Citations

Background: Emerging evidence suggests that coronary intensive care units are evolving into intensive care environments with an increasing burden of non-cardiovascular illness, but previous studies have been limited to older populations or single center experiences. Methods: Canadian national health-care data was used to identify all patients ≥18 years admitted to dedicated coronary intensive care units (2005–2015) and admissions were categorized as primary cardiac or non-cardiac. The outcomes of interest included longitudinal trends in admission diagnoses, critical care therapies, and all-cause in-hospital mortality. Results: Among the 373,992 patients admitted to a coronary intensive care unit, minimal changes in the proportion of patients admitted with a primary cardiac (88.2% to 86.9%; p<0.001) and non-cardiac diagnoses (11.8% to 13.1%; p<0.001) were observed. Among cardiac admissions, a temporal increase in the proportion of ST-segment elevation myocardial infarction (19.4% to 24.1%, p<0.001), non-ST-segment elevation myocardial infarction (14.6% to 16.2%, p<0.001), heart failure (7.3% to 8.4%, p<0.001), shock (4.9% to 5.7%, p<0.001), and decline in unstable angina (4.9% to 4.0%, p<0.001) and stable coronary diseases (21.3% to 12.4%, p<0.001) was observed. The proportion of patients requiring critical care therapies (57.8% to 63.5%, p<0.001) including mechanical ventilation (9.6% to 13.1%, p<0.001) increased. In-hospital mortality rates for patients with primary cardiac (4.9% to 4.4%; adjusted odds ratio 0.71, 95% confidence interval 0.63–0.79) and non-cardiac (17.8% to 16.1%; adjusted odds ratio 0.84, 0.73–0.97) declined; results were consistent when stratified by academic vs community hospital, and by the presence of on-site percutaneous coronary intervention. Conclusion: In a national dataset we observed a changing case-mix among patients admitted to a coronary intensive care unit, though the proportion of patients with a primary cardiac diagnosis remained stable. There was an increase in clinical acuity highlighted by critical care therapies, but in-hospital mortality rates for both primary cardiac and non-cardiac conditions declined across all hospitals. Our findings confirm the changing coronary intensive care unit case-mix and have implications for future coronary intensive care unit training and staffing.

Ongoing investigations into the interactions between microbial communities and their associated hosts are changing how emerging diseases are perceived and ameliorated. Of the numerous host–microbiome–disease systems of study, the emergence of chytridiomycosis (caused by Batrachochytrium dendrobatidis , hereafter Bd ) has been implicated in ongoing declines and extinction events of amphibians worldwide. Interestingly, there has been differential survival among amphibians in resisting Bd infection and subsequent disease. One factor thought to contribute to this resistance is the host-associated cutaneous microbiota. This has raised the possibility of using genetically modified probiotics to restructure the host-associated microbiota for desired anti-fungal outcomes. Here, we use a previously described strain of Serratia marcescens ( Sm ) for the manipulation of amphibian cutaneous microbiota. Sm was genetically altered to have a dysfunctional pathway for the production of the extracellular metabolite prodigiosin. This genetically altered strain (Δ pig ) and the functional prodigiosin producing strain (wild-type, WT) were compared for their microbial community and anti- Bd effects both in vitro and in vivo . In vitro , Bd growth was significantly repressed in the presence of prodigiosin. In vivo , the inoculation of both Sm strains was shown to significantly influence amphibian microbiota diversity with the Δ pig-Sm treatment showing increasing alpha diversity, and the WT- Sm having no temporal effect on diversity. Differences were also seen in host mortality with Δ pig-Sm treatments exhibiting significantly decreased survival probability when compared with WT- Sm in the presence of Bd . These results are an important proof-of-concept for linking the use of genetically modified probiotic bacteria to host microbial community structure and disease outcomes, which in the future may provide a way to ameliorate disease and address critical frontiers in disease and microbial ecology.

