Citations

We show how switching from a regular diet to an HCHF increases cholesterol absorption in patients with normal weight and obesity. The decrease in cholesterol absorption from an HCHF to an LCLF, on the other hand, was only seen in normal-weight controls, underlining the importance of body weight in this regulation. In addition, changes in caloric and fat content had an immediate and direct effect on hepatic bile acid production.

Abstract Background: Uveal melanoma (UM) is a rare tumor of the eye which is biologically distinct from cutaneous melanoma (CM) and carries a poor prognosis once metastatic. We aimed to examine a multi-omics profile of UM as compared to CM. Methods: A total of 277 UM and 1,297 CM metastatic or primary samples were analyzed using next-generation sequencing (NextSeq, 592 genes and WES, NovaSeq, >700 genes) and whole transcriptome sequencing (WTS; NovaSeq) (Caris Life Sciences). Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cutoff >10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. T- cell inflamed score was calculated using gene expression data. Pathway gene enrichment analysis using WTS data was performed using GSEA. Biostatistical significance was determined using chi-square/Fisher-Exact or Wilcoxon rank sum test and adjusted for multiple comparisons. Results: For all cases (primary and metastatic), UM compared to CM had a higher rate of GNAQ/11 (93.8% vs. 2.1% p≤0.001), SF3B1 (20.4% vs 3% p≤0.001), and BAP1 (52.9% vs. 1.5% p≤0.001) mutations. UM also had higher levels of MYC (7% vs 0.9% p≤0.001), NCOA2 (3.1% vs 0.1% p≤0.001), and RUNX1T1 genomic amplifications (2.3% vs 0.2% p≤0.001). Assessing only samples of liver metastases, UM was shown to have higher abundance of M2 macrophages (P≤0.0001) and less abundance of M1 macrophages(P≤0.0001), monocytes(P≤0.0001), CD4 T-cells(P≤0.0001), and regulatory T-cells (p = 0.0003) as compared to CM. GSEA comparison between liver metastases of UM and CM samples showed G2M checkpoint (NES score, 1.60 p≤0.0001) and E2F targets (NES score, 1.58 p=0.002) to be higher in metastatic CM. When comparing T-cell inflamed, intermediate, and non-inflamed tumors from any site, CM or UM, the average Z scores for both G2M and E2F were highest for inflamed and lowest for non-inflamed, P≤0.0001. A similar trend of higher Z score was seen for TMB high vs TMB low tumors, p≤0.0001. Conclusions: UM and CM are characterized by significantly different genomic and transcriptomic alterations, and cellular composition of TME. Further understanding of these characteristics may lead to better treatment strategies for metastatic UM. Citation Format: Justin C. Moser, Yusra F. Shao, Joanne Xiu, Yasmine Baca, Takami Sato, Lauren A. Dalvin, Sourat Darabi, Michael Korn, Burton Eisenberg, Geoff Gibney, Evidio Domingo-Musibay, Gino In, Dave Hoon, Michael S. Gordon. Multi-omics and immune cell profiling of metastatic uveal melanomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 50.

LINKED CONTENTThis article is linked to Quinn et al papers. To view these articles, visit https://doi.org/10.1111/apt.16859 and https://doi.org/10.1111/apt.16954

LINKED CONTENTThis article is linked to Quinn et al papers. To view these articles, visit https://doi.org/10.1111/apt.16859 and https://doi.org/10.1111/apt.16916

INTRODUCTION: Cannabidiol (CBD), a CBR2 agonist with limited psychic effects, antagonizes CB1/CB2 receptors. Allelic variation CNR1 (gene for CBR1) rs806378 and FAAH rs324420 were associated with altered gut motility and sensation. This study aimed to compare the pharmacodynamics and clinical effects of a 4-week treatment with pharmaceutical-grade CBD vs placebo and assess the interactions of FAAH and CNR1 gene variants on the effects of CBD in patients with functional dyspepsia (FD). METHODS: We performed a randomized, double-blinded, placebo-controlled (1:1 ratio) study of CBD b.i.d. (20 mg/kg/d according to the US Food and Drug Administration escalation guidance) in FD patients with nondelayed gastric emptying (GE) at baseline. Symptoms were assessed by validated daily symptom diary (0–4 scale for upper abdominal pain, nausea, and bloating), weekly assessment of adequate relief, Leuven Postprandial Distress Scale (8 symptoms, adjectival scores rated 0–4 for severity), and quality of life (Short-Form Nepean Dyspepsia Index [average of 10 dimensions each on a 5-point scale]). After the 4-week treatment, all patients underwent measurements of GE of solids, gastric volumes, and Ensure nutrient satiation test. Statistical analysis compared 2 treatments for all endpoints and the effects of CBD in association with FAAH rs324420 and CNR1 rs806378. RESULTS: CBD and placebo effects on physiological functions and patient response outcomes were not significantly different. There were borderline CBD treatment-by-genotype interactions: rs806378 CNR1 with Leuven Postprandial Distress Scale ( P = 0.06) and GE solids ( P = 0.12). DISCUSSION: Approved doses of CBD used off-label do not relieve FD with normal baseline GE of solids or alter gastric motor functions and satiation. CBD treatment-by-gene interactions suggest potential benefits for postprandial distress with CNR1 rs806378 T allele.

