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BACKGROUND: Preoperative thrombocytopenia is associated with inferior outcomes in surgical patients, though concurrent anemia may obfuscate these relationships. This investigation assesses the prevalence and clinical significance of preoperative thrombocytopenia with thorough consideration of preoperative anemia status. METHODS: This is an observational cohort study of adults undergoing elective surgery with planned postoperative hospitalization from January 1, 2009 to May 3, 2018. Patients were designated into 4 groups: normal platelet and hemoglobin concentrations, isolated thrombocytopenia (ie, platelet count <100 × 10 9 /L), isolated anemia (ie, hemoglobin <12 g/dL women, <13.5 g/dL men), and thrombocytopenia with anemia. Thrombocytopenia was further defined as incidental (ie, previously undiagnosed) or nonincidental. Multivariable regression analyses were utilized to assess the relationships between thrombocytopenia status and clinical outcomes, with a primary outcome of hospital length of stay. RESULTS: A total of 120,348 patients were included for analysis: 72.3% (95% confidence interval [CI], 72.1-72.6) normal preoperative laboratory values, 26.3% (26.1-26.6) isolated anemia, 0.80% (0.75-0.86) thrombocytopenia with anemia, and 0.52% (0.48-0.56) isolated thrombocytopenia (0.38% [0.34-0.41] nonincidental, 0.14% [0.12-0.17] incidental). Thrombocytopenia was associated with longer hospital length of stay in those with concurrent anemia (multiplicative increase of the geometric mean 1.05 [1.00, 1.09] days; P = .034) but not in those with normal preoperative hemoglobin concentrations (multiplicative increase of the geometric mean 1.02 [0.96, 1.07] days; P = .559). Thrombocytopenia was associated with increased odds for intraoperative transfusion regardless of anemia status (nonanemic: 3.39 [2.79, 4.12]; P < .001 vs anemic: 2.60 [2.24, 3.01]; P < .001). Thrombocytopenia was associated with increased rates of intensive care unit (ICU) admission in nonanemic patients (1.56 [1.18, 2.05]; P = .002) but not in those with preoperative anemia (0.93 [0.73, 1.19]; P = .578). CONCLUSIONS: Preoperative thrombocytopenia is associated with clinical outcomes in elective surgery, both in the presence and absence of concurrent anemia. However, isolated thrombocytopenia is rare (0.5%) and is usually identified before preoperative testing. It is unlikely that routine thrombocytopenia screening is indicated for most patients.

Objective: We aimed to investigate eligibility for breast conserving surgery (BCS) pre- and post-neoadjuvant systemic therapy (NST), and trends in the surgical treatment of young breast cancer patients. Background: Young women with breast cancer are more likely to present with larger tumors and aggressive phenotypes, and may benefit from NST. Little is known about how response to NST influences surgical decisions in young women. Methods: The Young Women's Breast Cancer Study, a multicenter prospective cohort of women diagnosed with breast cancer at age ≤40, enrolled 1302 patients from 2006 to 2016. Disease characteristics, surgical recommendations, and reasons for choosing mastectomy among BCS-eligible patients were obtained through the medical record. Trends in use of NST, rate of clinical and pathologic complete response, and surgery were also assessed. Results: Of 1117 women with unilateral stage I-III breast cancer, 315 (28%) received NST. Pre-NST, 26% were BCS eligible, 17% were borderline eligible, and 55% were ineligible. After NST, BCS eligibility increased from 26% to 42% (P < 0.0001). Among BCS-eligible patients after NST (n = 133), 41% chose mastectomy with reasons being patient preference (53%), BRCA or TP53 mutation (35%), and family history (5%). From 2006 to 2016, the rates of NST (P = 0.0012), clinical complete response (P < 0.0001), and bilateral mastectomy (P < 0.0001) increased, but the rate of BCS did not increase (P = 0.34). Conclusion: While the proportion of young women eligible for BCS increased after NST, many patients chose mastectomy, suggesting that surgical decisions are often driven by factors beyond extent of disease and treatment response.

