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Contains fulltext : 288037.pdf (Publisher’s version ) (Closed access) BACKGROUND: The effects that therapies for inflammatory bowel disease (IBD) have on immune responses to SARS-CoV-2 vaccination are not yet fully known. Therefore, we sought to determine whether COVID-19 vaccine-induced antibody responses were altered in patients with IBD on commonly used immunosuppressive drugs. METHODS: In this multicentre, prospective, case-control study (VIP), we recruited adults with IBD treated with one of six different immunosuppressive treatment regimens (thiopurines, infliximab, a thiopurine plus infliximab, ustekinumab, vedolizumab, or tofacitinib) and healthy control participants from nine centres in the UK. Eligible participants were aged 18 years or older and had received two doses of COVID-19 vaccines (either ChAdOx1 nCoV-19 [Oxford-AstraZeneca], BNT162b2 [Pfizer-BioNTech], or mRNA1273 [Moderna]) 6-12 weeks apart (according to scheduling adopted in the UK). We measured antibody responses 53-92 days after a second vaccine dose using the Roche Elecsys Anti-SARS-CoV-2 spike electrochemiluminescence immunoassay. The primary outcome was anti-SARS-CoV-2 spike protein antibody concentrations in participants without previous SARS-CoV-2 infection, adjusted by age and vaccine type, and was analysed by use of multivariable linear regression models. This study is registered in the ISRCTN Registry, ISRCTN13495664, and is ongoing. FINDINGS: Between May 31 and Nov 24, 2021, we recruited 483 participants, including patients with IBD being treated with thiopurines (n=78), infliximab (n=63), a thiopurine plus infliximab (n=72), ustekinumab (n=57), vedolizumab (n=62), or tofacitinib (n=30), and 121 healthy controls. We included 370 participants without evidence of previous infection in our primary analysis. Geometric mean anti-SARS-CoV-2 spike protein antibody concentrations were significantly lower in patients treated with infliximab (156·8 U/mL [geometric SD 5·7]; p

Summary Background There is a paucity of evidence to support safe and effective management of patients with acute severe ulcerative colitis during the COVID-19 pandemic. We sought to identify alterations to established conventional evidence-based management of acute severe ulcerative colitis during the early COVID-19 pandemic, the effect on outcomes, and any associations with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and severe COVID-19 outcomes. Methods The PROTECT-ASUC study was a multicentre, observational, case-control study in 60 acute secondary care hospitals throughout the UK. We included adults (≥18 years) with either ulcerative colitis or inflammatory bowel disease unclassified, who presented with acute severe ulcerative colitis and fulfilled the Truelove and Witts criteria. Cases and controls were identified as either admitted or managed in emergency ambulatory care settings between March 1, 2020, and June 30, 2020 (COVID-19 pandemic period cohort), or between Jan 1, 2019, and June 30, 2019 (historical control cohort), respectively. The primary outcome was the proportion of patients with acute severe ulcerative colitis receiving rescue therapy (including primary induction) or colectomy. The study is registered with ClinicalTrials.gov , NCT04411784 . Findings We included 782 patients (398 in the pandemic period cohort and 384 in the historical control cohort) who met the Truelove and Witts criteria for acute severe ulcerative colitis. The proportion of patients receiving rescue therapy (including primary induction) or surgery was higher during the pandemic period than in the historical period (217 [55%] of 393 patients vs 159 [42%] of 380 patients; p=0·00024) and the time to rescue therapy was shorter in the pandemic cohort than in the historical cohort (p=0·0026). This difference was driven by a greater use of rescue and primary induction therapies with biologicals, ciclosporin, or tofacitinib in the COVID-19 pandemic period cohort than in the historical control period cohort (177 [46%] of 387 patients in the COVID-19 cohort vs 134 [36%] of 373 patients in the historical cohort; p=0·0064). During the pandemic, more patients received ambulatory (outpatient) intravenous steroids (51 [13%] of 385 patients vs 19 [5%] of 360 patients; p=0·00023). Fewer patients received thiopurines (29 [7%] of 398 patients vs 46 [12%] of 384; p=0·029) and 5-aminosalicylic acids (67 [17%] of 398 patients vs 98 [26%] of 384; p=0·0037) during the pandemic than in the historical control period. Colectomy rates were similar between the pandemic and historical control groups (64 [16%] of 389 vs 50 [13%] of 375; p=0·26); however, laparoscopic surgery was less frequently performed during the pandemic period (34 [53%] of 64] vs 38 [76%] of 50; p=0·018). Five (2%) of 253 patients tested positive for SARS-CoV-2 during hospital treatment. Two (2%) of 103 patients re-tested for SARS-CoV-2 during the 3-month follow-up were positive 5 days and 12 days, respectively, after discharge from index admission. Both recovered without serious outcomes. Interpretation The COVID-19 pandemic altered practice patterns of gastroenterologists and colorectal surgeons in the management of acute severe ulcerative colitis but was associated with similar outcomes to a historical cohort. Despite continued use of high-dose corticosteroids and biologicals, the incidence of COVID-19 within 3 months was low and not associated with adverse COVID-19 outcomes. Funding None.

Posterolateral corner injuries are complex injuries, and their therapeutic management varies from one individual to another. Biomechanical studies demonstrate that anatomic posterolateral corner reconstruction restores knee kinematics better than nonanatomic reconstruction. The purpose of this report is to describe an all-arthroscopic procedure for anatomic posterolateral corner reconstruction.

