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Abstract Background Debridement, antibiotics, and implant retention (DAIR) is appropriate for select acute postoperative and hematogenous periprosthetic joint infections (PJIs). However, the optimal duration of antimicrobial therapy in patients treated with DAIR has not been defined. Therefore, we aimed to identify the ideal duration of parenteral and oral antibiotics after DAIR. Methods We performed a retrospective study of patients >18 years of age with hip or knee PJI managed with DAIR between January 1, 2008, and December 31, 2018, at Mayo Clinic. PJI was defined using criteria adapted from the International Consensus Meeting on PJI. The outcome was defined as either PJI recurrence or unplanned reoperation due to infection. Joint-stratified Cox proportional hazards regression models with time-dependent covariates were used to assess nonlinear effects of antibiotic duration. Hazard ratios were computed based on prespecified time points for comparison, whereas p-values represented the overall effect across the entire range of durations. Results There were 247 unique episodes of PJI in 237 patients during the study period. Parenteral antibiotics were given in 99.2% of cases (n=245). This was followed by chronic oral antibiotic suppression in 92.2% (n=226) with a median duration of 2.2 years (1.0-4.1). DAIR failed in 65 cases over a median follow-up of 4.4 years, with a 5-year cumulative incidence of 28.1%. After adjustment for risk factors, there was no significant association between duration of parenteral antibiotics and treatment failure (p=0.203), with no difference between four versus six weeks (HR 1.11; 95% CI 0.71-1.75) (Figure 1). However, both use and longer duration of oral antibiotic therapy was associated with a lower risk of failure (p=0.006). To account for the possibility that this association was driven by results during early follow-up, conditional analyses at one- and two-year follow-up were performed. Both showed a significantly lower risk for a longer duration of antibiotics (Figure 2). Figure 1. Time-Dependent Analysis of Parenteral Antibiotic Duration Figure 2. Time-Dependent Analysis of Oral Antibiotic Suppression Duration Conclusion After DAIR, efficacy from four weeks of parenteral antibiotics was no different from six weeks when followed by chronic oral antibiotic suppression. Our results could not establish an optimal duration but suggested that continuing suppression portends a lower risk of failure of DAIR. Disclosures Elie Berbari, MD, Uptodate.com (Other Financial or Material Support, Honorary unrelated to this work) Matthew P. Abdel, MD, Stryker and AAOS Board of Directors (Board Member, Other Financial or Material Support, Royalties) Aaron J. Tande, MD, UpToDate.com (Other Financial or Material Support, Honoraria for medical writing)

Abstract Background Serial blood cultures are integral in managing Staphylococcus aureus bacteremia (SAB) as clinicians rely on the results to determine infectious complication risks and antibiotic duration. Current IDSA guidelines suggest a single set of negative blood cultures is adequate evidence of SAB clearance. Several studies, however, have identified the skip phenomenon (SP), which is the occurrence of intermittent negative blood cultures, and have recommended obtaining additional blood cultures to document bacterial clearance (Table 1). We therefore examined patients who manifested the SP to determine its clinical significance and to study this, associations were tested for SP in relation to various baseline factors as well as clinical outcomes. Methods We performed a retrospective, multicenter study of all patients with a positive blood culture for S. aureus from January 2019 to December 2019 using data collected from electronic health records and the clinical microbiology laboratory. Results A total of 602 patients with SAB were identified and 495 patients were included in the investigation (Figure 1). Overall, 25 (5.1%) patients had the SP. Significant differences between those who did and did not manifest the SP included higher rates of injection drug use, automatic implantable cardioverter defibrillator, and community onset of infection in the SP cohort (Table 2). Moreover, the median duration of SAB was longer (3.2 [2.3-5.4] vs 1.90 [1.2-2.9] days, p=0.002), and high-grade SAB, (88.0% vs 58.7%, p=0.004), complicated bacteremia (92.0% vs 67.9%, p=0.011) and IE diagnosis (28.0% vs 11.3%, p=0.013) were all more common in the SP group. In unadjusted outcome analyses, association of SP with hospital length of stay was not significant, although a higher risk of in-hospital mortality among SP patients approached statistical significance (p=0.055). Analysis of 435 hospital survivors revealed no significant differences in rates of 1-year mortality or 90-day relapse between the two groups (Table 3). Conclusion Findings of the current investigation demonstrates an increased risk of SAB complications in patients with the SP and support the notion that serial negative blood cultures are needed to document clearance of SAB. Disclosures Larry M. Baddour, MD, Boston Scientific (Individual(s) Involved: Self): Consultant; Botanix Pharmaceuticals (Individual(s) Involved: Self): Consultant; Roivant Sciences (Individual(s) Involved: Self): Consultant Muhammad R. Sohail, MD, Medtronic (Consultant)Philips (Consultant)