This study examines whether surgical resection of carotid body tumors (CBTs) is acceptable in light of potential significant neurologic complications. This IRB-approved retrospective study analyzed data from 24 patients undergoing surgical treatment for CBTs between April 1998 and April 2017 at Mayo Clinic (Florida campus only). For patients who underwent multiple CBT resections, only data from the first surgery was used in this analysis. CBT resection occurred in 24 patients with the following demographics: fourteen patients (58.3%) were female, median age was 56.5 years, median BMI was 29. A prior history of neoplasm was found in ten patients (41.7%). A known family history of paraganglioma was present in five patients (20.8%). Two patients were positive for succinate dehydrogenase mutation (8.3%). Multiple paragangliomas were present in seven patients (29.2%). There was nerve sacrifice in three patients (12.5%) during resection. Carotid artery reconstruction and patch angioplasty occurred in one patient (4.2%). Complete resection occurred in 24 patients (100.0%). Postoperatively, one patient (4.2%) suffered stroke. No mortalities occurred within or beyond 30 days of surgery. Persistent cranial nerve injury occurred in two patients (8.3%) with vocal cord paralysis. There was no recurrence of CBT through last follow-up. Five patients (20.8%) were diagnosed with other neoplasms after resection, including basal cell carcinoma, contralateral carotid body tumor, glomus vagale, and glomus jugulare. There was 100% survival at 1 year in patients followed for that time ( n = 17). Surgical treatment remains the first-line curative treatment to relieve symptoms and ensure non-recurrence. While acceptable, neurologic complications are significant and therefore detailed preoperative informed consent is mandatory.

AbstractBackgroundThe potential adverse effects of exposures to general anesthesia on the developing human brain remain controversial. It has been hypothesized that hypotension accompanying anesthesia could be contributory. We hypothesized that among children exposed to multiple anesthetics prior to age 3, children developing adverse neurodevelopmental outcomes would be more likely to have intraoperative hypotension.MethodsTwo previously published study cohorts were utilized for analysis: the retrospective and prospective Mayo Anesthesia Safety in Kids cohorts. The two lowest consecutive systolic blood pressure measurements were abstracted and standardized by calculating a z‐score for noninvasive blood pressure reference ranges for children. The lowest systolic blood pressure z‐score (continuous variable) and intraoperative hypotension (lowest systolic blood pressure z‐score <−1.0) were used to assess the association of intraoperative hypotension with the incidence of learning disabilities or attention‐deficit/hyperactivity disorder(retrospective cohort) and factor scores/cluster membership (prospective cohort).ResultsOne hunderd and sixteen and 206 children with multiple exposures to general anesthesia were analyzed in the retrospective and prospective cohorts with mean lowest systolic blood pressure z‐scores −0.26 (SD 1.02) and −0.62 (SD 1.10), respectively. There was no overall association of the lowest z‐score or hypotension with learning disabilities or attention‐deficit/hyperactivity disorder in the retrospective cohort. In the prospective cohort, there was no overall association of the lowest systolic blood pressure or hypotension with factor scores or cluster membership.ConclusionsWe did not find evidence to support the hypothesis that, among children exposed to multiple anesthetics prior to age 3, children developing adverse neurodevelopmental outcomes would be more likely to have intraoperative hypotension compared with those who did not.

Abstract Purpose Peripheral nerve stimulation (PNS) is a rapidly expanding field within neuromodulation; however, there is limited data on therapeutic efficacy. This study describes the indications and clinical outcomes for patients undergoing PNS for chronic pain states. Patients and Methods This is a retrospective case series of adults undergoing PNS implantation from 2004 to 2017 at an academic medical center. The primary outcomes were changes in numeric rating scale (NRS) pain scores, opioid utilization in oral morphine milligram equivalent (MME), and self‐reported patient functioning at 6 months postoperatively. Infectious and device‐related complications were also assessed. Results A total of 72 patients underwent PNS implantation, including 59 patients that received a preceding PNS trial (59/78; 76% progression rate) and 13 that did not receive a PNS trial. The most common indication for stimulation was occipital neuralgia (47%) followed by lower‐extremity neuropathies (17%). PNS implantation was associated with 6‐month reductions in pain scores (7 [6, 8] baseline vs. 4 [2, 5] 6 months; P < 0.001) and opioid utilization (eg, median 60 [31, 104] vs. 18 [0, 52] MME among those with baseline opioid use; P < 0.001). Median functional improvement was 73% (50%, 88%). Seven patients (10%) suffered a postoperative surgical site infection at a median of 50 (30, 124) days, of which five devices were removed. Conclusion Peripheral nerve stimulation was associated with reduced pain scores, lower opioid utilization, and improved patient function at 6 months. These data support PNS as a potentially effective nonopioid analgesic modality in chronic pain, though prospective multicenter evaluation is warranted to evaluate longer‐term outcomes.

