Clinical Utility of the Molecular Microscope Diagnostic System in a Real-World Transplant Cohort: Moving Towards a New Paradigm.

Objectives: To evaluate the clinical implications of adjunctive molecular gene expression analysis (MMDx ) of biopsy specimens in heart transplant (HT ) recipients with suspected rejection. Introduction: Histopathological evaluation remains the standard method for rejection diagnosis in HT. However, the wide interobserver variability combined with a relatively common incidence of "biopsy-negative" rejection has raised concerns about the likelihood of false-negative results. MMDx, which uses gene expression to detect early signs of rejection, is a promising test to further refine the assessment of HT rejection. Methods: Single-center prospective study of 418 consecutive for-cause endomyocardial biopsies performed between November 2022 and May 2024. Each biopsy was graded based on histology and assessed for rejection patterns using MMDx. MMDx results were deemed positive if borderline or definitive rejection was present. The impact of MMDx results on clinical management was evaluated. Primary outcomes were 1-year survival and graft dysfunction following MMDx-guided clinical management. Secondary outcomes included changes in donor-specific antibodies, MMDx gene transcripts, and donor-derived cell-free DNA (dd-cfDNA) levels. Results: We analyzed 418 molecular samples from 237 unique patients. Histology identified rejection in 32 cases (7.7%), while MMDx identified rejection in 95 cases (22.7%). Notably, in 79 of the 95 cases where MMDx identified rejection, histology results were negative, with the majority of these cases being antibody-mediated rejection (62.1%). Samples with rejection on MMDx were more likely to show a combined elevation of dd-cfDNA and peripheral blood gene expression profiling than those with borderline or negative MMDx results (36.7% vs 28.0% vs 10.3%; p<0.001). MMDx results led to the implementation of specific antirejection protocols or changes in immunosuppression in 20.4% of cases, and in 73.4% of cases where histology was negative and MMDx showed rejection. 1-year survival was better in the positive MMDx group where clinical management was guided by MMDx results (87.0% vs 78.6%; log rank p=0.0017). Conclusions: In our cohort, MMDx results more frequently indicated rejection than histology, often leading to the initiation of antirejection treatment. Intervention guided by positive MMDx results was associated with improved outcomes.

How does sleeve gastrectomy impact long-term eating-related symptoms, distress, and behavior? A cross-sectional study using the BODY-Q patient-reported outcome measures.

BACKGROUND: Patients undergoing sleeve gastrectomy (SG) experience transformative changes in eating-related experiences that include eating-related symptoms, emotions, and habits. Long-term assessment of these endpoints with rigorous patient-reported outcome measures (PROMs) is limited. We assessed patients undergoing SG with the Body-Q Eating Module PROMs. METHODS: All patients evaluated at the Emory Bariatric Center were given the Body-Q Eating Modules questionnaire at preoperative/postoperative clinic visits. Rasch scores and prevalence of relevant endpoints were assessed across six time-points of interest: preoperatively, post-operative months 0-6, 7-12, 12-24, 24-36, and over 36. Student's t-test and Chi-square test were used for analysis. RESULTS: Overall, 1,352 questionnaires were completed pre-operatively and 493 postoperatively. Survey compliance was 81%. Compared to the pre-operative group, the post-operative group had lower BMI (39.7 vs. 46.4, p < 0.001) and higher age (46.3 vs. 44.9, p = 0.019). Beginning one year after SG, patients experience more frequent eating-related pain, nausea and constipation compared to pre-operative baseline (p < 0.05). They also more frequently experience eating-related regurgitation and dumping syndrome-related symptoms beginning post-operative year two (p < 0.05). In the first year after SG, patients more rarely feel eating-related embarrassment, guilt, and disappointment compared to pre-operative baseline (p < 0.05). These improvements disappear one year after SG, after which patients more frequently experience feeling out of control, unhappy, like a failure, disappointed, and guilty (p < 0.05). In the first year after SG, patients experience an increased frequency in positive eating behaviors (ate healthy foods, showed self-control, stopped before full; (p < 0.05). Only two eating-related behavior improvements persist long-term: feeling in control and eating the right amount (p < 0.05). CONCLUSIONS: Patients undergoing SG may experience more frequent eating-related symptoms, distress, and behavior in the long-term. These findings can enhance the pre-operative informed consent and guide development of a more tailored approach to postoperative clinical management such as more frequent visits with the dietician.