ABSTRACT Purpose This study aimed to evaluate the incidence and characteristics of exertional rhabdomyolysis (ER) in a population-based cohort. Methods A retrospective cohort study was performed in Olmsted County, Minnesota, from 2003 to 2015. Incident ER cases were ascertained through the Rochester Epidemiology Project medical record linkage system through electronic searches of the International Classification of Diseases, Ninth Revision , codes and clinical note text. Population incidence rate was calculated using the corresponding Rochester Epidemiology Project census populations specific to calendar year and sex. Descriptive statistics were used. Results Of the 430 patients, 431 cases met the inclusion criteria for rhabdomyolysis; 4.9% of cases ( n = 20; males n = 18; Caucasian n = 17) were ER, with one recurrence. There were no deaths secondary to ER. The age- and sex-adjusted incidence rate of ER was 1.06 ± 0.24 (95% confidence interval = 0.59–1.52) per 100,000 person-years. Endurance activity ( n = 7), manual labor ( n = 5), and weight lifting ( n = 4) were common causes. Complications included kidney injury ( n = 5), mild electrolyte abnormalities ( n = 10), elevated transaminases ( n = 12), and minor electrocardiographic abnormalities ( n = 4). A majority of patients were hospitalized ( n = 16) for a median of 2 d, had mild abnormalities in renal and liver function and electrolytes, and were discharged without sequelae. Conclusion ER in the civilian population occurs at a much lower incidence than the military population. The most common causes were endurance exercise, manual labor, and weight lifting. The majority of cases were treated conservatively with intravenous fluid resuscitation during a brief hospital stay, and all were discharged without sequela. Only one case of recurrence occurred in this cohort, indicating the recurrence rate was low.

Abstract Background The etiological basis of glioma is poorly understood. We have used genetic markers in a Mendelian Randomisation (MR) framework to examine if lifestyle, cardiometabolic and inflammatory factors influence the risk of glioma. This methodology reduces bias from confounding and is not affected by reverse causation. Methods We identified genetic instruments for 37 potentially modifiable risk factors and evaluated their association with glioma risk using data from a genome-wide association study of 12,488 glioma patients and 18,169 controls. We used the estimated odds ratio of glioma associated with each of the genetically defined traits to infer evidence for a causal relationship with the following exposures: lifestyle and dietary factors (height, plasma IGF-1, blood carnitine, blood methionine, blood selenium, blood zinc, circulating adiponectin, circulating carotenoids, iron status, serum calcium, vitamin [A1, B12, B6, E and 25-hydroxyvitamin D], fatty acids levels [mono-unsaturated, omega-3 and omega-6] and circulating fetuin-A); cardiometabolic factors (birth weight, HDL cholesterol, LDL cholesterol, total cholesterol, total triglycerides, basal metabolic rate, body fat percentage, body mass index, fasting glucose, fasting proinsulin, HbA1C levels, diastolic and systolic blood pressure, waist circumference, waist-to-hip ratio) were included; inflammatory factors (C-reactive protein (CRP), plasma IL-6 sRa and serum IgE). Results After correction for the testing of multiple potential risk factors and excluding associations driven by one single nucleotide polymorphism (SNP) no significant association with glioma risk was observed (i.e. PCorrected > 0.05). Conclusions This study did not provide evidence supporting any of the 37 factors examined as having a significant influence on glioma risk.

