to assess the myocardial tolerance to exsanguination cardiac arrest before successful return of spontaneous circulation (ROSC) following resuscitation with SAAP, and 1-hour survival.

Method
23 male adult swine were anaesthetised and instrumented. Controlled hemorrhage was performed until cardiac arrest defined by MAP &lt;20 mmHg. Animals were randomized into 3 groups: 5, 10 and 15 minutes of cardiac arrest before resuscitation with SAAP. Following ROSC animals were observed for 60 minutes.

Result
Baseline characteristics were similar between groups (P &gt; 0.05). ROSC was 100% (8/8) in the 5 min group, 75% (6/8) and 43% (3/7) in 10- and 15-min groups respectively (P = 0.042). 60 min survival was 75%, 50% and 14% in 5-, 10- and 15-min groups respectively (P = 0.015). 1-hour survivors in the 5 min group required less noradrenaline 23.6 (±7.4) compared to other animals 40.9 (±25.8), (P = 0.008).

Conclusion
Selective aortic arch perfusion is an effective resuscitative tool in eliciting ROSC in a swine model of exsanguination cardiac arrest lasting &gt;5 min. Sustainable resuscitability using SAAP declines after 10 min of exsanguination cardiac arrest.

Take-home Message
SAAP is an emerging resuscitation technique with promising outcomes in exsanguination cardiac arrest and may be a segway to Extracorporeal life support. The time limit for resuscitability of the myocardium lies somewhere between 10 and 15 min after the start of exsanguination cardiac arrest.
O21 Is hypoalbuminaemia associated with amputation-free survival in chronic limb-threatening ischaemia? A retrospective cohort study
Authors: Nickinson A T O , Black I , Houghton J S M , Sayers R D 
Published: July 2021

Abstract

Introduction
Serum albumin is a recognised marker of nutritional status. Whilst associated with post-operative outcomes, the relationship with amputation-related outcomes in chronic limb-threatening ischaemia (CLTI) remains unclear. It is also uncertain whether any relationship may be confounded by systematic inflammation. We aimed to investigate whether hypoalbuminaemia is associated with amputation-related outcomes and evaluate its relationship with other inflammatory markers.

Method
A retrospective study of patients managed for CLTI at a vascular centre between 01/01/2013–31/12/2015 was undertaken. Patients were identified from local coding databases. Patient demographics and comorbidities, results of admission bloods and procedural data were recorded from electronic records. Hypoalbuminaemia was defined as albumin concentration &lt;35 g/L. One-year amputation-free survival (AFS) was the primary outcome. Cox’s proportional hazard models were calculated to compare the risk of amputation/death. Linear regression was performed to investigate the relationship between albumin and other inflammatory markers.

Result
374 patients were included (mean albumin concentration = 38.8g/L [SD = 5.2]), with 72 patients being hypoalbuminaemic. No differences were observed in sex (P=0.678), age (P=0.207), history of tissue loss (P=0.057), or cardiovascular comorbidities between groups, however a greater proportion of patients with hypoalbuminaemia had COPD (P=0.002). Patients with hypoalbuminaemia had a significantly higher combined risk of 1-year amputation/death compared to those with normal albumin concentration (HR 1.94, 95% CI 1.29–2.91). White cell count and CRP concentration were significant predictors of albumin concentration (r2=0.113, P&lt;0.001).

Conclusion
Hypoalbuminaemia is an important prognostic biomarker of AFS in CLTI, however this association may relate to a complex relationship between nutritional status and inflammation.

Take-home Message
Albumin is more than just a marker of nutritional status in patients with chronic limb-threatening ischaemia.
O22 Risk of death following pulmonary complications of surgery with and without SARS-CoV-2 infection: a comparative analysis of pre-pandemic and pandemic cohort studies
Authors:   STARSurg Collaborative & COVIDSurg Collaborative
Published: July 2021

Abstract

Introduction
No comparison has been made between the risk of death following pulmonary complications in patients with and without SARS-CoV-2 infection. This study aimed to determine the incidence and impact of pulmonary complications before and during the SARS-CoV-2 pandemic.

Method
A patient-level comparative analysis of two international prospective cohort studies; conducted pre-pandemic (22 January to 19 October 2019) and during the SARS-CoV-2 pandemic (local emergence of COVID-19 up to 19 April 2020). Patients undergoing elective resection of an intra-abdominal cancer with curative intent across five surgical oncology disciplines were included in analysis. The primary outcome measure was the mortality within 30 days of surgery.

