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BackgroundFrequently used fluoroquinolones have been subject to increasing safety concerns and regulatory alerts. This study characterized ambulatory fluoroquinolone utilization in the United States and evaluated the impact of 2016 Food and Drug Administration (FDA) safety advisories on its use.MethodsWe used IQVIA’s National Disease and Therapeutic Index to quantify adult outpatient fluoroquinolone use (“treatment visits”). Descriptive statistics and segmented regression were used to report trends and quantify the varied use before and after FDA’s 2016 alerts.ResultsBetween 2015 to 2019, fluoroquinolone use decreased by 26.7% (18.7 million treatment visits in 2015 to 13.7 million treatment visits in 2019). Annual use declined by 44%, 24%, and 24% for respiratory, urogenital, and gastrointestinal conditions, respectively; and by 66% among providers ≤44 years old vs negligible decline among those ≥65 years old. Before 2016 FDA advisories, there were approximately 4.8 million fluoroquinolone treatment visits/quarter, which had a statistically significant immediate drop by 641035 visits (95% confidence interval [CI], –937368 to –344702; P=.000) after FDA’s 2016 advisories. A statistically significant difference of approximately 45000 visits/quarter (95% CI, –85956 to –3122; P=.036) was observed after the advisories.ConclusionsLarge reductions in ambulatory fluoroquinolone use in the United States have coincided with increasing evidence of safety concerns and FDA advisories. However, fluoroquinolone use varies significantly based on patient and provider characteristics, suggesting heterogeneous effects of emerging risks on clinical practice.

This comment revisits a long-standing debate about alternative dispute resolution (ADR) and public values. In Against Settlement, Fiss argued that ADR would undermine popular commitments to “public values” (1984). For Fiss, public values are moral truths about rights, justice, and social cohesion that all who comprise “the public” should want to uphold, and which the state is obligated to enforce. Fiss distinguished public values from subjective preference, or what any one individual actually desires. He submitted that by resolving disputes according to individual preference, ADR would replace public values with individual interests and replace state power with private social ordering. Hence, Fiss declared himself against settlement....

Purpose Solid organ transplant recipients are at increased risk of morbidity and mortality from coronavirus disease 2019 (COVID-19), but limited vaccine access and vaccine hesitancy can complicate efforts for expanded vaccination. We report patient perspectives and outcomes from a vaccine outreach initiative for a vulnerable population of transplant recipients living in New York City. Methods This was a retrospective review of qualitative perspectives from a COVID-19 vaccine outreach initiative. In the outreach effort, kidney and pancreas transplant recipients under care at the transplant center at NewYork-Presbyterian Hospital were initially contacted electronically with educational material about vaccination followed by telephone outreach to eligible unvaccinated patients. Calls were used to schedule vaccine appointments for patients who agreed, answer questions, and assess attitudes and concerns for patients not yet ready to be vaccinated, with conversational themes recorded. Results Of the 1,078 patients living in the 5 New York City boroughs who had not reported receiving COVID-19 vaccination, 320 eligible patients were contacted by telephone. Of these, 210 patients were scheduled for vaccination at our vaccine site (including 13 who agreed to vaccination after initially declining), while 110 patients were either not ready or not interested in being vaccinated. The total number of patients willing to be vaccinated was 554 when also including those already vaccinated. Unwillingness to be vaccinated was associated with younger age (median age of 47 vs 60 years, P < 0.001), Black race (P = 0.004), and residence in Bronx or Brooklyn counties (P = 0.018) or a zip code with a medium level of poverty (P = 0.044). The most common issues raised by patients who were ambivalent or not interested in vaccination were regarding unknown safety of the vaccines in general, a belief that there was a lack of data about the vaccines in transplant recipients, and a lack of trust in the scientific process underlying vaccine development, with 34% of the patients contacted expressing vaccine hesitancy overall. Conclusion Our qualitative summary identifies determinants of COVID-19 vaccine hesitancy in a diverse transplant patient population, supporting the need for transplant centers to implement tailored interventions to increase vaccine acceptance in this vulnerable population.

Introduction Evaluation of health status benefits, cost-effectiveness, and value of new heart failure therapies is critical for supporting their use. The Kansas City Cardiomyopathy Questionnaire (KCCQ) measures patients’ heart failure-specific health status but does not provide utilities needed for cost-effectiveness analyses. We mapped the KCCQ scores to EQ-5D scores so that estimates of societal-based utilities can be generated to support economic analyses. Methods Using data from two US cohort studies, we developed models for predicting EQ-5D utilities (3L and 5L versions) from the KCCQ (23- and 12-item versions). In addition to predicting scores directly, we considered predicting the five EQ-5D health state items and deriving utilities from the predicted responses, allowing different countries’ health state valuations to be used. Model validation was performed internally via bootstrap and externally using data from two clinical trials. Model performance was assessed using R2, mean prediction error, mean absolute prediction error, and calibration of observed vs. predicted values. Results The EQ-5D-3L models were developed from 1000 health status assessments in 547 patients with heart failure and reduced ejection fraction (HFrEF), while the EQ-5D-5L model was developed from 3925 patients with HFrEF. For both versions, models predicting individual EQ-5D items performed as well as those predicting utilities directly. The selected models for the 3L had internally validated R2 of 48.4–50.5% and 33.7–45.6% on external validation. The 5L version had validated R2 of 57.7%. Conclusion Mappings from the KCCQ to the EQ-5D can yield the estimates of societal-based utilities to support cost-effectiveness analyses when EQ-5D data are not available.

