Radiotherapy to the prostate for men with metastatic prostate cancer in the UK and Switzerland: Long-term results from the STAMPEDE randomised controlled trial (2022)

Type of publication:
Randomised controlled trial

Author(s):
Parker CC; James ND; Brawley CD; Clarke NW; Ali A; Amos CL; Attard G; Chowdhury S; Cook A; Cross W; Dearnaley DP; Douis H; Gilbert DC; Gilson C; Gillessen S; Hoyle A; Jones RJ; Langley RE; Malik ZI; Mason MD; Matheson D; Millman R; Rauchenberger M; Rush H; Russell JM; Sweeney H; Bahl A; Birtle A; Capaldi L; Din O; Ford D; Gale J; Henry A; Hoskin P; Kagzi M; Lydon A; O'Sullivan JM; Paisey SA; Parikh O; Pudney D; Ramani V; Robson P; *Srihari NN; Tanguay J; Parmar MKB; Sydes MR; STAMPEDE Trial Collaborative Group

Citation:
PLoS Medicine, 2022 Jun 07; Vol. 19 (6), pp. e1003998

Abstract:
Background: STAMPEDE has previously reported that radiotherapy (RT) to the prostate improved overall survival (OS) for patients with newly diagnosed prostate cancer with low metastatic burden, but not those with high-burden disease. In this final analysis, we report long-term findings on the primary outcome measure of OS and on the secondary outcome measures of symptomatic local events, RT toxicity events, and quality of life (QoL).Methods and Findings: Patients were randomised at secondary care sites in the United Kingdom and Switzerland between January 2013 and September 2016, with 1:1 stratified allocation: 1,029 to standard of care (SOC) and 1,032 to SOC+RT. No masking of the treatment allocation was employed. A total of 1,939 had metastatic burden classifiable, with 42% low burden and 58% high burden, balanced by treatment allocation. Intention-to-treat (ITT) analyses used Cox regression and flexible parametric models (FPMs), adjusted for stratification factors age, nodal involvement, the World Health Organization (WHO) performance status, regular aspirin or nonsteroidal anti-inflammatory drug (NSAID) use, and planned docetaxel use. QoL in the first 2 years on trial was assessed using prospectively collected patient responses to QLQ-30 questionnaire. Patients were followed for a median of 61.3 months. Prostate RT improved OS in patients with low, but not high, metastatic burden (respectively: 202 deaths in SOC versus 156 in SOC+RT, hazard ratio (HR) = 0·64, 95% CI 0.52, 0.79, p < 0.001; 375 SOC versus 386 SOC+RT, HR = 1.11, 95% CI 0.96, 1.28, p = 0·164; interaction p < 0.001). No evidence of difference in time to symptomatic local events was found. There was no evidence of difference in Global QoL or QLQ-30 Summary Score. Long-term urinary toxicity of grade 3 or worse was reported for 10 SOC and 10 SOC+RT; long-term bowel toxicity of grade 3 or worse was reported for 15 and 11, respectively.Conclusions: Prostate RT improves OS, without detriment in QoL, in men with low-burden, newly diagnosed, metastatic prostate cancer, indicating that it should be recommended as a SOC.Trial Registration: ClinicalTrials.gov NCT00268476, ISRCTN.com ISRCTN78818544.

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Effectiveness of a web-based virtual journal club to promote medical education (Web-Ed): protocol of a multicentre pragmatic randomised trial (2022)

Type of publication:Randomised controlled trial

Author(s):Michael Rimmer, Nagla Elfaki, Cheryl Dunlop, Damien Coleburt, Neil Cowan, Olivia Raglan, Jhia Jiat Teh, Maria Fisher, Sarah Mcrobbie, Nilaani Murugesu, Meera Ramcharn, Mohamed Abdelrahman, *Yazid Jibrel, *Matthew Wood, *William Parry-Smith, Bassel H Al Wattar

Citation:BMJ Open, 2022 Vol.12, Issue 6

Abstract:Introduction: A journal club (JC) is a commonly used medical educational tool. Videoconferencing technology can facilitate the delivery of JCs, however, there remains no evidence on the role of web-based virtual JCs in promoting the acquisition and retention of medical knowledge. The Web-Ed trial aims to evaluate the educational benefits, feasibility and acceptability of web-based virtual JCs compared with traditional face-to-face ones.

Methods and analysis: Web-Ed is a multicentre pragmatic parallel-group randomised trial across teaching hospitals within the UK National Health Service (NHS). We will enrol qualified doctors or medical students who are >18 years old, proficient in English and able to use online videoconferencing software. Block randomisation will be used to allocate participants in 1:1 ratio to either intervention group. Both groups will be presented with the same educational material and follow a standardised JC structure hosted by nominated moderators and medical faculty members.

The primary outcome is the difference in participants’ knowledge acquisition and retention 7 days after the JCs evaluated using standardised multiple-choice questions. We will report secondarily on the feasibility and acceptability of the JCs using Likert scale questionnaires. Assuming a 30% drop-out rate, we aim to enrol 75 participants to detect a 20% improvement in knowledge acquisition at 80% power and 5% significance. We will report using mean difference or risk ratio with 95% CIs and assess significance using parametric/non-parametric testing. Where relevant, we will adjust for predetermined characteristics (age, grade of training and session duration) using multivariate regression analyses.

Ethics and dissemination: Web-Ed was designed by doctors in training to address their learning needs and evaluate the preferred mode of learning. The trial results will be published in peer-reviewed journals and presented at relevant scientific conferences. The trial has been approved by the NHS Health Regulation Authority (21/HRA/3361).

Trial registration number: ISRCTN18036769.

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Validation of the OAKS prognostic model for acute kidney injury after gastrointestinal surgery (2022)

Type of publication:Journal article

Author(s):STARSurg Collaborative and EuroSurg Collaborative (includes Chohan K.; Dhuna S.; Haq T.; Kirby S.; Lacy-Colson J.; Logan P.; Malik Q.; McCann J.; Mughal Z.; Sadiq S.; Sharif I.; Shingles C.; Simon A.; Chaudhury N.; Rajendran K.; Akbar Z.)