Abstract Catheter-tissue coupling is crucial for effective delivery of radiofrequency (RF) energy during catheter ablation. Force sensing catheters provide a metric of mechanical tissue contact and catheter stability, while local impedance has been shown to provide sensitive information on real-time tissue heating. The complementary use of force and local impedance during RF ablation procedures could provide an advantage over the use of one metric alone. This study evaluates a prototype ablation catheter that measures both contact force (CF) using inductive sensors and local catheter impedance (LI) using only catheter electrodes. The complementary nature was assessed with discrete lesions in vitro and an intercaval line in vivo. A force-sensing catheter with LI was evaluated in explanted swine hearts (n=14) in an in vivo swine model (n=9, 50–70kg) using investigational electroanatomical mapping software. In vitro, discrete lesions were created in ventricular tissue at a range of forces (0–40g) controlled externally. RF energy was applied at a range of powers (20W, 30W, and 40W), durations (10s-60s), and catheter orientations (0°, 45°, and 90°). Lesions were stained with TTC and measured. LI drop relative to baseline during RF in the bench studies was used to inform the in vivo study. In a separate subset of animals in vivo, an intercaval line was created in three experimental groups: LI blinded, 20Ω ΔLI, and 30Ω ΔLI. CF was maintained between 15 and 25g in all groups. All ablations were performed with a power of 30W. In the LI blinded group, all lesions were delivered for 30s. In the 20Ω ΔLI group, the investigator ablated until a 20Ω drop or 30 seconds was achieved. Likewise, in the 30Ω ΔLI, the investigator ablated until a 30Ω drop or 30 seconds was achieved. In vitro, 137 discrete ventricular lesions were created. LI drop during ablation correlated strongly with lesion depth using a monoexponential fit (R=0.84) while force time integral (FTI) did not correlate as strongly (R=0.56). In the intercaval LI blinded group, starting LI ranged from 126–163Ω with a median of 138Ω. LI drops ranged from 13Ω-44Ω, with a median of 26Ω. In the 20Ω ΔLI group, starting LI ranged from 137–211Ω with a median of 161Ω and LI drop ranged from 7Ω-35Ω, with a median of 22Ω. In the 30Ω ΔLI group, starting LI ranged from 130–256Ω with a median of 171Ω and LI drop ranged from 20Ω-52Ω, with a median of 31Ω. Notably, RF time for the LI blinded group was 13±0.1 minutes while RF time in the 20Ω ΔLI group was 6.4±1.9 minutes and 7.5±0.7 minutes in the 30Ω ΔLI group. A catheter incorporating CF-sensing and LI capabilities provides a powerful tool for RF ablation. Bench studies demonstrate a strong correlation between LI drop and lesion dimensions, which guided the use of LI in vivo. In vivo, the confirmation of stable mechanical contact and viewing of real-time LI drops enabled a significant reduction in RF time while creating a continuous intercaval line. Acknowledgement/Funding This study was funded by Boston Scientific.

Objective: To date, prediction models for estimating risk of acquiring non-serviceable hearing in subjects with observed vestibular schwannoma (VS) have evaluated outcomes primarily based on features at initial diagnosis. Herein, we evaluate the association of rate of hearing decline during the initial period of observation with time to non-serviceable hearing. If significant, rate of hearing decline may inform decision making after an introductory period of observation. Setting: Two tertiary care centers. Patients: VS patients with serviceable hearing who underwent at least three audiograms and two magnetic resonance imaging (MRI) studies before intervention or being lost to follow-up. The rate of change in pure-tone average (PTA) and word recognition score (WRS) was calculated as the score from the second audiogram minus the score from the first audiogram, divided by the duration in months between the two. Main Outcome Measure(s): Serviceable hearing, defined as PTA ≤50 dB HL and WRS ≥50%. Results: Among 266 patients meeting inclusion criteria, 52 developed non-serviceable hearing at last follow-up. Kaplan–Meier estimated rates of maintaining serviceable hearing (95% CI; number still at risk) at 1, 3, 5, 7, and 10 years were 97% (95–100; 206), 78% (72–85; 98), 68% (60–77; 39), 60% (50–73; 17), and 44% (29–67; 2), respectively. In a univariable setting, each 1 dB increase per month in the rate of initial PTA change was associated with a 96% increased likelihood of acquiring non-serviceable hearing (hazard ratio [HR] 1.96; 95% CI 1.44–2.68; p < 0.001). Each 1% increase per month in the rate of initial WRS change was associated with a decreased likelihood of acquiring non-serviceable hearing (hazard ratio [HR] 0.79; 95% confidence interval [CI] 0.66–0.94; p = 0.009). After multivariable adjustment, both rate of PTA change (HR 2.42; 95% CI 1.72–3.41; p < 0.001) and rate of WRS change (HR 0.81; 95% CI 0.67–0.99; p = 0.043) remained statistically significantly associated with time to non-serviceable hearing. Conclusion: Rate of early PTA and WRS decline during the initial period of observation are significantly associated with time to development of non-serviceable hearing. This information may facilitate accurate patient counseling and inform decision-making regarding prospective disease management.