To determine (1) the demographic characteristics as well as radiographic findings of medial versus lateral meniscal root tears at time of presentation, (2) treatment decisions and clinical outcomes of patients undergoing medial versus lateral root repair, and (3) risk factors for worse clinical and radiographic outcomes.A retrospective review was performed to identify patients with symptomatic, medial, or lateral meniscus posterior root tears with a minimum 2-year follow-up. Radiographs were graded using Kellgren-Lawrence scores. Subanalysis was performed on 62 patients who underwent root repair. Tegner, Lysholm, International Knee Documentation Committee scores, and progression to arthroplasty were analyzed in the repair groups. Patient demographics, radiographic findings, and clinical outcomes were compared between medial meniscus posterior horn root tear (MMRT) and lateral meniscus root repair (LMRT).Of the 141 root tears, 109 were MMRTs, 30 were LMRTs, and 2 patients had both. At the time of injury, patients with MMRTs had a significantly higher age (MMRT = 51.4 vs LMRT=24.6, P.0001), body mass index (MMRT = 32.1 vs LMRT 25.8, P.0001), Kellgren-Lawrence score (MMRT = 1.3 vs LMRT=0.6, P.0001), and higher rate of major meniscal extrusion (MMRT = 72% vs LMRT = 20%, P.0001). Of the 30 LMRT, 30/30 (100.0%) were treated with meniscal repair. With MMRT, 52/109 (48%) were treated nonoperatively, 27/109 (25%) with partial meniscectomy, and 30/109 (27%) with meniscal repair. Sixty-two patients underwent meniscus root repair with an average 41-month follow-up. LMRT had significantly increased International Knee Documentation Committee (LMRT = 89.5, MMRT = 80.4, P = .02) and Tegner scores (LMRT = 6.5, MMRT = 5.1, P.05) compared with MMRT.Compared with MMRTs, LMRTs occur in younger male patients with lower body mass index, less cartilage degeneration, less extrusion on magnetic resonance imaging, and more commonly with a ligament injury. Although good to excellent clinical outcomes were attained in select patients for both medial and lateral meniscus root repair, LMRTs may have better results after repair, suggesting that differences in injury and patient characteristics may contribute to differences in these outcomes.Retrospective comparative study, Level III.

BACKGROUND: Anti-TNF drugs are effective treatments for the management of Crohn's disease but treatment failure is common. We aimed to identify clinical and pharmacokinetic factors that predict primary non-response at week 14 after starting treatment, non-remission at week 54, and adverse events leading to drug withdrawal. METHODS: The personalised anti-TNF therapy in Crohn's disease study (PANTS) is a prospective observational UK-wide study. We enrolled anti-TNF-naive patients (aged ≥6 years) with active luminal Crohn's disease at the time of first exposure to infliximab or adalimumab between March 7, 2013, and July 15, 2016. Patients were evaluated for 12 months or until drug withdrawal. Demographic data, smoking status, age at diagnosis, disease duration, location, and behaviour, previous medical and drug history, and previous Crohn's disease-related surgeries were recorded at baseline. At every visit, disease activity score, weight, therapy, and adverse events were recorded; drug and total anti-drug antibody concentrations were also measured. Treatment failure endpoints were primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. We used regression analyses to identify which factors were associated with treatment failure. FINDINGS:We enrolled 955 patients treated with infliximab (753 with originator; 202 with biosimilar) and 655 treated with adalimumab. Primary non-response occurred in 295 (23·8%, 95% CI 21·4-26·2) of 1241 patients who were assessable at week 14. Non-remission at week 54 occurred in 764 (63·1%, 60·3-65·8) of 1211 patients who were assessable, and adverse events curtailed treatment in 126 (7·8%, 6·6-9·2) of 1610 patients. In multivariable analysis, the only factor independently associated with primary non-response was low drug concentration at week 14 (infliximab: odds ratio 0·35 [95% CI 0·20-0·62], p=0·00038; adalimumab: 0·13 [0·06-0·28], p

Several reconstructive techniques exist to treat posterior cruciate ligament (PCL) deficiency. The purpose of this study is to report knee function and clinical stability after PCL reconstruction (PCLR) using an all-inside technique. Thirty-two patients with isolated or combined PCL injuries treated with all-inside PCLR using soft tissue allograft were included. Documented physical examination findings including ligamentous stability examination were recorded. All-inside, single-bundle PCLR demonstrated satisfactory clinical and functional outcomes comparable with previous other PCLR techniques. The advantages of this technique include bone preservation, minimizing risk of tunnel convergence, and allowing for sequential graft tensioning.

SARS-CoV-2 has caused a global health crisis and mass vaccination programmes provide the best opportunity for controlling transmission and protecting populations. Despite the impressive clinical trial results of the BNT162b2 (Pfizer/BioNTech), ChAdOx1 nCoV-19 (Oxford/AstraZeneca), and mRNA-1273 (Moderna) vaccines, important unanswered questions remain, especially in patients with pre-existing conditions. In this position statement endorsed by the British Society of Gastroenterology Inflammatory Bowel Disease (IBD) section and IBD Clinical Research Group, we consider SARS-CoV-2 vaccination strategy in patients with IBD. The risks of SARS-CoV-2 vaccination are anticipated to be very low, and we strongly support SARS-CoV-2 vaccination in patients with IBD. Based on data from previous studies with other vaccines, there are conceptual concerns that protective immune responses to SARS-CoV-2 vaccination may be diminished in some patients with IBD, such as those taking anti-TNF drugs. However, the benefits of vaccination, even in patients treated with anti-TNF drugs, are likely to outweigh these theoretical concerns. Key areas for further research are discussed, including vaccine hesitancy and its effect in the IBD community, the effect of immunosuppression on vaccine efficacy, and the search for predictive biomarkers of vaccine success.