Discovery and Preclinical Characterization of BIIB129, a Covalent, Selective, and Brain-Penetrant BTK Inhibitor for the Treatment of Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic disease with an underlying pathology characterized by inflammation-driven neuronal loss, axonal injury, and demyelination. Bruton's tyrosine kinase (BTK), a nonreceptor tyrosine kinase and member of the TEC family of kinases, is involved in the regulation, migration, and functional activation of B cells and myeloid cells in the periphery and the central nervous system (CNS), cell types which are deemed central to the pathology contributing to disease progression in MS patients. Herein, we describe the discovery of BIIB129 (25), a structurally distinct and brain-penetrant targeted covalent inhibitor (TCI) of BTK with an unprecedented binding mode responsible for its high kinome selectivity. BIIB129 (25) demonstrated efficacy in disease-relevant preclinical in vivo models of B cell proliferation in the CNS, exhibits a favorable safety profile suitable for clinical development as an immunomodulating therapy for MS, and has a low projected total human daily dose.

Achieving durable compliance with venous thromboembolism prophylaxis in bariatric surgery: 3-year data from a major academic medical center.

BACKGROUND: Metabolic and bariatric surgery (MBS) venous thromboembolism (VTE) prescribing practices vary widely. Our institutional VTE prophylaxis protocol has historically been unstandardized. OBJECTIVES: To create a standardized MBS VTE prophylaxis protocol, track protocol compliance, and identify barriers to protocol compliance and address them with Plan-Do-Study-Act (PDSA) cycles. SETTING: Single Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program-accredited academic hospital. METHODS: We conducted a retrospective study for all patients undergoing MBS (January 2019 to September 2022). A multidisciplinary group of bariatric clinicians reviewed literature and developed the following standardized VTE prophylaxis protocol: 5000 units preoperative subcutaneous (SC) heparin within 60 minutes of anesthesia induction and postoperative 40 mg SC low molecular weight heparin (LMWH) within 24 hours of surgery. This protocol was distributed to relevant clinical stakeholders. We assessed monthly compliance rates through chart review. Goal compliance was ≥90%. We identified sources of noncompliance and addressed them with PDSA methodology. RESULTS: A total of 796 patients were included. Preoperative heparin administration increased from a mean of 47% (107/228) preintervention to 96% (545/568) postintervention (P < .0001), and postoperative LMWH administration increased from 71% (47/66) to 96% (573/597, P = .0002). These compliance rates were sustained for 3 years. Barriers to protocol noncompliance included order set timing errors (n = 45), surgeon error (n = 44), surgeon discretion (n = 40), and nursing error (n = 20). No change in bleeding or VTE rates was observed. CONCLUSIONS: Developing a standardized VTE prophylaxis protocol, monitoring process measures, and engaging relevant stakeholders in PDSA cycles resulted in drastic and durable improvement in VTE prophylaxis compliance rates.

Robotic versus laparoscopic gastrectomy for adenocarcinoma in the US: a propensity score-matching analysis of 11,173 patients on oncological adequacy.

INTRODUCTION: Surgery remains the cornerstone treatment for gastric cancer. Previous studies have reported better lymphadenectomy with minimally invasive approaches. There is a paucity of data comparing robotic and laparoscopic gastrectomy in the US. Herein, we examined whether oncological adequacy differs between laparoscopic and robotic approaches. METHODS: The National Cancer Database was utilized to identify patients who underwent gastrectomy for adenocarcinoma between 2010 and 2019. A propensity score-matching analysis between robotic gastrectomy (RG) versus laparoscopic gastrectomy (LG) was performed. The primary outcomes were lymphadenectomy ≥ 16 nodes and surgical margins. RESULTS: A total of 11,173 patients underwent minimally invasive surgery for gastric adenocarcinoma between 2010 and 2019. Of those 8320 underwent LG and 2853 RG. Comparing the unmatched cohorts, RG was associated with a higher rate of adequate lymphadenectomy (63.5% vs 57.1%, p < .0.0001), higher rate of negative margins (93.8% vs 91.9%, p < 0.001), lower rate of prolonged length of stay (26.0% vs 29.6%, p < .0.001), lower 90-day mortality (3.7% vs 5.0%, p < 0.0001), and a better 5-year overall survival (OS) (56% vs 54%, p = 0.03). A propensity score-matching cohort with a 1:1 ratio was created utilizing the variables associated with lymphadenectomy ≥ 16 nodes. The matched analysis revealed that the rate of adequate lymphadenectomy was significantly higher for RG compared to LG, 63.5% vs 60.4% (p = 0.01), respectively. There was no longer a significant difference between RG and LG regarding the rate of negative margins, prolonged length of stay, 90-day mortality, rate of receipt of postoperative chemotherapy, and OS. CONCLUSIONS: This propensity score-matching analysis with a large US cohort shows that RG was associated with a higher rate of adequate lymphadenectomy compared to LR. RG and LG had a similar rate of negative margins, prolonged length of stay, receipt of postoperative chemotherapy, 90-day mortality, and OS, suggesting that RG is a comparable surgical approach, if not superior to LG.