AbstractBackgroundRecent studies with functional endoluminal imaging probe (EndoFLIP®) measure physiologic characteristics of the pylorus. EndoFLIP® has the potential to select optimal candidates for gastric peroral endoscopic myotomy (G‐POEM). Normative values of the pylorus using EndoFLIP® have not been established.MethodsTwenty‐four healthy volunteers (20–56 years old; 15 females) underwent unsedated, transoral EndoFLIP® measurements of the pylorus after 8 h of fasting. Measurements of diameter (DM), balloon pressure, and distensibility index (DI) of the pylorus were obtained twice over 5 min at 40, 50, and 60 ml balloon distensions.Key ResultsPyloric DM at 40, 50, and 60 ml balloon distensions were 13.0 ± 2.5, 14.3 ± 1.8, and 17.2 ± 2.0 mm, respectively. DM with 60 ml distension was notably higher than with 40 and 50 ml distensions. Pyloric DI at 40, 50, and 60 ml distensions were 10.9 ± 4.8, 11.3 ± 5.8, and 11.1 ± 4.3 mm2/mm Hg, respectively (p = 0.86). Linear regression and Bland–Altman plots showed similar distribution of the DM and DI during the second minute compared with the full 5‐min measurements at 50 ml distension, as well as between two sequential measurements using 50 ml distension. With 50 ml balloon distension, intraindividual coefficients of variation (COVintra) for DM and DI were 13.8% and 29.6%, respectively, and interindividual COV (COVinter) were 12.6% and 51.3%, respectively. Similar reproducibility was obtained with 40 ml balloon distension.Conclusions and InferencesUnsedated EndoFLIP® can be used to characterize human fasting pyloric diameter and distensibility, with best performance observed with 40 ml and 50 ml distensions and data collection during the second minute. Normative values reported serve as reference values for future studies.

AbstractBackgroundThe early phase of the coronavirus disease 2019 (COVID‐19) pandemic had a negative impact on the wellness of hospitalists and hospital medicine advanced practice providers (APPs). However, the burden of the pandemic has evolved and the change in hospitalist and hospital medicine APP wellness is unknown.ObjectiveTo evaluate the longitudinal trend in wellness of hospitalists and hospital medicine APPs during the COVID‐19 pandemic and guide wellness interventions.Design, Setting and ParticipantsBetween May 4, 2020, and June 6, 2021, we administered three surveys to Internal Medicine hospitalists (physicians) and hospital medicine APPs (nurse practitioners and physician assistants) at 16 Mayo Clinic hospitals in four U.S. states.MeasurementsWe evaluated the association of hospitalist and hospital medicine APP characteristics with PROMIS® measures of global wellbeing‐mental health, global wellbeing‐social activities and relationships, anxiety, social isolation, and emotional support, using logistic and linear regression models.ResultsThe response rates were 52.2% (n=154/295; May 2020), 37.1% (n=111/299; October 2020) and 35.5% (n=114/321; May 2021). In mixed models that included hospitalist and hospital medicine APP characteristics and survey period, APPs, compared with physicians, had lower odds of top global wellbeing‐social activities and relationships (adjusted odds ratio 0.42 [0.22–0.82]; p = .01), whereas survey period showed no association. The survey period showed an independent association with higher anxiety (May 2020 vs. others) and higher social isolation (October 2020 vs. others), whereas profession showed no association. Concern about contracting COVID‐19 at work was significantly associated with lower odds of top global wellbeing‐mental health and global wellbeing‐social activities and relationships, and with higher anxiety and social isolation. Hospitalist and hospital medicine APP characteristics showed no association with levels of emotional support.ConclusionsIn this longitudinal assessment of hospitalists and hospital medicine APPs, concern about contracting COVID‐19 at work remained a determinant of wellness. The trend for global wellbeing, anxiety, and social isolation may guide wellness interventions.