Abstract Background Novel secondary flap options are paramount for patients who are not candidates for common reconstructive methods. The purpose of this study is to identify the prevalence of single arterial pedicle supplying both the gracilis muscle and medial thigh tissue carried in a profunda artery perforator (PAP) flap. Such a pedicle could allow the creation of a chimeric gracilis and PAP flap with a single-arterial anastomosis. Methods We conducted a retrospective review of 157 lower extremity computed tomography (CT) angiograms to assess the vasculature of the thigh soft tissues. Imaging evaluation was supervised by a board-certified musculoskeletal radiologist. Results Prevalence of a single-arterial pedicle to a gracilis and PAP flap in each patient was 59% (31% within the right leg and 28% in the left leg). Furthermore, 16% of patients had a common arterial pedicle in both lower extremities. Conclusion Existence of a single-arterial pedicle to both the gracilis muscle and PAP flap tissues is frequently present in most patients in at least one lower extremity. This chimeric flap configuration could serve as a reconstructive avenue for patients, particularly those who have exhausted other more common flap options. Screening angiography is warranted in patients looking for this anatomic variation to establish its presence.

Abstract Background: The persistence of detectable MRD in complete remission (CR/CRi - CR with incomplete CBC recovery) has been reported to contribute to inferior outcome in younger AML patients (pts) in retrospective studies, however MRD has not been studied prospectively in older adults (age ≥60 yrs) receiving intensive therapy with curative intent. We performed a planned prospective study of MRD status after AML induction therapy in older adults, integrated into the large multicenter ECOG-ACRIN (E-A) E2906 Phase III trial. Methods Eligible patients age ≥60 yrs with AML were randomized 1:1 to receive either 'Standard' 7&3 (Dauno 60mg/m2) induction, with 2 cycles of intermediate dose Ara-C (1.5g/m2 x 12 doses; 6 doses if age ≥70) consolidation (Arm A); or single agent clofarabine (CLO) induction and consolidation (2 cycles) (Arm B). The design and primary clinical results for E2906 (n=727) have been reported previously (Foran et al, ASH #217a, 2015), demonstrating superior overall survival (OS) with standard therapy despite similar CR/CRi rates using stringent criteria, and similar 30-day induction mortality rates. Submission of diagnostic & remission bone marrow or peripheral blood samples was protocol mandated for prospective MRD assessment, and analysis was performed in the central E-A Leukemia Translational Research Lab (LTL) using 6-color multiparameter flow cytometry. MRD-positive (MRD+) was defined as ≥0.1%. LTL flow cytometric analysis was done blinded to treatment arm and outcome of patients. Only pt samples collected within +/-6 days of CR/CRi confirmation were included in this analysis. Statistical analysis was performed using X2 (categories) and Wilcoxon rank sum (continuous) tests to compare baseline patient and disease characteristics. Log-rank tests and multivariate Cox models stratified by treatment arm and adjusted for patient and disease variable (including WBC, cytogenetics, sex, performance status, secondary AML) were used to examine the MRD effect on OS and disease-free survival (DFS, relapse or death). Results The median follow-up is 47.8 months, and 297 of 685 evaluable patients (43.4%) achieved CR/CRi (Standard 44.6%; CLO 42.0%, p=ns). Remission MRD samples were only available for 147 CR/CRi patients (49.5%), owing to variability in sample viability and AML involvement, collection practices and timing of sample collection at individual sites, and patient/physician decision. 