To evaluate whether players with a history of an anterior cruciate ligament reconstruction (ACLR) before the National Football League (NFL) Combine played or started fewer games and/or participated in fewer eligible snaps compared with NFL Combine participants without a history of knee injury or surgery.We performed a retrospective review of all players who participated in the NFL Combine between 2009 and 2015 and who had a history of an ACLR. NFL Combine participants were included if they had a previous ACLR or combined anterior cruciate ligament (ACL) injury and nonoperatively managed medial collateral ligament injury. The number of games started, number of games played, draft number, overall draft pick, and snap percentage for each position were determined. The mean value of each outcome metric was compared between case and control players.We identified 110 players who had an ACL injury (n = 76) or a combined ACL and medial collateral ligament injury (n = 34). Players in the ACLR group had a significantly worse mean draft pick number (difference of 30.2, P = .002) and mean draft round (difference of 0.8, P = .019) versus controls. Compared with control players, players in the ACLR group started and played significantly fewer games in both season 1 (difference of 2.7 games started, P.001; difference of 2.7 games played, P.001) and season 2 (difference of 7.4 games started, P.001; difference of 3.0 games played, P = .003) and had a significantly lower snap percentage in both season 1 (difference of 23.1%, P.001) and season 2 (difference of 24.0%, P.001).Athletes at the NFL Combine who previously underwent an ACLR had significantly lower early-career NFL player metrics, including fewer games started, fewer games played, and a lower snap percentage, than uninjured controls. Defensive linemen, defensive backs, and linebackers were the 3 most affected positions. Players with a prior ACLR and combined meniscal-chondral pathology had significantly lower numbers of games started and games played in seasons 1 and 2 and a significantly lower season 2 snap percentage.Level III, case-control study.

Purpose (1) To determine the epidemiology, examination findings, imaging findings, and associated injuries of posterolateral corner (PLC) injuries in players participating in the National Football League (NFL) Combine and (2) to evaluate the impact of PLC injuries on performance compared with matched controls. Methods All PLC injuries identified at the NFL Combine between 2009 and 2015 were reviewed. The inclusion criteria were any player who had clinical findings or a previous surgical procedure consistent with a PLC injury and who participated in medical and performance testing at the NFL Combine. PLC injuries were identified by evaluating the side-to-side difference in lateral-compartment laxity with varus stress and reviewing magnetic resonance imaging studies. NFL performance outcomes (draft position and number of games played or started within the first 2 years) were compared with matched controls. Results Of the 2,285 players assessed at the NFL Combine, 16 (0.7%) were identified with a history of a grade II or III PLC tear and surgical management whereas 7 additional players (0.3%) had a PLC injury diagnosed on clinical examination, for 23 total PLC injuries (1%). On examination, 13 of 22 knees (59%) were shown to be stable; however, most of those managed surgically had significantly improved stability (13 of 15 stable) versus none of those managed nonsurgically (0 of 7 stable). Surgically managed PLC-injured athletes started significantly fewer games than controls (5.3 vs 10.5, P = .03); the mean draft position for players with surgically treated PLC injuries was 139.7 versus controls' mean draft position of 111.3. Of the 16 athletes treated operatively, 2 reported a PLC injury recurrence; both were managed nonoperatively. Conclusions A small percentage of players at the NFL Combine had evidence of a previous PLC injury (1%), with 0.4% having residual varus asymmetry on clinical examination. A worse overall mean draft position for isolated PLC-injured athletes versus controls was found: 132.8 versus 111.3 ( P = .02). It is recommended that the use of varus stress radiographs be considered for NFL Combine athletes to objectively determine their grade of injury. Level of Evidence Level IV, retrospective case series.

Purpose To report on the clinical and radiologic outcomes and complications after surgical treatment in National Football League (NFL) Combine athletes with a history of a scaphoid fracture. Methods The medical records of 2,285 athletes participating in the NFL Combine from 2009 to 2015 were evaluated for a history of scaphoid, hand, or wrist injury. Clinical outcomes, including grip strength, pinch test, range of motion, and presence of pain and stiffness, were recorded. Imaging studies were evaluated for the percentage of healing, fixation treatment type, hardware complications, radiographic deformity, and presence of osteoarthritis. Results Of the 2,285 athletes evaluated, 56 presented with a history of a scaphoid fracture. Most fractures were in the middle and proximal aspects of the scaphoid. Of the scaphoid fractures, 76% (43 players) were treated with screw fixation. Of the athletes, 36 (72%) had normal range of motion of the affected wrist, 52 (93%) reported no pain, and 44 (83%) reported no stiffness in the affected wrist. The grip strength and pinch strength were 91% and 96%, respectively, of the uninjured side. The fracture was healed in 75% of the cases; however, 34% had degenerative changes. Hardware complications were found in 15% of the athletes. Conclusions Good clinical outcomes can be achieved after scaphoid fractures in prospective NFL athletes. However, the rates of nonunion (25%), degenerative changes (34%), and hardware complications (15%) in this study suggest the need for close postoperative radiographic follow-up in this population of patients because their athletic demands may lead to higher rates of the aforementioned complications. Level of Evidence Level IV, retrospective study.

Posterolateral corner injuries are a severe and often unrecognized pathology. Injuries to these structures are difficult to identify using magnetic resonance images. Physical examination tests including the dial test, frog-leg test, and varus stress test can be difficult to perform. In addition it is difficult to correctly evaluate the results in a multiligament injury setting. The correct diagnosis of this pathology is essential to determine the proper treatment and improve outcomes. Furthermore, failure to recognize this pathology is associated with a high risk of failure following isolated anterior cruciate ligament reconstructions. The purpose of this Technical Note is to present an alternative method for the evaluation of posterolateral corner injuries using radiographic images.

