Background:Dexrazoxane (DRZ) has been shown to have cardioprotective effects among doxorubicin-treated childhood cancer survivors up to 5-years after therapy completion, including effects on ...fractional shortening (FS%) and other parameters of left ventricular anatomy and function. However, data on longer-term effects are lacking.
Methods: COG protocols P9404 (T-cell acute lymphoblastic leukemia/lymphoma; cumulative doxorubicin 360 mg/m2), P9425 (advanced stage Hodgkin lymphoma; cumulative doxorubicin 180-300 mg/m2), and P9426 (low/intermediate stage Hodgkin; cumulative doxorubicin 100-200 mg/m2) were phase 3 randomized clinical trials conducted between 1996 and 2001. Patients were randomly assigned to treatment with or without DRZ (10:1 mg dose ratio of DRZ:doxorubicin); DRZ was given as an intravenous bolus before each doxorubicin dose. Beginning in 2014, a subset of COG institutions began prospectively reassessing the cardiovascular health of long-term survivors in first complete remission treated on these 3 protocols, including echocardiography and selected blood biomarkers (e.g., high-sensitivity troponins, b-type natriuretic peptides BNP, N-terminal NT proBNP). Echocardiograms and blood analytes were all processed centrally, with DRZ status masked.
Results: To date, 94 participants (54% DRZ+; 57% male; average doxorubicin dose 279 mg/m2; current mean age 28 years and 16 years since cancer diagnosis) have been recruited from 30 institutions. Participants were similar with respect to demographic and treatment characteristics when compared by DRZ status. Overall, compared with DRZ+ participants, DRZ- participants had non-significantly reduced FS% (mean±SD: 33.0±4.8 vs. 34.8±4.6; p=0.10), but greater myocardial wall stress and dysfunction as measured by BNP (mean±SD: 18.3±14.7 vs. 11.3±10.6 pg/mL; p=0.02) and NT-proBNP (64.8±55.5 vs. 44.5±39.0 pg/mL; p=0.06). When the analysis was restricted to those who received the greatest doxorubicin exposure (P9404 participants, n=41), differences all became statistically significant (FS%: 31.3±3.9 vs. 34.9±3.7, p<0.01; BNP and NT-proBNP: p=0.03 for both). Only a subset of participants (n=43) had ejection fraction evaluable, but DRZ+ patients also were more likely to have greater values (mean±SD: 56.8±6.3 vs. 61.2±6.4; p=0.03). Among all participants, the effects of DRZ on FS% appeared to vary by sex, with females showing significant differences (DRZ- 31.7±2.2 vs. DRZ+ 36.3±4.2; p<0.001) but not males (DRZ- 34.0±6.0 vs. DRZ+ 34.0±4.6; p=0.99). DRZ status was significantly associated with FS% and both BNP and NT-proBNP in multivariate analyses that adjusted for sex, original protocol, race/ethnicity, current age, and age at cancer diagnosis (p<0.05). Other parameters of systolic dysfunction and myocardial injury including wall thickness/dimension ratio and high-sensitivity troponins were similar across study arms, both overall and in subanalyses. Overall, only 3 participants had FS% <28 (DRZ+, n=2). Two other participants reported a history of clinical cardiomyopathy (both DRZ+, one currently on medications). Globally, regardless of DRZ status, participants had a high burden of comorbid cardiovascular conditions: 57% overweight/obese, 37% pre-/hypertensive, 50% with dyslipidemia, and 11% pre-/diabetic.
Conclusion: In this preliminary analysis, long-term survivors of childhood cancer treated with doxorubicin and DRZ appeared to have more preserved systolic function and reduced myocardial wall stress compared with survivors treated with doxorubicin alone. Secondary prevention efforts should be directed at treating common but potentially modifiable cardiovascular risk factors in this high-risk young adult population. Accrual of remaining eligible study participants is ongoing and may provide more refined estimates of DRZ's cardioprotective effects in the future.