Introduction: Higher body mass index (BMI) is an independent risk factor for incident atrial fibrillation (AF). However, its impact on management strategies and clinical outcomes among patients with prevalent AF is unclear. Methods: The study cohort included patients with AF enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry from June 2010 through August 2011. Participants with BMI > 18.5 kg/m2 were stratified into normal (18.5 - 25 kg/m2), overweight (25 - 30 kg/m2), Class I obese (30 - 35 kg/m2), Class II obese (35 - 40 kg/m2), and Class III obese (>40 kg/m2) categories. Unadjusted and adjusted Cox frailty models were constructed to assess the categorical and continuous association of BMI with AF progression, mortality, and incidence of thromboembolic events. Results: We evaluated 9,606 patients with AF (mean age: 74 + 11 years; 42% women) from 174 US ORBIT participating practices. Patients in the higher BMI categories were younger and had a higher prevalence of comorbidities such as diabetes, hypertension, and obstructive sleep apnea. AF symptom burden was greatest among patients in extreme BMI categories. Proportional use of anticoagulation, antiarrhythmic drugs, and invasive rhythm control strategies was significantly greater among patients in higher BMI categories. Rates for mortality and stroke/non-CNS embolism decreased in a near linear fashion across successively higher BMI categories (P<0.001; Table). After multivariable adjustment, higher BMI categories were associated with lower risk for mortality (p = 0.0002), with the lowest risk observed among overweight patients [Hazard Ratio (HR) (95% CI): 0.65 (0.54 - 0.79) ref. group: normal weight]. For every 5-kg/m2 increase in BMI, the odds of risk-adjusted mortality were 6% lower [HR (95% CI): 0.94 (0.89 - 0.98)]. In contrast, the association between BMI and risk for stroke/non-CNS embolism was significant on unadjusted analysis (P <0.001) but attenuated after adjustment for risk factors (P = 0.78; Table). No significant association was observed between BMI and AF progression rates in either unadjusted (P = 0.35) or adjusted analyses (P = 0.17). Conclusion: Among patients with AF, higher BMI was associated with a greater use of anticoagulation, rhythm control strategies, and lower mortality risk.

SummaryBackgroundMost patients experience good functional outcomes following ileal pouch‐anal anastomosis (IPAA) for ulcerative colitis.AimWe aimed to determine if asymptomatic patients with an IPAA had findings consistent with normal defecation on standard objective anorectal tests.MethodsPatients 18–65 years old with IPAA and self‐reported healthy pouch function were recruited. Patients with chronic pouchitis, Crohn’s disease, anastomotic stricture, or indication for IPAA other than ulcerative or indeterminate colitis were excluded. Patients underwent an interview with an abbreviated Rome Questionnaire followed by high‐resolution ano‐pouch manometry, balloon expulsion test, pouch barostat, and magnetic resonance (MR) defecography.ResultsTwenty patients completed all testing. Six patients were excluded from the final analysis due to symptoms suggestive of pouch evacuation disorder on the abbreviated Rome Questionnaire (n = 2), structural abnormality on MR imaging (n = 3), or both (n = 1). Of the remaining 14 patients, mean anal resting pressure during high‐resolution manometry was 72 ± 16 mmHg, mean anal squeeze pressure was 247 ± 69 mmHg, and mean pouch‐anal gradient during the simulated evacuation was −27 ± 37 mmHg. The meantime to balloon expulsion was 54 seconds. During dynamic MR defecography, the mean descent of ano‐pouch junction was 2.6 cm, and mean pouch evacuation was 44.5% and 74.2% pre‐ and posttoilet phase, respectively.ConclusionsA substantial proportion of patients with IPAA and self‐reported healthy pouch function have anatomic and/or functional abnormalities of the pouch. In asymptomatic IPAA patients with an anatomically normal pouch, we have proposed normal parameters for high‐resolution ano‐pouch manometry, time to balloon expulsion, pouch barostat, and MR defecography.