Citation:BJS Open, 2022, 6(1)

Abstract:Background: Postoperative acute kidney injury (AKI) is a common complication of major gastrointestinal surgery with an impact on short- and long-term survival. No validated system for risk stratification exists for this patient group. This study aimed to validate externally a prognostic model for AKI after major gastrointestinal surgery in two multicentre cohort studies. Method(s): The Outcomes After Kidney injury in Surgery (OAKS) prognostic model was developed to predict risk of AKI in the 7 days after surgery using six routine datapoints (age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker). Validation was performed within two independent cohorts: a prospective multicentre, international study ('IMAGINE') of patients undergoing elective colorectal surgery (2018); and a retrospective regional cohort study ('Tayside') in major abdominal surgery (2011-2015). Multivariable logistic regression was used to predict risk of AKI, with multiple imputation used to account for data missing at random. Prognostic accuracy was assessed for patients at high risk (greater than 20 per cent) of postoperative AKI. Result(s): In the validation cohorts, 12.9 per cent of patients (661 of 5106) in IMAGINE and 14.7 per cent (106 of 719 patients) in Tayside developed 7-day postoperative AKI. Using the OAKS model, 558 patients (9.6 per cent) were classified as high risk. Less than 10 per cent of patients classified as low-risk developed AKI in either cohort (negative predictive value greater than 0.9). Upon external validation, the OAKS model retained an area under the receiver operating characteristic (AUC) curve of range 0.655-0.681 (Tayside 95 per cent c.i. 0.596 to 0.714; IMAGINE 95 per cent c.i. 0.659 to 0.703), sensitivity values range 0.323-0.352 (IMAGINE 95 per cent c.i. 0.281 to 0.368; Tayside 95 per cent c.i. 0.253 to 0.461), and specificity range 0.881-0.890 (Tayside 95 per cent c.i. 0.853 to 0.905; IMAGINE 95 per cent c.i. 0.881 to 0.899). Conclusion(s): The OAKS prognostic model can identify patients who are not at high risk of postoperative AKI after gastrointestinal surgery with high specificity.

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A single faecal bile acid stool test demonstrates potential efficacy in replacing SeHCAT testing for bile acid diarrhoea in selected patients (2022)

Type of publication:Journal article

Author(s):Kumar A; Al-Hassi HO; Jain M; Phipps O; Ford C; Gama R; Steed H; *Butterworth J; McLaughlin J; Galbraith N; Brookes MJ; Hughes LE

Citation:Scientific Reports, 2022 May 18; Vol. 12 (1), pp. 8313

Abstract:This study examines the validity of measuring faecal bile acids (FBA) in a single stool sample as a diagnostic tool for bile acid diarrhoea (BAD) by direct comparison to the 75 selenium-homotaurocholic acid (SeHCAT) scan. A prospective observational study was undertaken. Patients with chronic diarrhoea (> 6 weeks) being investigated for potential BAD with SeHCAT scan provided stool samples for measurement of FBA, using an enzyme-linked immunosorbent assay. Patients were characterised into four groups: SeHCAT negative control group, post-cholecystectomy, idiopathic BAD and post-operative terminal ileal resected Crohn's disease. Stool samples were collected at baseline and 8-weeks post treatment to determine whether FBA measurement could be used to monitor therapeutic response. 113 patients had a stool sample to directly compare with their SeHCAT result. FBA concentrations (μmol/g) and interquartile ranges in patients in the control group (2.8; 1.6-4.2), BAD (3.6; 1.9-7.2) and post-cholecystectomy cohort 3.8 (2.3-6.8) were similar, but all were significantly lower (p < 0.001) compared to the Crohn's disease cohort (11.8; 10.1-16.2). FBA concentrations in patients with SeHCAT retention of < 15% (4.95; 2.6-10.5) and < 5% (9.9; 4.8-15.4) were significantly higher than those with a SeHCAT retention > 15% (2.6; 1.6-4.2); (p < 0.001 and p < 0.0001, respectively). The sensitivity and specificity using FBA cut-off of 1.6 μmol/g (using ≤ 15% SeHCAT retention as diagnostic of BAD) were 90% and 25% respectively. A single random stool sample may have potential use in diagnosing severe BAD or BAD in Crohn's patients. Larger studies are now needed to confirm the potential efficacy of this test to accurately diagnose BAD in the absence of SeHCAT testing.

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The positive impact of GIRFT (getting it right first time) on arthroplasty services in times of COVID-19 (2022)

Type of publication:
Journal article

Author(s):
*Khan MM; *Khawar H; *Perkins R; Pardiwala A

Citation:
Annals of medicine and surgery, 2022 May; Vol. 77, pp. 103655

Abstract:
Background: This observational study evaluates the trends in arthroplasty services across National Health Services (NHS) following the COVID-19 pandemic about GIRFT (Getting it Right First Time) guidelines concerning National joint registry data (NJR data). Introduction: Since the advent of the COVID-19 crisis sustainability of elective arthroplasty services have become a burning question in NHS. Capacity crisis, unknown COVID-19 infection status, lack of ring-fenced beds, winter crisis, and unprecedented trauma have aggravated the situation further leading to severe impairment in quality of life and service provision. GIRFT guidelines have suggested a few solutions to this crisis and one of them is dividing the hospitals into Hot (trauma) and cold (elective) sites. Objectives: To review NJR data for pre and post COVID era along with the service structure of the hospital and test the hypothesis that whether redistribution of services into hot and cold sites is a possible solution for sustainable arthroplasty service across NHS. Methodology: A search was made into the NJR data from 2019, 2020, and 2021. The First 7 months were taken from each year I.e. From Ist January to 31st of July. A review of entries for arthroplasty was considered for all hospitals across England and Wales. Hospitals in Scotland, Ireland, and Isles of Man and major trauma centers were excluded. Any hospital that was recording at least 15 arthroplasty cases for 4 out of 7 months in 2021 was considered for review. A brief evaluation of their service structure was made, and hospitals were divided into Elective Centres (EC), Urgent Care Centres (UCC), and District General Hospitals (DGH) with in-house emergency services based on the information provided on their official website. In NJR data "completed operations by submission date" column was considered as a reference for data collection. A total of 1807, 1800, and 1810 were identified for 2019, 2020, and 2021 respectively. However, after applying inclusion criteria total number of entries was reduced to 120 hospitals. Data analysis and selection of hospitals were reviewed twice by two authors (MMK and AP) at different times to avoid any bias and reduce the chances of human error that can affect the outcome. A sub-analysis of data for the last 3 months (May, June, and July) was also performed for the respective years to get a better picture of arthroplasty trends and reduce the flaws of data interpretation. Ethical Approval and Data Consideration: A formal approval was taken from the NJR team in the UK before the data processing was initiated. The data source being used was available for public review on the NJR website. The team was happy for us to process and evaluate the data as per needs of our study. However, they requested a disclaimer and appreciation note for the members of the NJR team and hospital personnel across the UK that have made the provision of data and subsequent analysis leading to this study feasible. Results: 18 EC were included. The mean number of cases recorded per center was 427, 68, 348 for 2019, 2020, and 2021 respectively.20 UCC were identified. The mean number of cases performed were 213, 24, and 195 in 2019, 2020, and 2021 respectively. Similarly, 60 DGH with emergency services were included and the average number of cases recorded were 194, 27, and 166 for 2019, 2020, and 2021 respectively. Compared to 2019 out of 148 DGH in 2019 only 60 can provide a sustainable arthroplasty service signifying a drop of 40% in 2021 in the number of DGH which are contributing to elective services. Conclusions: The overall productivity of theatres in terms of arthroplasty services has decreased since the reinitialization of services in 2021. There is a need of hour to divide the services into hot and cold sites in terms of A/E and elective centers to provide safe and uninterrupted provision of arthroplasty services and address long waiting times for patients. Provisional of ring-fenced beds and arthroplasty wards is more technically feasible in centers that are not providing in-house emergency admission pathways or are specialist, dedicated elective centers