Abstract Objective: Dyad learning has been shown to be an effective tool for teaching procedural skills, but little is known about how dyad learning may impact the stress, anxiety, and cognitive load that a student experiences when learning in this manner. In this pilot study, we investigate the relationship between dyad training on stress, anxiety, cognitive load, and performance in a simulated bradycardia scenario. Methods: Forty-one fourth-year medical school trainees were randomized as dyads (n=24) or individuals (n=17) for an education session on Day 1. Reassessment occurred on Day 4 and was completed as individuals for all trainees. Primary outcomes were cognitive load (Paas scale), stress (Cognitive Appraisal Ratio), and anxiety levels (abbreviated State-Trait Anxiety Inventory). Secondary outcomes were time-based performance metrics. Results: On Day 1 we observed significant differences for change in anxiety and stress measured before and after the training scenario between groups. Individuals compared to dyads had larger mean increases in anxiety, (19.6 versus 7.6 on 80-point scale, p=0.02) and stress ratio (1.8 versus 0.9, p=0.045). On the Day 4 post-intervention assessment, no significant differences were observed between groups. Secondary outcomes were significant for shorter time to diagnosis of bradycardia (p=0.01) and time to initiation of pacing (p=0.04) in the dyad group on Day 1. On Day 4, only time to recognizing the indication for pacing was significantly shorter for individual training (Hazard ratio [HR] = 2.26, p = 0.02).Conclusions: Dyad training results in lower stress and anxiety levels with similar performance compared to individual training.

