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Background and Aims Anti-tumour necrosis factor [TNF] treatment failure in patients with inflammatory bowel disease [IBD] is common and frequently related to low drug concentrations. In order to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy, we sought to define epigenetic biomarkers in whole blood at baseline associated with anti-TNF drug concentrations at week 14. Methods DNA methylation from 1104 whole blood samples from 385 patients in the Personalised Anti-TNF Therapy in Crohn's disease [PANTS] study were assessed using the Illumina EPIC Beadchip [v1.0] at baseline and weeks 14, 30, and 54. We compared DNA methylation profiles in anti-TNF-treated patients who experienced primary non-response at week 14 if they were assessed at subsequent time points and were not in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 94], with patients who responded at week 14 and when assessed at subsequent time points were in remission at week 30 or 54 [infliximab n = 99, adalimumab n = 93]. Results Overall, between baseline and week 14, we observed 4999 differentially methylated positions [DMPs] annotated to 2376 genes following anti-TNF treatment. Pathway analysis identified 108 significant gene ontology terms enriched in biological processes related to immune system processes and responses. Epigenome-wide association [EWAS] analysis identified 323 DMPs annotated to 210 genes at baseline associated with higher anti-TNF drug concentrations at Week 14. Of these, 125 DMPs demonstrated shared associations with other common traits [proportion of shared CpGs compared with DMPs] including body mass index [23.2%], followed by C-reactive protein [CRP] [11.5%], smoking [7.4%], alcohol consumption per day [7.1%], and IBD type [6.8%]. EWAS of primary non-response to anti-TNF identified 20 DMPs that were associated with both anti-TNF drug concentration and primary non-response to anti-TNF with a strong correlation of the coefficients [Spearman's rho = -0.94, p <0.001]. Conclusion Baseline DNA methylation profiles may be used as a predictor for anti-TNF drug concentration at week 14 to identify patients who may benefit from dose optimisation at the outset of anti-TNF therapy. [ABSTRACT FROM AUTHOR]

How is new information organized in memory? According to latent state theories, this is determined by the level of surprise, or prediction error, generated by the new information: a small prediction error leads to the updating of existing memory, large prediction error leads to encoding of a new memory. We tested this idea using a protocol in which rats were first conditioned to fear a stimulus paired with shock. The stimulus was then gradually extinguished by progressively reducing the shock intensity until the stimulus was presented alone. Consistent with latent state theories, this gradual extinction protocol (small prediction errors) was better than standard extinction (large prediction errors) in producing long-term suppression of fear responses, and the benefit of gradual extinction was due to updating of the conditioning memory with information about extinction. Thus, prediction error determines how new information is organized in memory, and latent state theories adequately describe the ways in which this occurs. [ABSTRACT FROM AUTHOR]

Background: Because of the increased prevalence of revision anterior cruciate ligament (ACL) reconstruction, there has been a desire to understand the role of posterior tibial slope on increased anterior tibial translation and increased ACL graft forces. One potential concern in supratubercle anterior closing wedge proximal tibial osteotomy (ACW-PTO) for decreasing the posterior tibial slope is the risk of altering the patellar height. Purpose: To radiographically assess changes in (1) patellar height, (2) anterior tibial translation, and (3) posterior tibial slope after supratubercle ACW-PTO. Study Design: Case series; Level of evidence, 4. Methods: Patients who underwent supratubercle ACW-PTO by a single surgeon between July 2019 and June 2023 were included. Standardized lateral knee weightbearing radiographs to assess patellar height (via the Caton-Deschamps index), anterior tibial translation of the lateral tibial plateau relative to the lateral femoral condyle, and posterior tibial slope were obtained at 4 time points (preoperatively and 1 day, 3 months, and 6 months postoperatively). Paired t test was used to compare differences between preoperative, 1-day, and 3- and 6-month values for patellar height as measured using the Caton-Deschamps index and for posterior tibial slope. Paired t test was also used to compare differences in the preoperative and 6-month postoperative values for anterior tibial translation. Results: In 20 patients after ACW-PTO, the Caton-Deschamps index demonstrated a significant increase in patellar height on postoperative day 1 (P <.001) but no significant differences at 3 (P =.057) and 6 (P =.176) months postoperatively. Anterior tibial translation on standing lateral knee radiographs was significantly decreased by a mean of 8.9 mm from preoperatively to 6 months postoperatively (P <.001). Posterior tibial slope was significantly decreased by a mean of 11.2° from preoperatively to 6 months postoperatively (P <.001). Conclusion: Supratubercle ACW-PTO performed for ACL reconstruction failure in the setting of an increased posterior tibial slope did not induce significant changes in patellar height postoperatively. Furthermore, after ACW-PTO, there was a significant decrease in anterior tibial translation and posterior tibial slope. [ABSTRACT FROM AUTHOR]