Development of a PET Tracer for OGA with Improved Kinetics in the Living Brain.

O-GlcNAcylation is thought to play a role in the development of tau pathology in Alzheimer's disease because of its ability to modulate tau's aggregation propensity. O-GlcNAcylation is regulated by 2 enzymes: O-GlcNAc transferase and O-GlcNAcase (OGA). Development of a PET tracer would therefore be an essential tool for developing therapeutic small-molecule inhibitors of OGA, enabling clinical testing of target engagement and dose selection. Methods: A collection of small-molecule compounds was screened for inhibitory activity and high-affinity binding to OGA, as well as favorable PET tracer attributes (multidrug resistance protein 1 efflux, central nervous system PET multiparameter optimization, etc.). Two lead compounds with high affinity and selectivity for OGA were selected for further profiling, including OGA binding to tissue homogenate using a radioligand competition binding assay. In vivo pharmacokinetics were established using a microdosing approach with unlabeled compounds in rats. In vivo imaging studies were performed in rodents and nonhuman primates (NHPs) with 11C-labeled compounds. Results: Two selected candidates, BIO-735 and BIO-578, displayed promising attributes in vitro. After radiolabeling with tritium, [3H]BIO-735 and [3H]BIO-578 binding in rodent brain homogenates demonstrated dissociation constants of 0.6 and 2.3 nM, respectively. Binding was inhibited, concentration-dependently, by homologous compounds and thiamet G, a well-characterized and structurally diverse OGA inhibitor. Imaging studies in rats and NHPs showed both tracers had high uptake in the brain and inhibition of binding to OGA in the presence of a nonradioactive compound. However, only BIO-578 demonstrated reversible binding kinetics within the time frame of a PET study with a 11C-labeled molecule to enable quantification using kinetic modeling. Specificity of tracer uptake was confirmed with a 10 mg/kg blocking dose of thiamet G. Conclusion: We describe the development and testing of 2 11C PET tracers targeting the protein OGA. The lead compound BIO-578 demonstrated high affinity and selectivity for OGA in rodent and human postmortem brain tissue, leading to its further testing in NHPs. NHP PET imaging studies showed that the tracer had excellent brain kinetics, with full inhibition of specific binding by thiamet G. These results suggest that the tracer [11C]BIO-578 is well suited for further characterization in humans.

The utilization of molecular microscope in management of heart transplant recipients in the era of noninvasive monitoring.

INTRODUCTION: Monitoring for graft rejection is a fundamental tenet of post-transplant follow-up. In heart transplantation (HT) in particular, rejection has been traditionally assessed with endomyocardial biopsy (EMB). EMB has potential complications and noted limitations, including interobserver variability in interpretation. Additional tests, such as basic cardiac biomarkers, cardiac imaging, gene expression profiling (GEP) scores, donor-derived cell-free DNA (dd-cfDNA) and the novel molecular microscope diagnostic system (MMDx) have become critical tools in rejection surveillance beyond standard EMB. METHODS: This paper describes an illustrative case followed by a review of MMDx within the context of other noninvasive screening modalities for rejection. CONCLUSIONS: We suggest MMDx be used to assist with early detection of rejection in cases of discordance between EMB and other noninvasive studies.

Implementation of an Online Intraoperative Assessment of Technical Performance for Surgical Trainees.