Asselin:Jazz Pharmaceuticals: Consultancy, Speakers Bureau; Sigma Tau Pharamceuticals: Consultancy. Lipshultz:Clinigen Group: Consultancy, Other: Travel/accommodations for consulting related meeting; Pfizer: Research Funding; Roche Diagnostics: Research Funding.
IFN-γ priming sensitizes monocytes/macrophages to lipopolysaccharide (LPS) stimulation, resulting in augmented expression of a set of genes including
TNF
. Here, we demonstrate that IFN-γ priming of ...LPS-stimulated
TNF
transcription requires a distal
TNF/LT
locus element 8 kb upstream of the
TNF
transcription start site (hHS-8). IFN-γ stimulation leads to increased DNase I accessibility of hHS-8 and its recruitment of IRF1, and subsequent LPS stimulation enhances H3K27 acetylation and induces enhancer RNA synthesis at hHS-8. Ablation of IRF1 or targeting the hHS-8 IRF1 binding site
in vivo
with Cas9 linked to the KRAB repressive domain abolishes IFN-γ priming while LPS induction of the gene is unaffected. Thus, IFN-γ poises a distal enhancer in the
TNF/LT
locus by chromatin remodeling and IRF1 recruitment, which then drives enhanced
TNF
gene expression in response to a secondary TLR stimulus.
Abstract
Background
Candida auris can be transmitted in healthcare settings, and patients can become asymptomatically colonized, increasing risk for invasive infection and transmission. We ...investigated an ongoing C. auris outbreak at a 30-bed long-term acute care hospital to identify colonization for C. auris prevalence and risk factors.
Methods
During February–June 2017, we conducted point prevalence surveys every 2 weeks among admitted patients. We abstracted clinical information from medical records and collected axillary and groin swabs. Swabs were tested for C. auris. Data were analyzed to identify risk factors for colonization with C. auris by evaluating differences between colonized and noncolonized patients.
Results
All 101 hospitalized patients were surveyed, and 33 (33%) were colonized with C. auris. Prevalence of colonization ranged from 8% to 38%; incidence ranged from 5% to 20% (figure). Among colonized patients with available data, 19/27 (70%) had a tracheostomy, 20/31 (65%) had gastrostomy tubes, 24/33 (73%) ventilator use, and 12/27 (44%) had hemodialysis. Also, 31/33 (94%) had antibiotics and 13/33 (34%) antifungals during hospitalization. BMI for colonized patients (mean = 30.3, standard deviation (SD) = 10) was higher than for noncolonized patients (mean = 26.5, SD = 7.9); t = −2.1; P = 0.04). Odds of colonization were higher among Black patients (33%) vs. White patients (16%) (odds ratio OR 3.5; 95% confidence interval CI 1.3–9.8), and those colonized with other multidrug-resistant organism (MDRO) (72%) vs. noncolonized (44%) (OR 3.2; CI 1.3–8.0). Odds of death were higher among colonized patients (OR 4.6; CI 1.6—13.6).
Conclusion
Patients in long-term acute care facilities and having high prevalences of MDROs might be at risk for C. auris. Such patients with these risk factors could be targeted for enhanced surveillance to facilitate early detection of C. auris. Infection control measures to reduce MDROs’ spread, including hand hygiene, contact precautions, and judicious use of antimicrobials, could prevent further C. auris transmission.
Acknowledgements
The authors thank Janet Glowicz and Kathleen Ross.
Disclosures
All authors: No reported disclosures.
Abstract
Background
Patients in long-term acute care hospitals (LTACHs) and skilled nursing facilities with ventilator units (VSNFs) are at high risk for Candida auris colonization; among patients ...colonized with this emerging pathogen, 5%–10% develop invasive disease with >45% mortality. In September 2018, a California LTACH-affiliated laboratory began enhanced C. auris surveillance by classifying species of Candida isolated from routine urine specimens. In February 2019, the first known Southern California case was detected in an Orange County (OC) LTACH; the patient had not traveled outside the region, indicating local acquisition. We performed point prevalence surveys (PPS) and infection prevention (IP) assessments at all OC LTACHs and VSNF subacute units to identify patients colonized with C. auris and control transmission.
