Citations

ABSTRACT Introduction Calcineurin inhibitors (CNIs) are the cornerstone of lung transplant immunosuppression but are associated with nephrotoxicity and other adverse effects. Although dose reduction and combination with Sirolimus, a mammalian target of rapamycin inhibitor (mTORi), have been explored, full conversion to Sirolimus remains uncommon. This study describes the characteristics and outcomes of lung transplant recipients who underwent complete CNI withdrawal and conversion to Sirolimus. Methods This retrospective case series included 52 lung transplant recipients transitioned to Sirolimus‐based immunosuppression between 2010 and 2021. Data on demographics, transplant characteristics, immunosuppression, and outcomes were collected from electronic medical records. Results The cohort included 31 males (59.6%) with a median age of 58.4 years (IQR 52.3–63.5). The primary indication for CNI withdrawal was renal dysfunction (73.1%). Sirolimus discontinuation occurred in 69.2%, most commonly due to edema (25.0%), lung toxicity (19.4%), rejection (19.4%), and surgical needs (22.2%). Clinically significant rejection occurred in 13.5%, with four patients progressing to chronic lung allograft dysfunction (CLAD) and two deaths. Sixteen patients (30.8%) tolerated CNI withdrawal for over a year. Conclusion Full conversion from CNI to Sirolimus is poorly tolerated due to side effects and has a high incidence of rejection. Further studies are needed to optimize patient selection and risk mitigation strategies.

Abstract Background We investigated the relationship between cumulative, historical antibiotic therapy and the presence of ceftriaxone-resistant (CRO-R) Enterobacterales bloodstream infections (BSI) from urinary sources. Methods Adult patients established with primary care at Mayo Clinic with a first episode of monomicrobial Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, or Proteus mirabilis BSI from a urinary source from May 2019 to May 2023 were included. Antibiotic therapy over the year prior to BSI was quantified as days of therapy (DOT), cumulative modified Antibiotic Spectrum Index (mASI), and cumulative Days of Antibiotic Spectrum Coverage (DASC) using prescription data. Patients with CRO-R urinary pathogens prior to antibiotic therapy assessment were excluded. Results In total, 721 adults had monomicrobial gram-negative BSI, including 70 patients (9.7%) with a CRO-R pathogen and 651 patients (90.3%) with a ceftriaxone-susceptible (CRO-S) pathogen. In the 12 months prior to BSI, levels of antibiotic DOT, mASI, and DASC were significantly greater among patients with CRO-R BSI than CRO-S BSI (P < .001). The median time from blood culture collection to appropriate antibiotic therapy was significantly longer in the CRO-R group (24 hours, interquartile range [IQR] 16–48) than the CRO-S group (1 hour, IQR 0–2) (P < .001). Increasing cumulative antibiotic therapy prior to BSI, as quantified by the mASI, was significantly associated with increased risk of 1-year CDI after BSI (P = .027). Conclusions Patients with first episode CRO-R Enterobacterales BSI had significantly greater prior antibiotic exposure than patients with CRO-S BSI and experienced significant delay of appropriate therapy. Routine quantitation and reporting of prior antibiotic therapy may improve empiric prescribing.

Abstract Background FGFR alterations are known to be driver alterations in several tumor types. We aimed to assess the efficacy of pemigatinib, an oral FGFR1-3 inhibitor, in patients with metastatic or unresectable colorectal cancer whose tumors harbored FGF/FGFR alterations. Patients and Methods The ACCRU-GI-1701 is a single-arm phase II trial which enrolled patients with previously treated FGF/FGFR-altered metastatic colorectal cancer to receive oral pemigatinib daily in 21-day cycles. The primary endpoint is objective response. Secondary endpoints include clinical benefit, progression-free survival, overall survival, quality of life, and adverse events (AEs). This trial was registered with ClinicalTrials.gov (NCT04096417). Results Of the 14 patients included in the interim analysis, the objective response rate as well as clinical benefit rate were 0%. Given these results, the trial closed to enrollment after stage one due to futility. A total of 42.9% of patients had at least one grade 3 or higher AE, the most common being anemia and fatigue. Conclusion Pemigatinib monotherapy did not lead to objective responses in patients with chemorefractory metastatic colorectal cancer harboring FGF/FGFR alterations, although it was overall relatively well tolerated with no new safety signals. Notably, 93% (n = 13) of patients had only FGF/FGFR mutations and amplifications; one patient had an FGFR3-WHSC1 fusion at a low cfDNA percentage (0.02%).

ABSTRACTBackgroundThe intestinal barrier protects humans from potentially deleterious ingested material. It consists of several components: commensal organisms, mucus, and transepithelial pathways, and immune functions.AimsTo review, with major focus on human studies, the methods to measure intestinal barrier function in vivo and the impaired intestinal barrier function in non‐inflammatory conditions, and the deleterious or beneficial effects of dietary components on the intestinal barrier.MethodsPUBMED literature search was intentionally focused, when possible, on human studies conducted in vivo.ResultsAlthough many gastrointestinal, rheumatological, and degenerative neurological diseases are attributed to impaired intestinal barrier function, often termed “leaky gut,” methods of accurate measurement of intestinal barrier function in vivo in humans are still being developed. In vivo measurements provide an overall assessment of barrier function at a whole organ level, whereas ex vivo or in vitro measurements using mucosal biopsies address mechanistic information at the cellular level. Several dietary components are detrimental to the barrier, including ethanol, fat, sugars, gliadin, food additives, emulsifiers, and microbial transglutaminase. Conversely, dietary components improving barrier function include fibre and metabolites such as short‐chain fatty acids, anthocyanins, polyphenols, vitamins (such as A and D), zinc, specific amino acids (such as glutamine) and probiotics.ConclusionsCurrently, data are not exclusively from human studies, and research is needed to corroborate observations in animals or further validate in humans. There are several practical dietary approaches that can be instituted for restoration of the intestinal barrier in humans.