Abstract Background Invasive fungal infection (IFI) in heart transplant recipients is associated with poor outcomes. Estimated risk of 1‐year IFI in heart transplant recipients is 3.4–8.6% with risk factors inconsistently identified in previous studies. The role of antifungal prophylaxis is unclear. The transplant program at Mayo Clinic provides 6 months of universal azole prophylaxis for those heart transplant recipients in Arizona. We sought to define risk factors for 1‐year IFI and determine the effect of antifungal prophylaxis. Methods We conducted a retrospective cohort study of patients undergoing heart transplantation at Mayo Clinic from January 2000 to March 2019. We analyzed demographics, details of transplant hospitalization, antifungal prophylaxis, and fungal infection. Multivariable Cox analyses were performed to identify risk factors of 1‐year IFI and impact of IFI on posttransplant mortality. Results A total of 966 heart transplant recipients were identified with a median age of 56 years (IQR 47, 62). A total of 444 patients received antifungal prophylaxis. Over 1‐year follow‐up, 62 patients developed IFI with a cumulative incidence of 6.4%. In multivariable analysis, factors associated with IFI were renal replacement therapy (RRT) (HR 3.24, 95% CI 1.65–6.39), allograft rejection (HR 2.33, 95% CI 1.25–4.34), and antifungal prophylaxis (HR 0.32, 95% CI 0.11–0.96). RRT was also associated with invasive mold infection (HR 3.00, 95% CI 1.29–6.97). Conclusions RRT and allograft rejection after transplantation are associated with 1‐year IFI, and RRT is also associated with invasive mold infection. Antifungal prophylaxis appears to be protective and further study is needed in the heart transplant population.

Background: In 2007, the American Heart Association (AHA) infective endocarditis (IE) prevention guidelines recommended that antibiotic prophylaxis before invasive dental procedures for the “moderate risk” (MR) group, which represented the bulk of patients who were to receive prophylaxis before 2007, be eliminated. This decision was met with much concern among some healthcare providers and that concern persists today. We therefore evaluated dental office records in Olmsted County (OC), Minnesota to determine whether patients included in the MR group continue to receive antibiotic prophylaxis despite the 2007 AHA recommendations. Methods: Eligible patients include all adult (≥18 years) residents of OC, classified as having MR cardiac condition for IE (i.e. mitral valve prolapse [MVP], bicuspid aortic valve [BAV], hypertrophic obstructive cardiomyopathy [HOCM], acquired valvular dysfunction [AVD]), with at least one dental visit between January 1, 2005 and June 1, 2015. Eight dental offices located within OC were sampled to identify both dental procedures and whether antibiotic prophylaxis was administered according to AHA guidelines. Results: We identified 334 MR patients. Approximately 62% of MR patients received antibiotic prophylaxis prior to the change in AHA guidelines in 2007. There was a decrease to 7% post-2007 AHA guidelines (P<.001). The magnitude of decline was greater among visits for dental cleanings (from 63% to 6%), as compared to other invasive procedures (57% to 11%; P=0.003) (Figure 1). AVD was the most common cardiac condition (85%), followed by MVP (8%), and BAV (4%). Conclusion: Following publication of the 2007 AHA IE prevention guidelines, there was a rapid, 9-fold decrease in antibiotic prophylaxis in patients with MR cardiac conditions who underwent invasive dental procedures in OC. These data are also critical as we attempt to evaluate the impact, if any, of this practice on the incidence of IE due to viridans group streptococci.