58/147 evaluable CR/CRi patients achieved MRD-negative (MRD-) status (Standard 40.7%, CLO 47.9%, p=0.74). Women (56.9% vs. men 43.1%, p=0.003) were more likely to be MRD-, but there was no other significant difference in MRD status stratified by clinical or disease features. MRD+ status at CR/CRi was associated with significantly inferior OS (p=0.031, Figure 1) and also inferior overall DFS (p=0.02); this was most pronounced for DFS after CLO (Arm B, Figure 2) (p=0.005), but not Standard (Arm A) therapy (p=0.41). The impact of MRD+ was confirmed on multivariate analysis using Cox Model Fitting, for OS: OS for All MRD+ pts, HR 1.64 (95% CI 1.00-2.68) (p=0.05); OS for Standard (Arm A) MRD+ pts, HR 1.06 (95% CI 0.51-2.21) (p=0.87); and OS for CLO (Arm B) MRD+ pts, HR 2.30 (95% CI 1.05-5.06) (p=0.04). There was a similar impact for DFS on multivariate analysis using Cox Model Fitting: DFS for All MRD+ pts, HR 1.86 (95% CI 1.16-2.98) (p=0.01); DFS for Standard (Arm A) MRD+ pts, HR 1.15 (95% CI 0.60-2.19) (p=0.67); and DFS for CLO (Arm B) MRD+ pts, HR 3.45 (95% CI 1.47-8.09) (p=0.004). Post-remission therapy was not stratified by MRD in E2906, and 33% of MRD-evaluable pts underwent allogeneic transplantation (no difference in transplant rate for MRD+ vs. MRD-). Conclusions MRD+ ≥0.1% is common (60.5%) after induction therapy in older adults & is significantly associated with inferior OS and DFS in 1st CR/CRi. However we observed excellent outcomes for MRD- pts in first CR/CRi regardless of induction regimen or post-remission therapy used. MRD+ pts in CR/CRi who went on to receive CLO consolidation had significantly poorer outcomes than those who went on to receive intermediate dose Ara-C consolidation. This observation differs strikingly from younger AML, and suggests that intensified Ara-C may abrogate the adverse impact of MRD in older pts in CR. These results strongly support incorporation of centralized MRD at the time of remission into future studies to guide optimal post-remission strategies in older pts with AML. Disclosures Foran: Agios: Research Funding; Xencor, Inc.: Research Funding. Lazarus:Pluristem Ltd.: Consultancy. Altman:Bayer: Other: payment to the institution to conduct clinical trial work; Pfizer: Other: payment to the institution to conduct clinical trial work; Boeringer Ingelheim: Other: payment to the institution to conduct clinical trial work; Epizyme: Other: payment to the institution to conduct clinical trial work; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Immune Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Cyclacel: Other: payment to the institution to conduct clinical trial work; Incyte: Other: payment to the institution to conduct clinical trial work; GSK: Other: payment to the institution to conduct clinical trial work; Agios: Other: Payment to the institution to conduct the trial ; Astellas Pharma: Other; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: payment to the institution to conduct clinical trial work; BMS: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Ariad: Other: payment to the institution to conduct clinical trial work; FujiFilm: Other: payment to the institution to conduct clinical trial work; Genetech: Other: Payment to the institution to conduct clinical trial work; Celator: Other: payment to the institution to conduct clinical trial work. Al-Kali:Novartis: Research Funding. Pratz:Millenium/Takeda: Research Funding; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Boston Scientific: Consultancy. Powell:Rafael Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Tallman:ADC Therapeutics: Research Funding; BioSight: Other: Advisory board; Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; AROG: Research Funding; AbbVie: Research Funding; Cellerant: Research Funding.

Abstract Background: Non-endemic Burkitt lymphoma (BL) is a rare B-cell malignancy characterized by extreme tumor proliferation, frequent extranodal involvement, and the genetic hallmark of a MYC gene rearrangement. Despite an often dramatic initial presentation featuring tumor compression of vital organs and/or spontaneous tumor lysis syndrome, most patients who survive intensive immunochemotherapy induction are cured. Despite limited evidence of benefit, the current NCCN guidelines recommend that BL patients in CR are reviewed every 3 months for 2 years and every 6 months thereafter. Aims: To investigate outcomes, including relative survival and relapse risks conditional on event-free survival (EFS) milestones, in an international study of real-world BL patients treated with intensive immunochemotherapy. Patients and methods: This is a retrospective study of newly diagnosed BL patients identified from relevant population or hospital-based registers in Australia (Perth), Denmark (the Danish Lymphoma Registry), Sweden (the Swedish Lymphoma Registry) and Norway (Health Region South East). Patients who met the following criteria were included irrespective of HIV status: 1) age ≥18 years at diagnosis, 2) diagnosed during the period 2005-2017, 3) histology and immunohistochemistry consistent with BL, 4) MYC translocation detected by fluorescence in situ hybridization (FISH), and 5) intensive first line immunochemotherapy including rituximab (R-CHOEP or more intensive). Patient data were collected from registers and chart reviews. Overall survival (OS) was defined as time until death and EFS was defined as time to death, relapse/progression, or unplanned treatment, whichever came first. Prognostic features at baseline were evaluated using univariate Cox models with EFS as outcome. Standardized mortality ratios (SMRs), conditional relative survival estimates, and relapse risks were computed for the subset of patients achieving complete remission (CR or CRu), with follow-up measured from response evaluation and from different EFS milestones. Results: In total, 159 patients fulfilled the inclusion criteria of the study. The median age was 48 years (range 18-81) and the male:female ratio was 2.9. The baseline characteristics included stage III-IV (75%), elevated serum LDH (75%), extranodal involvement (83% - bone or bone marrow in 42% and CNS in 8%), B symptoms (60%), and ECOG performance score >1 (30%). The chemotherapy protocols used were CHOEP (2%), DA-EPOCH (13%), HYPER-CVAD (26%), CODOX-M/IVAC (28%), BFM or GMALL (31%), and others (1%). Clinical tumor lysis syndrome defined by severe electrolyte derangement, renal impairment, and/or cardiac arrhythmia, was noted in 16% of the patients, but no fatal episodes occurred. The overall response rate to first-line treatment was 88% (87% in CR/CRu) with 67% assessed by PET technology. The five-year EFS and OS estimates for the total population were 75% (95% CI 68-82%) and 82% (95% CI 76-88%), respectively, and the EFS and OS of patients <50 years of age were 81% (95% CI 71-90%) and 89% (95% CI 82-96%), respectively. In univariate analyses, age, advanced stage, and elevated LDH were associated with worse EFS. Among patients in CR/CRu (n=137), the 5-year EFS and OS from the time of response evaluation were 86% (95% CI 79-93%) and 91% (95% CI 86-96%), respectively. The 5-year cumulative incidence of relapse from the time of response assessment was 5% (95% CI 1-9%) in CR/CRu patients. The corresponding estimate was 3% (95% CI 0-6%) for patients alive after 6 months without events (EFS6), whereas no patients relapsed after 12 (EFS12, Figure 1). For CR/CRu patients, the 5-year relative survival after EFS6 and EFS12 was 97% (95% CI 93-102%) and 100% (95% CI 97-103%), respectively. In most subgroups, the SMRs gradually decreased with increased remission duration (Table 1). Conclusions: Outcomes of adult BL patients treated with intensive immunochemotherapy are excellent with no relapses occurring for patients reaching EFS12 and with a normalized relative survival after EFS6. For patients reaching EFS12, follow-up in late effects clinics, or discharging to primary care providers with a focus on survivorship issues rather than detection of recurrent lymphoma, should be considered. Updated analyses including patients from British Columbia (Canada) and the University of Iowa/Mayo Clinic SPORE MER register (USA) will be presented at the meeting. Disclosures Molin: Takeda Pharmaceuticals: Research Funding; Bristol-Myers Squibb: Honoraria; Roche Holding AG: Honoraria; Merck & Co., Inc: Honoraria. Ekstroem Smedby:Janssen Pharmaceuticals: Other: The Department have recieved partial funding from Janssen Pharmaceuticals.