Background: Despite the association of insulin resistance (IR) in the pathophysiology of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD), few studies have evaluated the utility of acanthosis nigricans (AN) as a clinical predictor for this condition. Thus, we aimed to determine the role of AN as a risk factor and clinical predictor of MASLD. Methods: This cross-sectional study conducted a comprehensive clinical history and physical examination. The presence of acanthosis nigricans was assessed in the neck, elbows, axillae, and knuckles. Liver biochemical parameters were measured, hepatic fat was analyzed using the controlled attenuation parameter (CAP), while hepatic stiffness was evaluated in kilopascals (kPA) with the FibrosScan 530 Compact and Smart Exam software. Multiple analyses were performed to determine the relationship between acanthosis nigricans and MASLD. Results: We recruited 251 adult participants. The mean BMI was 29.9 ± 7.3 kg/m 2 , including 40.2% of participants with obesity and 63.7% with AN. Transient elastography evaluation resulted in 65.7% and 6% participants with hepatic steatosis (S3, 48.6%) and fibrosis, respectively. A non-adjusted (OR 2.63, 95% CI 1.57-4.52) and adjusted model (OR 1.97, 95% CI 0.95-4.12) were determined for AN as a risk factor for liver steatosis. Furthermore, the presence of AN in knuckles resulted in an association to predict liver steatosis (OR 2.09, 95% CI 1.01-4.35), while a multivariate analysis indicated that AN predicts a higher steatosis grade (S2 OR = 6.58, CI 95% 1.18-36.53; S3 OR = 2.36, CI 95% 1.04-5.3). Conclusions: Acanthosis nigricans demonstrated to predict a higher steatosis grade in adults with overweight and obesity. Our study supports the clinical applicability of AN as a screening tool for MASLD to identify high-risk subjects in resource-limited settings. Additional studies are needed to define alternative diagnostic tools for the early identification of metabolic risk factors in populations with specific clinical or demographic characteristics.

Background and Objectives: Evidence on the relationship between formative assessment engagement and summative assessment outcomes in practicing physicians is sparse. We evaluated the relationship between engagement in the American Board of Family Medicine (ABFM) formative Continuous Knowledge Self-Assessment (CKSA) and performance on high-stakes summative assessments. Methods: This retrospective cohort study included 24,926 ABFM diplomates who completed CKSA modules and summative assessments between 2017 and 2023. We analyzed CKSA engagement metrics—such as the number of quarters completed, time of completion, and self-reported confidence—against performance on summative assessments, measured by z scores. Multivariable regression models controlled for demographic factors and prior assessment performance. Results: The overall cohort summative assessment pass rate during the study period was 90.3%. Greater CKSA engagement was strongly associated with higher summative assessment performance. Diplomates who completed all four CKSA quarters had significantly higher summative assessment z scores than those completing fewer quarters (P<.001). Early CKSA completion and spending more time on low-confidence questions were also positively correlated with both CKSA and summative assessment scores (P<.001). These effects were observed across different levels of prior exam performance. Conclusions: Engagement in formative assessments like CKSA, particularly early and consistent participation and reviewing incorrect or low-confidence questions, is linked to better outcomes on high-stakes assessments. Future research should explore the mechanisms underlying these associations and consider developing an index of engagement to identify physicians at risk of poor performance. Incorporating structured, longitudinal self-assessments like CKSA into certification requirements could enhance continuous learning and improve summative exam readiness.

Abstract Rationale A subset of patients with group 1 pulmonary hypertension (PH) have superimposed left heart abnormalities with unclear metabolic implications. Objectives To compare serum/transpulmonary metabolome between group 1 PH stratified by heart failure with preserved ejection fraction (HFpEF) probability. Methods Patients with group 1 PH were stratified into low (<25%) and high (⩾75%) HFpEF-ABA (age, body mass index, and atrial fibrillation) probability, with healthy control subjects and subjects with clinical HFpEF used for comparison of venous and transpulmonary metabolomics. Measurements and Main Results Group 1 PH + high HFpEF probability (n = 131) was associated with a significant increase in 207 metabolites (false discovery rate [FDR] P < 0.05 and fold change >1) (n = 193, t test) and a significant decrease in 231 metabolites (FDR P < 0.05 and fold change <1) (n = 193, t test) compared with group 1 PH + low HFpEF probability (n = 62). Group 1 PH + high HFpEF probability was associated with enhanced tryptophan metabolism with higher downstream kynurenine metabolite concentrations and lower serotonin concentrations (FDR P < 0.002 for all, n = 193, t test). Linoleate (precursor to arachidonic acid and prostaglandins) and arginine and homoarginine (precursors to nitric oxide) were all lower in group 1 PH + high HFpEF probability (FDR P < 0.03 for all, n = 193, t test). Metabolome changes in group 1 PH + high HFpEF probability overlapped with clinical HFpEF (n = 240) but were abnormal relative to control subjects (n = 85) (P < 0.0001 for all, n = 456, t test). There was no evidence of differential transpulmonary uptake/release of most metabolites, suggesting probable nonpulmonary origin (except for serotonin, interaction P = 0.04; and kynurenine, interaction P = 0.03; n = 433, mixed model). Conclusions Patients with group 1 PH + high HFpEF probability have a unique metabolome characterized by enhanced tryptophan-kynurenine pathway breakdown, deficiency of amino acids (such as glycine and serine), lower serotonin, and decreased prostaglandin and nitric oxide precursors. Despite fulfilling clinical criteria for group 1 PH, these metabolome changes were comparable with clinical HFpEF, supporting biological overlap between these two forms of PH.