Result
This study included 7402 patients from 50 countries; 3031 (40.9%) were operated pre-pandemic and 4371 (59.1%) during the pandemic. 5.1% (n = 224/4371) of patients during the pandemic developed a postoperative SARS-CoV-2 infection. Despite selection of lower risk cases during the pandemic, the rates of pulmonary complications pre were similar (6.3% vs 6.9%, P = 0.280). However, the risk of death after surgery was higher during the pandemic (2.0% vs 0.7%, P &lt; 0.001). The population attributable fraction of deaths due to pulmonary complications was 37.7% (95% CI: 15.2–64.7%) pre-pandemic and 66.0% (95% CI: 48.6–79.3%) during the pandemic. The increased mortality was largely attributable to SARS-CoV-2 infection; 68.9% (n = 31/45) of deaths patients with pulmonary complications occurred following SARS-CoV-2 infection.

Conclusion
Pulmonary complications are the primary driver of death after elective surgery during the pandemic. Care providers must urgently reconfigure surgical services to protect patients from perioperative SARS-CoV-2 infection.

Take-home Message
Pulmonary complications are the primary driver of death after elective surgery during the pandemic. Care providers must urgently reconfigure surgical services to protect patients from perioperative SARS-CoV-2 infection.
O25 Expression of polymeric immunoglobulin receptor (PIGR) and the effect of PIGR overexpression on breast cancer cells
Authors: Asanprakit W , Lobo D N , Eremin O , Bennett A J 
Published: July 2021

Abstract

Introduction
Polymeric immunoglobulin receptor (PIGR) has a major role in mucosal immunity as a transporter of polymeric immunoglobulin across the epithelial cells. PIGR expression increases in various cancers and relates to patient outcomes. Functional roles of PIGR have been explored in several cancers such as hepatocellular, pancreatic and lung cancer. The aim of this study was to determine the effect of PIGR on cellular behaviours and chemo-sensitivity of MCF7 and MDA-MB468 breast cancer cell lines.

Method
Basal levels of PIGR mRNA and protein expression in MCF7 and MDA-MB468 cells were evaluated by real time quantitative polymerase chain reaction and Western blotting, respectively. MCF7/PIGR and MDA-MB468/PIGR stable cell lines, overexpressing the PIGR gene, were generated using a lentiviral vector with tetracycline dependent induction of expression. Cell viability, cell proliferation and chemo-sensitivity of PIGR transfected cells were evaluated and compared with un-transfected cells to determine the effect of PIGR overexpression on cell phenotype.

Result
The levels of PIGR mRNA and protein expression were significantly higher in MDA-MB468 cells than in MCF7 cells (380-fold, P &lt; 0.0001). However, the differential expression of PIGR in these two cell lines did not lead to significant differences in chemo-sensitivity. Viral overexpression of PIGR was also not found to change any of the parameters measured in either cell line.

Conclusion
PIGR per se does not affect cellular behaviours and chemo-sensitivity of these breast cancer cell lines. It may be a marker which works through other factors rather than being a direct contributor of the favourable outcome in patients.

Take-home Message
PIGR may be a marker of favourable outcome in breast cancer patients which works through other factors rather than being a direct contributor.
O27 The diameter of an anorectal physiology catheter in the anal canal influences the results
Authors: Byrne C M , Kiff E S , Sharma A , Telford K J 
Published: July 2021

Abstract

Introduction
Conventional “catheter-based” anorectal physiology systems may influence anal canal pressures by stretching the sphincters thereby increasing tension. Anal acoustic reflectometry (AAR) is a “catheter-less” technique as the flexible thin catheter does not distort the anal canal. The aim of this study was to explore whether the size of rigid tube in the anal canal had any effect on tension.

Method
Participants with no anorectal dysfunction were included. Baseline resting/squeeze AAR measurements were recorded, then repeated with a 6 mm and 10 mm rigid tube placed along-side the AAR catheter. This process was repeated for anorectal manometry (ARM) and Opening pressure (AAR) and mean resting pressure (MRP) were used to calculate tension (pressure (mmHg) x radius (mm)).

Result
9 participants were included (7 female/2male) with median age 22 years (21–31 years). Tension at rest (no additional tube) for AAR and ARM was 14 and 135 N/m respectively and 33 and 238 N/m during squeeze. Tension increased in a linear fashion, for both resting and squeeze, as the size of additional rigid tube increased. The largest increase in tension from baseline AAR and ARM measurements was recorded with the 10 mm additional tube (1,807% and 102% respectively).

Conclusion
The thin AAR catheter exerted the lowest tension at baseline. A large increase in tension was observed as the size of tube increased and therefore the diameter of catheter used in the assessment of anal physiology will affect the results. ARM measurements carried out by devices of different diameter will not be comparable.

Take-home Message
The diameter of the anorectal physiology catheter in the anal canal influences the results.
O30 Aberrant expression of noggin has a subtype specific association with survival of breast cancer patients
Authors: Liu Ming , Jiang Wen G , Ye Lin 
Published: July 2021

Abstract

Introduction
Noggin is an antagonist of bone morphogenetic proteins (BMP). High Noggin expression contributes formation of osteolytic bone lesions from breast cancer. However, the exact role of noggin in breast cancer is yet to be clarified.

Method
Expression of Noggin was analysed in both RNA sequencing data of breast cancer cohort (n = 1097) from The Cancer Genome Atlas (TCGA) and a gene array database of breast cancer (E-MTAB-6703, n = 2088). Expression of Noggin was analysed using ANOVA and Kaplan-Meier analysis. Correlation between Noggin and angiogenic markers was evaluated using Spearman test. Impact on tumour growth was determined in a murine xenograft model by implant a triple negative breast cancer cell line (MDA-MB-231) with Noggin overexpression.

Result
Down-regulation of Noggin is revealed in both TCGA breast cancer cohort and the E-MTAB-6703. Reduced Noggin presents a correlation with poor relapse free survival. Moreover, patients with shorter overall survival exhibited higher expression of Noggin. Further analysis indicated that Noggin plays differential role in different subtypes of breast cancer. Lower expression of Noggin was seen in Her2 positive breast cancer compared with Luminal and Triple negative breast cancer (0.09(0.05–0.15) vs 0.13(0.06–0.24) vs 0.10(0.04–0.25) P &lt; 0.001). Noggin expression is positively correlated with BMP2, ACVR2A and ACVR1B and also fibroblast growth factor (FGF). Noggin reduced the in vivo tumour growth.

Conclusion
Noggin is reduced in breast cancer. Noggin expression has a subtype specific association with patients' survival in which the Noggin targeted BMP ligands and downstream receptors might be involved. Noggin inhibited in vivo tumour growth of MDA-MB-231 cells.

Take-home Message
Noggin is reduced in breast cancer. Noggin expression has s subtype specific association with patients’ survival in which the Noggin targeted BMP ligands and downstream receptors might be involved.
O36 The impact of the COVID-19 pandemic on undergraduate medical education: a survey of students’ safety and satisfaction during breast surgery clinical placement
Authors: Gasiea Rehab , Gasiea Rayhan , Yip Christina 
Published: July 2021

Abstract

Introduction
COVID-19 is affecting all medical education and training. The University used in the collection of data suspended all clinical placement from mid-March 2020, resuming in-person teaching from September. To enable social distancing, the medical school and Breast Unit introduced: 1. one student per clinician per clinical activity (3-hours), 2. online learning (1-hr) and patient exposure (2 hours) in some clinical activities, 3. remote learning via Teams, and 4. personal protective equipment.

Method
We sent a 24-question survey to 31, 3rd and 4th year, students, who had breast surgery clinical placement between 07/09/20 and 18/12/20. The aim was to assess whether clinical activities could still feasibly be carried out, the effectiveness of COVID-19 protection, and students’ learning satisfaction.

Result
Our survey achieved a 65% response-rate. Over two-thirds of students had at least 3 days’ clinical placement, attending clinics, theatre, mammography, multidisciplinary team meetings and a 3-hr lecture via Teams. 90% of students had face-to-face patient interaction and 70% conducted physical examinations. All students were provided with hand-gel and masks and, at clinics, 35% of students were provided with face-shields. None of the students reported COVID-19 related symptoms during or after placement. 85% of students felt safe during their clinical placement and 95% reported satisfaction with the quality of teaching.

Conclusion
Notwithstanding COVID-19 restrictions, a blend of face-to-face with online clinical teaching can be safely delivered.

Take-home Message
Notwithstanding COVID-19 restrictions, a blend of face-to-face with online clinical teaching can be safely delivered.
O38 Variations in orthopedic trauma presentation during COVID-19 lockdown
Authors: Chaudhry Mansoor N , Ahmad Mahmood , Butt Abeeda 
Published: July 2021

Abstract

Introduction
The first national lockdown was imposed in Ireland from 27th March 2020, to combat the spread of Coronavirus. All non-essential travel, businesses, sporting activities and schools were closed. The elderly were advised to cocoon. The roadmap to easing the restrictions started in May. The lockdown measures resulted in people spending more time indoors, with impact on social and personal wellbeing. This had the potential to increase alcohol consumption, self inflicted injuries and neglect. The purpose of our study is to analyze the variations in orthopedic trauma presentations during the pandemic compared to similar period in 2018 and 2019.

Method
Retrospective data was collected from Orthopedic theatre registry of Our Lady of Lourdes Hospital, Drogheda, Co Louth, Ireland. Patients operated by orthopedic trauma team in three months period (March, April & May) in 2018, 2019 and 2020 were selected for analysis and comparison.

Result
Total number of surgeries performed in March-May 2018, 2019 and 2020 were 551, 505 and 373 showing a significant reduction in 2020 as compared to previous years. Trauma surgeries performed on children in March-May 2018,2019 and 2020 were 132,131 and 90 respectively, showing a similar downward trend. Surgeries were further categorized into Major +, Major, Intermediate and Minor according to their level of complexity. Although there was a significant reduction seen in Major, Intermediate and Minor surgeries, no significant difference was observed in Major + surgeries (73 in March-May 2020 vs. 79 in March-May 2019 and 57 in March-May 2018).

Conclusion
Significant reduction was seen in overall trauma surgeries which is attributable to lockdown measures. The difference in trend between Major + and other categories of surgeries can be explained by the reduction in sporting injuries and injuries in children whereas no significant difference was noted in hip fractures.
O41 Quantifying the burden of survivorship associated with infra-renal abdominal aortic aneurysm repair: a systematic review
Authors: Patel K , Sounderajah V , Normahani P , Acharya A , Ashrafian H , Bicknell C 
Published: July 2021

Abstract

Introduction
Survivorship encompasses the physical, psychological, social, functional and economic experience of living with a chronic condition for both patients and their caregivers. It comprises 9 distinct domains and remains understudied in non-oncological pathologies, including infra-renal abdominal aortic aneurysmal disease (IRAAA). This review aims to quantify the extent to which existing IRAAA literature addresses the burden of survivorship in patients following surgical intervention.

Method
The databases; MEDLINE, EMBASE and PsychINFO, were searched from 1989 through to July 2020. Randomised controlled trials, observational studies and case series studies were included. Eligible studies had to detail outcomes related to survivorship following IRAAA surgery. Due to heterogeneity between studies and outcomes, no meta-analysis was conducted. Study quality was assessed with specific risk of bias tools.

Result
112 studies were included and only 4 of the 9 domains of survivorship have been previously studied—treatment complications, physical functioning, co-morbidities and caregivers. The available evidence is of variable quality; the majority of studies display a moderate to high risk of bias, are of an observational study design, are based within a limited number of countries and consist of an insufficient follow up period.

Conclusion
This review highlights the absence of robust evidence regarding survivorship following IRAAA surgery, regardless of repair modality. Consequently, contemporary treatment guidelines are reliant upon historic quality of life data that is narrow in scope and non-representative of contemporary clinical practice. As such, there is an urgent need to re-evaluate the scope and methodology associated with this research theme moving forwards.

Take-home Message
There is an urgent need to re-evaluate the scope and methodology associated with traditional quality of life centred IRAAA studies moving forwards in order to better empower patient decision making as well as inform treatment guidelines and health policy initiatives.
O44 Gender bias and sexual discrimination in orthopaedics: time for change
Authors: Halim U A , Elbayouk A , Ali A M , Cullen C M , Javed S 
Published: July 2021

Abstract

Introduction
Gender bias and sexual discrimination (GBSD) have been widely recognized across a range of fields and are now part of the wider social consciousness. Such conduct can occur in the medical workplace, with detrimental effects on recipients. The aim of this review was to identify the prevalence and impact of GBSD in orthopaedic surgery, as well as mitigating strategies.

Method
A systematic review was conducted by searching Medline, EMCARE, CINAHL, PsycINFO, and the Cochrane Library Database. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Original research papers pertaining to the prevalence and impact of GBSD, or mitigating strategies, within orthopaedics were reviewed.

Result
Of 570 papers, 27 were eligible for inclusion. These were published between 1998 and 2020. 13 papers discussed the prevalence of GBSD, 13 related to the impact of these behaviours, and six discussed mitigating strategies. GBSD was found to be common in the orthopaedic workplace, with all sources showing women to be the subjects. Effects include poor workforce representation, lower salaries, and less career success for women in orthopaedics. Mitigating strategies in the literature are focused on providing female role models, mentors, and educational interventions.

Conclusion
GBSD is common in orthopaedic surgery, with a substantial impact on sufferers. A small number of mitigating strategies have been tested but these are limited in their scope. As such, the orthopaedic community is obliged to participate in more thoughtful and proactive strategies that mitigate against GBSD, by improving female recruitment and retention within the specialty.

Take-home Message
Gender bias and sexual discrimination remain common within orthopaedics. The international orthopaedic community is obliged to do more to tackle this problem.