Citations

Blast-induced traumatic brain injury is typically regarded as a signature medical concern for military personnel who are exposed to explosive devices in active combat zones. However, soldiers as well as law enforcement personnel may be repeatedly exposed to low-level blasts during training sessions with heavy weaponries as part of combat readiness. Service personnel who sustain neurotrauma from repeated low-level blast (rLLB) exposure do not display overt pathological symptoms immediately but rather develop mild symptoms including cognitive impairments, attention deficits, mood changes, irritability, and sleep disturbances over time. Recently, we developed a rat model of rLLB by applying controlled low-level blast pressures (≤ 70 kPa) repeated five times successively to mimic the pressures experienced by service members. Using this model, we assessed anxiety-like symptoms, motor coordination, and short-term memory as a function of time. We also investigated the role of the NLRP3 inflammasome, a complex involved in chronic microglial activation and pro-inflammatory cytokine interleukin (IL)-1β release, in rLLB-induced neuroinflammation. NLRP3 and caspase-1 protein expression, microglial activation, and IL-1β release were examined as factors likely contributing to these neurobehavioral changes. Animals exposed to rLLB displayed acute and chronic short-term memory impairments and chronic anxiety-like symptoms accompanied by increased microglial activation, NLRP3 expression, and IL-1β release. Treatment with MCC950, an NLRP3 inflammasome complex inhibitor, suppressed microglial activation, reduced NLRP3 expression and IL-1β release, and improved short-term memory deficits after rLLB exposure. Collectively, this study demonstrates that rLLB induces chronic neurobehavioral and neuropathological changes by increasing NLRP3 inflammasome protein expression followed by cytokine IL-1β release.

Isocitrate Dehydrogenase-1 (IDH1) is commonly mutated in lower-grade diffuse gliomas. The IDH1R132H mutation is an important diagnostic tool for tumor diagnosis and prognosis; however, its role in glioma development, and its impact on response to therapy, is not fully understood. We developed a murine model of proneural IDH1R132H-mutated glioma that shows elevated production of 2-hydroxyglutarate (2-HG) and increased trimethylation of lysine residue K27 on histone H3 (H3K27me3) compared to IDH1 wild-type tumors. We found that using Tazemetostat to inhibit the methyltransferase for H3K27, Enhancer of Zeste 2 (EZH2), reduced H3K27me3 levels and increased acetylation on H3K27. We also found that, although the histone deacetylase inhibitor (HDACi) Panobinostat was less cytotoxic in IDH1R132H-mutated cells (either isolated from murine glioma or oligodendrocyte progenitor cells infected in vitro with a retrovirus expressing IDH1R132H) compared to IDH1-wild-type cells, combination treatment with Tazemetostat is synergistic in both mutant and wild-type models. These findings indicate a novel therapeutic strategy for IDH1-mutated gliomas that targets the specific epigenetic alteration in these tumors.

The evaluation, classification, and treatment of significant bone loss after total knee arthroplasty (TKA) continue to be a complex and debated topic in revision TKA (rTKA). Despite the introduction of new evidence and innovative technologies aimed at addressing the approach and care of severe bone loss in rTKA, there is no single document that systematically incorporates these newer surgical approaches. Therefore, a comprehensive review of the treatment of severe bone loss in rTKA is necessary. The Stavros Niarchos Foundation Complex Joint Reconstruction Center Hospital for Special Surgery, dedicated to clinical care and research primarily in revision hip and knee replacement, convened a Management of Bone Loss in Revision TKA symposium on June 24, 2022. At this meeting, the 42 international invited experts were divided into groups; each group was assigned to discuss questions related to 1 of the 4 topics: (1) assessing preoperative workup and imaging, anticipated bone loss, classification system, and implant surveillance; (2) achieving durable fixation in the setting of significant bone loss in revision TKA; (3) managing patellar bone loss and the extensor mechanism in cases of severe bone loss; and (4) considering the use of complex modular replacement systems: hinges, distal femoral, and proximal tibial replacements. Each group came to consensus, when possible, based on an extensive literature review and interactive discussion on their group topic. This document reviews each these 4 areas, the consensus of each group, and directions for future research.