Background Pericardiectomy for post-radiation constrictive pericarditis has been reported to generally have unfavorable outcomes. This study sought to evaluate surgical outcomes in a large cohort of patients undergoing pericardiectomy for radiation-associated pericardial constriction. Methods A retrospective analysis of all patients (≥18years) who underwent pericardiectomy for a diagnosis of constrictive pericarditis with a prior history of mediastinal irradiation from June 2002 to June 2019 was conducted. There were 100 patients (mean age 57.2±10.1 years, 49% females) who met the inclusion criteria. Records were reviewed to look at surgical approach, extent of resection, early mortality and late survival. Results The overall operative mortality was 10.1% (n=10). The rate of operative mortality decreased over the study period; however, the test of trend was not statistically significant (P=0.062). Hodgkin’s disease was the most common malignancy (64%) for which mediastinal radiation had been received. Only 27% patients had an isolated pericardiectomy, and concomitant pericardiectomy and valve surgery was performed in 46% patients. Radical resection was performed in 50% patients, whereas 47% patients underwent a subtotal resection. Prolonged ventilation (26%), atrial fibrillation (21%) and pleural effusion (16%) were the most common post-operative complications. The overall 1,5- and 10-years survival was 73.6%, 53.4% and 32.1% respectively. Increasing age (HR 1.044, 95%CI 1.017-1.073) appeared to have a significant negative effect on overall survival in the univariate model. Conclusion Pericardiectomy performed for radiation associated constrictive pericarditis has poor long-term outcomes. The early mortality, though high (~10%), has been showing a decreasing trend in the test of time.

Objective Activated platelets serve as a catalyst for thrombin generation. Furthermore, oral MHT may carry greater thrombotic risk than transdermal products. This study compared effects of oral and transdermal MHT on platelet characteristics including platelet‐derived microvesicles (MV) in recently menopausal women. Methods Platelets and MV were prepared from blood of a subset of women (n=117) enrolled in the Kronos Early Estrogen Prevention Study prior to and after 4 years of treatment with either oral conjugated equine estrogen (0.45 mg, oCEE), transdermal 17β estradiol (50 µg/day, tE2), each with intermittent progesterone (200 mg/day for 12 days a month), or placebo pills and patch. Results Platelet count, and activated platelet P‐selectin and fibrinogen‐binding receptor expression were similar across groups. Numbers of tissue factor positive and platelet‐derived MV increased significantly in the tE2 compared to placebo. Conclusions Four years of MHT did not increase thrombogenic characteristics of platelets. Thrombotic risk associated with oral MHT most likely involves liver‐derived proteins than platelets per se. Differential effects of oCEE and tE2 on circulating MV may reflect the hormonal composition of the two formulations on non‐genomic pathways in circulating platelets. Funding This work was supported by grants from the Aurora Foundation to the Kronos Longevity Research Institute, NIH HL90639, UL1TR00013 1 , American Heart Association‐ Scientist Development Grant, AHA 08‐30503Z, American Heart Association, Grant‐in‐Aid, 12GRNT12050147, and the Mayo Foundation.