INTRODUCTION: Assessment of surgical resident technical performance is an integral component of any surgical training program. Timely assessment delivered in a structured format is a critical step to enhance technical skills, but residents often report that the quality and quantity of timely feedback received is lacking. Moreover, the absence of written feedback with specificity can allow residents to seemingly progress in their operative milestones as a junior resident, but struggle as they progress into their postgraduate year 3 and above. We therefore designed and implemented a web-based intraoperative assessment tool and corresponding summary "dashboard" to facilitate real-time assessment and documentation of technical performance. MATERIALS AND METHODS: A web form was designed leveraging a cloud computing platform and implementing a modified Ottawa Surgical Competency Operating Room Evaluation instrument; this included additional, procedure-specific criteria for select operations. A link to this was provided to residents via email and to all surgical faculty as a Quick Response code. Residents open and complete a portion of the form on a smartphone, then relinquish the device to an attending surgeon who then completes and submits the assessment. The data are then transferred to a secure web-based reporting interface; each resident (together with a faculty advisor) can then access and review all completed assessments. RESULTS: The Assessment form was activated in June 2021 and formally introduced to all residents in July 2021, with residents required to complete at least one assessment per month. Residents with less predictable access to operative procedures (night float or Intensive Care Unit) were exempted from the requirement on those months. To date a total of 559 assessments have been completed for operations performed by 56 trainees, supervised by 122 surgical faculty and senior trainees. The mean number of procedures assessed per resident was 10.0 and the mean number per assessor was 4.6. Resident initiation of Intraoperative Assessments has increased since the tool was introduced and scores for technical and nontechnical performance reliably differentiate residents by seniority. CONCLUSIONS: This novel system demonstrates that an online, resident-initiated technical assessment tool is feasible to implement and scale. This model's requirement that the attending enter performance ratings into the trainee's electronic device ensures that feedback is delivered directly to the trainee. Whether this aspect of our assessment ensures more direct and specific (and therefore potentially actionable) feedback is a focus for future study. Our use of commercial cloud computing services should permit cost-effective adoption of similar systems at other training programs.

Does the use of a suction calibration system (SCS) reduce stapler load firings and operative time? A randomized controlled trial comparing use of endoscopic calibration vs. SCS in laparoscopic sleeve gastrectomy.

BACKGROUND: It is critical to ensure appropriate and consistent sleeve size and orientation during laparoscopic sleeve gastrectomy (LSG). Various devices are used to achieve this, including weighted rubber bougies, esophagogastroduodenoscopy (EGD), and suction calibration systems (SCS). Prior reports suggest that SCSs may decrease operative time and stapler load firings but are limited by single-surgeon experience and retrospective design. We performed the first randomized controlled trial comparing SCS against EGD in patients undergoing LSG to investigate whether the SCS decreases the number of stapler load firings. METHODS: This was a randomized, non-blinded study from a single MBSAQIP-accredited academic center. Appropriate LSG candidates ≥ 18 years of age were randomized to EGD or SCS calibration. Exclusion criteria included prior gastric or bariatric surgery, detection of hiatal hernia before surgery, and intraoperative hiatal hernia repair. A randomized block design was employed controlling for body mass index, gender, and race. Seven surgeons employed a standardized LSG operative technique. The primary endpoint was the number of stapler load firings. Secondary endpoints were operative duration, reflux symptoms, and change in total body weight (TBW). Endpoints were analyzed via t-test. RESULTS: A total of 125 LSG patients (84% female) underwent study enrollment, with an average age of 44 ± 12 years and average BMI of 49 ± 8 kg/m2. Overall, 117 patients were randomized to receive EGD (n = 59) or SCS (n = 58) calibration. No significant differences in baseline characteristics were identified. The mean number of stapler load firings for EGD and SCS groups were 5.43 ± 0.89 and 5.31 ± 0.81, respectively (p = 0.463). The mean operative times for EGD and SCS groups were 94.4 ± 36.5 and 93.1 ± 27.9 min, respectively (p = 0.83). There were no significant differences in post-operative reflux, TBW loss, or complications. CONCLUSION: Use of EGD and SCS resulted in a similar number of LSG stapler load firings and operative duration. Additional research is needed to compare LSG calibration devices in different patients and settings to optimize surgical technique.

Development of a Novel [11C]CO-Labeled Positron Emission Tomography Radioligand [11C]BIO-1819578 for the Detection of O-GlcNAcase Enzyme Activity.