Abstract Background Minimally invasive surgery (MIS) has been associated with lower rates of postoperative complications in ulcerative colitis (UC), both in the elective and emergency setting, compared to the traditional open approach. Despite these findings, some clinical guidelines state that minimally invasive surgery is not superior to open surgery in UC and emphasize an individual approach based on the surgeon’s judgment. This study analyzed the trends in open and minimally invasive approaches in total colectomies for UC. Methods A retrospective analysis was conducted on the ACS-NSQIP database encompassing all patients undergoing total colectomy for UC from 2012 to 2021. The primary endpoint involved analyzing open, laparoscopic, hand-assisted, and robotic surgery trends. A time series analysis was performed to forecast the future direction of these surgical techniques. Quarter (Q) and admission year were reported for time trend analysis. Dynamic relationships between various time series representing different surgical techniques were modeled using Vector Autoregressive (VAR) models. These models were employed to predict future trends in operative approaches until Q2 of 2025, along with 95% confidence intervals. Results A total of 7099 patients (44.5% female) were included, with a mean age of 45.1 (±17.8) years and mean BMI of 25.5 (±7.7) kg/m². Smoking was reported in only 8.7% of patients, with 49.1% classified as ASA 3 and 41.4% as ASA 2. Most patients (71.5%) were on steroids or immunosuppressants at the time of intervention. At the beginning of the study period, nearly half of the interventions were performed with an open approach (45.2%), followed by laparoscopy (35.7%) and hand-assisted laparoscopy (19%). Trends indicated a decline in open surgery to 17.7% by Q2 of 2021, with an increase in laparoscopic (45%), hand-assisted (25%), and a consistent growth of robotic surgery to 12.3%. Forecasting shown in Figure 1 suggested a continuous decrease in open surgery until Q2 of 2025 (8.7%, 95% CI 0-32.5%), with laparoscopic (51.2%, 95% CI 26.4-75.9%), hand-assisted (29.1%, 95% CI 11.9-46.3%), and robotic (11.0%, 95% CI 7.5-14.6%) approaches on the rise. Conclusion Minimally invasive surgical techniques have steadily grown over the past decade in the treatment of ulcerative colitis. Predictions indicate continued growth, displacing traditional open approach, which may persist as a rescue procedure.

Abstract Background Abdominal pain (AP) is common in patients with active inflammatory bowel disease (IBD) and has been associated with poor quality of life (QOL). Despite greater therapeutic options, symptoms persist in a subset of patients. Data is lacking regarding AP in patients with objectively documented quiescent disease. Among endoscopic quiescent disease: (1) estimate prevalence of AP, (2) assess predictors of worse AP, (3) describe its impact on validated QOL measures. Methods This cross-sectional study used prospectively collected data from SPARC (Study of a Prospective Adult Research Cohort) IBD, a multicenter longitudinal study of well-phenotyped adult IBD patients initiated by the Crohn’s & Colitis Foundation in 2016. Quiescent IBD was defined as Mayo endoscopy score <2 for ulcerative colitis (UC) and SES-CD score <3 for Crohn’s disease (CD). Patient reported outcomes (PROs) within 30 days of endoscopy were analyzed. Patients with ostomy or IPAA were excluded. Self-reported AP was categorized as none, mild, or moderate/severe. Univariate statistics used Pearson’s Chi-square and Kruskal-Wallis tests. Results A total of 973 patients with quiescent IBD (606 CD; 367 UC) were included in the study (Table 1). AP was more commonly reported in quiescent CD (31.2% mild, 15.5% moderate/severe) as compared to quiescent UC (23.4% mild, 10.1% moderate/severe) (p<0.001). In the entire quiescent cohort, those with mild or moderate/severe AP were more likely to be female sex (63.1% mild; 67.4% moderate/severe; p<0.001), higher BMI (28.4 mild; 30.0 moderate/severe; p=0.008) and have more recent tobacco use (p=0.004). Ileocolonic involvement was more commonly seen in moderate/severe AP. Mild and moderate/severe AP was associated with subjective fecal urgency, stool frequency, and bloody stool (all p<0.001). Disease behavior in CD was not associated with abdominal pain. General well-being was poorer for those with more severe AP (p<0.001), though this did not appear to result in more frequent recent ED visits or hospitalizations. Figure 1 depicts the PROMIS responses. Overall, worse AP was associated with universal worse scores on all PROMIS measures and subscales (all p<0.001). Data suggested that more severe AP had the greatest impacts on the "Fatigue" subscale. Conclusion In this study of patients in SPARC IBD with endoscopic quiescent IBD the overall prevalence of AP was 41.7% overall and more commonly reported in CD as compared to UC. AP was associated with a greater prevalence of other symptoms, worse general well-being, and poorer quality of life across all measures. Further research is needed to elucidate the pathophysiology for presence of AP in quiescent IBD and develop personalized management approaches.

