Despite recent developments in therapy for inflammatory bowel diseases (IBDs), there have been limited advances in diagnostic tools available to aid in disease management. A growing body of evidence suggests that there are important host-microbe interactions at the mucosal interface that modulate the inflammatory response in patients with IBD. Additionally, the importance of mucosal integrity and its disruption appears to be important in the pathophysiology and perpetuation of the disease. The ability to characterize this interface may provide valuable information for both disease monitoring and identification of new treatment targets. Endoscopy remains the primary tool for disease monitoring, and mucosal healing is the primary therapeutic target in IBD treatment. However, establishing mucosal healing requires repetitive endoscopic procedures, and endoscopy is limited by factors such as invasiveness, cost, and risk of adverse events. Moreover, the use of a bowel preparation for colonoscopies alters the mucus layer and thus perturbs evaluation of the host-microbe interaction. Stool sampling may also be inaccurate because it reflects the end state of metabolites and proteins, failing to take into account the degradation or alteration of substrates of interest by bacterial proteases and other enzymes during passage through the colon. A novel sampling capsule, called the Recoverable Sampling System (RSS), is being developed as a complementary tool to colonoscopy. The RSS is intended to be a platform for noninvasive autonomous sampling, preservation, handling, and storage of analytes of interest found in the gastrointestinal fluids. A proprietary preservative contained within the chambers of the capsule has been developed to stabilize DNA and proteins for ex vivo microbiome and metabolomics analyses. Surrogate markers such as SPP24 and GUCA2a have been identified to correlate with gut health, intestinal permeability, and inflammation and could be locally sampled by the RSS. The potential clinical utility of an RSS device is broad and would likely be able to guide therapy by allowing for more frequent disease monitoring, aiding in disease characterization, and facilitating in the identification of novel therapeutic targets.

Context Hypothalamic obesity is a rare, treatment-resistant form of obesity. In preliminary studies, the hypothalamic hormone oxytocin (OXT) has shown promise as a potential weight loss therapy. Objective To determine whether 8 weeks of intranasal OXT (vs. 8 weeks of placebo) promotes weight loss in children, adolescents, and young adults with hypothalamic obesity. Design Randomized, double-blind, placebo-controlled, cross-over pilot trial (NCT02849743). Setting Outpatient academic medical center. Participants Aged 10y to 35y, hypothalamic obesity from hypothalamic/pituitary tumors. Intervention Intranasal OXT (Syntocinon, 40 USP units/mL, 4 IU/spray) vs. excipient-matched placebo, 16-24 IU three times daily at mealtimes. Main outcome measure(s) Weight loss attributable to OXT vs. placebo, safety (adverse events). Results Of 13 individuals randomized (54% female, 31% pre-pubertal, median age 15.3y, IQR 13.3-20.6), 10 completed the entire study. We observed a non-significant within-subject weight change of -0.6 kg (95% CI: -2.7, 1.5) attributable to OXT vs. placebo. A subset (2/18 screened, 5/13 randomized) had prolonged QTc interval on electrocardiography (ECG) prior to screening and/or in both treatment conditions. Overall, OXT was well-tolerated, and adverse events (epistaxis and nasal irritation, headache, nausea/vomiting, and changes in heart rate, blood pressure, and QTc interval) were similar between OXT and placebo. In exploratory analyses, benefits of OXT for anxiety and impulsivity were observed. Conclusions In this pilot study in hypothalamic obesity, we did not detect a significant impact of intranasal OXT on body weight. OXT was well-tolerated, so future larger studies could examine different dosing, combination therapies, as well as potential psychosocial benefits.