Context Testosterone treatment of hypogonadal men improves their hemoglobin, but the mechanism is not understood. Objective To investigate possible mechanisms by which testosterone stimulates erythropoiesis in hypogonadal older men with unexplained or iron-deficiency anemia. Design The Anemia Trial of The Testosterone Trials, a placebo-controlled study in older, hypogonadal men. Setting Twelve academic medical centers. Participants A total of 95 hypogonadal men (testosterone < 275 ng/mL) ≥65 years with anemia (hemoglobin < 12.7 g/dL). They were classified as having unexplained (n = 58) or iron deficiency anemia (n = 37). Intervention Testosterone or placebo gel for 1 year. Main Outcome Measures Markers of iron metabolism during the first 3 months of treatment. Results Testosterone replacement significantly (P < 0.001) increased hemoglobin in the 58 men who had unexplained anemia (adjusted mean difference 0.58 g/dL; 95% confidence interval, 0.31-0.85). Testosterone replacement tended to increase hemoglobin in the 37 men who had iron deficiency (0.38 g/dL; −0.19, 0.95), but the response was more variable and not statistically significant (P = 0.19). In men with unexplained anemia, testosterone replacement suppressed hepcidin (−8.2 ng/mL; −13.7, −2.7; P = 0.004) and ferritin (−19.6 µg/L; −32.8, −6.3; P = 0.004), but in men with iron deficiency, testosterone replacement did not. The decrease in hepcidin was moderately correlated with the increase in hemoglobin in the men with unexplained anemia (correlation coefficient −0.35, P = 0.01) but not in those with iron deficiency anemia (correlation coefficient −0.07, P = 0.73). Conclusions Testosterone replacement of older hypogonadal men with unexplained anemia stimulates erythropoiesis associated with increased iron mobilization. This effect appears to be attenuated by iron deficiency.

Endogenous Cushing’s syndrome (CS) is a rare, serious disorder caused by chronically elevated cortisol. A phase 3, open-label study (SONICS) of levoketoconazole in adults with CS and mean urinary free cortisol (mUFC) ≥1.5 × upper limit of normal (ULN) at baseline demonstrated normalization of mUFC in 62% of those completing 6 months of maintenance treatment (Fleseriu M, et al. Lancet Diabetes Endocrinol. 2019;7[11]:855-865). LOGICS is an ongoing, phase 3, double-blind, placebo-controlled, randomized-withdrawal study further investigating the safety and efficacy of levoketoconazole in patients who completed the SONICS study, or patients with CS who are levoketoconazole treatment-naive (ClinicalTrials.gov identifier: NCT03277690). The primary objective of LOGICS is to evaluate the effect of withdrawing levoketoconazole treatment to placebo, versus continuing treatment with levoketoconazole, on the cortisol therapeutic response established during open-label levoketoconazole therapy. The study includes (1) a screening phase (up to 13 weeks to allow for washout of CS medications); (2) a dose titration-maintenance phase (150-600 mg BID [dosed as needed to target mUFC normalization]) of ≥14 weeks, with at least the final 4 weeks demonstrating mUFC normalization prior to advancing to the randomized-withdrawal (R-W) phase; (3) a double-blind, placebo-controlled R-W phase (levoketoconazole or placebo; up to 8 weeks); and (4) a double-blind restoration phase (levoketoconazole and placebo; 8 weeks). Patients are randomized 1:1 in the R-W phase to continue their therapeutic dose of levoketoconazole, established during the dose titration-maintenance phase, or to receive an equivalent number of placebo tablets. Up to ~54 subjects are targeted for randomization. The primary efficacy endpoint, assessed at the completion of R-W phase, is the proportion of patients with loss of therapeutic response to levoketoconazole (mUFC ≥1.5x ULN, >40% above baseline if baseline value is >ULN [SONIC-completer cohort only], or early rescue criterion met) upon withdrawing to placebo, compared with continuing treatment with levoketoconazole, during the R-W phase. Secondary endpoints include changes from baseline to all postbaseline visits in R-W phase for mUFC, late-night salivary cortisol, CS cardiovascular biomarkers (fasting glucose, fasting insulin, hemoglobin A1c, homeostatic model assessment-insulin resistance, total and LDL cholesterol, high-sensitivity C-reactive protein), CS clinical signs and symptoms (acne, hirsutism [women only], and peripheral edema scores), and patient-reported outcomes of QoL (Cushing QoL questionnaire score) and depression (Beck Depression Inventory II). Potential liver toxicity, QT prolongation, and adrenal insufficiency are prespecified adverse events of special interest.