Methods
During March–August 2019, we conducted PPS at facilities by collecting composite axilla and groin swabs for C. auris polymerase chain reaction testing and reflex culture from all patients who assented. Facilities with ≥1 C. auris-colonized patient repeated a PPS every 2 weeks to assess for new transmission. Isolate relatedness was assessed by whole-genome sequencing (WGS). We evaluated hand hygiene (HH) adherence, access to alcohol-based hand rubs (ABHR), and cleaning of high-touch surfaces to guide IP recommendations.
Results
The first PPS at all OC LTACHs (n = 3) and adult VSNFs (n = 14) identified 45 C. auris-colonized patients in 3 (100%) LTACHs and 6 (43%) VSNFs; after repeated PPS, the total count reached 124. Most patients (70%) were at 2 facilities (Table 1). Three of 124 patients developed candidemia. To date, isolates from 48 patients have completed WGS; all were highly related (<11 single-nucleotide polymorphisms) in the African clade. Of 9 facilities with C. auris, 5 had HH adherence < 50%, 3 had limited ABHR, and at 2, <60% of assessed high-touch surfaces were clean. We recommended regular HH and cleaning audits, and increased ABHR.
Conclusion
Our investigation, prompted by enhanced surveillance, identified C. auris at 9 OC facilities. WGS indicated a single introduction and local transmission. Early detection, followed by rapid county-wide investigation and IP support, enabled containment efforts for C. auris in OC.
Disclosures
All authors: No reported disclosures.
Abstract
Background
Candida auris is an often multidrug-resistant yeast that causes invasive infections and, unlike most Candida species, spreads in healthcare facilities. CDC released a clinical ...alert in June 2016 requesting reporting of C. auris cases. We investigated cases to contain transmission and inform prevention measures for this novel organism.
Methods
Clinical cases were defined as C. auris from any clinical specimen from a patient in the United States. Response to cases included implementation of infection control measures, enhanced cleaning and disinfection, and testing of close contacts for C. auris colonisation (isolation from a person’s axilla or groin was defined as a screening case). Microbiology records were reviewed at reporting facilities for missed cases. All isolates were forwarded to CDC for confirmation, antifungal susceptibility testing, and whole-genome sequencing (WGS).
Results
As of April 13, 2017, 61 clinical cases of C. auris were reported from six states: New York (39), New Jersey (15), Illinois (4), Indiana (1), Maryland (1), and Massachusetts (1). All but two occurred since 2016 (Figure). An additional 32 screening cases were identified among contacts. Median age of clinical case-patients was 70 years (range 21–96); 56% were male. Nearly, all had underlying medical conditions and extensive exposure to healthcare facilities before infection. Most clinical isolates were from blood (38, 62%), followed by urine (8, 13%) and respiratory tract (5, 8%). Among the first 35 isolates, 30 (86%) were resistant to fluconazole, 15 (43%) to amphotericin B, and one (3%) to caspofungin. No isolate was resistant to all three. WGS revealed isolates from each state were highly related and different from other states, suggestive of transmission. Microbiology record reviews did not identify additional cases before 2016.
Conclusion
C. auris is an emerging pathogen, with similarities to multidrug-resistant bacteria, that has been transmitted in US healthcare settings. CDC and public health partners are committed to prompt and aggressive action through investigation of cases and heightened infection control practices to halt its spread.
Disclosures
All authors: No reported disclosures.