Paste abstract here and remove the remaining text. *For structured abstracts, begin each section under a separate, bolded subheading. Suggested subheadings are below Introduction: Anterior Cruciate Ligament (ACL) tears are one of the most frequent injuries in young athletes. Given the importance of its biomechanical function in knee stability, ACL tears are treated surgically whenever there is sports activities demand. There are key factors in the ACL reconstruction such as graft choice, tunnel positioning, and graft diameter. Grafts less than 8 mm in diameter are a risk factor for re-rupture and relapse. This is especially important if hamstring grafts are used in female patients younger than 20 years old. Objectives: To describe in detail different hamstring graft preparation techniques to obtain an optimal and individualized graft according to patient´s anatomy and the ideal diameter and length for the reconstruction of the ACL. Methods: In the surgical lab, different hamstring graft preparation techniques with allografts, Endobutton femoral cortical suspension device (Smith and Nephew), FiberWire # 2 and FiberLoop # 2 (Arthrex) braided suture were prepare above the graft preparation station. Results: Different techniques of hamstring graft preparation were described in detail: Two-Strand with one tendon; Three-Strand with one tendon; Four-Strand with one and with two tendons; Five-Strand with two tendons; Six-Strand with two tendons and Eight-Strand with two tendons. Conclusion: It is essential to master the different hamstring graft preparation techniques in order to obtain an individualized graft with the appropriate diameter and length according to the patient´s anatomy, height and physical demand.

Chondral lesions of the knee can occur secondary to limb malalignment. To address these interrelated problems, a high tibial osteotomy with concomitant osteochondral allograft transfer may be performed. It is important to address these chondral lesions as they often affect the young and active population and cause morbidity in an otherwise healthy population. Although numerous approaches for the treatment of chondral lesions have been described, long-term results demonstrating regeneration of hyaline cartilage have yet to be reported. Furthermore, larger, full-thickness cartilage defects, which can be caused by limb malalignment, have proven to be particularly challenging to treat. This Technical Note details our technique for multicompartmental osteochondral allograft transplantation with concomitant high tibial osteotomy in a patient with 2 focal cartilage lesions in the knee.

A humeral avulsion of the glenohumeral ligament, or HAGL lesion, is an uncommon yet disabling shoulder injury, which leads to complaints of pain and overall inability to properly use the shoulder from patients. The diagnosis of a HAGL lesion is particularly challenging. To arrive at an accurate diagnosis, the use of a magnetic resonance arthrogram is suggested along with high clinical suspicion. A HAGL lesion may be anterior or posterior. This difference dictates the type of surgical treatment to be undertaken. Although a posterior HAGL lesion is repaired arthroscopically, an anterior HAGL lesion is treated through an open approach. The purpose of this Technical Note is to describe our preferred technique to surgically treat an anterior HAGL lesion through an open approach.

Symptomatic scapular winging resulting in scapular dyskinesia leads to a wide spectrum of clinical complaints, most notably periscapular pain. The malpositioning of the scapula, termed through use of the acronym SICK (scapular malposition, inferior-medial border prominence, coracoid pain and malposition, and dyskinesia of scapular movement), is due to the irregular activity of one or more of the periscapular muscles. In particular, the serratus anterior, innervated by the long thoracic nerve, is a key muscle that stabilizes the scapula and provides coordinated scapulohumeral rhythm. If the long thoracic nerve is injured, this results in significant shoulder dysfunction and scapular winging that may require surgical intervention. The purpose of this Technical Note is to present our preferred technique to treat symptomatic scapular winging due to long thoracic nerve palsy through transfer of the pectoralis major with its bone insertion to the inferior edge of the scapula.

Background & Aims The number of people living with previous hepatitis C infection that have attained a sustained viral response (SVR) is expected to grow rapidly. So far, the prognosis of this group relative to the general population is unclear. Methods Individuals attaining SVR in Scotland in 1996–2011 were identified using a national database. Through record-linkage, we obtained cause-specific mortality data complete to Dec 2013. We calculated standardised mortality ratios (SMRs) to compare the frequency of mortality in SVR patients to the general population. In a parallel analysis, we used Cox regression to identify modifiable patient characteristics associated with post-SVR mortality. Results We identified 1824 patients, followed on average for 5.2years after SVR. In total, 78 deaths were observed. Overall, all-cause mortality was 1.9 times more frequent for SVR patients than the general population (SMR: 1.86; 95% confidence interval (CI): 1.49–2.32). Significant cause-specific elevations were seen for death due to primary liver cancer (SMR: 23.50; 95% CI: 12.23–45.16), and death due to drug-related causes (SMR: 6.58, 95% CI: 4.15–10.45). Together these two causes accounted for 66% of the total excess death observed. All of the modifiable characteristics associated with increased mortality were markers either of heavy alcohol use or injecting drug use. Individuals without these behavioural markers (32.8% of cohort) experienced equivalent survival to the general population (SMR: 0.70; 95% CI: 0.41–1.18) Conclusions Mortality in Scottish SVR patients is higher overall than the general population. The excess was driven by death from drug-related causes and liver cancer. Health risk behaviours emerged as important modifiable determinants of mortality in this population. Lay summary Patients cured of hepatitis C through treatment had a higher mortality rate overall than the general population. Most of the surplus mortality was due to drug-related causes and death from liver cancer. A history of heavy alcohol and injecting drug use were associated with a higher mortality risk.

A. Palotie on työryhmän Int IBD Genetics Consortium jäsen. One goal of human genetics is to understand the genetic basis of disease, a challenge for diseases of complex inheritance because risk alleles are few relative to the vast set of benign variants. Risk variants are often sought by association studies in which allele frequencies in case subjects are contrasted with those from population-based samples used as control subjects. In an ideal world we would know population-level allele frequencies, releasing researchers to focus on case subjects. We argue this ideal is possible, at least theoretically, and we outline a path to achieving it in reality. If such a resource were to exist, it would yield ample savings and would facilitate the effective use of data repositories by removing administrative and technical barriers. We call this concept the Universal Control Repository Network (UNICORN), a means to perform association analyses without necessitating direct access to individual-level control data. Our approach to UNICORN uses existing genetic resources and various statistical tools to analyze these data, including hierarchical clustering with spectral analysis of ancestry; and empirical Bayesian analysis along with Gaussian spatial processes to estimate ancestry-specific allele frequencies. We demonstrate our approach using tens of thousands of control subjects from studies of Crohn disease, showing how it controls false positives, provides power similar to that achieved when all control data are directly accessible, and enhances power when control data are limiting or even imperfectly matched ancestrally. These results highlight how UNICORN can enable reliable, powerful, and convenient genetic association analyses without access to the individual-level data.