Background Small molecules are being added to the treatment armamentarium of ulcerative colitis (UC). In contrast to monoclonal antibodies, very little is known about their pharmacokinetic-pharmacodynamic profile. We therefore assessed pharmacokinetic-pharmacodynamic changes in Tofacitinib (TFC) treated UC patients, with a focus on STAT3 phosphorylation, as it has been proposed as a marker of efficacy. Methods Thirty UC patients initiating TFC therapy, 10mg BID were prospectively monitored (Table, 1). At week, 8, patients could de-escalate to, 5mg BID or maintain, 10mg BID depending on their response. Endoscopic assessment and sampling (colonic tissue and serum) was performed at baseline and, 8–16 weeks after TFC initiation. Endoscopic improvement was defined as Mayo endoscopic subscore, 0–1. TFC was extracted from tissue using acetonitrile, dried down and quantitated using mass spectrometry. Both total as well as phosphorylated STAT3 were measured in lysed tissue using specific antibodies with an ultrasensitive luminescent oxygen channelling assay. Results TFC tissue and serum concentrations correlated significantly (r=0.92, p<0.001), though were significantly higher in tissue (median, 520.19ng/g vs, 17.35ng/mL, p<0.001). In contrast to TFC serum exposure (p=0.26), TFC tissue exposure at the end of induction was associated with endoscopic improvement by week, 16 (p=0.04) (Figure, 1). In TFC responders (n=14), TFC tissue exposure exceeded the concentration required to block, 90% of the target (IC90) reported in literature (median tissue exposure, 1,055.00ng/g; IC90, 823ng/g). TFC tissue exposure in non-responders (n=16) was lower, but clearly exceeded the IC50. Although IL-6 was not significantly downregulated after TFC induction, a significant decrease in the ratio of mucosal IL-6 driven phosphorylated STAT3 over total STAT3 (pSTAT3/STAT3) was observed in responders (p=0.05), but not in non-responders (p=0.88). The pSTAT3/STAT3 ratio also correlated significantly with faecal calprotectin (r=0.35, p=0.05), but only weakly with the Mayo endoscopic sub score (r=0.22, p=0.13). Baseline mucosal pSTAT3/STAT3 did not differ significantly between future responders and non-responders. Tofacitinib tissue (A) and serum (B) exposure at the end of high dose induction in relation to the achievement of endoscopic improvement at week, 16, defined by a Mayo endoscopic sub-score of, 0–1. Conclusion We could demonstrate for the first time a mucosal exposure-response relationship with TFC in UC patients. Additionally, pSTAT3/STAT3 ratio was identified as potential molecular marker to track response directly linked to the mode-of-action of TFC. Whether an increased local dose of TFC could result in better efficacy without compromising safety should be further explored.

Multi ligament knee injuries (MLKIs) are highly complex injuries with associated complications and often present with difficult management strategies. MLKIs may affect the anterior cruciate ligament (ACL), posterior cruciate ligament (PCL), medial collateral ligament (or posteromedial corner (PMC)), and lateral collateral ligament (or posterolateral corner (PLC)) in addition to other structures including the menisci, common peroneal nerve, and popliteal artery. MLKIs are highly associated with the male sex and are commonly seen in high-velocity motor vehicle accidents and low-velocity sports injuries. Given the multiple planes of movement in the knee and various primary and secondary stabilizers throughout those planes, there is great heterogeneity in an injury pattern and most involve the ACL and PCL. Initial evaluation of this injury includes assessment of lower extremity sensation, distal pulses, and ankle-brachial index (ABI). If vascular compromise is suspected, computed tomography angiography (CTA) or magnetic resonance angiography (MRA) are indicated to evaluate the vasculature. As opposed to CTA, MRA offers visualization of the soft-tissue structures that are commonly damaged in MLKIs. Initial management typically includes closed reduction of the knee with subsequent external fixation. Classification systems guide initial assessments; however, further management is unclear and leads the surgical team to decide the best, individualized management option for each patient. As a result, optimal surgical and postoperative treatment options remain complicated, and clinical outcomes remain difficult to predict. The purpose of this review is to consolidate the most up-to-date practices of the diagnostic workup, management, and treatment of MLKIs.

Despite recent drug approvals for the treatment of inflammatory bowel diseases (IBD), there remains a high unmet need for new technologies that can increase drug efficacy by improving site-specific drug delivery while reducing systemic exposure. These technologies must address challenges with formulation; in particular, drugs that are liquid, peptides or proteins are difficult to formulate using existing delayed and extended oral release technologies. They also have the potential to improve efficacy and reduce systemic exposure for certain drugs by delivering higher doses directly to the site of inflammation. A novel drug delivery system (DDS2) is being developed for delivery at a pre-specified part of the gastrointestinal tract. This autonomous mechanical capsule uses an algorithm based on reflected light to deliver soluble formulations of drugs to the predefined location. This system has significant advantages over other traditional delayed release oral formulations because it functions independently of human physiological variables such as pH and transit time and can deliver liquid formulations, peptides, and proteins. Such a system can ensure a predictable high luminal drug exposure and limited degradation or systemic absorption in the upper gastrointestinal tract and would therefore be ideal for treatment of disorders such as IBD and colon cancer.