Implementation and Effectiveness of Opioid Prescribing Guidelines After Hiatal Hernia Repair.

INTRODUCTION: We defined institutional opioid prescribing patterns, established prescribing guidelines, and evaluated the adherence to and effectiveness of these guidelines in association with opioid prescribing after hiatal hernia repair (HHR). METHODS: A retrospective chart review was completed for patients who underwent transthoracic (open) or laparoscopic HHR between January and December 2016. Patient-reported opioid use after surgery was used to establish prescribing recommendations. Guideline efficacy was then evaluated among patients undergoing HHR after implementation (August 2018 to June 2019). Data are reported in oral morphine equivalents (OMEs). RESULTS: The initial cohort included n = 87 patients (35 open; 52 laparoscopic) with a 68% survey response rate. For open repair, median prescription size was 338 mg OME (interquartile range [IQR] 250-420) with patient-reported use of 215 mg OME (IQR 78-308) (P = 0.002). Similarly, median prescription size was 270 mg OME (IQR 200-319) with patient-reported use of 100 mg OME (IQR 4-239) (P < 0.001) for laparoscopic repair. Opioid prescribing guidelines were defined as the 66th percentile of patient-reported opioid use. Postguideline implementation cohort included n = 108 patients (36 open; 72 laparoscopic). Median prescription amount decreased by 54% for open and 43% laparoscopic repair, with no detectable change in the overall refill rate after guideline implementation. Patient education, opioid storage, and disposal practices were also characterized. CONCLUSIONS: Evidence-based opioid prescribing guidelines can be successfully implemented for open and laparoscopic HHR with a high rate of compliance and without an associated increase in opioid refills.

Blocking the IL-1 receptor reduces cardiac transplant ischemia and reperfusion injury and mitigates CMV-accelerated chronic rejection.

Ischemia-reperfusion injury (IRI) is an important risk factor for accelerated cardiac allograft rejection and graft dysfunction . Utilizing a rat heart isogeneic transplant model, we identified inflammatory pathways involved in IRI in order to identify therapeutic targets involved in disease. Pathway analyses identified several relevant targets, including cytokine signaling by the IL-1 receptor (IL-1R) pathway and inflammasome activation. To investigate the role of IL-1R signaling pathways during IRI, we treated syngeneic cardiac transplant recipients at 1-hour posttransplant with Anakinra, a US Food and Drug Administration (FDA)-approved IL-1R antagonist; or parthenolide, a caspase-1 and nuclear factor kappa-light-chain-enhancer of activated B cells inhibitor that blocks IL-1ß maturation. Both Anakinra and parthenolide significantly reduced graft inflammation and cellular recruitment in the treated recipients relative to nontreated controls. Anakinra treatment administered at 1-hour posttransplant to recipients of cardiac allografts from CMV-infected donors significantly increased the time to rejection and reduced viral loads at rejection. Our results indicate that reducing IRI by blocking IL-1Rsignaling pathways with Anakinra or inflammasome activity with parthenolide provides a promising approach for extending survival of cardiac allografts from CMV-infected donors.

Macrophage depletion of CMV latently infected donor hearts ameliorates recipient accelerated chronic rejection.

Cytomegalovirus (CMV) infection is linked to acceleration of solid organ transplant vascular sclerosis (TVS) and chronic rejection (CR). Donor latent CMV infection increases cardiac-resident macrophages and T cells leading to increased inflammation, promoting allograft rejection. To investigate the role of cardiac-resident passenger macrophages in CMV-mediated TVS/CR, macrophages were depleted from latently ratCMV (RCMV)-infected donor allografts prior to transplantation. Latently RCMV-infected donor F344 rats were treated with clodronate, PBS, or control liposomes 3 days prior to cardiac transplant into RCMV-naïve Lewis recipients. Clodronate treatment significantly increased graft survival from post-operative day (POD)61 to POD84 and decreased TVS at rejection. To determine the kinetics of the effect of clodronate treatment's effect, a time study revealed that clodronate treatment significantly decreased macrophage infiltration into allograft tissues as early as POD14; altered allograft cytokine/chemokine protein levels, fibrosis development, and inflammatory gene expression profiles. These findings support our hypothesis that increased graft survival as a result of allograft passenger macrophage depletion was in part a result of altered immune response kinetics. Depletion of donor macrophages prior to transplant is a strategy to modulate allograft rejection and reduce TVS in the setting of CMV + donors transplanted into CMV naïve recipients.