Imaging O-GlcNAcase OGA by positron emission tomography (PET) could provide information on the pathophysiological pathway of neurodegenerative diseases and important information on drug-target engagement and be helpful in dose selection of therapeutic drugs. Our aim was to develop an efficient synthetic method for labeling BIO-1819578 with carbon-11 using 11CO for evaluation of its potential to measure levels of OGA enzyme in non-human primate (NHP) brain using PET. Radiolabeling was achieved in one-pot via a carbon-11 carbonylation reaction using [11C]CO. The detailed regional brain distribution of [11C]BIO-1819578 binding was evaluated using PET measurements in NHPs. Brain radioactivity was measured for 93 min using a high-resolution PET system, and radiometabolites were measured in monkey plasma using gradient radio HPLC. Radiolabeling of [11C]BIO-1819578 was successfully accomplished, and the product was found to be stable at 1 h after formulation. [11C]BIO-1819578 was characterized in the cynomolgus monkey brain where a high brain uptake was found (7 SUV at 4 min). A pronounced pretreatment effect was found, indicating specific binding to OGA enzyme. Radiolabeling of [11C]BIO-1819578 with [11C]CO was successfully accomplished. [11C]BIO-1819578 binds specifically to OGA enzyme. The results suggest that [11C]BIO-1819578 is a potential radioligand for imaging and for measuring target engagement of OGA in the human brain.

Gastric Cancer Surgery in the US: a Contemporary Trend Analysis of Lymphadenectomy and the Impact of Minimally Invasive Approaches.

BACKGROUND: The National Comprehensive Cancer Network guidelines recommend harvesting 16 or more lymph nodes for the adequate staging of gastric adenocarcinoma. This study examines the rate of adequate lymphadenectomy over recent years, its predictors, and its impact on overall survival(OS). STUDY DESIGN: The National Cancer Database was utilized to identify patients who underwent surgical treatment for gastric adenocarcinoma between 2006-2019. Trend analysis was performed for lymphadenectomy rates during the study period. Logistic regression, Kaplan-Meier survival plots, and Cox proportional hazard regression were utilized. RESULTS: A total of 57,039 patients who underwent surgical treatment for gastric adenocarcinoma were identified. Only 50.5% of the patients underwent a lymphadenectomy of ≥ 16 nodes. Trend analysis showed that this rate significantly improved over the years, from 35.1% in 2006 to 63.3% in 2019 (p < .0001). The main independent predictors of adequate lymphadenectomy included high-volume facility with ≥ 31 gastrectomies/year (OR: 2.71; 95%CI:2.46-2.99), surgery between 2015-2019 (OR: 1.68; 95%CI: 1.60-1.75), and preoperative chemotherapy (OR:1.49; 95%CI:1.41-1.58). Patients with adequate lymphadenectomy had better OS than patients who did not: median survival: 59 versus 43 months (Log-Rank: p < .0001). Adequate lymphadenectomy was independently associated with improved OS (HR:0.79; 95%CI:0.77-0.81). Laparoscopic and robotic gastrectomies were independently associated with adequate lymphadenectomy compared to open, OR: 1.11, 95%CI:1.05-1.18 and OR: 1.24, 95%CI:1.13-1.35, respectively. CONCLUSION: Although the rate of adequate lymphadenectomy improved over the study period, a large number of patients still lacked adequate lymph node dissection, negatively impacting their OS despite multimodality therapy. Laparoscopic and robotic surgeries were associated with a significantly higher rate of lymphadenectomy ≥ 16 nodes.

The financial impact of the COVID-19 pandemic on sleeve gastrectomy at a major academic institution.

INTRODUCTION: The COVID-19- pandemic significantly impacted metabolic and bariatric surgery (MBS) practices due to large-scale surgery cancellations along with staff and supply shortages. We analyzed sleeve gastrectomy (SG) hospital-level financial metrics before and after the COVID-19 pandemic. METHODS: Hospital cost-accounting software (MicroStrategy, Tysons, VA) was reviewed for revenues, costs, and profits per SG at an academic hospital (2017-2022). Actual figures were obtained, not insurance charge estimates or hospital projections. Fixed costs were obtained through surgery-specific allocation of inpatient hospital and operating-room costs. Direct variable costs were analyzed with sub-components including: (1) labor and benefits, (2) implants, (3) drug costs, and 4) medical/surgical supplies. The pre-COVID-19 period (10/2017-2/2020) and post-COVID-19 period (5/2020-9/2022) financial metrics were compared with student's t-test. Data from 3/2020 to 4/2020 were excluded due to COVID-19-related changes. RESULTS: A total of 739 SG patients were included. Average length of stay (LOS), Center for Medicaid and Medicare Case Mix Index (CMI), and percentage of patients with commercial insurance were similar pre vs. post-COVID-19 (p > 0.05). There were more SG performed per quarter pre-COVID-19 than post-COVID-19 (36 vs. 22; p = 0.0056). Pre-COVID-19 and post-COVID-19 financial metrics per SG differed significantly for, respectively, revenues ($19,134 vs. $20,983) total variable cost ($9457 vs. $11,235), total fixed cost ($2036 vs. $4018), total profit ($7571 vs. $5442), and labor and benefits cost ($2535 vs. $3734; p < 0.05). CONCLUSIONS: The post-COVID-19 period was characterized by significantly increased SG fixed cost (i.e., building maintenance, equipment, overhead) and labor costs (increased contract labor), resulting in precipitous profit decline that crosses the break-even in calendar year quarter (CQ) 3, 2022. Potential solutions include minimizing contract labor cost and decreasing LOS.