Background and Aims This study assessed whether baseline triggering receptor expressed on myeloid cells [ TREM-1 ] whole blood gene expression predicts response to anti-tumour necrosis factor [anti-TNF] therapy in patients with ulcerative colitis [UC] or Crohn's disease [CD]. Methods TREM-1 whole blood gene expression was analysed by RNA sequencing in patients with moderately to severely active UC or CD treated with adalimumab in the Phase 3 SERENE-UC and SERENE-CD clinical trials. The predictive value of baseline TREM-1 expression was evaluated and compared according to endoscopic and clinical response vs non-response, and remission vs non-remission, at Weeks 8 and 52 [SERENE-UC], and Weeks 12 and 56 [SERENE-CD]. Results TREM-1 expression was analysed in 95 and 106 patients with UC and CD, respectively, receiving standard-dose adalimumab induction treatment. In SERENE-UC, baseline TREM-1 expression was not predictive of endoscopic response [ p  = 0.48], endoscopic remission [ p  = 0.53], clinical response [ p  = 0.58], or clinical remission [ p  = 0.79] at Week 8, or clinical response [ p  = 0.60] at Week 52. However, an association was observed with endoscopic response [ p  = 0.01], endoscopic remission [ p  = 0.048], and clinical remission [ p  = 0.04997] at Week 52. For SERENE-CD, baseline TREM-1 expression was not predictive of endoscopic response [ p  = 0.56], endoscopic remission [ p  = 0.33], clinical response [ p  = 0.07], or clinical remission [ p  = 0.65] at Week 12, or endoscopic response [ p  = 0.61], endoscopic remission [ p  = 0.51], clinical response [ p  = 0.62], or clinical remission [ p  = 0.97] at Week 56. Conclusions Baseline TREM-1 gene expression did not uniformly predict adalimumab response in SERENE clinical trials. Further research is needed to identify potential blood-based biomarkers predictive of response to anti-TNF therapy in patients with inflammatory bowel disease. Clinicaltrials.gov identifiers NCT02065622 ; NCT02065570 [ABSTRACT FROM AUTHOR]

Background: The fabella is a sesamoid bone that is a normal anatomic variant yet a rare cause of pathology in the posterolateral portion of the knee. The fabella can cause chronic knee pain in patients with knee osteoarthritis and athletes at all levels and in rare cases can cause neuropathy. Initially, treatment for a painful fabella includes conservative measures, with surgical intervention after conservative treatments have failed. This technique describes our arthroscopic-assisted fabella removal technique with a concomitant medial meniscus revision repair. Indications: The goal of treatment is to relieve pain and numbness. Conservative measures (i.e., nonsteroidal anti-inflammatory drugs [NSAIDs], range of motion exercises, heel cord stretching, etc.) are the initial step in treatment. Patients are treated surgically after conservative measures have failed. The surgical approach involves an open incision, arthroscopy, or a combination. Technique Description: With the patient in the supine position, a physical examination is performed under anesthesia to compare to validate clinical findings. An open lateral knee approach helps to locate the fabella which is grasped with an Alice clap. An arthroscopy is performed, and viewing posterolaterally will confirm that the fabella is within the grips of the Alice clamp. After repair of the meniscus, the surgical bed is repositioned to identify the fabella properly. Excision of the fabella is performed sharply from the lateral gastrocnemius tendon, and palpation is demonstrated to ensure complete removal. Caution is essential to avoid complications including damage to nearby anatomic structures, such as the lateral gastrocnemius tendon, and incomplete fabella removal. Results: A clinical study by Dekker et al reported that 80% of patients were able to return to full activities and postoperative patient-reported outcomes improved from preoperative to postoperative. Fabella excision is recommended for patients with fabella pain who do not respond to conservative treatment. Discussion: We describe a technique for removing the fabella with arthroscopic assistance. Patients who have not responded appropriately to conservative treatment for a painful fabella should consider surgical intervention. With the early initiation of rehabilitation, patients will have an increased likelihood of decreased pain, resolution of symptoms, and reduced knee stiffness. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication. [ABSTRACT FROM AUTHOR]

Background and Aims Anti-tumour necrosis factor [anti-TNF] therapy is widely used for the treatment of inflammatory bowel disease, yet many patients are primary non-responders, failing to respond to induction therapy. We aimed to identify blood gene expression differences between primary responders and primary non-responders to anti-TNF monoclonal antibodies [infliximab and adalimumab], and to predict response status from blood gene expression and clinical data. Methods The Personalised Anti-TNF Therapy in Crohn's Disease [PANTS] study is a UK-wide prospective observational cohort study of anti-TNF therapy outcome in anti-TNF-naive Crohn's disease patients [ClinicalTrials.gov identifier: NCT03088449]. Blood gene expression in 324 unique patients was measured by RNA-sequencing at baseline [week 0], and at weeks 14, 30, and 54 after treatment initiation [total sample size = 814]. Results After adjusting for clinical covariates and estimated blood cell composition, baseline expression of major histocompatibility complex, antigen presentation, myeloid cell enriched receptor, and other innate immune gene modules was significantly higher in anti-TNF responders vs non-responders. Expression changes from baseline to week 14 were generally of consistent direction but greater magnitude [i.e. amplified] in responders, but interferon-related genes were upregulated uniquely in non-responders. Expression differences between responders and non-responders observed at week 14 were maintained at weeks 30 and 54. Prediction of response status from baseline clinical data, cell composition, and module expression was poor. Conclusions Baseline gene module expression was associated with primary response to anti-TNF therapy in PANTS patients. However, these baseline expression differences did not predict response with sufficient sensitivity for clinical use. [ABSTRACT FROM AUTHOR]