Impact of center volume and the adoption of laparoscopic donor nephrectomy on outcomes in pediatric kidney transplantation.

Reports for pediatric kidney transplant recipients suggested better outcomes for ODN compared to LDN. Contemporary outcomes stratified by donor type and center volume have not been evaluated in a national dataset. UNOS data (2000-2014) were analyzed for pediatric living donor kidney transplant recipients. The primary outcome was GF; secondary outcomes were DGF, rejection, and patient survival. Live donor nephrectomies for pediatric recipients decreased 30% and transitioned from ODN to LDN. GF rates did not differ for ODN vs LDN (P = .24). GF was lowest at high volume centers (P < .01). Donor operative approach did not contribute to GF. LDN was associated with less rejection than ODN (OR 0.66, CI 0.5-0.87, P < .01). Analysis of the 0- to 5-yr recipient group showed no effect of ODN vs LDN on GF or rejection. For the contemporary era, there was no association between DGF and LDN in the 0- to 5-yr group (OR 1.12, CI 0.67-1.89, P = .67). Outcomes of kidney transplants in pediatric recipients following LDN have improved since its introduction and LDN should be the approach for live donor nephrectomy regardless of recipient age. The association between case volume and improved outcomes highlights future challenges in organ transplantation.

Diagnostic Workup and Therapeutic Intervention of Hiatal Hernias Discovered as Incidental Findings on Computed Tomography.

BACKGROUND: Computed tomography imaging routinely detects incidental findings; most research focuses on malignant findings. However, benign diseases such as hiatal hernia also require identification and follow-up. Natural language algorithms can help identify these non-malignant findings. METHODS: Imaging of adult trauma patients from 2010 to 2020 who underwent CT chest/abdomen/pelvis was evaluated using an open-source natural language processor to query for hiatal hernias. Patients who underwent subsequent imaging, endoscopy, fluoroscopy, or operation were retrospectively reviewed. RESULTS: 1087(10.6%) of 10 299 patients had incidental hiatal hernias: 812 small (74.7%) and 275 moderate/large (25.3%). 224 (20.7%) had subsequent imaging or endoscopic evaluation. Compared to those with small hernias, patients with moderate/large hernias were older (66.3 ± 19.4 vs 79.6 ± 12.6 years, P < .001) and predominantly female (403[49.6%] vs 199[72.4%], P < .001). Moderate/large hernias were not more likely to grow (small vs moderate/large: 13[7.6%] vs 8[15.1%], P = .102). Patients with moderate/large hernias were more likely to have an intervention or referral (small vs moderate/large: 6[3.5%] vs 7[13.2%], P = .008). No patients underwent elective or emergent hernia repair. Three patients had surgical referral; however, only one was seen by a surgeon. One patient death was associated with a large hiatal hernia. CONCLUSIONS: We demonstrate a novel utilization of natural language processing to identify patients with incidental hiatal hernia in a large population, and found a 10.6% incidence with only 1.2%. (13/1087) of these receiving a referral for follow-up. While most incidental hiatal hernias are small, moderate/large and symptomatic hernias have high risk of loss-to-follow-up and need referral pipelines to improve patient outcomes.

The State of Racial and Gender Diversity in Cardiothoracic Surgery Training.

BACKGROUND: The field of cardiothoracic surgery has been striving to increase its gender and racial diversity. We sought to examine changes in gender and racial diversity in cardiothoracic fellowships and integrated residencies in the past decade. METHODS: Accreditation Council for Graduate Medical Education data were obtained from 2011 to 2019. Linear trends were assessed for year-by-year data. Average percentages of women and underrepresented minorities were then calculated in 3-year intervals. Intervals were compared with Student's t test and χ2 tests. RESULTS: There was no statistically significant increase in percent female trainees in cardiothoracic fellowships (18.5% to 22.1%, P = .10) or integrated residencies (22.8% to 27.8%, P = .17), despite a significant increase in percent female applicants to fellowship (18.2% to 35.3%, P < .01) and integrated residency (8.9% to 33.0%, P < .01). Cardiothoracic fellowships had no increase in underrepresented minority trainees (8.3% to 9.4%, P = .48). Underrepresented minority trainees in integrated residencies increased from 2.7% to 6.9% (P = .03). Although there was no significant increase in underrepresented minority applicants to fellowships (10.2% to 11.3%, P = .66), the percent of underrepresented minority applicants to integrated residencies increased from 13.1% to 19.3% (P < .01). CONCLUSIONS: Cardiothoracic surgery training programs are attracting more female applicants, but that has not yet resulted in a higher percentage of female trainees. Although percentages of underrepresented minorities increased among integrated residency applicants and trainees, they remain low compared with other specialties. These data reflect positive changes but also highlight that much remains to be done to increase diversity in cardiothoracic surgery training.