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Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476) (2022)

Type of publication:Randomised controlled trial

Author(s):James N.D.; Clarke N.W.; Cook A.; Ali A.; Hoyle A.P.; Attard G.; Brawley C.D.; Chowdhury S.; Cross W.R.; Dearnaley D.P.; de Bono J.S.; Montana C.D.; Gilbert D.; Gillessen S.; Gilson C.; Jones R.J.; Langley R.E.; Malik Z.I.; Matheson D.J.; Millman R.; Parker C.C.; Pugh C.; Rush H.; Russell J.M.; Berthold D.R.; Buckner M.L.; Mason M.D.; Ritchie A.W.; Birtle A.J.; Brock S.J.; Das P.; Ford D.; Gale J.; Grant W.; Gray E.K.; Hoskin P.; Khan M.M.; Manetta C.; McPhail N.J.; O'Sullivan J.M.; Parikh O.; Perna C.; Pezaro C.J.; Protheroe A.S.; Robinson A.J.; Rudman S.M.; Sheehan D.J.; *Srihari N.N.; Syndikus I.; Tanguay J.; Thomas C.W.; Vengalil S.; Wagstaff J.; Wylie J.P.; Parmar M.K.; Sydes M.R.

Citation:
International Journal of Cancer. 151(3) (pp 422-434), 2022. Date of Publication: 01 Aug 2022.

Abstract:Abiraterone acetate plus prednisolone (AAP) previously demonstrated improved survival in STAMPEDE, a multi-arm, multi-stage platform trial in men starting long-term hormone therapy for prostate cancer. This long-term analysis in metastatic patients was planned for 3yrs after the first results. Standard-of-care (SOC) was androgen deprivation therapy. The comparison randomized patients 1:1 to SOC-alone with or without daily abiraterone acetate 1000mg+prednisolone 5mg (SOC+AAP), continued until disease progression. The primary outcome measure was overall survival. Metastatic disease risk group was classified retrospectively using baseline CT and bone scans by central radiological review and pathology reports. Analyses used Cox proportional hazards & flexible parametric models, adjusted for baseline stratification factors. 1003 patients were contemporaneously randomized (Nov-2011–Jan-2014): median age 67yr; 94% newly-diagnosed; metastatic disease risk group: 48% high, 44% low, 8% un-assessable; median PSA 97ng/mL. At 6.1yr median follow-up, 329 SOC-alone deaths (118 low-risk, 178 high-risk) and 244 SOC+AAP deaths (75 low-risk, 145 high-risk) were reported. Adjusted HR = 0.60 (95%CI:0.50-0.71; P =0.31×10-9 ) favoured SOC+AAP, with 5-yr survival improved from 41% SOC-alone to 60% SOC+AAP. This was similar in low-risk (HR = 0.55; 95%CI:0.41-0.76) and high-risk (HR = 0.54; 95%CI:0.43-0.69) patients. Median and current maximum time on SOC+AAP was 2.4yr and 8.1yr. Toxicity at 4yr post-randomisation was similar, with 16% patients in each group reporting grade 3 or higher toxicity. A sustained and substantial improvement in overall survival of all metastatic prostate cancer patients was achieved with SOC+abiraterone acetate + prednisolone, irrespective of metastatic disease risk group.

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Patient Outcomes Related to In-Hospital Delays in Appendicectomy for Appendicitis: A Retrospective Study (2022)

Type of publication:
Journal article

Author(s):
Claydon O; Down B; *Kumar S

Citation:
Cureus, 2022 Mar 10; Vol. 14 (3), pp. e23034

Abstract:
Background and objective In many hospitals, the availability of operating theatres and access to senior surgical and anaesthetic support diminish during night hours. Therefore, urgent surgery is sometimes postponed until the following morning rather than performed overnight, if it is judged to be safe. In this study, we aimed to determine if a delay in laparoscopic appendicectomy in cases of acute appendicitis of over 12 hours, analogous to an overnight delay, correlated with worse patient outcomes. Our primary outcome was delayed discharge from the hospital. Our secondary outcomes were appendicitis severity, conversions, and postoperative complications. Methods We undertook a retrospective review of the medical records of patients who underwent laparoscopic appendicectomy for appendicitis at a UK district general hospital between 01/01/2018 and 30/08/2019. For each patient, clinical and demographic information, and time of hospital admission, surgery, and discharge were collected. Delayed discharge was defined as "time to discharge" >24 hours after surgery. Results A total of 446 patients were included in the study. In 137 patients (30.7%), "time to surgery" was under 12 hours; in 309 patients (69.3%) "time to surgery" was over 12 hours. Of note, 319 patients (71.5%) had a delayed discharge; 303 patients (67.9%) had complicated appendicitis, and 143 patients had severe appendicitis (32.1%). No statistically significant association between "time to surgery" and delayed discharge, appendicitis severity, conversion, or 30-day re-presentations was observed. Conclusion Time from admission to the start of appendicectomy did not affect patient outcomes. Short in-hospital delays in appendicectomy, such as an overnight delay, may be safe in certain patients and should be determined based on clinical judgement.