Abstract Background Crohn's disease (CD) is a chronic inflammatory bowel disorder that can cause transmural inflammation throughout the digestive tract. When CD affects the colon, it is known as Crohn's colitis (CC), a serious condition often requiring surgical resection. Surgical trends in CC have changed significantly over the past decade, shifting towards minimally invasive surgery, with laparoscopic and robotic procedures becoming increasingly common. This study examines how surgical trends in CC have changed in recent years and predicts how they may change. Methods We conducted a retrospective analysis using the ACS-NSQIP database, focusing on patients who underwent colonic resections for CC between 2012 and 2021, including 20,109 patients. Our main goal was to examine trends in open, laparoscopic, hand-assisted, and robotic surgery. We utilized time series analysis, specifically quarter and year of admission data, and employed Vector Autoregressive (VAR) models to explore the dynamic relationships among these surgical techniques. To analyze the time trends, we reported the quarter (Q) and year of admission. These models enabled us to forecast future trends, accompanied by 95% confidence intervals, extending our predictions up until Q2 of 2025. Results As shown in Figure 1, open surgery has been the most common approach to CC since Q1 2012, accounting for 52.3% of all procedures. Laparoscopic surgery was the next most common approach, at 33.3%, followed by hand-assisted laparoscopy at 14.4%. Laparoscopy rapidly expressed market supremacy, by steadily becoming the most widespread approach by Q2 of 2017, representing 42.2% of CC surgery and peaking in Q2 2020 at 43.5%. This growth in laparoscopy came at the expense of open surgery, which experienced a significant decline, reaching its lowest point of 28.5% in Q2 2021. Hand-assisted procedures gradually increased in popularity over the years but remained less popular than open and laparoscopic methods, peaking at 24.0% in Q4 2019. Robotic procedures experienced slow but steady growth, from 1.9% in Q1 2013 to 10% in Q2 2021. Future trends suggest that laparoscopy will continue to grow steadily, reaching 45% (95% CI 28.2-61.7%) by the end of our prediction period. Robotic surgery is poised to significantly shift CC surgery trends, with resections expected to reach 12.6% (95% CI 9.3-15.8%) by Q2 2025, while a subsequent decline in open procedures to 20.8% (95% CI 0-43%). Conclusion Laparoscopic surgery has emerged as the favored surgical approach in CC and is expected to maintain its supremacy into the near future. Open colonic resections are anticipated to decline, making way for the increasing prevalence of robotic surgery.

