Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis

Objective Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications. Design We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes. Results We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07x10(-9)). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells. Conclusion We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.Peer reviewe

Patient Age, Sex, and Inflammatory Bowel Disease Phenotype Associate With Course of Primary Sclerosing Cholangitis

BACKGROUND & AIMS: Primary sclerosing cholangitis (PSC) is an orphan hepatobiliary disorder associated with inflammatory bowel disease (IBD). We aimed to estimate the risk of disease progression based on distinct clinical phenotypes in a large international cohort of patients with PSC. METHODS: We performed a retrospective outcome analysis of patients diagnosed with PSC from 1980 through 2010 at 37 centers in Europe, North America, and Australia. For each patient, we collected data on sex, clinician-reported age at and date of PSC and IBD diagnoses, phenotypes of IBD and PSC, and date and indication of IBD-related surgeries. The primary and secondary endpoints were liver transplantation or death (LTD) and hepatopancreatobiliary malignancy, respectively. Cox proportional hazards models were applied to determine the effects of individual covariates on rates of clinical events, with time-to-event analysis ascertained through Kaplan-Meier estimates. RESULTS: Of the 7121 patients in the cohort, 2616 met the primary endpoint (median time to event of 14.5 years) and 721 developed hepatopancreatobiliary malignancy. The most common malignancy was cholangiocarcinoma (n = 594); patients of advanced age at diagnosis had an increased incidence compared with younger patients (incidence rate: 1.2 per 100 patient-years for patients younger than 20 years old, 6.0 per 100 patient-years for patients 21-30 years old, 9.0 per 100 patient-years for patients 31-40 years old, 14.0 per 100 patient-years for patients 4150 years old, 15.2 per 100 patient-years for patients 51-60 years old, and 21.0 per 100 patient-years for patients older than 60 years). Of all patients with PSC studied, 65.5% were men, 89.8% had classical or large-duct disease, and 70.0% developed IBD at some point. Assessing the development of IBD as a time-dependent covariate, Crohn's disease and no IBD (both vs ulcerative colitis) were associated with a lower risk of LTD (unadjusted hazard ratio [HR], 0.62; PPeer reviewe

Indication and technique for arthroscopic stabilization of anterior shoulder instability with multidirectional laxity

<jats:title>Abstract</jats:title><jats:p>As concomitant hyperlaxity has been identified as an independent risk factor for failure following anterior shoulder stabilization, the treatment of this special pathology remains challenging. There is a broad consensus that a clear differentiation to multidirectional instability and isolated anteroinferior instability should be ensured to avoid unsatisfactory outcomes. Typical features of this patient collective include positive clinical tests for anteroinferior instability and multidirectional shoulder hyperlaxity, findings of an anterior labral lesion and general capsular redundancy in the radiologic assessment, while tests for posterior instability are negative. Surgical treatment should consist of an anteroinferior capsulolabroplasty with concomitant posteroinferior plication to reduce pathological capsular volume. Although there is a lack of clinical evidence, biomechanical investigations suggest that a four-anchor construct with three anterior anchors and one posteroinferior anchor may be sufficient to restore glenohumeral stability. This surgical approach is presented and discussed in the current article.</jats:p&gt

Patients return to sports and to work after successful treatment of septic arthritis following anterior cruciate ligament reconstruction