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Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity (2022)

Type of publication:
Journal article

Author(s):
Fallerini C.; Picchiotti N.; Baldassarri M.; Zguro K.; Daga S.; Fava F.; Benetti E.; Amitrano S.; Bruttini M.; Palmieri M.; Croci S.; Lista M.; Beligni G.; Valentino F.; Meloni I.; Tanfoni M.; Minnai F.; Colombo F.; Cabri E.; Fratelli M.; Gabbi C.; Mantovani S.; Frullanti E.; Gori M.; Crawley F.P.; Butler-Laporte G.; Richards B.; Zeberg H.; Lipcsey M.; Hultstrom M.; Ludwig K.U.; Schulte E.C.; Pairo-Castineira E.; Baillie J.K.; Schmidt A.; Frithiof R.; Mari F.; Renieri A.; Furini S.; Montagnani F.; Tumbarello M.; Rancan I.; Fabbiani M.; Rossetti B.; Bergantini L.; D'Alessandro M.; Cameli P.; Bennett D.; Anedda F.; Marcantonio S.; Scolletta S.; Franchi F.; Mazzei M.A.; Guerrini S.; Conticini E.; Cantarini L.; Frediani B.; Tacconi D.; Raffaelli C.S.; Feri M.; Donati A.; Scala R.; Guidelli L.; Spargi G.; Corridi M.; Nencioni C.; Croci L.; Caldarelli G.P.; Spagnesi M.; Romani D.; Piacentini P.; Bandini M.; Desanctis E.; Cappelli S.; Canaccini A.; Verzuri A.; Anemoli V.; Pisani M.; Ognibene A.; Pancrazzi A.; Lorubbio M.; Vaghi M.; Monforte A.D.; Miraglia F.G.; Mondelli M.U.; Girardis M.; Venturelli S.; Busani S.; Cossarizza A.; Antinori A.; Vergori A.; Emiliozzi A.; Rusconi S.; Siano M.; Gabrieli A.; Riva A.; Francisci D.; Schiaroli E.; Paciosi F.; Tommasi A.; Scotton P.G.; Andretta F.; Panese S.; Baratti S.; Scaggiante R.; Gatti F.; Parisi S.G.; Castelli F.; Quiros-Roldan E.; Antoni M.D.; Zanella I.; Monica M.D.; Piscopo C.; Capasso M.; Russo R.; Andolfo I.; Iolascon A.; Fiorentino G.; Carella M.; Castori M.; Aucella F.; Raggi P.; Perna R.; Bassetti M.; Biagio A.D.; Sanguinetti M.; Masucci L.; Guarnaccia A.; Valente S.; Vivo O.D.; Doddato G.; Tita R.; Giliberti A.; Mencarelli M.A.; Rizzo C.L.; Pinto A.M.; Perticaroli V.; Ariani F.; Carriero M.L.; Sarno L.D.; Alaverdian D.; Bargagli E.; Mandala M.; Giorli A.; Salerni L.; Zucchi P.; Parravicini P.; Menatti E.; Trotta T.; Giannattasio F.; Coiro G.; Lena F.; Lacerenza L.G.; Coviello D.A.; Mussini C.; Martinelli E.; Mancarella S.; Tavecchia L.; Belli M.A.; Crotti L.; Parati G.; Sanarico M.; Raimondi F.; Biscarini F.; Stella A.; Rizzi M.; Maggiolo F.; Ripamonti D.; Suardi C.; Bachetti T.; Rovere M.T.L.; Sarzi-Braga S.; Bussotti M.; Capitani K.; Dei S.; Ravaglia S.; Artuso R.; Andreucci E.; Gori G.; Pagliazzi A.; Fiorentini E.; Perrella A.; Bianchi F.; Bergomi P.; Catena E.; Colombo R.; Luchi S.; Morelli G.; Petrocelli P.; Iacopini S.; Modica S.; Baroni S.; Segala F.V.; Menichetti F.; Falcone M.; Tiseo G.; Barbieri C.; Matucci T.; Grassi D.; Ferri C.; Marinangeli F.; Brancati F.; Vincenti A.; Borgo V.; Stefania L.; Lenzi M.; Pietro M.A.D.; Vichi F.; Romanin B.; Attala L.; Costa C.; Gabbuti A.; Roberto M.; Zuccon U.; Vietri L.; Ceri S.; Pinoli P.; Casprini P.; Merla G.; Squeo G.M.; Maffezzoni M.; Bruno R.; Vecchia M.; Colaneri M.; Ludovisi S.; Marincevic-Zuniga Y.; Nordlund J.; Luther T.; Larsson A.; Hanslin K.; Gradin A.; Galien S.; Anderberg S.B.; Rosen J.; Rubertsson S.; Clohisey S.; Horby P.; Millar J.; Knight J.; Montgomery H.; Maslove D.; Ling L.; Nichol A.; Walsh T.; Hinds C.; Semple M.G.; Openshaw P.J.M.; Ho A.; McAuley D.; Ponting C.; Rowan K.; Griffiths F.; Oosthuyzen W.; Meikle J.; Finernan P.; Furniss J.; Mcmaster E.; Law A.; Paterson T.; Wackett T.; Armstrong R.; Murphy L.; Fawkes A.; Coutts A.; Donnelly L.; Gilchrist T.; Hafezi K.; Macgillivray L.; Maclean A.; McCafferty S.; Morrice K.; Weaver J.; Boz C.; Golightly A.; Ward M.; Mal H.; Szoor-McElhinney H.; Hendry R.; Stenhouse A.; Cullum L.; Law D.; Law S.; Law R.; Swets M.; Day N.; Taneski F.; Duncan E.; Zechner M.; Parkinson N.; Klaric L.; Bretherick A.D.; Rawlik K.; Pasko D.; Walker S.; Fourman M.H.; Russell C.D.; Richmond A.; Gountouna E.; Harrison D.; Wang B.; Wu Y.; Meynert A.; Kousathanas A.; Moutsianas L.; Yang Z.; Zhai R.; Zheng C.; Grimes G.; Shih B.; Yang J.; Shen X.; Ponting C.P.; Tenesa A.; Vitart V.; Wilson J.F.; Wood S.; Zak A.; Borra C.; Matharu M.; May P.; Alldis Z.; Mitchelmore O.; Bowles R.; Easthorpe A.; Bibi F.; Lancoma-Malcolm I.; Gurasashvili J.; Pheby J.; Shiel J.; Bolton M.; Patel M.; Zongo O.; Ebano P.; Harding P.; Astin-Chamberlain R.; Choudhury Y.; Cox A.; Kallon D.; Burton M.; Hall R.; Blowes S.; Prime Z.; Biddle J.; Prysyazhna O.; Newman T.; Tierney C.; Kassam J.; Shankar-Hari M.; Ostermann M.; Campos S.; Bociek A.; Lim R.; Grau N.; Jones T.O.; Whitton C.; Marotti M.; Arbane G.; Bonner S.; Hugill K.; Reid