Recent successes and FDA approvals of CD19 redirected chimeric antigen receptor T cell (CART19) therapy have been achieved in pivotal clinical trials in patients with B cell malignancies. However, durable response rates in non-Hodgkin B cell lymphoma (B-NHL) and chronic lymphocytic leukemia (CLL) are low. Tumor-associated macrophages have emerged as key mediators of tumor-induced CART cell immunosuppression. Axl receptor tyrosine kinase (Axl-RTK) is overexpressed in various human cancers including B-NHL or CLL and correlates with poor overall survival. Thus, several Axl-RTK inhibitors are currently being investigated in clinical trials. We have previously reported that the Axl-RTK inhibitor TP-0903 modulates CART19 function by Th1 polarization. Moreover, we observed a significant reduction in myeloid-derived cytokines in preclinical models. This led us to hypothesize that Axl-RTK inhibition also modulates monocytes which in turn affects CART function. To test our hypothesis, we interrogated the interactions between Axl-RTK inhibition, monocytes, and CART. First, we isolated CD14+ monocytes from peripheral mononuclear cells (PBMCs) from healthy donors by magnetic negative selection. Flow cytometric analysis revealed a robust Axl expression on monocytes (Fig.1A). Monocytes were maintained in ImmunoCult Macrophage Medium (STEMCELL Technologies) and differentiated with lipopolysaccharide and interferon-γ for M1-type and interleukin (IL)-4 for M2-type macrophages. After confirming the macrophage phenotypes, cells were assessed for Axl expression. Flow cytometric analysis demonstrated that M2-type macrophages expressed higher Axl compared to M1 macrophages (Fig.1B). Then, we treated PBMCs from healthy donors with TP-0903 for 24 hours to determine the specific cell types affected by Axl-RTK inhibition. Flow cytometric analysis revealed that monocytes were significantly inhibited by TP-0903 compared to B cells or T cells (Fig.1C). Having demonstrated that TP-0903 strongly suppresses monocytes and that M2-type macrophages express Axl on their surface, we then performed a cytotoxicity assay against CD19+ mantle cell lymphoma cell line, JeKo-1, to study the impact of Axl-RTK inhibition on monocyte-induced CART suppression. We used CART19 generated in our laboratory (FMC63-41BBζ). CART19, JeKo-1, and M2-type macrophages were co-cultured at 1:2:1 ratio and incubated for 3 days. The data revealed that M2-type macrophages strongly suppress CART19 killing (Fig.1D) which could be overcome with TP-0903 (Fig.1E). Next we studied monocyte-induced CART19 suppression with antigen-specific proliferation. CART19, JeKo-1, and monocytes were co-cultured at 1:5:1 ratio and incubated for 5 days. Flow cytometric analysis revealed that in the presence of monocytes, antigen-specific proliferation of CART19 was significantly suppressed, which was reversed in the presence of TP-0903 (Fig.1F). To assess how Axl inhibition modulates myeloid cell-derived cytokines/chemokines, we performed Multiplex (Millipore-Sigma) with the supernatants obtained from these co-culture assays. The presence of monocytes resulted in a significant increase in IL-17a, IL-6, IL-1 receptor agonist, IL-1β, and soluble CD40 ligand. However, Axl-RTK inhibition resulted in selective reduction of those cytokines/chemokines (Fig.1G) while preserving other effector cytokines. Finally, we tested whether Axl-RTK inhibition with TP-0903 could overcome the negative effects of monocytes in vivo. Here, immunocompromised NSG mice were injected with 1x106 luciferase+ JeKo-1 cells intravenously. Ten days later, mice were injected with freshly isolated monocytes derived from a healthy donor. Two weeks after JeKo-1 inoculation, tumor burden was assessed with bioluminescence imaging. Mice were then randomized according to the tumor burden to receive 0.5x106 CART19 as a monotherapy or in combination with 20 mg/kg/day of oral TP-0903. The combination therapy resulted in superior anti-tumor effects and overall survival compared to CART19 monotherapy (Fig.1H-I). In summary, Axl-RTK inhibition with TP-0903 demonstrates a direct suppression of inhibitory monocytes, which in turn enhances CART cell function. Our findings support the strategy of further refining and testing the novel and potent combination of Axl-RTK inhibition and CART cell therapy for the treatment of B cell malignancies. Figure 1 Disclosures Sakemura: Humanigen: Patents & Royalties. Cox:Humanigen: Patents & Royalties. Mouritsen:Sumitomo Dainippon Pharma Oncology, Inc.: Current Employment. Foulks:Tolero Pharmaceuticals, Inc.: Current Employment. Warner:Tolero Pharmaceuticals, Inc.: Current Employment. Ding:Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; DTRM: Research Funding; Astra Zeneca: Research Funding; Abbvie: Research Funding; Octapharma: Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Membership on an entity's Board of Directors or advisory committees; alexion: Membership on an entity's Board of Directors or advisory committees; Beigene: Membership on an entity's Board of Directors or advisory committees. Parikh:GlaxoSmithKline: Honoraria; Verastem Oncology: Honoraria; Genentech: Honoraria; Ascentage Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Merck: Research Funding; TG Therapeutics: Research Funding; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; MorphoSys: Research Funding; Pharmacyclics: Honoraria, Research Funding. Kay:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding; MEI Pharma: Research Funding; Abbvie: Research Funding; Tolero Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Meyer Squib: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Research Funding; Sunesis: Research Funding; Astra Zeneca: Membership on an entity's Board of Directors or advisory committees; Agios Pharma: Membership on an entity's Board of Directors or advisory committees; Cytomx: Membership on an entity's Board of Directors or advisory committees; Morpho-sys: Membership on an entity's Board of Directors or advisory committees; Rigel: Membership on an entity's Board of Directors or advisory committees; Oncotracker: Membership on an entity's Board of Directors or advisory committees; Dava Oncology: Membership on an entity's Board of Directors or advisory committees; Juno Theraputics: Membership on an entity's Board of Directors or advisory committees. Kenderian:Mettaforge: Patents & Royalties; Lentigen: Research Funding; MorphoSys: Research Funding; Sunesis: Research Funding; Tolero: Research Funding; BMS: Research Funding; Juno: Research Funding; Gilead: Research Funding; Kite: Research Funding; Novartis: Patents & Royalties, Research Funding; Torque: Consultancy; Humanigen: Consultancy, Patents & Royalties, Research Funding.

IMPORTANCE Hospitalizations are associated with cognitive decline in older adults. OBJECTIVE To determine the association between hospitalization characteristics and the trajectory of cognitive function in older adults. DESIGN Population‐based longitudinal study of cognitive aging. SETTING Olmsted Medical Center and Mayo Clinic, the only centers in Olmsted County, Minnesota, with hospitalization capacity. PARTICIPANTS Individuals without dementia at baseline, with consecutive cognitive assessments from 2004 through 2017, and at least one visit after the age of 60. MEASUREMENTS The primary outcome was longitudinal changes in global cognitive z ‐score. Secondary outcomes were changes in four cognitive domains: memory, attention/executive function, language, and visuospatial skills. Hospitalization characteristics analyzed included elective versus nonelective, medical versus surgical, critical care versus no critical care admission, and long versus short duration admissions. RESULTS Of 4,587 participants, 1,622 had 1 and more hospital admission. Before hospitalization, the average slope of the global z ‐score was −0.031 units/year. After hospitalization, the rate of annual global z ‐score accelerated by −0.051 (95% CI = −0.057, −0.045) units, P < .001, resulting in an estimated annual slope after the first hospitalization of −0.082. The accelerated decline was found in all four cognitive domains (memory, visuospatial, language, and executive, all P < .001). The acceleration of the decline in global z ‐score following hospitalization was greater for medical compared to surgical hospitalizations (slope change following hospitalization = −0.064 vs −0.034 for medical vs surgical, P < .001), and nonelective compared to elective admissions (slope change following hospitalization = −0.075 vs −0.037 for nonelective vs elective, P < .001). The acceleration of cognitive decline was not different for hospitalization with intensive care unit admission versus not. CONCLUSIONS Hospitalization of older adults is associated with accelerated decline of global and domain‐specific cognitive domains, with the rate of decline dependent upon type of admission. The clinical impact of this accelerated decline will depend on the individual's baseline cognitive reserve and expected longevity.

AbstractBackground and ObjectivesOptimizing perioperative analgesia for patients undergoing major lower‐extremity amputation remains a considerable challenge. The utility of liposomal bupivacaine as a component of peripheral nerve blockade for lower‐extremity amputation is unknown.MethodsWe conducted an observational study comparing three different perioperative analgesic techniques for adults undergoing major lower‐extremity amputation under general anesthesia between 2012 and 2017 at an academic medical center: (1) no regional anesthesia, (2) peripheral nerve blockade with standard bupivacaine, and (3) peripheral nerve blockade with a mixture of standard and liposomal bupivacaine. The primary outcome of cumulative opioid oral morphine milligram equivalent utilization in the first 72 hours postoperatively was compared across groups utilizing multivariable linear regression.ResultsA total of 631 unique anesthetics were included for 578 unique patients, including 416 (66%) without regional anesthesia, 131 (21%) with peripheral nerve blockade with a mixture of standard and liposomal bupivacaine, and 84 (13%) with peripheral nerve blockade with standard bupivacaine alone. Cumulative morphine equivalents were lower in those receiving peripheral nerve blockade with combined standard and liposomal bupivacaine compared with those not receiving regional anesthesia (multiplicative increase 0.67; 95% CI 0.50 to 0.90; P = 0.007). There were no significant differences in opioid utilization between peripheral nerve blockade groups (P = 0.59).ConclusionsPeripheral nerve blockade is associated with reduced opioid requirements after lower‐extremity amputation compared with general anesthesia alone. However, the incorporation of liposomal bupivacaine is not significantly different to blockade employing only standard bupivacaine.

AbstractBackgroundThe COVID‐19 pandemic has placed great strain on blood resources. In an effort to extend platelet (PLT) shelf life and minimize waste, our institution transitioned room temperature to cold‐stored PLTs for administration to bleeding patients.Study Design and MethodsWe describe the administrative and technical processes involved in transitioning room temperature PLTs to cold storage in April 2020. Additionally, we describe the clinical utilization of cold‐stored PLTs in the first month of this practice change, with a focus on changes in PLT counts after transfusion, hemostasis, and safety outcomes.ResultsA total of 61 cold‐stored PLT units were transfused to 40 bleeding patients, with a median (interquartile range [IQR]) of 1 (1‐2) units per patient. The median age was 68 (59‐73) years; 58% male. Median pretransfusion and posttransfusion PLTs counts were 88 (67‐109) and 115 (93‐145). A total of 95% of transfusions were administered in the operating room: 57% cardiac surgery, 20% vascular surgery, 8% general surgery, and 5% solid organ transplantation. Hemostasis was deemed to be adequate in all cases after transfusion. There were no transfusion reactions. One patient (3%) experienced a fever and infection within 5 days of transfusion, which was unrelated to transfusion. Median (IQR) hospital length of stay was 8.5 (6‐17) days. Two patients (5%) died in the hospital of complications not related to transfusion.ConclusionCold‐stored PLT utilization was associated with adequate hemostasis and no overt signal for patient harm. Conversion from room temperature to cold‐stored PLTs may be one method of reducing waste in times of scarce blood inventories.