Purpose!#!To determine specific return to sports (RTS) and return to work (RTW) rates of patients with septic arthritis following anterior cruciate ligament reconstruction (ACLR), and to assess for factors associated with a diminished postoperative return to physical activity after successful eradication of the infection.!##!Methods!#!In this study, patients who were treated for postoperative septic arthritis of the knee following anterior cruciate ligament reconstruction between 2006 and 2018 were evaluated at a minimum follow-up (FU) of 2 years. Patients' outcomes were retrospectively analyzed using standardized patient-reported outcome scores including the Lysholm score and the subjective IKDC score, as well as return to sports and return to work questionnaires to assess for the types, number, and frequency of sports performed pre- and postoperatively and to evaluate for potential occupational changes due to septic arthritis following ACLR. To assess for the signifiance of the graft at follow-up, outcomes were compared between patients with a functioning graft at FU and those without, as well as between patients with initial graft retention and those with graft removal and consecutive revision ACLR.!##!Results!#!Out of 44 patients eligible for inclusion, 38 (86%) patients at a mean age of 36.2 ± 10.3 years were enrolled in this study. At a mean follow-up of 60.3 ± 39.9 months, the Lysholm score and the subjective IKDC score reached 80.0 ± 15.1 and 78.2 ± 16.6 points, respectively. The presence of a graft at FU yielded statistically superior results only on the IKDC score (p = 0.014). There were no statistically significant differences on the Lysholm score (n.s.) or on the IKDC score (n.s.) between patients with initial graft retention and those with initial removal who had undergone revision ACLR. All of the included 38 patients were able to return to sports at a median time of 8 (6-16) months after their last surgical intervention. Among patients who performed pivoting sports prior to their injury, 23 (62.2%) returned to at least one pivoting sport postoperatively. Overall, ten patients (26.3%) returned to all their previous sports at their previous frequency. The presence of a graft at FU resulted in a significantly higher RTS rate (p = 0.010). Comparing patients with initial graft retention and those with graft removal and consecutive revision ACLR, there was no statistically significant difference concerning the RTS rate (n.s.). Thirty-one patients (83.8%) were able to return to their previous work.!##!Conclusion!#!Successful eradication of septic arthritis following anterior cruciate ligament reconstruction allows for a postoperative return to sports and a return to work particularly among patients with ACL-sufficient knees. However, the patients' expectations should be managed carefully, as overall return rates at the pre-injury frequency are relatively low.!##!Level of evidence!#!IV

Complex patellofemoral reconstruction leads to improved physical and sexual activity in female patients suffering from chronic patellofemoral instability

Purpose!#!To analyze postoperative physical and sexual activity as well as Quality of Life (QoL) after complex patellofemoral reconstructions in female patients suffering from chronic patellofemoral instability (PFI).!##!Methods!#!Female patients aged > 18 years undergoing complex patellofemoral reconstruction for chronic PFI were included. Complex patellofemoral reconstruction was defined as medial patellofemoral ligament reconstruction (MPFL-R) combined with at least one major bony procedure (distal femoral osteotomy, high tibial osteotomy, and trochleoplasty). Outcome was evaluated retrospectively after a minimum follow-up of 12 months using Tegner activity scale, Banff Patellofemoral Instability Instrument 2.0 (BPII 2.0), EuroQol-5D-3L (EQ-5D-3L), EuroQol Visual analog scale (EQ-VAS), and a questionnaire about sexual activity.!##!Results!#!A total of 34 females (mean age, 26 ± 5 years) with a mean follow-up of 45 ± 16 months were included. Seventy-seven percent had one major bony correction + MPFL-R and 24% had at least two major bony corrections + MPFL-R. The re-dislocation rate was 6%. Median Tegner activity scale improved from 3 (range 0-10) to 4 (range 2-6) (n.s.) and an improved activity level was observed in 49% of subjects. QoL scores showed an EQ-5D-3L Index Value of 0.89 ± 0.15, EQ-VAS of 80.3 ± 11.4, and BPII of 68.3 ± 19.1. Thirty-four percent of patients reported restrictions of sexual activities due to PFI preoperatively with an improved sexual function observed in 60% postoperatively due to less pain, improved mobility, and less apprehension. Postoperative return to sexual activity was 91%, whereof 19% reported current restrictions of sexual function because of pain and/or limited range of motion.!##!Conclusion!#!Despite the complexity and invasiveness of complex patellofemoral reconstruction, combined bony procedures and MPFL-R resulted in a low redislocation rate, improved physical activity and QoL comparable to values reported after isolated MPFL-R. Furthermore, sexual activity was improved in 60% of females with preoperative restrictions.!##!Level of evidence!#!IV