J.; Welters I.; Waugh V.; Williams K.; Shaw D.; Fernandez Roman J.; Lopez Martinez M.; Johnson E.; Waite A.; Johnson B.; Hamilton O.; Mulla S.; McPhail M.; Smith J.; Barclay L.; Hope D.; McCulloch C.; McQuillan L.; Clark S.; Singleton J.; Priestley K.; Rea N.; Callaghan M.; Andrew G.; Marshall L.; McKechnie S.; Hutton P.; Bashyal A.; Davidson N.; Summers C.; Polgarova P.; Stroud K.; Pathan N.; Elston K.; Agrawal S.; Battle C.; Newey L.; Rees T.; Harford R.; Brinkworth E.; Williams M.; Murphy C.; White I.; Croft M.; Bandla N.; Gellamucho M.; Tomlinson J.; Turner H.; Hussain I.; Thompson C.; Parker H.; Bradley R.; Griffiths R.; Gill J.; Puxty A.; Cathcart S.; Turner L.; Duffy K.; Puxty K.; Joseph A.; Herdman-Grant R.; Simms R.; Swain A.; Naranjo A.; Crowe R.; Sollesta K.; Loveridge A.; Baptista D.; Morino E.; Davey M.; Golden D.; Moreno Cuesta J.; Haldeos A.; Bakthavatsalam D.; Vincent R.; Elhassan M.; Xavier K.; Ganesan A.; Purohit D.; Abdelrazik M.; Morgan J.; Akeroyd L.; Bano S.; Warren D.; Bromley M.; Sellick K.; Gurr L.; Wilkinson B.; Nagarajan V.; Szedlak P.; Cupitt J.; Stoddard E.; Benham L.; Preston S.; Slawson N.; Bradshaw Z.; Brown J.; Caswell M.; Melling S.; Bamford P.; Faulkner M.; Cawley K.; Jeffrey H.; London E.; Sainsbury H.; Nagra I.; Nasir F.; Dunmore C.; Jones R.; Abraheem A.; Al-Moasseb M.; Girach R.; Brantwood C.; Alexander P.; Bradley-Potts J.; Allen S.; Felton T.; Manna S.; Farnell-Ward S.; Leaver S.; Queiroz J.; Maccacari E.; Dawson D.; Castro Delgado C.; Pepermans Saluzzio R.; Ezeobu O.; Ding L.; Sicat C.; Kanu R.; Durrant G.; Texeira J.; Harrison A.; Samakomva T.; Willis H.; Hopkins B.; Thrasyvoulou L.; Jackson M.; Zaki A.; Tibke C.; Bennett S.; Woodyatt W.; Kent A.; Goodwin E.; Brandwood C.; Clark R.; Smit L.; Rooney K.; Thomson N.; Rodden N.; Hughes E.; McGlynn D.; Clark C.; Clark P.; Abel L.; Sundaram R.; Gemmell L.; Brett M.; Hornsby J.; MacGoey P.; Price R.; Digby B.; O'Neil P.; McConnell P.; Henderson P.; Henderson S.; Sim M.; Kennedy-Hay S.; Rooney L.; Baxter N.; Pogson D.; Rose S.; Daly Z.; Brimfield L.; Phull M.K.; Hussain M.; Pogreban T.; Rosaroso L.; Salciute E.; Grauslyte L.; Wraith E.; MacCallum N.; Bercades G.; Hass I.; Smyth D.; Reyes A.; Martir G.; Clement I.D.; Webster K.; Hays C.; Gulati A.; Hodgson L.; Margarson M.; Gomez R.; Baird Y.; Thirlwall Y.; Folkes L.; Butler A.; Meadows E.; Moore S.; Raynard D.; Fox H.; Riddles L.; King K.; Kimber S.; Hobden G.; McCarthy A.; Cannons V.; Balagosa I.; Chadbourn I.; Gardner A.; Horner D.; McLaughlanv D.; Charles B.; Proudfoot N.; Marsden T.; McMorrow L.; Blackledge B.; Pendlebury J.; Harvey A.; Apetri E.; Basikolo C.; Catlow L.; Doonan R.; Knowles K.; Lee S.; Lomas D.; Lyons C.; Perez J.; Poulaka M.; Slaughter M.; Slevin K.; Thomas V.; Walker D.; Harris J.; Drummond A.; Tully R.; Dearden J.; Philbin J.; Munt S.; Rishton C.; O'Connor G.; Mulcahy M.; Dobson E.; Cuttler J.; Edward M.; Sloan B.; Buckley S.; Brooke H.; Smithson E.; Charlesworth R.; Sandu R.; Thirumaran M.; Wagstaff V.; Cebrian Suarez J.; Kaliappan A.; Vertue M.; Riches J.; Solesbury A.; Kittridge L.; Forsey M.; Maloney G.; Cole J.; Davies M.; Davies R.; Hill H.; Thomas E.; Duffin D.; Player B.; Radhakrishnan J.; Gibson S.; Lyle A.; McNeela F.; Patel B.; Gummadi M.; Sloane G.; Dormand N.; Salmi S.; Farzad Z.; Cristiano D.; Liyanage K.; Thwaites V.; Varghese M.; Meredith M.; Mills G.; Willson J.; Harrington K.; Lenagh B.; Cawthron K.; Masuko S.; Raithatha A.; Bauchmuller K.; Ahmad N.; Barker J.; Jackson Y.; Kibutu F.; Bird S.; Watson G.; Martin J.; Bevan E.; Wrey Brown C.; Trodd D.; English K.; Bell G.; Wilcox L.; Katary A.; Gopal S.; Lake V.; Harris N.; Metherell S.; Radford E.; Scriven J.; Moore F.; Bancroft H.; Daglish J.; Sangombe M.; Carmody M.; Rhodes J.; Bellamy M.; Garg A.; Kuravi A.; Virgilio E.; Ranga P.; Butler J.; Botfield L.; Dexter C.; Fletcher J.; Shanmugasundaram P.; Hambrook G.; Burn I.; Manso K.; Thornton D.; Tebbutt J.; Penn R.; Hulme J.; Hussain S.; Maqsood Z.; Joseph S.; Colley J.; Hayes A.; Ahmed C.; Haque R.; Clamp S.; Kumar R.; Purewal M.; Baines B.; Frise M.; Jacques N.; Coles H.; Caterson J.; Gurung Rai S.; Brunton M.; Tilney E.; Keating L.; Walden A.; Antcliffe D.; Gordon A.; Templeton M.; Rojo R.; Banach D.; Sousa Arias S.; Fernandez Z.; Coghlan P.; Williams D.; Jardine C.; Bewley J.; Sweet K.; Grimmer L.; Johnson R.; Garland Z.; Gumbrill B.; Ortiz-Ruiz de Gordoa L.; Peasgood E.; Tridente A.; Shuker K.; Greer S.; Lynch C.; Turner K.; Singh J.; Sera Howe G.; Paul P.; Gill M.; Wynter I.; Ratnam V.; Shelton S.; Naisbitt J.; Melville J.; Baruah R.; Morrison S.; McGregor A.; Mpelembue M.; Srikaran S.; Dennis C.; Sukha A.; Williams A.; Verlande M.; Holding K.; Riches K.; Downes C.; Swan C.; Rostron A.; Roy A.; Woods L.; Cornell S.; Wakinshaw F.; Creagh-Brown B.; Blackman H.; Salberg A.; Smith E.; Donlon S.; Mtuwa S.; Michalak-Glinska N.; Stone S.; Beazley C.; Pristopan V.; Nikitas N.; Lankester L.; Wells C.; Raj A.S.; Fletcher K.; Khade R.; Tsinaslanidis G.; McMahon M.; Fowler S.; Coventry T.; Stewart R.; Wren L.; Mwaura E.; Mew L.; Rose A.; Scaletta D.; Williams F.; Inweregbu K.; Nicholson A.; Lancaster N.; Cunningham M.; Daniels A.; Harrison L.; Hope S.; Jones S.; Crew A.; Wray G.; Matthews J.; Crawley R.; Carter J.; Birkinshaw I.; Ingham J.; Scott Z.; Howard K.; Joy R.; Roche S.; Purvis S.; Morrison A.; Strachan D.; Clements S.; Black K.; Parmar C.; Altabaibeh A.; Mostoles L.; Gilbert K.; Ma L.; Alvaro A.; Thomas M.; Faulkner B.; Worner R.; Hayes K.; Gendall E.; Blakemore H.; Borislavova B.; Goff E.; Vuylsteke A.; Mwaura L.; Zamikula J.; Garner L.; Mitchell A.; Mepham S.; Cagova L.; Fofano A.; Holcombe H.; Praman K.; Szakmany T.; Heron A.E.; Cherian S.; Cutler S.; Roynon-Reed A.; Randell G.; Convery K.; Stammers K.; Fottrell-Gould D.; Hudig L.; Keshetprice J.; Peters M.; O'Neill L.; Ray S.; Belfield H.; McHugh T.; Jones G.; Akinkugbe O.; Tomas A.; Abaleke E.; Beech E.; Meghari H.; Yussuf S.; Bamford A.; Hairsine B.; Dooks E.; Farquhar F.; Packham S.; Bates H.; McParland C.; Armstrong L.; Kaye C.; Allan A.; Medhora J.; Liew J.; Botello A.; Anderson F.; Cusack R.; Golding H.; Prager K.; Williams T.; Leggett S.; Golder K.; Male M.; Jones O.; Criste K.; Marani M.; Anumakonda V.; Amin V.; Karthik K.; Kausar R.; Anastasescu E.; Reid K.; Jacqui M.; Hormis A.; Walker R.; Collier D.; Duncan T.; Uriel A.; Ustianowski A.; T-Michael H.; Bruce M.; Connolly K.; Smith K.; Partridge R.; Griffin D.; McDonald M.; Muchenje N.; Martin D.; Filipe H.; Eastgate C.; Jackson C.; Gratrix A.; Foster L.; Martinson V.; Stones E.; Abernathy C.; Parkinson P.; Reed A.; Prendergast C.; Rogers P.; Woodruff M.; Shokkar R.; Kaul S.; Barron A.; Collins C.; Beavis S.; Whileman A.; Dale K.; Hawes J.; Pritchard K.; Gascoyne R.; Stevenson L.; Jha R.; Lim L.; Krishnamurthy V.; Parker R.; Turner-Bone I.; Wilding L.; Reddy A.; Whiteley S.; Wilby E.; Howcroft C.; Aspinwall A.; Charlton S.; Ogg B.; Menzies D.; Pugh R.; Allan E.; Lean R.; Davies F.; Easton J.; Qiu X.; Kumar S.; Darlington K.; Houston G.; O'Brien P.; Geary T.; Allan J.; Meikle A.; Hughes G.; Balasubramaniam M.; Latham S.; McKenna E.; Flanagan R.; Sathe S.; Davies E.; Roche L.; Chablani M.; Kirkby A.; Netherton K.; Archer S.; Yates B.; Ashbrook-Raby C.; Cole S.; Cabrelli L.; Chapman S.; Casey M.; Austin P.; Hutcheon A.; Whyte C.; Almaden-Boyle C.; Pattison N.; Cruz C.; Vochin A.; Kent H.; Murdoch S.; David B.; Penacerrada M.; Lubimbi G.; Bastion V.; Wulandari R.; Valentine J.; Clarke D.; Serrano-Ruiz A.; Hierons S.; Ramos L.; Demetriou C.; Mitchard S.; White K.; White N.; Pitts S.; Branney D.; Frankham J.; Watters M.; Langton H.; Prout R.; Page V.; Varghes T.; Kay A.; Potts K.; Birt M.; Kent M.; Wilkinson A.; Jude E.; Turner V.; Savill H.; McCormick J.; Clark M.; Coulding M.; Siddiqui S.; Mercer O.; Rehman H.; Potla D.; *Capps N.; *Donaldson D.; *Jones J.; *Button H.; *Martin T.; *Hard K.; *Agasou A.; *Tonks L.; *Arden T.; *Boyle P.; *Carnahan M.; Strickley J.; Adams C.; Childs D.; *Rikunenko R.; *Leigh M.; *Breekes M.; *Wilcox R.; *Bowes A.; *Tiveran H.; *Hurford F.; *Summers J.; *Carter A.; *Hussain Y.; *Ting L.; *Javaid A.; *Motherwell N.; *Moore H.; *Millward H.; *Jose S.; *Schunki N.; *Noakes A.; *Clulow C.; Sadera G.; Jacob R.; Jones C.; Blunt M.; Coton Z.; Curgenven H.; Mohamed Ally S.; Beaumont K.; Elsaadany M.; Fernandes K.; Ali Mohamed Ali I.; Rangarajan H.; Sarathy V.; Selvanayagam S.; Vedage D.; White M.; Smith M.; Truman N.; Chukkambotla S.; Keith S.; Cockerill-Taylor J.; Ryan-Smith J.; Bolton R.; Springle P.; Dykes J.; Thomas J.; Khan M.; Hijazi M.T.; Massey E.; Croston G.; Reschreiter H.; Camsooksai J.; Patch S.; Jenkins S.; Humphrey C.; Wadams B.; Bhatia N.; Msiska M.; Adanini O.; Attwood B.; Parsons P.; Tatham K.; Jhanji S.; Black E.; Dela Rosa A.; Howle R.; Thomas B.; Bemand T.; Raobaikady R.; Saha R.; Staines N.; Daniel A.; Finn J.; Hutter J.; Doble P.; Shovelton C.; Pawley C.; Kannan T.; Hill M.; Combes E.; Monnery S.; Joefield T.; Popescu M.; Thankachen M.; Oblak M.; Little J.; McIvor S.; Brady A.; Whittle H.; Prady H.; Chan R.; Ahmed A.; Morris A.; Gibson C.; Gordon E.; Keenan S.; Quinn H.; Benyon S.; Marriott S.; Zitter L.; Park L.; Baines K.; Lyons M.; Holland M.; Keenan N.; Young M.; Garrioch S.; Dawson J.; Tolson M.; Scholefield B.; Bi R.; Richardson N.; Schumacher N.; Cosier T.; Millen G.; Higham A.; Simpson K.; Turki S.; Allen L.; Crisp N.; Hazleton T.; Knight A.; Deery J.; Price C.; Turney S.; Tilbey S.; Beranova E.; Wright D.; Georg L.; Twiss S.; Cowton A.; Wadd S.; Postlethwaite K.; Gondo P.; Masunda B.; Kayani A.; Hadebe B.; Whiteside J.; Campbell R.; Clarke N.; Donnison P.; Trim F.; Leadbitter I.; O'Sullivan S.; Purewal B.; Bell S.; Rivers V.; O'Leary R.; Collins E.; Anderson S.; Hammerton K.; Andrews E.; Burns K.; Edmond I.; Salutous D.; Todd A.; Donnachie J.; Turner P.; Prentice L.; Symon L.; Runciman N.; Auld F.; Halkes M.; Mercer P.; Thornton L.; Debreceni G.; Wilkins J.; Crickmore V.; Subramanian G.; Marshall R.; Jennings C.; Latif M.; Bunni L.; Spivey M.; Bean S.; Burt K.; Linnett V.; Ritzema J.; Sanderson A.; Bokhari M.; Kapoor R.; Loader D.; Ayers A.; Harrison W.; North J.; Belagodu Z.; Parasomthy R.; Olufuwa O.; Gherman A.; Fuller B.; Stuart C.; Kelsall O.; Davis C.; Wild L.; Wood H.; Thrush J.; Durie A.; Austin K.; Archer K.; Anderson P.; Vigurs C.; Thorpe C.; Thomas A.; Knights E.; Boyle N.; Price A.; Kubisz-Pudelko A.; Wood D.; Lewis A.; Board S.; Pippard L.; Perry J.; Beesley K.; Rattray A.; Lee E.; Lennon L.; Douglas K.; Bell D.; Boyle R.; Nauman Akhtar M.; Dent K.; Potoczna D.; Pearson S.; Horsley E.; Spencer S.; Phillips C.; Mullan D.; Skinner D.; Gaylard J.; Ortiz-Ruizdegordoa L.; Barber R.; Hewitt C.; Hilldrith A.; Shepardson S.; Wills M.; Jackson-Lawrence K.; Gupta A.; Easthope A.; Timlick E.; Gorman C.; Otaha I.; Gales A.; Coetzee S.; Raj M.; Peiu M.; Parris V.; Quaid S.; Watson E.; Elliott K.; Mallinson J.; Chandler B.; Turnbull A.; Quinn A.; Finch C.; Holl C.; Cooper J.; Evans A.; Collins A.; Treus Gude E.; Love N.; van Koutrik L.; Hunt J.; Kaye D.; Fisher E.; Brayne A.; Tuckey V.; Jackson P.; Parkin J.; Brealey D.; Raith E.; Tariq A.; Houlden H.; Tucci A.; Hardy J.; Moncur E.; Highgate J.; Cowley A.; Mitra A.; Stead R.; Behan T.; Burnett C.; Newton M.; Heeney E.; Pollard R.; Hatton J.; Patel A.; Kasipandian V.; Allibone S.; Genetu R.M.; Otahal I.; O'Brien L.; Omar Z.; Perkins E.; Davies K.; Tetla D.; Pothecary C.; Deacon B.; Shelley B.; Irvine V.; Williams S.; Williams P.; Birch J.; Goodsell J.; Tutton R.; Bough L.; Winter-Goodwin B.; Kitson R.; Pinnell J.; Wilson A.; Nortcliffe T.; Wood T.; Home M.; Holdroyd K.; Robinson M.; Shaw R.; Greig J.; Brady M.; Haigh A.; Matupe L.; Usher M.; Mellor S.; Dale S.; Gledhill L.; Shaw L.; Turner G.; Kelly D.; Anwar B.; Riley H.; Sturgeon H.; Ali A.; Thomis L.; Melia D.; Dance A.; Hanson K.; Humphreys S.; Frost I.; Gopal V.; Godden J.; Holden A.; Swann S.; Clapham M.; Poultney U.; Harper R.; Rice P.; Khaliq W.; Reece-Anthony R.; Gurung B.; Moultrie S.; Odam M.; Mayer A.; Bellini A.; Pickard A.; Bryant J.; Roe N.; Sowter J.; Butcher D.; Lang K.; Taylor J.; Barry P.; Hobrok M.; Tench H.; Wolf-Roberts R.; McGuinness H.; Loosley R.; Hawcutt D.; Rad L.; O'Malley L.; Saunderson P.; Seddon G.; Anderson T.; Rogers N.; Ruddy J.; Harkins M.; Taylor M.; Beith C.; McAlpine A.; Ferguson L.; Grant P.; MacFadyen S.; McLaughlin M.; Baird T.; Rundell S.; Glass L.; Welsh B.; Hamill R.; Fisher F.; Smith T.; Gregory J.; Brown A.; Rolker S.; Nothen M.M.; Fazaal J.; Keitel V.; Jensen B.; Feldt T.; Knopp L.; Schroder J.; Maj C.; Brand F.; Berger M.M.; Brenner T.; Hinney A.; Witzke O.; Bals R.; Herr C.; Ludwig N.; Walter J.; Schneider J.; Erber J.; Spinner C.D.; Wendtner C.M.; Winter C.; Protzer U.; Casadei N.; Ossowski S.; Motameny S.; Riess O.H.; Kwasniewski M.; Korotko U.; Chwialkowska K.; Niemira M.; Jaroszewicz J.; Sobala-Szczygiel B.; Puzanowska B.; Parfieniuk-Kowerda A.; Martonik D.; Moniuszko-Malinowska A.; Pancewicz S.; Zarebska-Michaluk D.; Simon K.; Pazgan-Simon M.; Mozer-Lisewska I.; Bura M.; Adamek A.; Tomasiewicz K.; Pawlowska M.; Piekarska A.; Berkan-Kawinska A.; Horban A.; Kowalska J.; Podlasin R.; Wasilewski P.; Azzadin A.; Czuczwar M.; Czaban S.; Olszewski P.; Bogocz J.; Ochab M.; Kruk A.; Uszok S.; Bielska A.; Szalkowska A.; Raczkowska J.; Sokolowska G.; Chorostowska-Wynimko J.; Jezela-Stanek A.; Rozy A.; Lechowicz U.; Polowianiuk U.; Grubczak K.; Starosz A.; Eljaszewicz A.; Izdebska W.; Kretowski A.; Flisiak R.; Moniuszko M.; Abedalthagafi M.; Alaamery M.; Massadeh S.; Fawzy M.; AlBardis H.; Aljawini N.; Alsuwailm M.; Almalki F.; Mangul S.; Jung J.; Mbarek H.; Saad C.; Al-Sarraj Y.; Al-Muftah W.; Badji R.; Thani A.A.; Ismail S.I.;