The Early Impact of the COVID-19 Pandemic on Lung, Colorectal, and Breast Cancer Screening and Treatment at a Tertiary Cancer Center.

OBJECTIVES: During the coronavirus-19 pandemic, experts recommended delaying routine cancer screening and modifying treatment strategies. We sought to understand the sequalae of these recommendations. MATERIALS AND METHODS: We performed a retrospective single-center analysis of screening, diagnosis, and treatment of lung, colorectal, and breast cancer. Data was collected from our institutional cancer registry. Prepandemic (2016-2019) was compared with pandemic (2020) data. RESULTS: Three thousand three sixty one screening chest computed tomography scans (CTs), 35,917 colonoscopies, and 48,093 screening mammograms were performed. There was no difference in CTs [81.0 (SEM10.0) vs. 65.6 (SEM3.29), P =0.067] or mammograms [1017.0 (SEM171.8) vs. 809.4 (SEM56.41), P =0.177] in 2020 versus prepandemic. There were fewer colonoscopies in 2020 [651.4 (SEM103.5) vs. 758.91 (SEM11.79), P =0.043]. There was a decrease in cancer diagnoses per month in 2020 of lung [22.70 (SEM1.469) vs. 28.75 (SEM0.8216), P =0.003] and breast [38.56 (SEM6.133) vs. 51.82 (SEM1.257), P =0.001], but not colorectal [13.11 (SEM1.467) vs. 15.88 (SEM0.585), P =0.074] cancer. There was no change in stage at presentation for lung ( P =0.717), breast ( P =0.115), or colorectal cancer ( P =0.180). Lung had a shorter time-to-treatment in 2020 [38.92 days (SEM 2.48) vs. 66 (SEM1.46), P =0.002]. CONCLUSIONS: In 2020, there was no difference in screening studies for lung and breast cancer but there was a decrease in new diagnoses. Although there were fewer colonoscopies performed in 2020, there was no change in new colorectal cancer diagnoses. Despite changes in guidelines during the pandemic, the time-to-treatment for lung cancer was shorter and was unchanged for colorectal and breast cancer. These findings highlight the importance of continuing care for a vulnerable patient population despite a pandemic.

Rat Cytomegalovirus Virion-Associated Proteins R131 and R129 Are Necessary for Infection of Macrophages and Dendritic Cells.

Cytomegalovirus (CMV) establishes persistent, latent infection in hosts, causing diseases in immunocompromised patients, transplant recipients, and neonates. CMV infection modifies the host chemokine axis by modulating chemokine and chemokine receptor expression and by encoding putative chemokine and chemokine receptor homologues. The viral proteins have roles in cellular signaling, migration, and transformation, as well as viral dissemination, tropism, latency and reactivation. Herein, we review the contribution of CMV-encoded chemokines and chemokine receptors to these processes, and further elucidate the viral tropism role of rat CMV (RCMV) R129 and R131. These homologues of the human CMV (HCMV)-encoded chemokines UL128 and UL130 are of particular interest because of their dual role as chemokines and members of the pentameric entry complex, which is required for entry into cell types that are essential for viral transmission and dissemination. The contributions of UL128 and UL130 to acceleration of solid organ transplant chronic rejection are poorly understood, and are in need of an effective in vivo model system to elucidate the phenomenon. We demonstrated similar molecular entry requirements for R129 and R131 in the rat cells, as observed for HCMV, and provided evidence that R129 and R131 are part of the viral entry complex required for entry into macrophages, dendritic cells, and bone marrow cells.

Progenitor migration to the thymus and T cell lineage commitment.

T cells developing in the thymus are ultimately derived from bone marrow (BM) hematopoietic stem cells (HSCs). An understanding of the developmental steps between HSCs and T cells is important for gaining insight into cancers of the T lineage, improving T cell reconstitution after BM transplantation, and also to help ameliorate immunological defects in aging. In this article, we summarize our current understanding of the inter-related fields of early T cell development and thymic aging, and briefly discuss major unresolved questions in this field.