Extended postoperative venous thromboembolism prophylaxis after bariatric surgery: a comparison of existing risk-stratification tools and 5-year MBSAQIP analysis.

BACKGROUND: Venous thromboembolism (VTE) is a leading cause of 30-day mortality after metabolic and bariatric surgery (MBS). Multiple predictive tools exist for VTE risk assessment and extended VTE chemoprophylaxis determination. OBJECTIVE: To review existing risk-stratification tools and compare their predictive abilities. SETTING: MBSAQIP database. METHODS: Retrospective analysis of the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program (MBSAQIP) database was performed (2015-2019) for primary minimally invasive MBS cases. VTE clinical factors and risk-assessment tools were evaluated: body mass index threshold of 50 kg/m2, Caprini risk-assessment model, and 3 bariatric-specific tools: the Cleveland Clinic VTE risk tool, the Michigan Bariatric Surgery Collaborative tool, and BariClot. MBS patients were deemed high risk based on criteria from each tool and further assessed for sensitivity, specificity, and positive predictive value. RESULTS: Overall, 709,304 patients were identified with a .37% VTE rate. Bariatric-specific tools included multiple predictors: procedure, age, race, gender, operative time, length of stay, heart failure, and dyspnea at rest; operative time was the only variable common to all. The body mass index cutoff and Caprini risk-assessment model had higher sensitivity but lower specificity when compared with the Michigan Bariatric Surgery Collaborative and BariClot tools. While the sensitivity of the tools varied widely and was overall low, the Cleveland Clinic tool had the highest sensitivity. The bariatric-specific tools would have recommended extended prophylaxis for 1.1%-15.6% of patients. CONCLUSIONS: Existing MBS VTE risk-assessment tools differ widely for inclusion variables, high-risk definition, and predictive performance. Further research and registry inclusion of all significant risk factors are needed to determine the optimal risk-stratified approach for predicting VTE events and determining the need for extended prophylaxis.

Utilizing Simulation to Evaluate Robotic Skill Acquisition and Learning Decay.

BACKGROUND: We aim to evaluate how new robotic skills are acquired and retained by having participants train and retest using exercises on the robotic platform. We hypothesized that participants with a 3-month break from the robotic platform will have less learning decay and increased retention compared with those with a 6-month break. METHODS: This was a prospective randomized trial in which participants voluntarily enrolled and completed an initial training phase to reach proficiency in 9 robot simulator exercises. They were then instructed to refrain from practicing until they retested either 3 or 6 months later. This study was completed at an academic medical center within the general surgery department. Participants were medical students, and junior-level residents with minimal experience in robotic surgery were enrolled. A total of 27 enrolled, and 13 participants completed the study due to attrition. RESULTS: Overall, intragroup analysis revealed that participants performed better in their retest phase compared with their initial training in terms of attempts to reach proficiency, time for completion, penalty score, and overall score. Specifically, during the first attempt in the retesting phase, the 3-month group did not deviate far from their final attempt in the training phase, whereas the 6-month group experienced significantly worse time to complete and overall score in interrupted suturing {[-4 (-18 to 20) seconds vs. 109 (55 to 118) seconds, P =0.02] [-1.3 (-8 to 1.9) vs. -18.9 (-19.5 to (-15.0)], P =0.04} and 3-arm relay {[3 (-4 to 23) seconds vs. 43 (30 to 50) seconds, P =0.02] [0.4 (-4.6 to 3.1) vs. -24.8 (-30.6 to (-20.3)], P =0.01] exercises. In addition, the 6-month group had a significant increase in penalty score in retesting compared with the 3-month group, which performed similarly to their training phase [3.3 (2.7 to 3.3) vs. 0 (-0.8 to 1.7), P =0.03]. CONCLUSIONS: This study identified statistically significant differences in learning decay, skills retention, and proficiency between 3-month and 6-month retesting intervals on a robotic simulation platform.

Apigenin improves cytotoxicity of antiretroviral drugs against HTLV-1 infected cells through the modulation of AhR signaling.