Background: Anti-tumour necrosis factor (TNF) drugs have revolutionised Crohn's disease management but treatment failure is common. We sought clinical and pharmacokinetic factors that predict and mitigate primary non-response at week 14, non-remission at week 54, and adverse events leading to drug withdrawal. Methods: We conducted a prospective observational UK-wide study in 1610 biologic naive patients with active luminal Crohn's disease (955 infliximab [753 Remicade; 202 biosimilar CT-P13] and 655 adalimumab). Findings: Primary non-response (PNR) occurred in 23·8% (95% CI 21·4%-26·2%), non-remission in 63·1% (95% CI 60·3%-65·8%), and adverse events curtailed treatment in 7·8% (95% CI 6·6%-9·2%) patients. The only independent risk factor for PNR was low drug level. The optimal week 14 drug levels associated with remission at weeks 14 and 54 were 7 mg/L and 12 mg/L for infliximab and adalimumab, respectively. Continuing standard dosing regimens after PNR was rarely helpful: only 12·4% (14/113; 95% CI 6·9%-19·9%) entered remission by week 54. Obesity, smoking, low albumin levels, higher baseline markers of disease activity, and development of anti-drug antibodies were associated with low drug levels, which mediated week 54 non-remission. Immunogenicity rates at week 54 were 62·8% (95% CI 59·0-66·3%) for infliximab and 28·5% (95% CI 24·0-32·7%) for adalimumab. For both drugs, sub-optimal week 14 drug levels were the main determinant of immunogenicity; whilst subsequent anti-drug antibody formation was the principle factor accounting for low drug levels. Combination thiopurine or methotrexate therapy mitigated this risk with similar effect sizes for both anti-TNF drugs and for infliximab led to lower week 54 non-remission rates. Interpretation: Anti-TNF treatment failure is common and associated with low drug levels, partly mediated by immunogenicity Clinical trials are required to investigate whether personalised induction regimens and treatment-to-target dose intensification improve outcomes. Funding: Charities: CORE, CCUK, C3. Unrestricted grants: Abbvie, Merck Sharp & Dohme, NAPP, Pfizer and Celltrion. Declaration of Interest: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and declare: N.A.K has consulted for Falk and received honoraria from Falk, Allergan, Pharmacosmos and Takeda for unrelated topics and is a deputy editor of Alimentary Pharmacology & Therapeutics Journal; G.A.H reports non-financial support from AbbVie, outside the submitted work; and that he is now an employee of AbbVie and owns stock in the company; M.R. is an employee of AbbVie and owns stock in the company; D.G. reports honoraria from AbbVie; G.J.W has consulted for AbbVie and received honoraria from Falk and AbbVie for unrelated topics and a fellowship from NIHR; A.H has served as consultant, advisory board member or speaker for AbbVie, Atlantic, Bristol-Myers Squibb, Celltrion, Falk, Ferring, Janssen, MSD, Napp Pharmaceuticals, Pfizer, Pharmacosmos, Shire and Takeda and also serves on the Global Steering Committee for Genentech outside the submitted work;. S.S reports personal fees from AbbVie, Merck, Takeda, grants from Takeda, Tillotts, AbbVie, Merck, outside the submitted work; P.M.I reports personal fees from Abbvie, Janssen, Pfizer, Sandoz, VH squared, Samsung Bioepis, and Ferring , grants from MSD, grants and personal fees from Takeda, non-financial support from Falk, outside the submitted work; D.McG reports grants from NIH and Helmsley Charitable Trust, during the conduct of the study; grants and personal fees from Janssen, Precision IBD Inc, Second Genome, Qu Biologics, Pfizer, Gilead and Takeda, outside the submitted work; C.W.L reports grants and personal fees from Abbvie and Gilead personal fees from GSK, Janssen, Takeda, Amgen, Pfizer, Samsung Bioepis, Celgene, grants outside the submitted work; J.R.F.C reports personal fees from Abbvie, grants and personal fees from Takeda, Hospira and Biogen, personal fees from Janssen, MSD, Celltrion, NAPP, and Sandoz, outside the submitted work; J.L has served as consultant, advisory board member or speaker for Shire (International/UK) AbbVie, Atlantic, BMS, Celltrion, Falk, Ferring (International/UK), Janssen, MSD, Napp Pharmaceuticals, Pfizer, GSK, Allergan, Cornerstone US, and Takeda and has received travel support from AbbVie, Warner Chilcot, Takeda and Pfizer outside the submitted work; R.K.R reports honoraria from Abbvie, Ferring , Therakos and Celltrion, grants from Nestec, outside the submitted work; J.R.G received honoraria from Falk, Abbvie and Shield therapeutics for unrelated topics. T.A has received unrestricted research grants, advisory board fees, speaker honorariums and support to attend international meetings from AbbVie, Merck, Janssen, Takeda, Ferring, Tillotts, Ferring, Pfizer, NAPP, Celltrion, Hospira for unrelated topics, no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work. H.G, B.H, C.B, M.H.P, T.M, A.T, R.N, 473 S.B, N.C, N.M.H, P.H, S.L, M.P, J.C.M have no conflicts of interest to declare. Ethical Approval: The South West Research Ethics committee approved the study (REC Reference: 12/SW/0323) in January 2013.

Introduction Actuellement les differentes techniques de reconstruction du point d’angle posterolateral (PAPL) sont realisees a ciel ouvert. Certains auteurs ont decrit des techniques de reconstruction sous arthroscopie d’une des 3 principales structures du PAPL tel que le ligament popliteo-fibulaire (LPF), le tendon poplite (TP) ou le ligament fibulaire collateral (FCL). D’apres la litterature aucune reconstruction arthroscopique de ces 3 structures n’est decrite dans le meme temps operatoire. Hypothese Le but de cette etude etait d’etablir une technique de reconstruction sous arthroscopie du TP, du FCL et du LPF. Materiel Huit genoux cadaveriques ont ete utilises pour reconstruire le PAPL sous arthroscopie. La realisation de voies d’abord standard anterieure et posterieure ainsi que d’une voie trans septale etait necessaire. Le demi-tendineux et le long fibulaire ont ete preleves pour reconstruire respectivement le TP et l’association FCL-LPF. La technique de reconstruction du PAPL selon Laprade a ete utilisee avec un tunnel tibial et fibulaire ainsi que deux tunnels borgnes femoraux. Resultats Les trois structures posterolaterales ont ete reconstruites sous arthroscopie pour chaque genou avec une technique reproductible et fiable. En effet, le nerf fibulaire etait sous vision arthroscopique a chaque moment de la procedure en regard de sa portion posterieure. Conclusion Le point d’angle posterolateral comprenant le TP, le LPF et le FCL peut etre reconstruit sous arthroscopie avec une complete visibilite des reperes osseux et musculo-tendineux contrairement a ciel ouvert notamment pour le tunnel tibial.

Background & Aims The global burden associated with hepatitis C virus (HCV) infection has prompted a scale-up of antiviral therapy. Hitherto, no data exist on the impact of scaling-up, on the characteristics of treated populations, or on sustained viral response (SVR) rates. We assessed the country-wide scale-up of antiviral therapy in Scotland, a country which nationally monitors uptake of and response to HCV treatment. Methods Data for patients, initiated on combined pegylated interferon and ribavirin therapy at 13 specialist HCV clinics in 2001–2010, were extracted from the Scottish HCV Clinical Database (n=3895). Patient characteristics included age, genotype, PWID (people who inject drugs) status, prison referral, and diagnosed cirrhosis. Temporal trends in covariates and adjusted effects on a SVR were examined via mixed-effects regression. Results The number of patients starting treatment increased from 237 in 2001–2002 to 1560 in 2009–2010, with an increasing trend in SVR from 44% to 57% over this period. For a given clinic, between 2001/2 and 2010 there was a decrease in the odds of those treated being diagnosed with cirrhosis (odds ratio [OR]=0.84 per year), and increasing temporal trends for those treated being PWID (OR=1.08) and prison referrals (OR=1.06). Adjusting for covariates, the proportion of a given clinic's patients achieving SVR was positively associated with the percentage of PWID (OR=1.01 per percent increase; 95% confidence interval [CI]: 1.00–1.02) and genotype 2/3 (OR=1.03; 95% CI: 1.02–1.04). Conclusions Despite changes in patient characteristics, a country-wide scale-up of antiviral therapy did not compromise SVR rates. Results are highly relevant to countries planning on scaling-up treatment, given the forthcoming availability of new interferon-free therapies.

Introduction Malgre la proximite des elements vasculo-nerveux, l’arthroscopie du compartiment posterieur du genou a rapidement evoluee ces dernieres annees. Actuellement, aucune approche sous arthroscopie de point d’angle posterolateral du genou n’est decrite. But de l’etude Le but de cette etude etait de decrire une technique d’arthroscopie permettant d’exposer le tendon poplite (TP), la partie posterieure de la tete fibulaire, le ligament collateral fibulaire (LCF), le ligament popliteo-fibulaire (LPF), le biceps femoral (BF) et le nerf fibulaire. Methode Huit genoux cadaveriques ont ete disseque sous arthroscopie en utilisant des voies d’abord anterieures et posterieures classiques. L’utilisation d’une voie trans septale etait obligatoire. Le TP, la partie postero-mediale de la tete fibulaire, le LCF, le LPF, le BF et le nerf fibulaire devaient etre identifies et exposes. Resultats Chaque structure du PLC a pu etre individualisee et exposee sous arthroscopie pour tous les genoux cadaveriques. Le FCL et le TP ont egalement ete exposes au niveau de leur insertion femorale. Conclusion Cette technique d’approche athroscopique permet d’identifier les principales structures du PLC necessitant le plus souvent une reconstruction en cas de lesions du point d’angle posterolateral. Cette approche pourrait mener a une reconstruction arthroscopique du point d’angle posterolateral.

In the past decade, there have been fundamental advances in our understanding of genetic factors that contribute to the inflammatory bowel diseases (IBDs) Crohn’s disease and ulcerative colitis. The latest international collaborative studies have brought the number of IBD susceptibility gene loci to 163. However, genetic factors account for only a portion of overall disease variance, indicating a need to better explore gene-environment interactions in the development of IBD. Epigenetic factors can mediate interactions between the environment and the genome; their study could provide new insight into the pathogenesis of IBD. We review recent progress in identification of genetic factors associated with IBD and discuss epigenetic mechanisms that could affect development and progression of IBD.