Biceps Brachii Alterations Following the Latarjet Procedure: A Prospective Multicenter Study

Purpose: To prospectively investigate the postoperative forearm supination and elbow flexion strength of both upper extremities and popeye deformity in patients who underwent a mini-open Latarjet procedure for anterior shoulder instability. Methods: Patients who underwent a mini-open Latarjet procedure at two specialized shoulder centers were prospectively evaluated preoperatively (T0) and at least 6 months (T1) after surgery. Subjects were tested for elbow flexion and forearm supination strength of both upper extremities using an isometric dynamometer and customized torque dynamometer. Clinical outcome was assessed by the Constant Score (CS), American Shoulder and Elbow Score (ASES) and Simple Shoulder test (SST). Popeye deformity was defined as a distalization of the greatest circumference of the biceps muscle belly towards the lateral epicondyle of the elbow. Results: A total of 20 patients with a mean age of 27 ± 6 years were included in the study. At a mean follow-up of 10 ± 3 months, the elbow flexion strength was restored to the preoperative state (p = 0.240). Forearm supination strength significantly decreased at final follow-up, to 88 % in the surgical arm (p = 0.015) vs. 90 % in the non-surgical arm (p = 0.023). There was no statistical difference when comparing both arms concerning elbow flexion strength (p = 0.510) and forearm supination strength (p = 0.495). No significant popeye deformity was observed in both arms (p = 0.111 vs. p = 0.508). Clinical outcome scores improved significantly from 73 ± 18 to 82 ± 13 (p = 0.014) for CS and 76 ± 22 to 89 ± 12 (p = 0.008) for ASES score preoperatively to final follow-up. No difference in the SST was documented (p = 0.10). Conclusion: The Latarjet procedure showed to preserve elbow flexion strength and provided comparable forearm supination strength compared to the uninjured arm with reliable clinical outcome in this study population. However, a decrease of forearm supination strength in both arms was persistent at a mean of 10 months postoperatively. No popeye deformity was noted in the postoperative examinations. Level of evidence: Case series, Level III

Reliable improvements in participation in low-impact sports following implantation of a patellofemoral inlay arthroplasty at mid-term follow-up

Purpose!#!The aim of this study was, to investigate the rate of return to sports (RTS) and physical activity after implantation of PFIA and to identify factors predictive of improved postoperative sporting ability.!##!Methods!#!Sixty-two patients with a mean age of 46 ± 11 years, who underwent implantation of PFIA at the senior authors' institution, were enrolled. They were prospectively evaluated preoperatively and at a minimum of 2 years postoperatively with a mean follow-up of 60 ± 25 months. Clinical outcomes, return to sports and activity, type of sport or activity, subjective satisfaction, and frequency were evaluated by questionnaire.!##!Results!#!The transformed overall Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score improved from 67 ± 16 to 77 ± 19 (p = 0.003), Tegner activity scale results improved from 3 ± 2 points to 4 ± 1 points (p < 0.001), and scores on the visual analog scale (VAS) pain scale decreased from 6 ± 2 points to 3 ± 2 points (p < 0.001). The sports frequency increased from 1 ± 2 sessions to 2 ± 1 sessions per week (p = 0.001). Ninety-four percent of the patients who did not fail could return to the same or higher level of sports, with 74% of the patients reporting an improved ability to perform sports. No preoperative factors could be detected to significantly influence RTS after surgery.!##!Conclusions!#!PFIA is a valid treatment option for the active patient with end-stage isolated patellofemoral OA. Reliable improvements in knee function, pain, and participation in low-impact sports were found.!##!Level of evidence!#!IV

Definition of the terms “acute” and “traumatic” in rotator cuff injuries: a systematic review and call for standardization in nomenclature

