Citations

Abstract Background and Aims Colchicine is an anti-inflammatory drug that may prevent post-operative atrial fibrillation (POAF). The effect of this drug has been inconsistently shown in previous clinical trials. We aimed to compare the efficacy and safety of colchicine vs. placebo to prevent POAF in patients undergoing cardiac surgery. Methods and results A systematic search of EMBASE, MEDLINE, SCOPUS, ClinicalTrials.gov, and the Cochrane Library for randomized controlled trials (RCTs) was conducted from inception till April 2023. The primary outcome was the incidence of POAF after any cardiac surgery. The secondary outcome was the rate of drug discontinuation due to adverse events and adverse gastrointestinal events. Risk ratios (RR) were reported using the Mantel Haenszel method. A total of eight RCTs comprising 1885 patients were included. There was a statistically significant lower risk of developing POAF with colchicine vs. placebo (RR: 0.70; 95% CI: 0.59–0.82; P < 0.01, I2 = 0%), and this effect persisted across different subgroups. There was a significantly higher risk of adverse gastrointestinal events (RR: 2.20; 95% CI: 1.38–3.51; P < 0.01, I2 = 55%) with no difference in the risk of drug discontinuation in patients receiving colchicine vs. placebo (RR: 1.33; 95% CI: 0.93–1.89; P = 0.11, I2 = 0%). Conclusion This meta-analysis of eight RCTs shows that colchicine is effective at preventing POAF, with a significantly higher risk of adverse gastrointestinal events but no difference in the rate of drug discontinuation. Future studies are required to define the optimal duration and dose of colchicine for the prevention of POAF.

AbstractDespite the known benefits of supportive work environments for promoting patient quality and safety and healthcare worker retention, there is no clear mandate for improving work environments within Learning Health Systems (LHS) nor an LHS wellness competency. Striking rises in burnout levels among healthcare workers provide urgency for this topic.MethodsWe brought three experts on moral injury, burnout prevention, and ethics to a recurring, interactive LHS training program “Design Shop” session, harnessing scholars’ ideas prior to the meeting. Generally following SQUIRE 2.0 guidelines, we evaluated the prework and discussion via informal content analysis to develop a set of pathways for developing moral injury and burnout prevention programs. Along these lines, we developed a new competency for moral injury and burnout prevention within LHS training programs.ResultsIn preparation for the session, scholars differentiated moral injury from burnout, highlighted the profound impact of COVID‐19 on moral injury, and proposed testable interventions to reduce injury. Scholar and expert input was then merged into developing the new competency in moral injury and burnout prevention. In particular, the competency focuses on preparing scholars to (1) demonstrate knowledge of moral injury and burnout, (2) measure burnout, moral injury, and their remediable predictors, (3) use methods for improving burnout, (4) structure training programs with supportive work environments, and (5) embed burnout and moral injury prevention into LHS structures.ConclusionsBurnout and moral injury prevention have been largely omitted in LHS training. A competency related to burnout and moral injury reduction can potentially bring sustainable work lives for scholars and their colleagues, better incorporation of their science into clinical practice, and better outcomes for patients.

Introduction: Obesity is associated with a higher burden of atrial fibrillation (AF) and related complications. Hypothesis: Bariatric surgery in patients with AF is associated with a reduction in mortality and long-term complications at 1 year. Methods: Patients with AF who underwent bariatric surgery were identified by analyzing the nationwide readmission database and incorporating the validated ICD-10 CM codes from October 2015 to December 2019. We performed the propensity score matching to adjust the confounders and cox proportional hazard regression to generate hazard ratios. Moreover, we generated Kaplan Meier curves for time-to-event analysis. The primary endpoint was all-cause mortality at 1 year, whereas secondary endpoints were ischemic stroke, major bleeding, and AF readmission at 1 year. Results: Out of 892488 obese patients with AF, 18766 underwent bariatric surgery. After propensity score matching, 18764 patients were identified in each group. At 1-year, patients undergoing bariatric surgery had a significant reduction in mortality (2.18% vs. 2.73%, HR: 0.91, 95% CI: 0.85-0.96, p=0.001). Additionally, risk of ischemic stroke was also reduced (1.98% vs. 2.29%, HR: 0.91, 95% CI: 0.86-0.97, p=0.01), whereas no difference was noted in AF readmissions (4.02% vs. 3.34%, HR: 0.97, 95% CI: 0.92-1.04, p=0.49) and risk of major bleeding was increased (5.74% vs. 3.42%, HR: 1.17, 95% CI: 1.10-1.25, p<0.0001) at 1 year in AF patients with bariatric surgery. (Figure 1) Conclusions: Bariatric surgery in patients with AF was associated with a reduction in 1-year mortality and ischemic stroke. However, the risk of major bleeding was noted to be increased and no difference was noted in AF readmission at 1 year.