Introduction Thiopurines are commonly used in the maintenance treatment of inflammatory bowel disease (IBD) but this is limited by myelosuppression in 7% of patients.1 Thiopurine S-methyltransferase (TPMT) variants only explain 20% of thiopurine-induced myelosuppression (TIM) in Europeans suggesting the presence of other genetic determinants.2 We aimed to identify the clinical features of TIM and to identify novel variants associated with TIM through a genome wide association study and whole exome sequencing. Method We recruited 491 IBD patients with TIM from 82 hospitals. Inclusion criteria included drug exposure in the 7 days prior to TIM, white blood cell count ≤2.5 ×109/L, or neutrophil count ≤1.0 ×109/L and that TIM necessitated dose reduction/drug withdrawal. After expert adjudication, 329 cases assigned a high likelihood of causality were genotyped and exome sequenced with 635 thiopurine-tolerant IBD controls for use in the final analyses. Results We first confirmed an association of TIM with TPMT in an initial GWAS. We then, using exome sequencing, discovered a novel 6 bp in-frame deletion (rs746071566; AGGAGTC/A,p.Gly17_Val18del) at position 48611918 of chromosome 13 in exon 1 of NUDT15 (5.8% cases, 0.2% controls, OR=38.2,p=1.33×10-8). This deletion was replicated in an independent cohort (3/75 [4%] cases vs. 2/785 [0.3%] thiopurine-tolerant IBD controls; OR=16.2, p=0.006). All NUDT15 coding variants were confirmed with complete concordance by Sanger sequencing. Multivariable logistic regression demonstrated that adjusted dose (OR 2.2,p=9.4×10-11), NUDT15 genotype (OR 21.7,p=2.0×10-8) and TPMT genotype (OR 2.2,p=2.6×10-4 for MUT/WT and OR 51.2,p=1.8×10-4 for MUT/MUT) were independently associated with TIM. Conclusion These are the largest ever clinical and genetic analyses of thiopurine-induced myelosuppression. We identified NUDT15 coding variants, including a novel 6 bp deletion; carriage of any coding variant confers a 22-fold increase in the odds of TIM, independent of TMPT genotype and thiopurine dose. Although NUDT15 variants are less common than TPMT variants, their effect size for heterozygotes is greater. The number of patients needed to genotype to prevent TIM due to NUDT15 coding variant heterozygosity is 100. The estimated absolute risk of TIM in NUDT15 heterozygotes is 59%. A future clinical decision tool incorporating NUDT15 and TPMT genotypes will offer personalised thiopurine therapy and prevent the considerable morbidity and costs associated with severe bone marrow toxicity. Reference . Gisbert JP & Gomollon F.doi10.1111/j.1572-0241.2008.01848.x (2008) . Yang SK et al. doi10.1038/ng.3060 (2014) Disclosure of Interest None Declared

Background Exploring DNA methylation in inflammatory bowel disease might provide an insight into the complex gene–environment interactions in disease pathogenesis. Our study aimed to characterise disease-associated methylation changes in newly diagnosed inflammatory bowel disease and explore its association with germline variation and gene expression. Methods Samples were obtained from new onset inflammatory bowel disease in six European centres (IBD-Character project). Genome-wide methylation was measured (450k platform, Illumina, San Diego, CA, USA) in 641 whole blood DNA samples (298 controls, 150 Crohn's disease, 167 ulcerative colitis, 26 inflammatory bowel disease unclassified). Genotyping and gene expression were performed using HumanOmniExpressExome-8 BeadChips (Illumina) and Ion AmpliSeq (ThermoFisher, Waltham, MA, USA) platforms, respectively. Correlation and pathway analyses were performed between the top differentially methylated regions and gene expression. Findings M195 probes exhibited Holm-significant inflammatory bowel disease-associated methylation differences, including MIR21 (p=3·7 × 10 − 20 ) and RPS6KA2 (p=1·1 × 10 −19 ) with only one probe differentiating Crohn's disease from ulcerative colitis ( NAV2 , p=6·82 × 10 −8 ). Paired genetic and methylation data showed 1037 significant methylation quantitative trait loci indicating a genetic influence on several key loci: RPS6KA2 (p=8·6 × 10 −34 ) and MIR21 (rs8078424, p=4·4 × 10 − 25 ; rs10853015, p=7·4 × 10 −21 ). 1543 differentially methylated regions (DMRs) were identified and included MIR21 , RPS6KA2 , and TNF . These DMRs mapped to 8214 mRNA profiles of which 1916 showed Holm-significant correlation with methylation such as IL32 (seven probes: r =–0·50 to −0·66, p=6·0 × 10 −76 ). GO term analyses of these highly correlated genes revealed pathways that regulate cell–cell adhesion and immune cell differentiation. Interpretation Our data provide a comprehensive multicentre genome-wide profile of the circulating methylome and give an insight into the complex interplay between differential methylation, germline variation, and gene expression in immune mediated disease. Funding RK and AA are funded by IBD-Character (a European Union 7th Framework Programme project).

The humoral response to DNA vaccination of mice with two important Fasciola antigens has been investigated. Both F. gigantica fatty acid binding protein (FABP) and F. hepatica cathepsin L5 (FhCatL5) were shown to be expressed in COS 7 cells and induced a humoral response when delivered as secretory constructs in mice. FABP induced an IgGl dominant response, with significant IgE, IgG2a, and IgG2b responses also present, indicating a mixed Th1/Th2 response. The total Ig response peaked at 1:24,500 and antibody titers were sustained for at least 32 weeks. In contrast, the delivery of FABP as a nonsecreted construct did not result in the induction of a measurable humoral response. FhCatL5 was delivered as a secretory construct, with secretion mediated by the native F. hepatica signal sequence, which was shown to operate in COS 7 cells. The humoral response peaked at 1:2000 at week 8 and was sustained for at least 20 weeks. Antibody isotype analysis demonstrated a Th2-like response, which was qualitatively different from that obtained for FABP with an IgE dominant response, and lower titers to IgG1 and IgG3. The results demonstrate that Fasciola antigens can be delivered as DNA vaccines, but that the quality of the response varies between antigens and is influenced by the method of vaccine delivery.