Objectives: HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neuroinflammatory autoimmune disease characterized by high levels of infected immortalized T cells in circulation, which makes it difficult for antiretroviral (ART) drugs to work effectively. In previous studies, we established that Apigenin, a flavonoid, can exert immunomodulatory effects to reduce neuroinflammation. Flavonoids are natural ligands for the aryl hydrocarbon receptor (AhR), which is a ligand activated endogenous receptor involved in the xenobiotic response. Consequently, we tested Apigenin's synergy in combination with ART against the survival of HTLV-1-infected cells. Methods: First, we established a direct protein-protein interaction between Apigenin and AhR. We then demonstrated that Apigenin and its derivative VY-3-68 enter activated T cells, drive nuclear shuttling of AhR, and modulate its signaling both at RNA and protein level. Results: In HTLV-1 producing cells with high AhR expression, Apigenin cooperates with ARTs such as Lopinavir (LPN) and Zidovudine (AZT), to impart cytotoxicity by exhibiting a major shift in IC50 that was reversed upon AhR knockdown. Mechanistically, Apigenin treatment led to an overall downregulation of NF-κB and several other pro-cancer genes involved in survival. Conclusions: This study suggest the potential combinatorial use of Apigenin with current first-line antiretrovirals for the benefit of patients affected by HTLV-1 associated pathologies.

Does CPT Modifier 22 Appropriately Reflect a Difficult Pancreaticoduodenectomy? Retrospective Analysis of Operative Outcomes and Cost.

BACKGROUND: CPT coding allows addition of a 2-digit modifier code to denote particularly difficult procedures necessitating additional reimbursement, called the modifier 22. The use of modifier 22 in relation to pancreatic surgery and outcomes, specifically pancreaticoduodenectomy (PD), has not been explored. STUDY DESIGN: All PDs performed from 2010 to 2019 at a quaternary healthcare system were analyzed for differences in preoperative characteristics, outcomes, and cost based on the use of modifier 22. Adjusted logistic regression analysis was used to identify factors predictive of modifier 22 use. RESULTS: A total of 1,284 patients underwent PD between 2010 and 2019; 1,173 with complete data were included, of which 320 (27.3%) were coded with modifier 22. Patients coded with modifier 22 demonstrated a significantly longer duration of surgery (365.9 ± 168.4 vs 227 ± 97.1; p < 0.001). They also incurred significantly higher cost of index admission ($37,446 ± 34,187 vs $28,279 ± 27,980; p = 0.002). An adjusted multivariable analysis (specifically adjusted for surgeon variation) revealed duration of surgery (p < 0.001), neoadjuvant chemotherapy (p = 0.039), class II obesity (p = 0.019), and chronic pancreatitis (p = 0.005) to be predictive of modifier 22 use. CONCLUSIONS: Despite the subjective nature of this CPT modifier, modifier 22 is an appropriate marker of intraoperative difficulty. Preoperative and intraoperative characteristics that lead to its addition may be used to further delineate difficult PDs.

Cognitive and neuroimaging outcomes in individuals with benign and low-grade brain tumours receiving radiotherapy: a protocol for a prospective cohort study.

INTRODUCTION: Radiation-induced cognitive decline (RICD) occurs in 50%-90% of adult patients 6 months post-treatment. In patients with low-grade and benign tumours with long expected survival, this is of paramount importance. Despite advances in radiation therapy (RT) treatment delivery, better understanding of structures important for RICD is necessary to improve cognitive outcomes. We hypothesise that RT may affect network topology and microstructural integrity on MRI prior to any gross anatomical or apparent cognitive changes. In this longitudinal cohort study, we aim to determine the effects of RT on brain structural and functional integrity and cognition. METHODS AND ANALYSIS: This study will enroll patients with benign and low-grade brain tumours receiving partial brain radiotherapy. Patients will receive either hypofractionated (>2 Gy/fraction) or conventionally fractionated (1.8-2 Gy/fraction) RT. All participants will be followed for 12 months, with MRIs conducted pre-RT and 6-month and 12 month post-RT, along with a battery of neurocognitive tests and questionnaires. The study was initiated in late 2018 and will continue enrolling through 2024 with final follow-ups completing in 2025. The neurocognitive battery assesses visual and verbal memory, attention, executive function, processing speed and emotional cognition. MRI protocols incorporate diffusion tensor imaging and resting state fMRI to assess structural connectivity and functional connectivity, respectively. We will estimate the association between radiation dose, imaging metrics and cognitive outcomes. ETHICS AND DISSEMINATION: This study has been approved by the Research Subjects Review Board at the University of Rochester (STUDY00001512: Cognitive changes in patients receiving partial brain radiation). All results will be published in peer-reviewed journals and at scientific conferences. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT04390906.