581 Background: Several studies have established the crucial role of preexisting immune response measured by tumor-infiltrating lymphocytes (TILs) in triple-negative breast cancer (TNBC). Emerging studies showed that not only the number of TILs but also the location of TILs is as critical. There are 3 distinct immune landscapes described based on the locations of TILs, namely immune enriched (IN), immune excluded (IE), and immune desert (ID), which are associated with outcomes in TNBC treated with immune-checkpoint inhibitors. Here we evaluated characteristics associated with each immune landscape. Methods: NanoString IO360, Digital Spatial Profiling (DSP), and CosMx, a spatial multi-omics single-cell imaging platform, were used. DSP was used to quantify 39 immune-related proteins in stromal and tumor-enriched segments from 44 TNBC samples from the FinXX trial (NCT00114816) and 276 samples from the Mayo Clinic (MC) TNBC cohort (Leon-Ferre BCRT 2018). CosMx was performed in 75 samples from the MC TNBC cohort. First, tumors with TIL quantified by H&E ≤ 30% were classified as ID. The rest of the tumors were categorized according to the intratumoral CD8 protein expression by DSP, with IE having intratumoral CD8 in the lower median and IN having intratumoral CD8 in the upper median. Differential expression listed as log fold change (FC) was estimated from the linear mixed model with significance defined as two-sided p < 0.05. Results: Using DSP in the FinXX trial, intratumoral and stromal higher HLA-DR (FC 1.68, p = 0.001), B2M (FC 0.8, p = 0.005), CD4 (FC 0.74, p = 0.01), and CD40 (FC 1.56, p = 0.001) were associated with IN compared to ID. When comparing IE and IN, higher intratumoral CD11c (FC 0.97, p = 0.01) and stromal CD4 (FC 0.89, p = 0.047), CD20 (FC 0.85, p = 0.016), CD40 (FC 0.95, p = 0.045), and CD27 (FC 0.84, p = 0.024) were associated with IN. Similar findings were observed in the MC cohort. Moreover, intratumoral NY-ESO-1 expression (FC 0.55, p = 0.03) was associated with IN. Using GSEA with IO360 in the FinXX trial, PI3K-Akt signaling was associated with ID compared to IN (p = 0.01). We further evaluated the differential gene expression in a spatially resolved manner using CosMx with single-cell sequencing in the MC cohort. Expressions of MHC class I and class II in tumor cells, including HLA-A, HLA-B, HLA-C, HLA-DRA, HLA-DRB1, HLA-DPA1, and HLA-E, were associated with IN compared to ID and IE. Conclusions: Using an in-depth analysis with spatially defined context, we identified characteristics associated with distinct immune landscapes in TNBC. Our study highlights the potential future implications of intratumoral MHC expression, CD40, and PI3K-AKT as biomarkers and therapeutic targets. Clinical trial information: NCT00114816 .

Abstract In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)—a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase &gt;3 × upper limit of normal, and a dual-expressor immunophenotype. Age &gt;60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicates that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant YAP activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating ‘indeterminate’ states of differentiation and suggesting that aberrant YAP signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after Streptococcus pneumoniae -induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz, and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both Yap1 and Wwtr1 (encoding Taz) or Wwtr1 alone in AT2 cell stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, the inactivation of only Yap1 in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz-mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.

