Background: Clinicians often utilize off-label dose escalation of ustekinumab (UST) in Crohn’s disease (CD) patients with disease refractory to standard dosing. Previous studies report mixed results with dose escalation of UST. Methods: A retrospective observational study of 143 adult patients with CD receiving UST over a 33-month time period was conducted. Patients receiving UST at standard dosage for a minimum of 16 weeks were included in the analysis. Primary outcomes collected were clinical response [Physician Global Assessment Score (PGA) by >1] and remission (PGA = 0). Changes in clinical parameters were calculated for dose-escalated patients beginning with the time of dose switch (~42 weeks) and compared with a group of patients who were classified as “failing” standard dosing at 42 weeks who were not dose escalated. Results: Dose escalation improved PGA by 0.47 ± 0.19 compared with patients remaining on every 8 weeks dosing (Q8 week), who worsened by 0.23 ± 0.23 ( p < 0.05). Dose escalation decreased CRP 0.33 ± 0.19 mg/L and increased serum albumin 0.23 ± 0.06 g/dL ( p < 0.05). Surprisingly, disease duration and prior CD surgeries inversely correlated with the need for dose escalation. Conclusion: Our results support UST Q4 week dose escalation for selected CD patients who fail to achieve remission on standard Q8 week dosing. Dose escalation improves clinical outcomes, prevents worsening disease severity, and positively impacts CRP and albumin levels. Together these data indicate that clinicians should attempt Q4 week UST dosing in refractory CD patients before switching to an alternative class of biologic therapy.
Adipose tissue dysfunction is strongly linked to the development of chronic inflammation and cardiometabolic disorders in aging. While much attention has been given to the role of resident adipose tissue immune cells in the disruption of homeostasis in obesity, age-specific effects remain understudied. Here, we identified and characterized a population of γδ T cells, which show unique age-dependent accumulation in the visceral adipose tissue (VAT) of both mice and humans. Diet-induced obesity likewise increased γδ T cell numbers; however, the effect was greater in the aged where the increase was independent of fat mass. γδ T cells in VAT express a tissue-resident memory T cell phenotype (CD44hiCD62LlowCD69+) and are predominantly IL-17A-producing cells. Transcriptome analyses of immunomagnetically purified γδ T cells identified significant age-associated differences in expression of genes related to inflammation, immune cell composition, and adipocyte differentiation, suggesting age-dependent qualitative changes in addition to the quantitative increase. Genetic deficiency of γδ T cells in old age improved the metabolic phenotype, characterized by increased respiratory exchange ratio, and lowered levels of IL-6 both systemically and locally in VAT. Decreased IL-6 was predominantly due to reduced production by non-immune stromal cells, primarily preadipocytes, and adipose-derived stem cells. Collectively, these findings suggest that an age-dependent increase of tissue-resident γδ T cells in VAT contributes to local and systemic chronic inflammation and metabolic dysfunction in aging.
BACKGROUND The migration rate of fully covered self-expandable metal stents (FCSEMSs) has been reported to be between 14% to 37%. Anchoring of FCSEMSs using a double-pigtail plastic stent (DPS) may decrease migration. AIM To compare stent migration rates between patients who received FCSEMS alone and those who received both an FCSEMS and anchoring DPS. METHODS We conducted a retrospective analysis of endoscopy reporting system and medical records of 1366 patients who underwent endoscopic retrograde cholangiopancreatography (ERCP) with FCSEMS placement at the University of Kentucky health care. Between July 2015 and April 2017, 203 patients with FCSEMS insertion for the treatment of malignant biliary stricture, benign biliary stricture, post-sphincterotomy bleeding, bile leak, and cholangitis drainage were identified. The review and analysis were conducted through our endoscopy reporting system (ProVation ® MD) and medical records. Categorical data were analyzed using Chi-Square and Fischer exact test and continuous data using non-parametric tests. A regression analysis was performed to identify factors independently associated with increased risk of stent migration. We determined an FCSEMS migration endoscopically if the stent was no longer visible in the major papilla. RESULTS 1366 patients had undergone ERCP by three advanced endoscopists over 21-mo period; among these, 203 patients had FCSEMSs placed. 65 patients had FCSEMSs with DPS, and 138 had FCSEMSs alone. 65 patients had FCSEMSs with DPS, and 138 had FCSEMSs alone. 95 patients had a malignant stricture, 82 patients had a benign stricture, 12 patients had bile leak, 12 patients had cholangitis, and nine patients had post-sphincterotomy bleeding. The migration rate in patients with anchored FCSEMSs with DPS was 6%, and those without anchoring DPS was 10% ( P = 0.35). Overall, migration was reported in 18 patients with FCSEMSs placement out of 203 patients with an overall migration rate of 9.7%. There was no significant association between anchoring the FCSEMSs with DPS and the risk of stent migration. Only patients with the previous sphincterotomy and begin biliary stricture were found to have a statistically significant difference in the migration rate between patients who had FCSEMS with DPS and FCSEMS alone ( P = 0.01). CONCLUSION The risk of migration of biliary FCSEMS was 9.7 %. Anchoring an FCSEMS with DPS does not decrease the risk of stent migration.
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