Early post-transplant leukopenia in heart transplant recipients and its impact on outcomes.

BACKGROUND: Leukopenia in the early period following heart transplantation (HT) is not well-studied. The aim of this study was to evaluate risk factors for the development of post-transplant leukopenia and its consequences for HT recipients. METHODS: Adult patients at a large-volume transplant center who received HT between January 1, 2010 and December 31, 2020 were included. The incidence of leukopenia (WBC ≤3 × 103 /µL) in the first 90-days following HT, individual risk factors, and its effect on 1-year outcomes were evaluated. RESULTS: Of 506 HT recipients, 184 (36%) developed leukopenia within 90-days. Median duration of the first leukopenia episode was 15.5 days (IQR 8-42.5 days). Individuals who developed leukopenia had lower pre-transplant WBC counts compared to those who did not (6.1 × 103 /µL vs. 6.9 × 103 /µL, p = .02). Initial immunosuppressive and infectious chemoprophylactic regimens were not significantly different between groups. Early leukopenia was associated with a higher mortality at 1-year (6.6% vs. 2.1%, p = .008; adjusted HR 3.0) and an increased risk of recurrent episodes. Rates of infection and rejection were not significantly different between the two groups. CONCLUSIONS: Leukopenia in the early period following HT is common and associated with an increased risk of mortality. Further study is needed to identify individuals at highest risk for leukopenia prior to transplant and optimize immunosuppressive and infectious chemoprophylactic regimens for this subgroup.

Management of Gastric Cancer.

Gastric adenocarcinoma is a complex disease that requires a thorough multidisciplinary approach for appropriate management. Management strategies vary in different regions of the world and have changed over time. In spite of improvements in chemotherapy and surgical techniques and an improvement in outcomes over the last several decades, overall survival remains low. The best outcomes are likely related to early detection, preoperative reduction of tumor burden with immunochemotherapy, consistent surgical technique for resection, and postoperative eradication of tumor cells. We aim to describe the management for gastric cancer, from the specifics of staging and imaging workup to the tenets of surgical resection and reconstruction as well as the adjuvant treatment strategies in this broad review of gastric cancer management.

S136-operationalizing an enhanced recovery protocol after bariatric surgery: single institutional pilot experience forging data-driven standard work.

BACKGROUND: Enhanced recovery protocols (ERPs) after metabolic and bariatric surgery (MBS) may help decrease length of stay (LOS) and postoperative nausea/vomiting but implementation is often fraught with challenges. The primary aim of this pilot study was to standardize a MBS ERP with a real-time data support dashboard and checklist and assess impact on global and individual element compliance. The secondary aim was to evaluate 30 day outcomes including LOS, hospital readmissions, and re-operations. METHODS AND PROCEDURES: An ERP, paper checklist, and virtual dashboard aligned on MBS patient care elements for pre-, intra-, and post-operative phases of care were developed and sequentially deployed. The dashboard includes surgical volumes, operative times, ERP compliance, and 30 day outcomes over a rolling 18 month period. Overall and individual element ERP compliance and outcomes were compared pre- and post-implementation via two-tailed Student's t-tests. RESULTS: Overall, 471 patients were identified (pre-implementation: 193; post-implementation: 278). Baseline monthly average compliance rates for all patient care elements were 1.7%, 3.7%, and 6.2% for pre-, intra-, and post-operative phases, respectively. Following ERP integration with dashboard and checklist, the intra-operative phase achieved the highest overall monthly average compliance at 31.3% (P < 0.01). Following the intervention, pre-operative acetaminophen administration had the highest monthly mean compliance at ≥ 99.1%. Overall TAP block use increased 3.2-fold from a baseline mean rate of 25.4-80.8% post-implementation (P < 0.01). A significant decrease in average intra-operative monthly morphine milligram equivalents use was noted with a 56% drop pre- vs. post-implementation. Average LOS decreased from 2.0 to 1.7 days post-implementation with no impact on post-operative outcomes. CONCLUSION: Implementation of a checklist and dashboard facilitated ERP integration and adoption of process measures with many improvements in compliance but no impact on 30 day outcomes. Further research is required to understand how clinical support tools can impact ERP adoption among MBS patients.