Aims The aim of this study was to determine the effect of ticagrelor monotherapy on clinically relevant bleeding and major ischaemic events in relation to clinical presentation with and without non-ST elevation acute coronary syndromes (NSTE-ACS) among patients undergoing percutaneous coronary intervention (PCI) with drug-eluting stents (DES). Methods and results We conducted a pre-specified subgroup analysis of The Ticagrelor With Aspirin or Alone in High Risk Patients After Coronary Intervention (TWILIGHT) trial, which enrolled 9006 patients with high-risk features undergoing PCI with DES. After 3 months of dual antiplatelet therapy (DAPT) with ticagrelor plus aspirin, 7119 adherent and event-free patients were randomized in a double-blind manner to ticagrelor plus placebo versus ticagrelor plus aspirin for 12 months. The primary outcome was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding while the composite of all-cause death, myocardial infarction (MI), or stroke was the key secondary outcome. Among patients with NSTE-ACS (n = 4614), ticagrelor monotherapy reduced BARC 2, 3, or 5 bleeding by 53% [3.6% vs. 7.6%; hazard ratio (HR) 0.47; 95% confidence interval (CI) 0.36–0.61; P < 0.001) and in stable patients (n = 2503) by 24% (4.8% vs. 6.2%; HR 0.76; 95% CI 0.54–1.06; P = 0.11; nominal P int = 0.03). Rates of all-cause death, MI, or stroke among those with (4.3% vs. 4.4%; HR 0.97; 95% CI 0.74–1.28; P = 0.84) and without (3.1% vs. 3.2%; HR 0.96; 95% CI 0.61–1.49; P = 0.85) NSTE-ACS were similar between treatment arms irrespective of clinical presentation (P int = 0.96). Conclusion Among patients with or without NSTE-ACS who have completed an initial 3-month course of DAPT following PCI with DES, ticagrelor monotherapy reduced clinically meaningful bleeding events without increasing ischaemic risk as compared with ticagrelor plus aspirin. The benefits of ticagrelor monotherapy with respect to bleeding events were more pronounced in patients with NSTE-ACS. Trial registration Clinicaltrials.gov identifier: NCT02270242.

PURPOSE To review data from DIPG Registry patients recorded to have received a second course of radiation therapy (rRT). METHODS The International DIPG Registry was searched for patients with DIPG who were treated with a known dose of rRT. Doses of rRT, timing from initial diagnosis and primary radiation therapy (pRT), radiographic response to rRT and survival from diagnosis (OS) were evaluated. RESULTS Sixty (11.2%) of 535 Registry patients underwent rRT; dose was provided for 44 patients. Median (range) data from those 44 revealed that rRT was given at 12 (2–65) months from initial diagnosis of DIPG and at 9.6 (1–61) months from completion of pRT at a dose of 26.7 (1.8–74) Gy. After completion of rRT, MRI showed response, progression, stable disease or was not available in 19, 8, 3 and 14 patients, respectively. Median PFS and OS were 11 and 18.1 months, respectively. 475 Registry patients did not undergo rRT; their ages, duration of symptoms, and primary treatment with or without chemotherapy were not significantly different from the rRT cohort. Median PFS and OS for the non-rRT patients were 6.9 and 10 months, respectively. rRT patients were more likely to have had radiographic evidence of tumor necrosis at diagnosis than non-rRT patients. CONCLUSIONS Administration of rRT to patients with DIPG has been inconsistent with respect to timing and dose. Toxicity, response and quality of life data are incomplete, but survival appears to be lengthened with rRT. Prospective clinical trials will elucidate benefits and risks of rRT.

Quantification of biological aging has been proposed for population surveillance of age-related decline in system integrity and evaluation of geroprotective therapies. However, methods of quantifying biological aging have been little studied in geriatric populations. We analyzed three clinical-biomarker-algorithm methods to quantify biological aging. Klemera–Doubal method Biological Age and homeostatic dysregulation algorithms were parameterized from analysis of U.S. National Health and Nutrition Examination Surveys (NHANES) data (N = 36,207) based on published methods. Levine method Biological Age was adapted from published analysis of NHANES data. Algorithms were applied to biomarker data from the Duke Established Populations for Epidemiologic Studies of the Elderly (Duke-EPESE) cohort of older adults (N = 1,374, aged 71–102 years, 35% male, 52% African American). We tested associations of biological aging measures with participant reported Activities of daily living (ADL), instrumental activities of daily living (IADL) dependencies, and mortality. We evaluated the sensitivity of results to the demographic composition of reference samples and biomarker sets used to develop biological aging algorithms. African American and white Duke-EPESE participants with more advanced biological aging reported dependence in more ADLs and IADLs and were at increased risk of death over follow-up through 2017. Effect sizes were similar across algorithms, but were strongest for Levine method Biological Age (per-quintile increase in ADL incidence rate ratio = 1.25, 95% confidence interval [1.17–1.37], IADL incidence rate ratio = 1.23 [1.15–1.32], mortality hazard ratio = 1.12 [1.08–1.16]). Results were insensitive to demographic composition of reference samples, but modestly sensitive to the biomarker sets used to develop biological aging algorithms. Blood-chemistry-based quantifications of biological aging show promise for evaluating the effectiveness of interventions to extend healthy life span in older adults.

OBJECTIVES: A converging body of evidence indicates elevated weight status is inversely related to memory forms that disproportionately rely on the hippocampus. However, much of this work has relied on BMI, resulting in a limited understanding of the impact of body composition on memory performance. Accordingly, this study investigated the influence of soft tissue compartments (i.e., lean and fat mass) on hippocampal-dependent memory function. Using a mnemonic discrimination task, we examined lure discrimination, a measure of hippocampal memory ability. It was anticipated that lean body mass would relate positively, and fat mass negatively to lure discrimination ability. METHODS: Participants included 216 individuals (134 females) between the ages of 25 and 46 years. Participants provided demographic information such as sex, age, and income. Dual energy x-ray absorptiometry (DXA) was used to assess height-adjusted lean and fat mass (LMI and FMI, respectively). Lure discrimination, the ability to correctly identify objects similar to those seen during encoding, was assessed using the Mnemonic Similarity Task (MST). Bivariate correlations were conducted to determine demographic predictors of task performance. Subsequently, a linear regression model controlling for significant predictors was used to determine LMI and FMI influence on lure discrimination. RESULTS: Preliminary data analysis showed a positive correlation between BMI and MST performance. Follow-up bivariate correlations revealed an underlying positive association between LMI and lure discrimination (r = .153, P = .029), while FMI and lure discrimination were not significantly associated (r = .087, P = .218). A linear regression model controlling for age and income showed LMI accounted for a significant proportion of variance in lure discrimination (R(2 )= .070, P = .002), adjusting for demographic variables. CONCLUSIONS: These findings indicate that while BMI is related to lure discrimination, this effect appears to be driven by LMI, but not FMI. Future studies are warranted to determine the impact of changes in lean mass on hippocampal memory performance. FUNDING SOURCES: Funding provided by the Department of Kinesiology and Community Health at the University of Illinois and the USDA National Institute of Food and Agriculture, Hatch Project 1009249. Partial support provided by the Hass Avocado Board.

OBJECTIVES: Xanthophyll carotenoids in the retina have been linked to visual and cognitive health. While genetic variations in genes related to carotenoid cleavage (e.g., beta-carotene-15,15′-monooxygenase [BCO1/BCMO1]) and xanthophyll transport (e.g., Cluster Determinant 36 [CD36]) proteins have been shown to influence MPOD in adults, it is unknown whether these relationships are evident in childhood. We examined the influence of genetic variation (single nucleotide polymorphisms [SNPs]) in BCO1 and CD36 on MPOD in 7–10 year-olds (N = 134). METHODS: Macular pigment optical density (MPOD) was assessed using heterochromatic flicker photometry. DNA was extracted from saliva samples and genotyped for six tag-selected SNPs, identified by previous work among adults. Ancestry informative markers (AIMs) were genotyped to account for ethnic heterogeneity. Dietary lutein and zeaxanthin (L + Z) was assessed using 3d food records among a subsample (N = 82). RESULTS: Minor allele frequencies of BCO1-rs7501331 (T), CD36-rs1527483 (T), CD36-rs3173798 (C) were 0.194, 0.090 and 0.213, respectively. In the partially adjusted (AIMs, age, sex, BMI %tile) models, three of the six SNPs were associated with MPOD. Carriers of the BCO1-rs7501331 T allele had significantly lower (∼18%) MPOD than the CC homozygotes (P = 0.042). Minor allele (T) carriers of CD36-rs1527483 exhibited lower MPOD (∼23%) than CC homozygotes (P = 0.043). CD36-rs3173798 C allele carriers had ∼32% lower MPOD than those with the TT genotype (P

Aims Limited data exist on the epidemiology, evaluation, and prognosis of otherwise unexplained anaemia of the elderly in heart failure (HF). Thus, we aimed to determine the incidence of anaemia, to characterize diagnostic testing patterns for potentially reversible causes of anaemia, and to evaluate the independent association between incident anaemia and long-term morbidity and mortality. Methods and results Within the Cardiovascular Research Network (CVRN), we identified adults age ≥65 years with diagnosed HF between 2005 and 2012 and no anaemia at entry. Incident anaemia was defined using World Health Organization (WHO) haemoglobin thresholds ( Conclusion Among older adults with HF, incident anaemia is common and independently associated with substantially increased risks of morbidity and mortality. Additional research is necessary to clarify the value of routine evaluation and treatment of potentially reversible causes of anaemia.

INTRODUCTION Irradiation-sparing approaches are used in young children with medulloblastoma (MB) given the vulnerability of the developing brain to neurocognitive impairment. Limited data are available following relapse for these patients. We aimed to describe the management and outcomes of young children with MB who relapsed after initial treatment without craniospinal irradiation (CSI). METHODS International retrospective study including patients with MB diagnosed between 1995–2017, ≤ 72 months old, initially treated without CSI, who subsequently relapsed. RESULTS Data are available for 52 patients (32 male). Median age at initial diagnosis was 27 months (range, 6–72) with 24 being metastatic. Initial therapy included conventional chemotherapy alone or high-dose chemotherapy (HDC) in 21 and 31 subjects, respectively. Three received upfront focal irradiation. Molecular subgrouping, available for 24 tumors, included 9 SHH and 15 non-WNT/non-SHH. Median time to relapse was 13 months (range, 3–63). Relapse was local, disseminated or combined in 20, 15, and 16, respectively. Salvage therapy with curative intent was given in 42/52 patients, including CSI in 28 subjects (median dose 36Gy, 18–41.4) or focal irradiation in 5 others. Three received HDC only. At a median follow-up time of 46 months (range, 4–255), 25 (48%) were alive, including 7/9 SHH and 7/15 non-WNT/non-SHH. The 2- and 5-year OS was 67% and 56% (SE, 7%), respectively. Two of 3 patients with SHH who did not receive salvage radiotherapy are survivors. CONCLUSION A substantial proportion of young children who relapse following irradiation-sparing strategies can be salvaged. Neurocognitive and ototoxicity outcomes are being evaluated.

Background: Detecting underlying biological wear and tear prior to diagnosed clinical dysfunction is increasingly providing clues to the aging process. Few studies have examined pathogen burden, a measure of the cumulative effects of multiple persistent pathogens, as potentially accelerating the pace of age-related biological decline by midlife. Methods: Using data from two waves of the National Health and Nutrition Examination Survey, we compared three alternative methods for measuring pathogen burden, composed of mainly persistent viral infections, using a cumulative deficits index (CDI) as an outcome: single pathogen associations, a pathogen burden summary score, and latent class analyses. The CDI was constructed by summing the number of 28 biomarkers (i.e. white blood cell count, calcium, etc.) for which an individual was in the dysfunctional range. The study sample was aged 20–49 years old. Seven pathogens were assessed in wave 1; five in wave 2. Results: We found significant heterogeneity in the distribution of the CDI by age, sex, race/ethnicity, and education. There was an association between pathogen burden and the CDI by all three metrics. The latent class classification of pathogen burden showed particularly strong associations with the CDI. Conclusions: Our results suggest that pathogen burden may influence early clinical indicators of poor health as measured by the CDI, even in a relatively young population. These findings suggest that reducing pathogen burden and the specific pathogens that drive the CDI may provide a target for preventing the early development of age-related physiological changes.

Atypical teratoid/rhabdoid tumor (AT/RT) and malignant rhabdoid tumor (MRT) are aggressive malignancies that typically occur in children < 3 years of age and historically have a survival of < 30%. Approximately 25% of patients harbor inactivating germline alterations in SMARCB1, which predispose carriers to develop rhabdoid tumors (RTs) between birth to 5 years (median 5 months). Surveillance guidelines for carriers of SMARCB1 (or SMARCA4) alterations recommend screening with brain MRI, abdominal ultrasound and total body MRI up to 5 years of age. We present 3 survivors of AT/RT with germline alterations in SMARCB1 who developed late primary (metachronous) RTs. Case 1 was diagnosed with a posterior fossa (PF) AT/RT at 3.5 years and developed a metachronous temporal lobe AT/RT at 17.8 years. Case 2 was diagnosed with a PF AT/RT and synchronous renal MRT at 2 months and developed a metachronous thalamic AT/RT at 8 years. Case 3 was diagnosed at 9 weeks with a lateral ventricle AT/RT and developed a metachronous disseminated retroperitoneal MRT at 11.5 years. Genetic analyses confirmed the 2 AT/RTs in case 1, the 2 AT/RTs and 1 MRT in case 2, and the 1 AT/RT and 1 MRT in case 3 to be distinct primary tumors. Due to advances in the treatment of AT/RT and MRT, survival rates are improving. The 3 cases presented in this report suggest that tumor surveillance beyond 5 years of age is indicated for patients with germline alterations who are predisposed to cancer.

Background Chronic mucocutaneous candidiasis (CMC) treatment often induces drug resistance, posing long-term challenges. A novel broad-spectrum fungal CYP51 inhibitor, VT-1598, specifically targets fungal CYP51, but not human CYP enzymes. Objectives To determine the efficacy of VT-1598 in the treatment of oral Candida infection caused by fluconazole-susceptible and -resistant clinical isolates. Methods The MICs of VT-1598 and fluconazole for 28 Candida isolates recovered from patients with inherited CMC were determined using CLSI M27-A3 and M27-S4 guidelines. Plasma and tongue VT-1598 or fluconazole concentrations were measured in mice following oral administration to determine tissue distribution. Tongue fungal load was determined in IL-17 signalling-deficient Act1-/- mice following sublingual Candida albicans infection and oral treatment with fluconazole or VT-1598. Results Among the 28 Candida isolates, 10 (36%) had fluconazole MICs of ≥4 mg/L, whereas VT-1598 demonstrated potent in vitro activity against all isolates (MIC90, 0.125 mg/L). After oral administration, VT-1598 levels in mouse plasma and tongue were significantly greater than those of fluconazole. In vivo, VT-1598 exhibited significant efficacy against fluconazole-susceptible and -resistant C. albicans, even at low drug doses. Furthermore, after a 10 day washout period, tongue fungal burdens in fluconazole-treated mice returned to vehicle control levels, whereas, in contrast, they were undetectable in mice treated with VT-1598. Conclusions VT-1598 effectively controls in vitro growth of mucosally derived Candida clinical isolates, including fluconazole-resistant strains. In vivo, VT-1598 eliminates C. albicans, even after a long washout period or at low doses. Therefore, VT-1598 is a promising drug candidate that may significantly improve treatment options for CMC patients.

A growing body of work suggests that collaboration can benefit memory. In our work on the neural substrates of collaborative learning, we find that many of these benefits extend even to individuals with profound memory impairment. We review this line of work highlighting the benefits and limits of collaborative learning in memory impaired populations. Understanding the contexts and circumstances of success and failure in collaborative learning in individuals with memory impairment advances scientific knowledge of how distinct forms of memory contribute to specific aspects of collaborative learning. Our discovery that memory-impaired individuals can benefit from collaborative learning under some conditions points to the promise of collaborative learning situations in the rehabilitation of memory and learning impairments.

A wide variety of manmade and naturally occurring air pollutants are known to cause cancer. Diverse exposures such as tobacco smoke, radionuclides (radon), chemicals (benzene, mustard gas, and volatile organic compounds), fibers (asbestos), and metals and metalloids (chromium, nickel, and arsenic) have long been classified as carcinogenic to humans. Historically, these classifications were based predominantly on high levels of exposure in occupational settings. Over the last thirty to forty years, scientific attention has focused on quantifying the adverse health effects of indoor and outdoor air pollutants at exposure levels several orders of magnitude lower than were studied initially. These include secondhand smoke, household exposure to radon, residential and environmental exposure to asbestos, soot from diesel-powered engines, ambient exposures to small particles (PM2.5), and indoor air pollution from the combustion of biomass and coal. This chapter provides an overview of recent epidemiologic studies of air pollutants and cancer.

It has long been acknowledged that co-operatives can buffer economic insecurity, offset some of the vagaries of market capitalism, and enhance social solidarity. An interesting—and in many respects peculiar—facet of the history of co-operativism is how worker (or producer) cooperatives and consumer cooperatives have evolved along completely separate trajectories. Yet production and consumption are inextricably bound up in tight configurations. Moreover, no one is exclusively a producer or consumer and we repeatedly and iteratively change roles, often numerous times during the course of a single day. We seem, though, to be at an auspicious moment to rectify this anomalous situation. This chapter outlines the notion of multi-stakeholder co-operativism and highlights how worker-consumer cooperatives can bridge this enduring divide. These organizations can also inculcate democratic values and solidaristic social relations that will be essential for easing the process of innovating a new system of social organization over the next few decades.

Physical function in the context of older populations has been well studied. Much of what is known about late-life function has been derived from studies that are often comprised exclusively of older adults. There is a paucity of studies that have common measures directly assessing physical performance across a full life span. Such studies present a unique opportunity to examine trajectories of successful or premature aging and identify characteristics associated with each. Furthermore, recent research has elucidated the influence of early childhood characteristics associated with accelerated aging.

The human aging process is associated with decline in physical performance resulting from dysregulated inflammatory and metabolic systems; each has an effect on circulating serum markers of inflammation and metabolism. Biomarker burden and robustness indices were developed from twenty inflammatory and metabolic markers using a combination of three cross-sectional studies conducted in older adults. Each biomarker was individually correlated with gait speed, and all biomarkers underwent selection by step-wise regression on multiple bootstrap samples with respect to burden and robustness of physical performance. Twelve and eight biomarkers, respectively, were included in the indices that correlated with steady, step-wise change in outcome. The biomarker indices predict physical performance better than individual markers and are the first of such indices to link multiple inflammatory/metabolic markers with physical performance. The biomarkers included in the model have physiological and clinical implications on development of, or resilience to, physical performance decline in the older adults.

Pediatric spinal ependymomas (pSP) are exceedingly rare central nervous system (CNS) tumors. Children with these tumours are likely to experience a more aggressive disease course, with a higher rate of local failure following treatment, and a higher rate of CNS metastasis, compared to adults. Because these tumours are uncommon, the molecular basis of pSP is poorly characterized. Microarray analysis of 66 pediatric ependymomas showed distinct expression patterns and detected up-regulation of several genes involved in development-related processes for spinal tumours. In addition, multiple biological processes that are less known for their involvement in pSP, oxidative phosphorylation, cellular respiration, electron transport, and cofactor metabolic process were also detected. When we compared the expression profiles of pSP to adult spinal ependymomas (aSP), we found a very low number of differentially expressed genes (12.5%) shared between pSP and aSP. Analysis of microRNA (miRNA) expression arrays on an overlapping cohort of 49 patients showed that six miRNAs (miR-196a, miR-27b, miR-23b, miR-144*, and miR-10a and 10b) were up-regulated and four (miR-26a, and miR-885-5p, miR-124, and miR-153) were down-regulated in pSP. The integrative miRNA-mRNA network and predicted miRNA target analysis revealed that the miR-23–27 cluster (miR23b/miR27b) coordinately repressed expression of cell differentiation genes (ACVR1C, CBFA2T3, GPSM1, and PKDCC), and the miR-10 family (miR10a/10b) that reside within the Hox clusters of developmental regulators, repressed expression of CAM2, HDAC4, IL1RAPL1, and MTSS1L. Furthermore, these miRNA-mRNA interactions were not detected in other cancers when we conducted the TCGA data analysis across ten different cancer types. Further investigation of gene expression and DNA methylation profiles in a larger cohort of pediatric ependymomas is on going, and will establish specific molecular characteristics of pSP. The identification of these candidate genes/miRNAs provides an evidence-based rationale for functional studies that will help to interrogate the initiation and progression of pSP.

INTRODUCTION: Diffuse intrinsic pontine glioma (DIPG) remains a devastating and incurable disease. The DIPG-BATs clinical trial incorporates diagnostic biopsy with molecularly determined treatment stratification. Here we present the initial genomic analysis of the DIPG-BATs cohort. METHODS: Children enrolled on the DIPG-BATs clinical trial underwent upfront diagnostic biopsies prior to commencement of therapy. RNA and DNA were extracted from single core biopsies and subjected to whole-genome sequencing (WGS) and RNA-sequencing. Tumor samples were also collected at autopsy if there was parental consent. RESULTS: Fifty-three patients were enrolled on study, of whom 50 underwent biopsy. There were no biopsy-related deaths. A mean of 5ug of RNA and 10ug of DNA were extracted from single frozen cores. WGS on 41 DIPG samples (including eight autopsy samples) revealed a mean mutation rate of 0.753 mutations per Mb. We confirmed TP53, PIK3CA, H3F3A, ACVR1, PPM1D, and HIST1H3B to be recurrently mutated in DIPG. Additional mutations were found in epigenetic modifiers including ASXL1. Copy-number analysis revealed PDGFRA to meet statistical significance as a recurrent amplification peak in DIPG (q

INTRODUCTION: Whilst there is an urgent need to expedite the development of new or repurposed drugs for children’s cancer, the additional challenge in the developing brain is to ensure the drug is delivered to the tumour at therapeutic and non toxic concentrations for sufficient duration to achieve the biological effect. This is the necessary focus for personalised medicine agendas in children’s brain tumours as they account for over 20% of childhood cancer and differ significantly in their biological characteristics from their adult counterparts. METHODS: The authors took part in an international CNS drug delivery London workshop funded by the charity Children with Cancer UK (CwC) in February 2016 where different experimental techniques aimed at optimising CNS drug delivery in children’s brain tumours were presented and discussed. RESULTS: The workshop was reported (1) and promoted through e-cancer (2). We were encouraged to develop a proposal, to establish an international research consortium to raise awareness and promote collaboration in the field. This is now to be funded for two years by Children with Cancer. The Children’s Brain Tumour Drug Delivery Consortium will organise and host discussions between an international, multi-disciplinary network of clinicians and researchers within pharma and academia as well as a range of funders and stakeholders. This Consortium seeks to strengthen collaborative developments by working closely with the international children’s brain tumour community. CONCLUSION: We present this abstract to the SNO Pediatric conference to launch this initiative in North America and invite collaborators to promote this research priority for children across the world and to consider joining the consortium, which will be presented at the conference. 1. NAILOR,A, WALKER,DA and ET AL, 2016. Highlights of Children with Cancer UK’s Workshop on Drug Delivery in Paediatric Brain Tumours eCancer. 10, 630. 2. http://ecancer.org/conference/831-drug-delivery-in-paediatric-brain-tumours.php

Motivational Interviewing (MI) is an evidence-based approach for fostering behavior change and holds potential to engage patients in behavior change related to fall prevention. A two-arm, unblinded, pilot randomized controlled trial was conducted in a hospital setting to determine the feasibility (recruitment and retention), establish suitable procedures for the intervention (duration and quality of MI), and to test study measurements (fear of falling, importance and confidence related to fall prevention, patient activation, fall prevention behaviors, and fall rates). Participants were high fall risk older inpatients (age ≥ 65). The intervention arm received MI at one time during hospitalization in addition to routine hospital fall prevention intervention. The control arm received the routine hospital care for fall prevention only. Measures were collected at baseline, 2-days, 1-week, 1-month, and 3-month. A total of 120 inpatients were contacted by the study team and 67 were randomized: intervention arm (n=36) and control arm (n=31). Approximately 66% of participants completed the study at the 3-month data collection and MI intervention took an average of 21 minutes and was of adequate quality. The intervention group reported less fear of falling after the MI intervention and maintained fall prevention behaviors over time (p

There is a sizeable and growing body of research on singing. Contributing to the potential for ever-expanding knowledge in this field is the ability to collect singing data in digital formats as compared to formats derived from the analogue devices of the past. New technologies have also led to the possibility of collecting recordings from the different locations where researchers work or travel and sharing data across the world, free from geographic restrictions. Analysis of raw singing data could thereafter be conducted by other researchers, who could then disseminate their findings to others. This chapter outlines some of the information technology resources that have been developed to collect and share singing and musical data, focusing on the development of a digital library as part of the Advancing Interdisciplinary Research on Singing (AIRS) project which aims to advance knowledge about singing with a focus on human development, education, and well-being.

Background Rigosertib (ON 01910.Na), a first-in-class Ras mimetic and small-molecule inhibitor of multiple signaling pathways including polo-like kinase 1 (PLK1) and phosphoinositide 3-kinase (PI3K), has shown efficacy in preclinical pancreatic cancer models. In this study, rigosertib was assessed in combination with gemcitabine in patients with treatment-naive metastatic pancreatic adenocarcinoma. Materials and methods Patients with metastatic pancreatic adenocarcinoma were randomized in a 2:1 fashion to gemcitabine 1000 mg/m2 weekly for 3 weeks of a 4-week cycle plus rigosertib 1800 mg/m2 via 2-h continuous IV infusions given twice weekly for 3 weeks of a 4-week cycle (RIG + GEM) versus gemcitabine 1000 mg/m2 weekly for 3 weeks in a 4-week cycle (GEM). Results A total of 160 patients were enrolled globally and randomly assigned to RIG + GEM (106 patients) or GEM (54). The most common grade 3 or higher adverse events were neutropenia (8% in the RIG + GEM group versus 6% in the GEM group), hyponatremia (17% versus 4%), and anemia (8% versus 4%). The median overall survival was 6.1 months for RIG + GEM versus 6.4 months for GEM [hazard ratio (HR), 1.24; 95% confidence interval (CI) 0.85–1.81]. The median progression-free survival was 3.4 months for both groups (HR = 0.96; 95% CI 0.68–1.36). The partial response rate was 19% versus 13% for RIG + GEM versus GEM, respectively. Of 64 tumor samples sent for molecular analysis, 47 were adequate for multiplex genetic testing and 41 were positive for mutations. The majority of cases had KRAS gene mutations (40 cases). Other mutations detected included TP53 (13 cases) and PIK3CA (1 case). No correlation between mutational status and efficacy was detected. Conclusions The combination of RIG + GEM failed to demonstrate an improvement in survival or response compared with GEM in patients with metastatic pancreatic adenocarcinoma. Rigosertib showed a similar safety profile to that seen in previous trials using the IV formulation.

Aims In the dual antiplatelet therapy (DAPT) study, continued thienopyridine beyond 12 months after drug-eluting stent placement was associated with increased mortality compared with placebo. We sought to evaluate factors related to mortality in randomized patients receiving either drug-eluting or bare metal stents in the DAPT study. Methods and results Patients were enrolled after coronary stenting, given thienopyridine and aspirin for 12 months, randomly assigned to continued thienopyridine or placebo for an additional 18 months (while taking aspirin), and subsequently treated with aspirin alone for another 3 months. A blinded independent adjudication committee evaluated deaths. Among 11 648 randomized patients, rates of all-cause mortality rates were 1.9 vs. 1.5% (continued thienopyridine vs. placebo, P = 0.07), cardiovascular mortality, 1.0 vs. 1.0% ( P = 0.97), and non-cardiovascular mortality, 0.9 vs. 0.5% ( P = 0.01) over the randomized period (Months 12–30). Rates of fatal bleeding were 0.2 vs. 0.1% ( P = 0.81), and deaths related to any prior bleeding were 0.3 vs. 0.2% ( P = 0.36), Months 12–33). Cancer incidence did not differ (2.0 vs. 1.6%, P = 0.12). Cancer-related deaths occurred in 0.6 vs. 0.3% ( P = 0.02) and were rarely related to bleeding (0.1 vs. 0, P = 0.25). After excluding those occurring in patients with cancer diagnosed before enrolment, rates were 0.4 vs. 0.3% ( P = 0.16). Conclusion Bleeding accounted for a minority of deaths among patients treated with continued thienopyridine. Cancer-related death in association with thienopyridine therapy was mainly not related to bleeding and may be a chance finding. Caution is warranted when considering extended thienopyridine in patients with advanced cancer. Trial Registration clinicaltrials.gov Identifier: [NCT00977938][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00977938&atom=%2Fehj%2F37%2F4%2F378.atom

Background Rapid detection and identification of sepsis causing pathogens are critical for optimizing antimicrobial therapy to improve patient survival and reduce healthcare costs. The T2Bacteria Panel RUO is a molecular diagnostic allowing detection of Gram-negative Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii and Gram-positive Staphylococcus aureus and Enterococcus faecium within a few hours. The purpose of our study was to determine the feasibility and efficacy of the T2Bacterial Panel RUO in an Emergency Medicine (ED) and Surgical Intensive Care Unit (SICU) setting. Methods An IRB-approved, prospective, observational study was implemented at a Safety-Net, Level One Trauma Center in Denver, Colorado. Patients were enrolled who received an order for a blood culture from the ED or SICU. Patients who had blood drawn for cultures had a concurrent draw for testing with a T2Bacteria Panel RUO. Results Sixty-six patients are included in the present interim analysis. Mean patient age was 51 years old (19–84), 36% were female, 86% Caucasian (34% Hispanic/Latino), and 74% of patients were enrolled upon presentation to the ED, 13% from the SICU, and 15% from the wards. 90% of blood sampling (culture and T2Bacteria) was done from peripheral stick while 7% were from the initial stick of a peripheral IV and 2% obtained from an indwelling catheter. 85% of blood cultures were negative. Of the 56 patients with negative blood culture, 53 had concordant negative T2Bacteria results, providing a specificity of 94.6%. 10 patients had positive blood cultures (15%) for T2Bacteria Panel RUO targets. Interestingly, only five of these (50%) had concordant positive T2Bacteria testing. Examining the discordant samples, all (5) blood culture positive, T2Bacteria negative were found to have clinically false-positive blood cultures. T2Bacteria positive samples were distributed as follows: two E.coli, one S. aureus, one K. pneumoniae, and one P. aeruginosa. No detections were made for E. faecium or A. baumannii. Conclusion In this interim analysis, T2Bacteria Panel RUO provides feasible rapid diagnostics for ED and surgical ICU settings with a high specificity and much shorter time to result when compared with gold standard blood cultures. Disclosures C. Robinson, T2 Biosystems: Research Coordinator for funded study from T2 Biosystems, Research support. R. Jackson, T2 Biosystems: Research Assistant for funded study from T2 Biosystems, Research support. M. Cohen, T2 Biosystems: PI on study being funded by T2 Biosystems, not paying for any part of salary, Research support.

Background Contaminated blood cultures remain a challenge for patients, physicians, and microbiology laboratories, often leading to unnecessary antibiotic treatment. One approach to reduce contamination is to avoid culturing the initial blood sample that can contain a contaminated plug of skin from the needle stick. Initial specimen diversion technique (ISDT) was associated with decreased rate of blood culture contamination, when applied by trained phlebotomists, using either sterile vacuum blood collection tubes or a designated device. The aim of this study was to test ISDT in real-life, using externally nonsterile regular vacuum sample tubes for the diversion, by any medical personnel taking blood cultures. Methods Adults from whom the treating physician planned to take blood cultures and additional blood chemistry tests, in the same venous puncture, were eligible and were randomly assigned to intervention or control arms. The hospital’s standard procedure for blood drawing was maintained, except that in the intervention arm, blood was aspirated to a green-capped tube, which was used for regular biochemistry tests, prior to the blood culture. Results Four hundred twenty-three blood cultures were obtained from 404 patients. Of 404 (11.1%) of the blood cultures, 45 yielded microbial growth, with 31 (7.7%) regarded as true pathogens and 14 (3.5%) as contaminants. Detection of true bloodstream infection was similar by the two methods, 16/181 (8.83%) with the ISDT, and 15/223 (6.72%) using the standard method. The ISDT was associated with a significantly less isolation of presumed contaminants compared with the standard method, 2/165 (1.2%) vs. 12/208 (5.76%), P = 0.02. Conclusion ISDT, by any medical personnel, through altered order of test tube vs. blood culture sampling significantly reduced contamination of blood cultures without loss of diverted blood. Disclosures All authors: No reported disclosures.

Aims Angina relief is a major goal of percutaneous coronary intervention (PCI); however, ∼1 in 5 patients continue to have angina after PCI. Understanding patient factors associated with residual angina would enable providers to more accurately calibrate patients'; expectations of angina relief after PCI, may support different follow-up strategies or approaches to coronary revascularisation, and could potentially serve as a marker of PCI quality. Methods and Results Among 2573 patients who had PCI at 10 US hospitals for stable angina, unstable angina or non-ST-elevation myocardial infarctions (NSTEMI), 24% reported angina 6-months after PCI, as assessed with the Seattle Angina Questionnaire Angina Frequency score (categorised as none vs. any angina; score=100 vs.