Background Break down of the blood brain barrier and activation of brain cells are implicated in progression of deposition of β‐amyloid that is associated with the pathophysiology of Alzheimer's disease. A previous study from our group indicated that deposition of β‐amyloid may be reduced in the brains of menopausal women treated with transdermal 17β‐estradiol. This study aimed to determine the association of peripheral microvesicles carrying markers of cells of the neurovascular unit with β‐amyloid in the brains of menopausal women and if the association was affected by prior menopausal hormone treatments (MHT). Methods Menopausal women previously enrolled in the Kronos Early Estrogen Prevention Study at Mayo Clinic underwent β‐amyloid positron emission tomography (PET) imaging of their brains 3 years following treatment with either placebo (PL, n=29), transdermal 17β‐estradiol (tE2; n=21), or oral conjugated equine estrogen (oCEE; n=17) for 4 years. Microvesicles (MV) were isolated from peripheral venous blood by differential centrifugation and analyzed by flow cytometry using fluorophore conjugated antibodies directed toward total tau, β‐amyloid 1‐42 (Ab1‐42), neuron specific class III β‐tubulin (Tuj1), microglia ionized calcium adaptor molecule 1(Iab‐1), glial fibrillar acid protein (GFAP), and low density lipoprotein receptor‐related protein 1. Principal components analysis was used to reduce the dimensionality of the 6 brain markers to 2 principal components (PCs). Proportional odds ordinal logistic regression analysis was used to regress deposition of β‐amyloid on the 2 PCs with and without adjustment for MHT group. Results Number of blood MV positive for Ab1‐42 differed significantly among MHT groups (median [IQR]: 6.06 [2.11, 12.55] in the PL; 2.49 [0.73, 3.59] in the tE2 and 4.96 [0.83, 10.31] in the oCEE; P=0.036). The first 2 PCs explain 58% of the variance of the 6 markers. PC#1 represented a contrast between MV‐Iab‐1 and the MV‐GFAP and MV‐Tuj1. In multivariable models, brain β‐amyloid load positively associated with the first PC after adjustment for MHT (P= 0.006). Conclusion MV derived from cells of the neurovascular unit can be detected in peripheral blood, and, when combined into summary scores, showed an association with deposition of β‐amyloid in the brain that is independent of MHT. Support or Funding Information Supported by grants from NIH P50 AG044170 and the Mayo Foundation This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Cerebrovascular reactivity to hypercapnia, an estimate of microvascular responses in the brain, is increased during menopausal hormone treatment (MHT) in postmenopausal women. It is unclear whether this effect of MHT continues beyond the treatment period. We hypothesized that prior MHT use would not affect cerebrovascular reactivity 3 years after treatment. In addition, we have previously shown that cerebrovascular reactivity is associated with vascular activation in postmenopausal women with elevated cardiovascular risk. We hypothesized that cerebrovascular reactivity is not associated with markers of intravascular cellular activation in postmenopausal women with low cardiovascular risk who are within 10 years of menopause. Cerebrovascular reactivity to hypercapnia was measured in 58 postmenopausal women from the Kronos Early Estrogen Prevention Study at Mayo Clinic 3 years after the cessation of MHT [oral conjugated equine estrogen (oCEE), n=15; transdermal 17β‐estradiol (tE2, n=22); or placebo (PLA, n=23)]. Cerebrovascular reactivity was estimated from the middle cerebral artery flow velocity (MCAv) response to hypercapnia. Mean arterial blood pressure (MAP) was measured continuously throughout the protocol. Fasting blood was analyzed for a set of 14 activation markers of platelet and endothelial cells, inflammation and thrombogenicity. Principal components (PC) analysis was used to reduce these measures to fewer dimensions on which the associations of intravascular cellular activation with cerebrovascular reactivity could be based. Women were 60±3 years of age with a body mass index of 28±4 Kg/m 2 . MAP (99±14 mmHg in PLA, 97±7 mmHg in tE2, 98±9 mmHg in oCEE; p>0.90) and MCAv (60±14 cm/s in PLA, 68±20 cm/s in tE2, 71±18cm/s in oCEE; p>0.16) did not differ among groups. Cerebrovascular reactivity did not differ among women based on previous MHT randomization (1.2±0.7 cm/s/mmHg in PLA, 1.4±1.0 cm/s/mmHg in tE2 and 1.7±1.0 cm/s/mmHg in oCEE; p>0.17). The 14 markers of intravascular cellular activation were reduced to five PC that did not differ based on prior MHT assignment. There was no overall association of cellular activation PC with cerebrovascular reactivity. Effects of MHT on cerebral microvascular reactivity do not extend beyond the time of menopausal hormone treatment. Intravascular cellular activation does not alter cerebrovascular reactivity to hypercapnia in postmenopausal women with low cardiovascular risk profiles 3 years after the cessation of MHT. Support or Funding Information NIH grant P50 AG44170 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .

Objective Blood thrombogenicity and vascular inflammation may influence development of white matter hyperintensities (WMH) in the brain. This study aimed to determine if menopausal hormone treatments (MHT) modified that association in recently menopausal women who were enrolled in the Kronos Early Estrogen Prevention Study (KEEPS) at Mayo Clinic. Methods Women (n=95) underwent MRI prior to and at 18, 36 and 48 months after randomization to either transdermal 17β‐estradiol (tE2, n=30), conjugated equine estrogen (oCEE, n=29) both with progesterone for 12 days per month or placebo pills and patch (PBO, n=36). Fasting blood was analyzed for a set of 14 activation markers of platelets and endothelial cells, inflammation, and thrombogenicity. Principal components (PC) analysis was used to reduce dimensionality of these markers, and the first 5 PC identified were then assessed for association with treatment and changes in WMH. Results WMH increased in all groups over the 48 months of treatment with greater increases in the oCEE compared to tE2 and PBO (P=0.015). The 5 PC explained 62% of the variation in cellular activation markers. A global test of these 5 PC revealed a borderline association with treatment group (P=0.059), with the PC reflecting total platelet count, platelet microaggregates and ATP secretion showing higher scores in the oCEE compared to the other groups (P=0.006). The change in WMH over the 48 months of MHT showed an overall association with the 5 PC (P=0.026), the most prominent of which was the first PC reflecting vascular inflammation by number of blood microveicles (MV) from activated monocytes and endothelial cells and MV positive for intercellular adhesion molecule 1 (P=0.001). There was no evidence that this association differed by MHT. Conclusion Markers of blood thrombogenicity and inflammation may influence development of WMH in the brain but this relationship may be influenced by factors other than the type of MHT used in the KEEPS study. Support or Funding Information NIH P50 AG44170 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .