Citations

AbstractBackgroundThis study investigates the impact of margin status after colorectal liver metastasis (CLM) resection on outcomes of patients after neoadjuvant treatment versus those who underwent upfront resection.MethodsAn international collaborative database of CLM patients who underwent surgical resection was used. Proportional hazard regression models were created for single and multivariable models to assess the relationship between independent measures and median overall survival (mOS).ResultsR1 was associated with worse OS in the neoadjuvant group (mOS: 51.8 m for R0 vs. 26.0 m for R1; HR: 2.18). In the patients who underwent upfront surgery, R1 was not associated with OS. (mOS: 46.7 m for R0 vs. 42.6 m for R1). When patients with R1 in each group were stratified by adjuvant treatment, there was no significant difference in the neoadjuvant group, while in the upfront surgery group with R1, adjuvant treatment was associated with significant improvement in OS (mOS: 42.6 m for adjuvant vs. 25.0 m for no adjuvant treatment; HR: 0.21).ConclusionR1 is associated with worse outcomes in the patients who receive neoadjuvant treatment with no significant improvement with the addition of adjuvant therapy, likely representing an aggressive tumor biology. R1 did not impact OS in patients with upfront surgery who received postoperative chemotherapy.

Background: Bipolar disorder (BD) involves significant mood and energy shifts reflected in speech patterns. Detecting these patterns is crucial for diagnosis and monitoring, currently assessed subjectively. Advances in natural language processing offer opportunities to objectively analyze them. Aims: To (i) correlate speech features with manic-depressive symptom severity in BD, (ii) develop predictive models for diagnostic and treatment outcomes, and (iii) determine the most relevant speech features and tasks for these analyses. Methods: This naturalistic, observational study involved longitudinal audio recordings of BD patients at euthymia, during acute manic/depressive phases, and after-response. Patients participated in clinical evaluations, cognitive tasks, standard text readings, and storytelling. After automatic diarization and transcription, speech features, including acoustics, content, formal aspects, and emotionality, will be extracted. Statistical analyses will (i) correlate speech features with clinical scales, (ii) use lasso logistic regression to develop predictive models, and (iii) identify relevant speech features. Results: Audio recordings from 76 patients (24 manic, 21 depressed, 31 euthymic) were collected. The mean age was 46.0 ± 14.4 years, with 63.2% female. The mean YMRS score for manic patients was 22.9 ± 7.1, reducing to 5.3 ± 5.3 post-response. Depressed patients had a mean HDRS-17 score of 17.1 ± 4.4, decreasing to 3.3 ± 2.8 post-response. Euthymic patients had mean YMRS and HDRS-17 scores of 0.97 ± 1.4 and 3.9 ± 2.9, respectively. Following data pre-processing, including noise reduction and feature extraction, comprehensive statistical analyses will be conducted to explore correlations and develop predictive models. Conclusions: Automated speech analysis in BD could provide objective markers for psychopathological alterations, improving diagnosis, monitoring, and response prediction. This technology could identify subtle alterations, signaling early signs of relapse. Establishing standardized protocols is crucial for creating a global speech cohort, fostering collaboration, and advancing BD understanding.