Citation:
Human Genetics. 2022, Vol 141(1) (pp 147-173)

Abstract:
The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene. An ensemble of LASSO logistic regression models was used to identify the most informative Boolean features with respect to the genetic bases of severity. The Boolean features selected by these logistic models were combined into an Integrated PolyGenic Score that offers a synthetic and interpretable index for describing the contribution of host genetics in COVID-19 severity, as demonstrated through testing in several independent cohorts. Selected features belong to ultra-rare, rare, low-frequency, and common variants, including those in linkage disequilibrium with known GWAS loci. Noteworthily, around one quarter of the selected genes are sex-specific. Pathway analysis of the selected genes associated with COVID-19 severity reflected the multi-organ nature of the disease. The proposed model might provide useful information for developing diagnostics and therapeutics, while also being able to guide bedside disease management.

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Learning curves in minimally invasive pancreatic surgery: a systematic review (2022)

Type of publication:Systematic Review

Author(s):Fung, Gayle; Sha, Menazir; Kunduzi, Basir; Froghi, Farid; *Rehman, Saad; Froghi, Saied

Citation:
Langenbeck's Archives of Surgery. 407(6) (pp 2217-2232), 2022. Date of Publication: September 2022.

Abstract:BACKGROUND The learning curve of new surgical procedures has implications for the education, evaluation and subsequent adoption. There is currently no standardised surgical training for those willing to make their first attempts at minimally invasive pancreatic surgery. This study aims to ascertain the learning curve in minimally invasive pancreatic surgery.
METHODS A systematic search of PubMed, Embase and Web of Science was performed up to March 2021. Studies investigating the number of cases needed to achieve author-declared competency in minimally invasive pancreatic surgery were included.
RESULTS In total, 31 original studies fulfilled the inclusion criteria with 2682 patient outcomes being analysed. From these studies, the median learning curve for distal pancreatectomy was reported to have been achieved in 17 cases (10-30) and 23.5 cases (7-40) for laparoscopic and robotic approach respectively. The median learning curve for pancreaticoduodenectomy was reported to have been achieved at 30 cases (4-60) and 36.5 cases (20-80) for a laparoscopic and robotic approach respectively. Mean operative times and estimated blood loss improved in all four surgical procedural groups. Heterogeneity was demonstrated when factoring in the level of surgeon's experience and patient's demographic.
CONCLUSIONS There is currently no gold standard in the evaluation of a learning curve. As a result, derivations are difficult to utilise clinically. Existing literature can serve as a guide for current trainees. More work needs to be done to standardise learning curve assessment in a patient-centred manner.

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Mapping the human genetic architecture of COVID-19 (2021)

Type of publication:Journal article

Author(s):

COVID-19 Host Genetics Initiative. Includes James Moon, Nigel Capps, Sanal Jose, Colene Adams, Anita Agasou, Amy Bowes, Pauline Boyle, Mandy Carnahan, Anne Carter, Danielle Childs, Kelly Hard, Yasmin Hussain, Michael Leigh, Rachel Rikunenko, Jo Stickley, Helen Tivenan, Rebecca Wilcox, Tracie Arden, Mandy Beekes, Heather Button, Denise Donaldson, Fran Hurford, Ayesha Javaid, James Jones, Terry Martin, Helen Millward, Nichola Motherwell, Julie Summers, Louise Ting & Louise Tonks of Shrewsbury and Telford Hospital NHS Trust

Citation:Nature. 2021, Vol. 600(7889) (pp 472-477)

Abstract:The genetic make-up of an individual contributes to the susceptibility and response to viral infection. Although environmental, clinical and social factors have a role in the chance of exposure to SARS-CoV-2 and the severity of COVID-19<sup>1,2</sup>, host genetics may also be important. Identifying host-specific genetic factors may reveal biological mechanisms of therapeutic relevance and clarify causal relationships of modifiable environmental risk factors for SARS-CoV-2 infection and outcomes. We formed a global network of researchers to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity. Here we describe the results of three genome-wide association meta-analyses that consist of up to 49,562 patients with COVID-19 from 46 studies across 19 countries. We report 13 genome-wide significant loci that are associated with SARS-CoV-2 infection or severe manifestations of COVID-19. Several of these loci correspond to previously documented associations to lung or autoimmune and inflammatory diseases<sup>3-7</sup>. They also represent potentially actionable mechanisms in response to infection. Mendelian randomization analyses support a causal role for smoking and body-mass index for severe COVID-19 although not for type II diabetes. The identification of novel host genetic factors associated with COVID-19 was made possible by the community of human genetics researchers coming together to prioritize the sharing of data, results, resources and analytical frameworks. This working model of international collaboration underscores what is possible for future genetic discoveries in emerging pandemics, or indeed for any complex human disease.

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