Proactive therapeutic drug monitoring and vedolizumab dose optimization in children with inflammatory bowel disease.

OBJECTIVES: Therapeutic drug monitoring (TDM) and dose optimization have been shown to improve clinical outcomes with antitumor necrosis factor and recent studies in adults suggest an exposure-response relationship with drug levels associated with improved clinical outcomes. However, these levels are not universally recognized as therapeutic targets for vedolizumab dosing. We aimed to assess the impact of a TDM quality improvement (QI) initiative on 52-week clinical outcomes and describe proactively obtained vedolizumab levels during the induction period in children with inflammatory bowel disease (IBD). METHODS: A QI initiative to proactively obtain TDM levels at Week 6 was implemented in 2019. A retrospective review of pediatric patients with IBD treated with vedolizumab from 2018 to 2022 was performed. Baseline demographic data, medication dosing details, disease characteristics, lab results, and 12-month clinical outcomes were recorded. For this study, we defined therapeutic target levels (>20 µg/mL at Week 6 and >12 µg/mL during maintenance) based on existing data correlating these levels with improved clinical outcomes. RESULTS: Fifty-nine patients (31 Crohn disease [CD], 28 ulcerative colitis [UC]/indeterminate colitis [IC]) were included in the study. In total, 68% (40/59) of patients had vedolizumab levels at Week 6 and 90% (53/59) had levels drawn at Week 6 or 14. Thirty-five percent of Week 6 trough levels were below our defined target of 20 µg/mL. Fifty-two of 59 patients had available data at 52 weeks. Over 80% (42/52) of patients remained on vedolizumab 52 weeks after initiation (CD 79% [23/29], UC/IC 83% [19/23]). Sixty-two percent (26/42) of patients that remained on vedolizumab at 52 weeks were treated with an intensified dosing interval of <8 weeks. Thirty-one of these 42 (74%) were in clinical remission (CR) rate at 52 weeks with 29/42 (69%) in corticosteroid-free remission. The CR rate for the entire cohort including those who discontinued therapy due to a lack of efficacy before 52 weeks was 60% (31/52). CONCLUSION: Proactive TDM and early dose optimization with vedolizumab may improve drug durability and clinical outcomes in pediatric patients with IBD.

Notch1 haploinsufficiency causes ascending aortic aneurysms in mice.

An ascending aortic aneurysm (AscAA) is a life-threatening disease whose molecular basis is poorly understood. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV), which is associated with AscAA. Here, we describe a potentially novel role for Notch1 in AscAA. We found that Notch1 haploinsufficiency exacerbated the aneurysmal aortic root dilation seen in the Marfan syndrome mouse model and that heterozygous deletion of Notch1 in the second heart field (SHF) lineage recapitulated this exacerbated phenotype. Additionally, Notch1+/- mice in a predominantly 129S6 background develop aortic root dilation, indicating that loss of Notch1 is sufficient to cause AscAA. RNA sequencing analysis of the Notch1.129S6+/- aortic root demonstrated gene expression changes consistent with AscAA. These findings are the first to our knowledge to demonstrate an SHF lineage-specific role for Notch1 in AscAA and suggest that genes linked to the development of BAV may also contribute to the associated aortopathy.

Developing a coaching mechanism for practicing surgeons.

BACKGROUND: While performance feedback and assessment are hallmarks of surgical training, they abruptly cease after training is completed. In their absence, performance may stagnate and poor habits persist. Our aim was to develop a coaching mechanism for practicing surgeons with feedback provision based on objective performance assessment. METHODS: Technical and nontechnical intraoperative video recordings from laparoscopic or robotic cholecystectomies, colectomies, and hysterectomies were assessed by a blinded surgeon and a human factors expert, respectively. Aspects of performance in need of improvement were noted, and a coaching session was developed for feedback provision to participating surgeons. This 4-hour coaching session consisted of a didactic lecture with video review and hands-on practice using procedural and mannequin-based simulation. RESULTS: Thirty-two practicing surgeons (18 general; 14 gynecologists) from 6 different hospitals were assessed, and 9 of them participated in coaching. Technical aspects identified for performance improvement included suboptimal trocar placement, inadequate critical view achievement during laparoscopic cholecystectomies, poor visualization of the operating field, bimanual dexterity, and dissection techniques, while nontechnical aspects included inappropriate handling of distractions and interruptions, poor ergonomic positioning and situational awareness, and inadequate mitigation of delays. Most surgeons appropriately accomplished some of the objectives of the distraction scenario, but none was able to achieve expert levels on Fundamentals of Laparoscopy tasks. Participants perceived the coaching sessions as highly valuable. CONCLUSION: Our study identified several technical and nontechnical skill sets of practicing surgeons in need of improvement and provided support for the implementation of coaching programs for surgeons on an ongoing basis.

A systematic review and meta-analysis of the diagnostic accuracy of MRI for suspected ACL and meniscal tears of the knee.