Background!#!Although of high relevance for clinical decision making, there exists no consensus throughout the literature of the terms 'acute' and 'traumatic' used in the classification of rotator cuff tears. With differing definitions, the comparability of outcome studies may be limited. The aim was to provide a detailed systematic review of the definitions used in the literature and present a suggestion for a standardization in nomenclature based on the findings.!##!Methods!#!Four different internet databases were searched in February 2020 using the terms ('acute' OR 'traumatic' OR 'trauma' OR 'athlete' OR 'young') AND ('rotator cuff tears' OR 'rotator cuff tear' OR 'rotator cuff' OR 'rotator cuff rupture' OR 'supraspinatus' OR 'infraspinatus' OR 'subscapularis' OR 'teres minor'). Prospective, retrospective, cohort and case-control studies as well as case series were included. Systematic reviews, cadaveric or laboratory studies and studies on non-traumatic or non-acute rotator cuff tears were excluded.!##!Results!#!The literature search conducted 10,349 articles of which 10,151 were excluded based on the title, 119 based on the abstract and 33 based on the manuscript. A total of 46 studies were finally included for review and subsequently analyzed. Overall, there exists no consensus neither on the term 'acute' nor on 'traumatic' in the context of rotator cuff tears in the literature. The time span for acute injuries ranged between 2 weeks and 6 months. For traumatic injuries, only 20% of the selected studies described a specific and adequate injury mechanism in combination with adequate imaging.!##!Conclusion!#!The term 'acute' should be reserved for RCT showing muscle edema, wavelike appearance of the central part of the torn tendon and joint effusion, which typically requires adequate imaging within 2 weeks from trauma. Repair of acute tears should occur within 8 weeks from trauma to benefit from possibly superior biological healing capacities. The term 'traumatic' should be used for a sudden onset of symptoms in a previously asymptomatic patient, triggered by an adequate trauma, e.g., a fall on the retroverted arm with an axial cranioventral force or a traumatic shoulder dislocation

Dislocated hinge fractures are associated with malunion after lateral closing wedge distal femoral osteotomy

Purpose!#!To evaluate the incidence, morphology, and associated complications of medial cortical hinge fractures after lateral closing wedge distal femoral osteotomy (LCW-DFO) for varus malalignment and to identify constitutional and technical factors predisposing for hinge fracture and consecutive complications.!##!Methods!#!Seventy-nine consecutive patients with a mean age of 47 ± 12 years who underwent LCW-DFO for symptomatic varus malalignment at the authors' institution between 01/2007 and 03/2018 with a minimum of 2-year postoperative time interval were enrolled in this retrospective observational study. Demographic and surgical data were collected. Measurements evaluating the osteotomy cut (length, wedge height, hinge angle) and the location of the hinge (craniocaudal and mediolateral orientation, relation to the adductor tubercle) were conducted on postoperative anterior-posterior knee radiographs and the incidence and morphology of medial cortical hinge fractures was assessed. A risk factor analysis of constitutional and technical factors predisposing for the incidence of a medial cortical hinge fracture and consecutive complications was conducted.!##!Results!#!The incidence of medial cortical hinge fractures was 48%. The most frequent morphological type was an extension fracture type (68%), followed by a proximal (21%) and distal fracture type (11%). An increased length of the osteotomy in mm (53.1 ± 10.9 vs. 57.7 ± 9.6; p = 0.049), an increased height of the excised wedge in mm (6.5 ± 1.9 vs. 7.9 ± 3; p = 0.040) as well as a hinge location in the medial sector of an established sector grid (p = 0.049) were shown to significantly predispose for the incidence of a medial cortical hinge fracture. The incidence of malunion after hinge fracture (14%) was significantly increased after mediolateral dislocation of the medial cortical bone > 2 mm (p < 0.05).!##!Conclusion!#!Medial cortical hinge fractures after LCW-DFO are a common finding. An increased risk of sustaining a hinge fracture has to be expected with increasing osteotomy wedge height and a hinge position close to the medial cortex. Furthermore, dislocation of a medial hinge fracture > 2 mm was associated with malunion and should, therefore, be avoided.!##!Level of evidence!#!Prognostic study; Level IV