Our understanding of tissue-resident memory T (T RM ) cell biology has been largely developed from acute infection models in which antigen is cleared and sterilizing immunity is achieved. Less is known about T RM cells in the context of chronic antigen persistence and inflammation. We investigated factors that underlie T RM maintenance in a kidney transplantation model in which T RM cells drive rejection. In contrast to acute infection, we found that T RM cells declined markedly in the absence of cognate antigen, antigen presentation, or antigen sensing by the T cells. Depletion of graft-infiltrating dendritic cells or interruption of antigen presentation after T RM cells were established was sufficient to disrupt T RM maintenance and reduce allograft pathology. Likewise, removal of IL-15 transpresentation or of the IL-15 receptor on T cells during T RM maintenance led to a decline in T RM cells, and IL-15 receptor blockade prevented chronic rejection. Therefore, antigen and IL-15 presented by dendritic cells play nonredundant key roles in CD8 T RM cell maintenance in settings of antigen persistence and inflammation. These findings provide insights that could lead to improved treatment of chronic transplant rejection and autoimmunity.

Objective: To report mid-term outcomes of renal-mesenteric target arteries (TAs) after fenestrated-branched endovascular aortic repair (FB-EVAR) of complex abdominal and thoracoabdominal aortic aneurysm. Background: TA instability (TAI) is the most frequent indication for reintervention after FB-EVAR. Methods: Data from consecutive patients enrolled in 9 prospective nonrandomized physician-sponsored investigational device exemption studies between 2005 and 2020 were reviewed. TA outcomes through 5 years of follow-up were analyzed for vessels incorporated by fenestrations or directional branches (DBs), including TA patency, endoleak, integrity failure, reintervention, and instability. Results: A total of 1681 patients had 6349 renal-mesenteric arteries were targeted using 3720 fenestrations (59%), 2435 DBs (38%), and 194 scallops (3%). Mean follow was 23 ± 21 months. At 5 years, TAs incorporated by fenestrations had higher primary (95 ± 1% vs 91 ± 1%, P < 0.001) and secondary patency (98 ± 1% vs 94 ± 1%, P < 0.001), and higher freedom from TAI (87 ± 2% vs 84 ± 2%, P = 0.002) compared with TAs incorporated by DBs, with no differences in other TA events. DBs targeted by balloon-expandable stent-grafts had significantly lower freedom from TAI (78 ± 4% vs 88 ± 1%, P = 0.006), TA endoleak (87 ± 3% vs 97 ± 1%, P < 0.001), and TA reintervention (83 ± 4% vs 95 ± 1%, P < 0.001) compared with those targeted by self-expandable stent-grafts Conclusions: Incorporation of renal and mesenteric TA during FB-EVAR is safe and durable with high 5-year patency rates and low freedom from TAI. DBs have lower patency rates and lower freedom from TAI than fenestrations, with better performance for self-expandable stent grafts as compared with balloon-expandable stent grafts.

Abstract Context Chronic hypoparathyroidism is conventionally treated with oral calcium and active vitamin D to reach and maintain targeted serum calcium and phosphorus levels, but some patients remain inadequately controlled. Objective To assess long-term safety and efficacy of recombinant human parathyroid hormone (1-84) (rhPTH(1-84)) treatment. Methods This was an open-label extension study at 12 US centers. Adults (n = 49) with chronic hypoparathyroidism were included. The intervention was rhPTH(1-84) for 6 years. The main outcome measures were safety, biochemical measures, oral supplement doses, bone indices. Results Thirty-eight patients (77.6%) completed the study. Throughout 72 months, mean albumin-adjusted serum calcium was within 2.00 to 2.25 mmol/L (8.0-9.0 mg/dL). At baseline, 65% of patients with measurements (n = 24/37) were hypercalciuric; of these, 54% (n = 13/24) were normocalciuric at month 72. Mean serum phosphorus declined from 1.6 ± 0.19 mmol/L at baseline (n = 49) to 1.3 ± 0.20 mmol/L at month 72 (n = 36). Mean estimated glomerular filtration rate was stable. rhPTH(1-84)-related adverse events were reported in 51.0% of patients (n = 25/49); all but 1 event were mild/moderate in severity. Mean oral calcium supplementation reduced by 45% ± 113.6% and calcitriol by 74% ± 39.3%. Bone turnover markers declined by month 32 to a plateau above pretreatment values; only aminoterminal propeptide of type 1 collagen remained outside the reference range. Mean bone mineral density z score fell at one-third radius and was stable at other sites. Conclusion 6 years of rhPTH(1-84) treatment was associated with sustained improvements in biochemical parameters, a reduction in the percentage of patients with hypercalciuria, stable renal function, and decreased supplement requirements. rhPTH(1-84) was well tolerated; no new safety signals were identified.