PURPOSE: To determine the diagnostic accuracy of magnetic resonance imaging (MRI) and ultrasound (US) in the diagnosis of anterior cruciate ligament (ACL), medial meniscus and lateral meniscus tears in people with suspected ACL and/or meniscal tears. METHODS: MEDLINE, Web of Science and the Cochrane library were searched from inception to March 2014. All prospective studies of the diagnostic accuracy of MRI or US against arthroscopy as the reference standard were included in the systematic review. Studies with a retrospective design and those with evidence of verification bias were excluded. Methodological quality of included studies was assessed using the QUADAS-2 tool. A meta-analysis of studies evaluating MRI to calculate the pooled sensitivity and specificity for each target condition was performed using a bivariate model with random effects. Sub-group and sensitivity analysis were used to examine the effect of methodological and other study variables. RESULTS: There were 14 studies included in the meta-analysis of the accuracy of MRI for ACL tears, 19 studies included for medial meniscal tears and 19 studies for lateral meniscal tears. The summary estimates of sensitivity and specificity of MRI were 87 % (95 % CI 77-94 %) and 93 % (95 % CI 91-96 %), respectively, for ACL tears; 89 % (95 % CI 83-94 %) and 88 % (95 % CI 82-93 %), respectively, for medial meniscal tears; and 78 % (95 % CI 66-87 %) and 95 % (95 % CI 91-97 %), respectively, for lateral meniscal tears. Magnetic field strength had no significant effect on accuracy. Most studies had a high or unclear risk of bias. There were an insufficient number of studies that evaluated US to perform a meta-analysis. CONCLUSION: This study provides a systematic review and meta-analysis of diagnostic accuracy studies of MRI and applies strict exclusion criteria in relation to the risk of verification bias. The risk of bias in most studies is high or unclear in relation to the reference standard. Concerns regarding the applicability of patient selection are also present in most studies. LEVEL OF EVIDENCE: III.

The Effectiveness of Corticosteroid Injection for De Quervain's Stenosing Tenosynovitis (DQST): A Systematic Review and Meta-Analysis.

De Quervain's stenosing tenosynovitis (DQST) treatments include corticosteroid injection around the tendon sheath; however there is some ambiguity concerning the efficacy of this treatment. The aim of this systematic review and meta-analysis is to examine the totality of evidence relating to the use of corticosteroid injection in DQST when compared to placebo or other active treatments. A systematic literature search was conducted in July 2014. Only randomized control trials (RCTs) were included. Outcome measures included impairment, activity limitation and participation restriction. Five RCTs were identified with 165 patients, 88 in the treatment group and 77 in the control group.Patients who received corticosteroid injection (n=142) had a higher rate of resolution of symptoms [RR 2.59, 95% CI: 1.25 to 5.37, p=0.05, I2=62%]. This group reported greater pain relief as assessed by Visual Analogue Scale (VAS) at first assessment [mean difference -2.51, 95% CI: -3.11 to -1.90, p=0.0003, I2=65%] and demonstrated a statistically significant improvement in function (n=78) as measured by the DASH score and Dutch AIMS-HFF score [SMD -0.83, 95% CI: -1.54 to -0.12, p=0.02, I2=48]. This review confirms that corticosteroid injection results in a statistically significant increase in resolution of symptoms, pain relief and increased function in the treatment of DQST.

Depletion of the ubiquitin-binding adaptor molecule SQSTM1/p62 from macrophages harboring cftr ΔF508 mutation improves the delivery of Burkholderia cenocepacia to the autophagic machinery.

Cystic fibrosis is the most common inherited lethal disease in Caucasians. It is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR), of which the cftr ΔF508 mutation is the most common. ΔF508 macrophages are intrinsically defective in autophagy because of the sequestration of essential autophagy molecules within unprocessed CFTR aggregates. Defective autophagy allows Burkholderia cenocepacia (B. cepacia) to survive and replicate in ΔF508 macrophages. Infection by B. cepacia poses a great risk to cystic fibrosis patients because it causes accelerated lung inflammation and, in some cases, a lethal necrotizing pneumonia. Autophagy is a cell survival mechanism whereby an autophagosome engulfs non-functional organelles and delivers them to the lysosome for degradation. The ubiquitin binding adaptor protein SQSTM1/p62 is required for the delivery of several ubiquitinated cargos to the autophagosome. In WT macrophages, p62 depletion and overexpression lead to increased and decreased bacterial intracellular survival, respectively. In contrast, depletion of p62 in ΔF508 macrophages results in decreased bacterial survival, whereas overexpression of p62 leads to increased B. cepacia intracellular growth. Interestingly, the depletion of p62 from ΔF508 macrophages results in the release of the autophagy molecule beclin1 (BECN1) from the mutant CFTR aggregates and allows its redistribution and recruitment to the B. cepacia vacuole, mediating the acquisition of the autophagy marker LC3 and bacterial clearance via autophagy. These data demonstrate that p62 differentially dictates the fate of B. cepacia infection in WT and ΔF508 macrophages.