AbstractBackgroundThermal ablation has recently become a key therapy for the treatment of colorectal liver metastasis (CLM). However, the role of ablation in combination with resection has not yet been firmly established. We hypothesize that in patients with CLM, those who undergo liver resection with ablation (RA) have similar outcomes compared with those who undergo liver resection only.MethodsWe reviewed a multicenter international database of 906 surgical procedures for CLM from 5 high volume hepatobiliary surgical units. Patients undergoing RA (n = 63) were matched based on the number of lesions and tumor size using a 1:1 balanced propensity score analysis with those having resection only (n = 63). Our primary outcomes were overall survival (OS) and disease‐free survival (DFS).ResultsThe mean age of our cohort was 58 ± 11 years, with 43% females. With a median follow‐up of 70.8 months, patients in the resection and RA group had a median OS of 45.1 and 54.8 months (p = 0.71), respectively. The median DFS was 22.7 and 14.2 months (p = 0.045), respectively. Using a multivariate Cox proportional hazards regression model, the treatment approach was not associated with OS (p = 0.94) or DFS (p = 0.059). A higher number of lesions is independently associated with worse DFS (hazard ratio: 1.12, p < 0.01). When there was disease recurrence, the region of recurrence was similar between the RA versus resection only groups (p = 0.27), but there was a shorter time to recurrence in the RA group (p = 0.002).ConclusionFor CLM, the treatment approach was not significantly associated with OS or DFS, while tumor biology likely played an important role. Prospective research on the quality and effectiveness of thermal ablation combined with hepatic resection is warranted.

Importance The clinical effects of risankizumab (a monoclonal antibody that selectively targets the p19 subunit of IL-23) for the treatment of ulcerative colitis are unknown. Objective To evaluate the efficacy and safety of risankizumab when administered as an induction and a maintenance therapy for patients with ulcerative colitis. Design, Setting, and Participants Two phase 3 randomized clinical trials were conducted. The induction trial was conducted at 261 clinical centers (in 41 countries) and enrolled 977 patients from November 5, 2020, to August 4, 2022 (final follow-up on May 16, 2023). The maintenance trial was conducted at 238 clinical centers (in 37 countries) and enrolled 754 patients from August 28, 2018, to March 30, 2022 (final follow-up on April 11, 2023). Eligible patients had moderately to severely active ulcerative colitis; a history of intolerance or inadequate response to 1 or more conventional therapies, advanced therapies, or both types of therapies; and no prior exposure to risankizumab. Interventions For the induction trial, patients were randomized 2:1 to receive 1200 mg of risankizumab or placebo administered intravenously at weeks 0, 4, and 8. For the maintenance trial, patients with a clinical response (determined using the adapted Mayo score) after intravenous treatment with risankizumab were randomized 1:1:1 to receive subcutaneous treatment with 180 mg or 360 mg of risankizumab or placebo (no longer receiving risankizumab) every 8 weeks for 52 weeks. Main Outcomes and Measures The primary outcome was clinical remission (stool frequency score ≤1 and not greater than baseline, rectal bleeding score of 0, and endoscopic subscore ≤1 without friability) at week 12 for the induction trial and at week 52 for the maintenance trial. Results Among the 975 patients analyzed in the induction trial (aged 42.1 [SD, 13.8] years; 586/973 [60.1%] were male; and 677 [69.6%] were White), the clinical remission rates at week 12 were 132/650 (20.3%) for 1200 mg of risankizumab and 20/325 (6.2%) for placebo (adjusted between-group difference, 14.0% [95% CI, 10.0%-18.0%], P &amp;lt; .001). Among the 548 patients analyzed in the maintenance trial (aged 40.9 [SD, 14.0] years; 313 [57.1%] were male; and 407 [74.3%] were White), the clinical remission rates at week 52 were 72/179 (40.2%) for 180 mg of risankizumab, 70/186 (37.6%) for 360 mg of risankizumab, and 46/183 (25.1%) for placebo (adjusted between-group difference for 180 mg of risankizumab vs placebo, 16.3% [97.5% CI, 6.1%-26.6%], P &amp;lt; .001; adjusted between-group difference for 360 mg of risankizumab vs placebo, 14.2% [97.5% CI, 4.0%-24.5%], P = .002). No new safety risks were detected in the treatment groups. Conclusion and Relevance Compared with placebo, risankizumab improved clinical remission rates in an induction trial and in a maintenance trial for patients with moderately to severely active ulcerative colitis. Further study is needed to identify benefits beyond the 52-week follow-up. Trial Registration ClinicalTrials.gov Identifiers: NCT03398148 and NCT03398135

This case report indicates that a recreationally trained 58-year-old man can reach similar or even higher values of energy expenditure (∼4 times their basal metabolic rate) than professional cyclists, who are likely near the ceiling of sustained energy expenditure for humans. This was possible owing to a total longer exercise time coupled with a lower absolute and relative intensity in the recreational athlete.