Introduction Advances in protein profiling using proximity extension assays (PEA) have transformed our ability to compare concentrations of multiple proteins across biological samples. PEA utilises the specificity of antibody proximity and the sensitivity of polymerase chain reaction (qPCR) to detect proteins of interest. As part of the EC funded IBD Character initiative to discover biomarkers for clinical use using multiomic technologies, we performed high-throughput prospective case-control serum profiling to identify protein biomarkers that can predict Inflammatory Bowel Disease (IBD). Method Utilising Proseek Multiplex panels (Olink Bioscience, Sweden), serum profiling was performed in patients with a new diagnosis of IBD. Our control group consisted of symptomatic individuals. Phenotypic data was captured including age, sex, diagnosis and IBD medications. Statistical analysis was performed using R. Data were normalised and then batch corrected using ComBAT. Linear models were created for each protein including age and sex as covariates. After quality control, data from 186 proteins was available for analysis. Results A total of 245 patient serum samples (n = 153) newly diagnosed IBD, n = 92 symptomatic controls) from 4 IBD centres from Norway, United Kingdom and Sweden were included in the study from December 2012 to June 2014. 70 had Crohn’s disease (CD), 70 ulcerative colitis (UC) and 13 Inflammatory Bowel Disease Unclassified (IBDU). The mean age of the entire cohort was 33 years (range 0–79 years) and 54% were female. Multivariable analysis identified a set of 48 protein markers that were significantly associated with IBD. The 5 most significant protein markers were MMP-12 (Holm-adjusted p = 3.3 × 10 –13 ), OSM (p = 2.4 × 10 –12 ), CXCL9 (p = 1.7 × 10 –9 ), MMP10 (p = 1.7 × 10 –9 ) and EGFR (p = 1.8 × 10 –9 ). Of these five, all except EGFR were upregulated in IBD. The top 2 markers, MMP-12 and OSM were able to discriminate IBD from controls with an area under the receiver operator characteristics curve of 0.81 and 0.75 respectively. Using linear discriminant analysis, a combined biomarker consisting of MMP-12 and OSM was able to discriminate IBD from controls with a sensitivity and specificity of 80% and 72% respectively. Conclusion We have identified serum biomarkers that can predict IBD. These data demonstrate a potential for a PEA multiplex technology in IBD diagnostics and its ability to identify novel proteins that may be relevant in disease pathogenesis. Disclosure of interest R. Kalla Grant/Research Support from: IBD Character, N. Kennedy Grant/Research Support from: Wellcome Trust, Conflict with: Abbvie, MSD, Warner Chilcott, Ferring speaker fees, F. Hjelm: None Declared, E. Modig: None Declared, M. Sundell: None Declared, J. Soderholm: None Declared, B. Andreassen: None Declared, D. Bergemalm: None Declared, N. Ventham Grant/Research Support from: IBD BIOM, H. Hjortswang: None Declared, R. Petr: None Declared, M. Vatn: None Declared, J. Halfvarson: None Declared, M. Gullberg: None Declared, J. Satsangi Grant/Research Support from: EC Grants, Wellcome, CSO, MRC, Consultant for: Takeda, Conflict with: MSD speaker fees.

Introduction Rutgeerts9 score is widely used for the assessment of endoscopic recurrence following ileocaecal (IC) resection for Crohn–s disease (CD). Higher scores have been shown to be associated with an increased risk of clinical recurrence. TOPPIC is a double-blind randomised, placebo-controlled trial of mercaptopurine for the prevention of post-operative recurrence after IC resection for CD and includes a secondary endpoint of endoscopic recurrence. Few published data are available on interobserver agreement of Rutgeerts9 score. This study aimed to assess the interobserver agreement of Rutgeerts9 score on images from endoscopies carried out as part of the TOPPIC trial. Method Five TOPPIC trial investigators were shown endoscopic images taken from 43 colonoscopies performed in Edinburgh as part of the TOPPIC trial. The investigators were blinded to the original report and were shown only the images with a description of the anatomical location from which each image was taken. Each investigator was independently asked to score each colonoscopy using the Rutgeerts9 score and a custom-designed application. Statistical analysis was performed using R and the psych package. The five scores for each colonoscopy were compared with each other and the score made by the original endoscopist. Shrout and Fleiss9 intraclass correlation and pairwise weighted Cohen–s kappa were calculated. Results The original scores for the colonoscopies were spread across the possible scores, with 11 i0, 10 i1, 7 i2, 10 i3 and 5 i4. Intraclass correlation for single ratings (ICC3) was 0.82 (95% confidence interval 0.74–0.88). The weighted Cohen–s kappa when assessed for each possible pair of scorers ranged from 0.72 to 0.86. A graphical representation of the agreement between the original score and the rescores is shown in the Figure 1. When scores were stratified into endoscopic recurrence or not, as defined by a score of i2 or greater, all five scorers agreed with the original score in 34/43 (79%). There was no significant difference in this agreement between those procedures with an original score ≥i2 or Conclusion Interobserver agreement for Rutgeerts9 score of endoscopic recurrence was generally good in this cohort of patients. Despite the limitation of using still images, agreement with the score of the original endoscopistwas also good. However, there was some variation in assessment, even when assessing the presence/absence of endoscopic recurrence. These findings are important when considering the reliability of outcome data in multicentre clinical trials. Disclosure of interest None Declared.

Background: Although endoscopy is the gold standard for the assessment of activity in Crohn's disease (CD), it should be integrated with clinical, laboratory, and radiological data. In particular, it is still unclear when MRI should be performed. Aim: To evaluate the advantages and limitations of endoscopy and MRI to assess disease activity and severity in a series of CD patients. Material and methods: 50 consecutive patients with endoscopically provenCD underwentMRI enterography for the staging at diagnosis or follow-up. Endoscopic activity was measured by SES-CD (range 0-40) with active mild,moderate ad severe disease defined as a scores 4-10,11-19 and >20 respectively. MRI activity was measured by a validated quantitative score which integrates both mural and extramural involvement (Magnetic Resonance Enterography global score,MEGS,range 0-296), with active disease present for a ≥ 1 score. CDAI, CRP and fecal calprotectin (FC) were measured in all participants (positivity cut-off respectively >0,50 mg/dl and >150 μg/gr). Results: We enrolled 20 males and 30 females (diagnosis in 62%, follow-up in 38%), mean age 38±15 years,mean disease duration 5,4±5 years. SES-CD and MEGS were well correlated (r=0,42, p=0.001); both SESCD andMEGS show correlation with clinical (CDAI r=0,51,r=0,59, p