Background The IBD-Control Questionnaire is a simple, generic measure of patient-perceived disease control used increasingly in clinical practice and research. We aimed to address knowledge gaps in its psychometric performance, to ensure that it can be used with confidence in a variety of contexts. Methods We analysed 7341 responses to the IBD Registry COVID-19 survey, sent to 40 911 patients who completed an online self-assessment tool during the pandemic. Questions covered demographics, comorbidities, inflammatory bowel disease [IBD] sub-type, and IBD-Control Questionnaire and symptom scores [CD-PRO2 or UC-PRO2]. Psychometric properties of IBD-Control-8 were tested overall and within subgroups (Crohn's disease [CD], ulcerative colitis [UC] and IBD unclassified; male and female; ≤65 and >65 years; number of co-morbidities; deprivation status). Results Internal consistency was very strong overall [α: 0.84, ω: 0.89] and for each subgroup [α range: 0.81–0.85; ω: 0.86–0.90]. Construct validity was demonstrated by moderate correlation of each item with global rating [VAS] [ r s range: 0.47–0.65], strong correlation between IBD-Control-8 score and VAS [ r s = 0.74], moderate-to-strong with PRO2 scores [CD: r s = −0.718; UC: r s = −0.602] and significantly higher IBD-Control-8 scores for PRO2-remission vs PRO2-active, consistent across subgroups. Exploratory and confirmatory factor analyses demonstrated a two-factor model (items loading onto 'Health-related Quality of Life' [HRQoL] or 'Treatment' domains). Extensive tests for factorial invariance confirmed consistency. Conclusions IBD-Control-8 is a psychometrically robust scale which can be used across a range of populations. It offers a quick, reliable, and valid method of assessing patient-perceived control. The construct of 'control' includes traditional HRQoL and a novel domain relating to treatment perception. [ABSTRACT FROM AUTHOR]

Background: The popliteus tendon is a primary stabilizer of external knee rotation and has been described as the "fifth ligament of the knee." Injuries involving the posterolateral corner of the knee commonly involve the popliteus tendon; isolated injury to the popliteus tendon is relatively rare and usually involves a rotatory injury mechanism and symptoms of instability and pain. In this patient, there was a concomitant injury to the proximal tibiofibular joint. Indications: Popliteus tendon reconstruction is indicated for patients with abnormal external rotation on examination and symptoms of pain and instability. Proximal tibiofibular joint reconstruction is indicated for patients with instability of the tibiofibular joint. Technique Description: Preoperative examination under anesthesia is essential to determine the extent of external rotation and assess for additional posterolateral pathology. The popliteus tendon procedure begins with a meticulous common peroneal nerve neurolysis to minimize nerve irritation and decrease the risk of a postoperative foot drop. Semitendinosus and gracilis graft harvest is performed with at least 16 cm of graft length followed by tunnel reaming of the popliteus tendon femoral attachment and tibia tunnel identification and reaming. The femoral attachment of the popliteus tendon is secured, and the semitendinosus graft is anatomically oriented along the native path and passed from posterior to anterior through the femoral tunnel. The gracilis graft for anatomic proximal tibiofibular joint reconstruction requires an anterior to posterior tunnel through the fibular head. Finally, both grafts are secured in the tibial tunnel with the application of an anterior traction force. Results: A cadaveric study by LaPrade et al reported that an anatomic popliteus tendon reconstruction with a semitendinosus autograft significantly reduced external rotation laxity compared with the sectioned state. In addition, popliteus tendon reconstruction resulted in significantly decreased varus laxity, anterior tibial translation, and internal rotation. Discussion: This is a technique that effectively restores external rotation knee stability utilizing an anatomically oriented reconstruction of the popliteus tendon and tibiofibular joint. The popliteus tendon serves as a primary stabilizer to external rotation and facilitates static function of the knee. The proximal tibiofibular joint reconstruction restores the function of the posterior proximal tibiofibular joint ligaments. Patient Consent Disclosure Statement: The author(s) attests that consent has been obtained from any patient(s) appearing in this publication. If the individual may be identifiable, the author(s) has included a statement of release or other written form of approval from the patient(s) with this submission for publication. [ABSTRACT FROM AUTHOR]

Background and Aims: We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with inflammatory bowel disease [IBD]., Methods: We conducted a prospective study including 213 IBD patients and 53 healthy controls: 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab, or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination, and interval between vaccination and sampling., Results: Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (geometric mean ratio 0.35 [95% confidence interval 0.20-0.60], p = 0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p = 0.0050), and tofacitinib (0.28 [0.14-0.57], p = 0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p = 0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p = 0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p = 0.017), and tofacitinib (0.23 [0.10-0.56], p = 0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 [r = 0.27; p = 0.0004] and H1N1 [r = 0.33; p < 0.0001]., Conclusions: Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to influenza/A, similar to COVID-19 vaccine-induced antibody responses., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)