Abstract Background Inflammatory regulatory T cells (Tregs) are one of the hallmarks of therapy resistance. Yet mechanisms leading to inflammatory Treg development and its contribution to inflammatory bowel disease (IBD) are unexplored. Methods Tregs derived from healthy PBMCS were characterized by immune and mitochondrial phenotyping. Transcripts were validated in dataset from IBD intestinal lesions. Wildtype (WT) and IL21 receptor-deleted (Il21r−/−) Tregs were examined in murine models of CD4+ T cell-induced colitis. Results Through in vitro cytokine challenge of Tregs and subsequent analysis, we found that IL21 induces Tregs co-expressing TNF, IFNγ and IL17. Transcriptomic and metabolomic integration revealed upregulation of mRNA and metabolites associated with glycolysis, and amino acid, nucleotide and lipid metabolism. Moreover, IL21-induced metabolic transcripts were more enriched in Treg cluster within scRNA-seq dataset from intestinal lesions of anti-TNF non-responders vs. non-responders. Mechanistically, cell imaging and real-time bioenergetic analysis revealed disruption to mitochondria-ER ultrastructure and function, coinciding with glycogen synthase kinase 3β (GSK3β) activation and glycolytic switch rather than pyruvate-mediated oxidative phosphorylation. GSK3β inhibition or methyl pyruvate supplementation rescued IL21-induced metabolic and inflammatory phenotypes. In contrast to WT Tregs, murine Il21r−/− Treg transfer efficiently prevented and rescued CD4+CD45Rbhigh T cell-induced colitis. Conclusions IL21-induced metabolic dysfunction can incapacitate Treg immunosuppressive function. Desensitizing Tregs to IL21 through various therapeutic approaches can alleviate IBD. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) K01DK124358, the Pilot & Feasibility Award by the Center for Cell Signaling in Gastroenterology (P30DK084567), and the Mayo Clinic Center for Biomedical Discovery Career Development Award, and David F. and Margaret T. Grohne Cancer Immunology and Immunotherapy (to AOB).

Background: NASH is the progressive form of NAFLD characterized by lipotoxicity, hepatocyte injury, tissue inflammation, and fibrosis. Previously, Rho-associated protein kinase (ROCK) 1 has been implicated in lipotoxic signaling in hepatocytes in vitro and high-fat diet-induced lipogenesis in vivo. However, whether ROCK1 plays a role in liver inflammation and fibrosis during NASH is unclear. Here, we hypothesized that pathogenic activation of ROCK1 promotes murine NASH pathogenesis. Methods and Results: Patients with NASH had increased hepatic ROCK1 expression compared with patients with fatty liver. Similarly, hepatic ROCK1 levels and activity were increased in mice with NASH induced by a western-like diet that is high in fat, fructose, and cholesterol (FFC). Hepatocyte-specific ROCK1 knockout mice on the FFC diet displayed a decrease in liver steatosis, hepatic cell death, liver inflammation, and fibrosis compared with littermate FFC-fed controls. Mechanistically, these effects were associated with a significant attenuation of myeloid cell recruitment. Interestingly, myeloid cell-specific ROCK1 deletion did not affect NASH development in FFC-fed mice. To explore the therapeutic opportunities, mice with established NASH received ROCKi, a novel small molecule kinase inhibitor of ROCK1/2, which preferentially accumulates in liver tissue. ROCK inhibitor treatment ameliorated insulin resistance and decreased liver injury, inflammation, and fibrosis. Conclusions: Genetic or pharmacologic inhibition of ROCK1 activity attenuates murine NASH, suggesting that ROCK1 may be a therapeutic target for treating human NASH.