Abstract Background Colorectal surgery in patients with inflammatory bowel disease (IBD) and cirrhosis is associated with high morbidity related to portal hypertension. Thought to reduce surgical risk, transjugular intrahepatic portosystemic shunt (TIPS) may be used to decrease portal pressures. In this study, we aimed to characterize surgical outcomes of patients with IBD and cirrhosis who underwent preoperative TIPS at a large tertiary care center. Methods We retrospectively identified patients with IBD and cirrhosis who had undergone TIPS between 2010-2023 for portal decompression prior to colorectal surgery. All other indications for TIPS led to patient exclusion. Demographic and medical data was collected, including surgical indication and portal pressure measurement. Data on surgical outcomes were compiled through chart review. Results We identified 10 patients (60% male) with IBD and history of decompensated cirrhosis who underwent preoperative TIPS for portal decompression (Table 1). Surgical indications were colonic dysplasia (50%), refractory IBD (50%), and stenosis or stricture (30%). All patients were deemed nonsurgical candidates due to significant surgical risk from portal hypertension. Following multidisciplinary coordination, patients underwent TIPS for portal decompression at a median of 47 days (IQR 34-80) prior to colorectal surgery. TIPS was associated with significant reduction in portal pressure (22.5 vs 18.5mmHg, p<0.01) and portosystemic gradient (12.5 vs 5.5mmHg, p<0.01) in all patients. Of 10 patients, 30% had TIPS-related complications (transient fluid overload and encephalopathy). In terms of surgical complications, 40% of patients required intraoperative blood transfusion (range: 1-4 units). Postoperatively, 30% of patients had surgical site bleeding and 10% had wound dehiscence, although none required reoperation. Systemic complications occurred in 30% of patients, with systemic signs of infection being the most common. Transaminitis (50%) and coagulopathy (40%) were also common. Median hospital stay was 7 days (IQR 5.5-9.3), with 40% of patients being readmitted within 30 days. Most common cause of readmission was systemic infection (75%), abdominal abscess (50%), or electrolyte abnormality (50%), with one patient requiring reoperation for wound dehiscence. Ninety-day and 1-year survival was 100% and 90% respectively. Conclusion In our series of patients with IBD and cirrhosis requiring surgery but deemed nonsurgical candidates, preoperative TIPS lead to portal decompression and facilitated successful surgical intervention despite heightened risk. Nevertheless, significant operative and postoperative complications were noted. Future studies are needed to determine optimal surgical timing following TIPS placement.

Abstract Background Ulcerative colitis (UC) has a detrimental impact on patients’ health-related quality of life (HRQoL).1 Long-term treatment goals for patients with moderately to severely active UC include restoration of HRQoL. This post-hoc analysis evaluated the effect of induction and maintenance treatment with risankizumab (RZB) on HRQoL outcomes. Methods Data from two Phase 2b/3 clinical trials (INSPIRE induction: NCT03398148 and COMMAND maintenance: NCT03398135) were evaluated. Patients received RZB 1200 mg intravenous (IV) or placebo (PBO) induction treatment at weeks 0, 4, and 8. Patients with a clinical response per Adapted Mayo score to RZB IV were randomised 1:1:1 to subcutaneous (SC) RZB 180 or 360 mg, or placebo (PBO [RZB withdrawal] SC) every 8 weeks for 52 weeks of maintenance. The proportion of patients achieving a meaningful within-person change (MWPC) for each HRQoL outcome was reported. HRQoL outcomes included Functional Assessment of Chronic Illness Therapy-Fatigue, disease-specific instruments such as Inflammatory Bowel Disease Questionnaire (IBDQ) and Ulcerative Colitis Symptom Questionnaire (UCSQ), as well as generic quality-of-life questionnaires like Work Productivity and Activity Index-Ulcerative Colitis (WPAI-UC), 36-Item Short-Form Survey (SF-36), and EuroQoL 5 Dimensions 5 Levels. MWPCs were measured from baseline to induction Week 12 and to maintenance Week 52. Estimated differences in proportions with 95% confidence intervals and p-values between RZB and PBO were compared using the Cochran-Mantel-Haenszel test adjusting for baseline strata. Results For RZB 1200 mg IV (n=650) versus PBO IV-treated (n=325) patients, a greater proportion of patients achieved MWPC across all HRQoL outcomes at Week 12 of induction (p<0.01; Table). At Week 52 of maintenance, a greater proportion of patients treated with RZB 180 mg SC (N=179) versus PBO (withdrawal) SC (N=183) achieved MWPC across all HRQoL outcomes (p<0.05), except for absenteeism from WPAI-UC (p=0.33). For RZB 360 mg SC (N=186) versus PBO (withdrawal) SC, a greater proportion of patients achieved MWPC for UCSQ, IBDQ, and SF-36 physical component summary (all p<0.05). Conclusion In this analysis, a greater proportion of patients treated with RZB versus PBO achieved MWPC on various HRQoL outcomes after completing 12-week induction IV therapy. HRQoL improvements were sustained up to Week 52 of treatment. This suggests RZB has the potential to help patients achieve restoration of HRQoL as a long-term goal of treatment in patients with moderately to severely active UC. 1. Mavroudis G. Therap Adv Gastroenterol. 2022;15:17562848211062406.