Early post-approval experience with transcatheter aortic valve replacement in the USA.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is changing the treatment of aortic stenosis. We compared cost and clinical outcomes of TAVR versus surgical aortic valve repair (SAVR) in the real-world setting since USA TAVR approval in 2012. METHODS: The Nationwide Inpatient Sample (NIS) dataset was analyzed by quarter (June 2012 to December 2014). Patients (>65 years old) undergoing TAVR or SAVR were identified and risk stratified based on APR-DRG Mortality risk score. Outcomes were in-hospital mortality, length of stay (LOS), discharge location, and hospitalization cost. RESULTS: TAVR cases per quarter increased from 1900 to 5445 over the study period. TAVR patients were older and had more comorbidities (P<0.001). TAVR patients had longer LOS (8 vs. 7 days; P<0.001), were less likely to discharge to home (67% vs. 73%; P<0.001), had higher inpatient mortality (5.5% vs. 0.69%; P<0.001) and overall hospital cost ($ 227,985 vs. $ 148,019; P<0.001) than SAVR patients. On multivariate analysis TAVR was associated with increased cost (ß=0.42; P<0.001) and increased mortality (OR=5.228, CI: 3.508-7.791; P<0.001) but not associated with increased LOS (ß=0.297; P=0.078) or discharge to facility (OR=1.004, CI: 0.833-1.213; P=0.960). In the last two quarters of 2014 there was no difference between TAVR and SAVR LOS, however TAVR cost did not decrease over the study period. CONCLUSIONS: TAVR patients represented a sicker population, however LOS and discharge location outcomes were equivalent to SAVR. TAVR remained significantly more expensive across all risk groups and cost did not fall over the course of the study.

Phase I study of the CD40 agonist antibody CP-870,893 combined with carboplatin and paclitaxel in patients with advanced solid tumors.

CD40 is a cell-surface molecule that critically regulates immune responses. CP-870,893 is a fully human, CD40-specific agonist monoclonal antibody (mAb) exerting clinical antineoplastic activity. Here, the safety of CP-870,893 combined with carboplatin and paclitaxel was assessed in a Phase I study. Patients with advanced solid tumors received standard doses of paclitaxel and carboplatin on day 1 followed by either 0.1 mg/Kg or 0.2 mg/Kg CP-870,893 on day 3 (Schedule A) or day 8 (Schedule B), repeated every 21 d. The primary objective was to determine safety and maximum-tolerated dose (MTD) of CP-870,893. Secondary objectives included the evaluation of antitumor responses, pharmacokinetics and immune modulation. Thirty-two patients were treated with CP-870,893, 16 patients on each schedule. Two dose-limiting toxicities were observed (grade 3 cytokine release and transient ischemic attack), each at the 0.2 mg/Kg dose level, which was estimated to be the MTD. The most common treatment-related adverse event was fatigue (81%). Of 30 evaluable patients, 6 (20%) exhibited partial responses constituting best responses as defined by RECIST. Following CP-870,893 infusion, the peripheral blood manifested an acute depletion of B cells associated with upregulation of immune co-stimulatory molecules. T-cell numbers did not change significantly from baseline, but transient tumor-specific T-cell responses were observed in a small number of evaluable patients. The CD40 agonist mAb CP-870,893, given on either of two schedules in combination with paclitaxel and carboplatin, was safe for patients affected with advanced solid tumors. Biological and clinical responses were observed, providing a rationale for Phase II studies.

Notch signaling augments T cell responsiveness by enhancing CD25 expression.

Notch receptors signal through a highly conserved pathway to influence cell fate decisions. Notch1 is required for T lineage commitment; however, a role for Notch signaling has not been clearly defined for the peripheral T cell response. Notch gene expression is induced, and Notch1 is activated in primary CD4(+) T cells following specific peptide-Ag stimulation. Notch activity contributes to the peripheral T cell response, as inhibition of endogenous Notch activation decreases the proliferation of activated T cells in a manner associated with the diminished production of IL-2 and the expression of the high affinity IL-2R (CD25). Conversely, forced expression of a constitutively active Notch1 in primary T cells results in increased surface expression of CD25, and renders these cells more sensitive to both cognate Ag and IL-2, as measured by cell division. These data suggest an important role for Notch signaling during CD4(+) T cell responses, which operates through augmenting a positive feedback loop involving IL-2 and its high affinity receptor.