The lithofacies architecture and depositional evolution of the Lower Mississippian (Tournaisian) Pekisko Formation in the subsurface of the Hawk Hills area in northwestern Alberta have been ...established by integrating detailed core work and well log data. The formation is composed of skeletal-peloidal limestones and argillaceous limestones that were deposited along the northern flank of the Peace River Embayment, a semi-restricted and tectonically active oceanic re-entrant located along the western margin of Laurasia at low paleolatitude. Lithofacies associations recognized in the study area include the outer ramp to slope (LA 1), outer ramp (LA 2) and mid ramp (LA 3), which are stacked into three decameter-scale, deepening-upward and aggradational cycles that are of regional extent and have meter-scale deepening and shallowing-upward trends. A previously unrecognized paleosol horizon at the top of decameter-scale cycle 2, indicating widespread subaerial exposure of the ramp, is interpreted as a sequence boundary that divides the Pekisko and Shunda formations in the study area (and possibly elsewhere in the Peace River Embayment) into two third-order sequences, each consisting of transgressive and highstand systems tracts. The Pekisko Formation in the study area is interpreted to represent a low-energy, temperature-stratified ramp that was mainly homoclinal, but with transient, distal steepening occurring in the southern part of the study area. Ramp deposition was strongly affected by basement-fault reactivation causing differential subsidence and uplift in the Peace River Embayment. The paleogeography and paleoceanographic conditions of the embayment favored upwelling currents and development of a temperature-stratified ramp, as well as the formation of heterozoan carbonate deposits and mid ramp facies of predominantly packstones and wackestones. This depositional scenario is atypical, as most other documented examples of the Pekisko Formation and other Lower Mississippian ramp successions in western North America and western Europe are characterized by moderate to high-energy, mid to inner ramp facies deposited in open-ocean conditions. The results of this study contribute to an improved understanding of the range of depositional settings along the western margin of Laurasia during the Early Mississippian and demonstrate the applicability of the thermocline-stratified ramp model, with some modification, to ramps in semi-restricted embayments and other low energy settings.
•Subsurface data analyses establish depositional evolution of a Mississippian ramp.•Heterozoan carbonates dominated low-paleolatitude, temperature-stratified ramp.•Semi-restricted embayment resulted in low-energy ramp facies.•Depositional patterns strongly influenced by basement fault reactivation.•Implications for a low-energy, temperature-stratified ramp model
Currently, there are two rapid antigen detection (RAD) kits from the WHO Emergency Use List for detecting SARS-CoV-2.
The Panbio COVID-19 Ag Rapid Test Device was selected to evaluate the performance ...for detecting SARS-CoV-2.
Analytical sensitivity for the detection of SARS-CoV-2 virus was determined by limit of detection (LOD) using RT-PCR as a reference method. Clinical sensitivity was evaluated by using respiratory specimens collected from confirmed COVID-19 patients.
The LOD results showed that the RAD kit was 100 fold less sensitive than RT-PCR. Clinical sensitivity of the RAD kit was 68.6 % for detecting specimens from COVID-19 patients.
The RAD kit evaluated in the present study shared similar performance with another kit from the WHO Emergency Use List, the Standard Q COVID-19 Ag. Understanding the clinical characteristics of RAD kits can guide us to decide different testing strategies in different settings.
Prenatal diagnosis of monogenic diseases, such as cystic fibrosis and β-thalassemia, is currently offered as part of public health programs. However, current methods based on chorionic villus ...sampling and amniocentesis for obtaining fetal genetic material pose a risk to the fetus. Since the discovery of cell-free fetal DNA in maternal plasma, the noninvasive prenatal assessment of paternally inherited traits or mutations has been achieved. Due to the presence of background maternal DNA, which interferes with the analysis of fetal DNA in maternal plasma, noninvasive prenatal diagnosis of maternally inherited mutations has not been possible. Here we describe a digital relative mutation dosage (RMD) approach that determines if the dosages of the mutant and wild-type alleles of a disease-causing gene are balanced or unbalanced in maternal plasma. When applied to the testing of women heterozygous for the CD41/42 (-CTTT) and hemoglobin E mutations on HBB, digital RMD allows the fetal genotype to be deduced. The diagnostic performance of digital RMD is dependent on interplay between the fractional fetal DNA concentration and number of DNA molecules in maternal plasma. To achieve fetal genotype diagnosis at lower volumes of maternal plasma, fetal DNA enrichment is desired. We thus developed a digital nucleic acid size selection (NASS) strategy that effectively enriches the fetal DNA without additional plasma sampling or experimental time. We show that digital NASS can work in concert with digital RMD to increase the proportion of cases with classifiable fetal genotypes and to bring noninvasive prenatal diagnosis of monogenic diseases closer to reality.
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