European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme

Background: Glufosfamide is a new alkylating agent in which the active metabolite of isophosphoramide mustard is covalently linked to β-d-glucose to target the glucose transporter system and increase intracellular uptake in tumor cells. We investigated this drug in a multicenter prospective phase II trial in recurrent glioblastoma multiforme (GBM). Patients and methods: Eligible patients had recurrent GBM following surgery, radiotherapy and no more than one prior line of chemotherapy. Patients were treated with glufosfamide 5000 mg/m2 administered as a 1-h intravenous infusion. Treatment success was defined as patients with either an objective response according to Macdonald's criteria or 6 months progression-free survival. Toxicity was assessed with the Common Toxicity Criteria (CTC) version 2.0. Results: Thirty-one eligible patients were included. Toxicity was modest, the main clinically relevant toxicities being leukopenia (CTC grade >3 in five patients) and hepatotoxicity (in three patients). No responses were observed; one patient (3%; 95% confidence interval 0 to 17%) was free from progression at 6 months. Pharmacokinetic analysis showed a 15% decrease in area under the curve and glufosfamide clearance in patients treated with enzyme-inducing antiepileptic drugs, but no effect of these drugs on maximum concentration and plasma half-life. Conclusion: Glufosfamide did not show significant clinical antitumor activity in patients with recurrent GB

European Organization for Research and Treatment of Cancer (EORTC) open label phase II study on glufosfamide administered as a 60-minute infusion every 3 weeks in recurrent glioblastoma multiforme

BACKGROUND: Glufosfamide is a new alkylating agent in which the active metabolite of isophosphoramide mustard is covalently linked to beta-D-glucose to target the glucose transporter system and increase intracellular uptake in tumor cells. We investigated this drug in a multicenter prospective phase II trial in recurrent glioblastoma multiforme (GBM). PATIENTS AND METHODS: Eligible patients had recurrent GBM following surgery, radiotherapy and no more than one prior line of chemotherapy. Patients were treated with glufosfamide 5000 mg/m(2) administered as a 1-h intravenous infusion. Treatment success was defined as patients with either an objective response according to Macdonald's criteria or 6 months progression-free survival. Toxicity was assessed with the Common Toxicity Criteria (CTC) version 2.0. RESULTS: Thirty-one eligible patients were included. Toxicity was modest, the main clinically relevant toxicities being leukopenia (CTC grade >3 in five patients) and hepatotoxicity (in three patients). No responses were observed; one patient (3%; 95% confidence interval 0 to 17%) was free from progression at 6 months. Pharmacokinetic analysis showed a 15% decrease in area under the curve and glufosfamide clearance in patients treated with enzyme-inducing antiepileptic drugs, but no effect of these drugs on maximum concentration and plasma half-life. CONCLUSION: Glufosfamide did not show significant clinical antitumor activity in patients with recurrent GBM

Trends in Prevalence of Advanced HIV Disease at Antiretroviral Therapy Enrollment - 10 Countries, 2004-2015.

Monitoring prevalence of advanced human immunodeficiency virus (HIV) disease (i.e., CD4+ T-cell count <200 cells/μL) among persons starting antiretroviral therapy (ART) is important to understand ART program outcomes, inform HIV prevention strategy, and forecast need for adjunctive therapies.*,†,§ To assess trends in prevalence of advanced disease at ART initiation in 10 high-burden countries during 2004-2015, records of 694,138 ART enrollees aged ≥15 years from 797 ART facilities were analyzed. Availability of national electronic medical record systems allowed up-to-date evaluation of trends in Haiti (2004-2015), Mozambique (2004-2014), and Namibia (2004-2012), where prevalence of advanced disease at ART initiation declined from 75% to 34% (p<0.001), 73% to 37% (p<0.001), and 80% to 41% (p<0.001), respectively. Significant declines in prevalence of advanced disease during 2004-2011 were observed in Nigeria, Swaziland, Uganda, Vietnam, and Zimbabwe. The encouraging declines in prevalence of advanced disease at ART enrollment are likely due to scale-up of testing and treatment services and ART-eligibility guidelines encouraging earlier ART initiation. However, in 2015, approximately a third of new ART patients still initiated ART with advanced HIV disease. To reduce prevalence of advanced disease at ART initiation, adoption of World Health Organization (WHO)-recommended "treat-all" guidelines and strategies to facilitate earlier HIV testing and treatment are needed to reduce HIV-related mortality and HIV incidence

Physical activity, black carbon exposure and airway inflammation in an urban adolescent cohort

Objective Regular physical activity can improve cardiopulmonary health; however, increased respiratory rates and tidal volumes during activity may increase the effective internal dose of air pollution exposure. Our objective was to investigate the impact of black carbon (BC) measured by personal sampler on the relationship between physical activity and fractional exhaled nitric oxide (FeNO), a marker of airway inflammation. We hypothesized that higher personal BC would attenuate the protective effect of physical activity on airway inflammation. Methods We performed a cross-sectional study nested in a birth cohort of African American and Dominican children living in the Bronx and Northern Manhattan, New York City. Children were recruited based on age (target 9–14 year olds) and presence (n=70) or absence (n=59) of current asthma. Children wore wrist mounted accelerometers for 6 days and were classified as ‘active’ if they had ≥60 min of moderate-to-vigorous activity (MVA) each day and ‘non-active’ if they had <60 min of MVA on any given day, based on CDC guidelines. Personal BC measured using a MicroAeth, was assessed during two 24-h periods, at the beginning and end of physical activity assessment. High BC was defined as the upper tertile of BC measured with personal sampler. FeNO measurements were sampled at the beginning and end of the of physical activity assessment. Results In multivariable linear regression models, ‘active’ children had 25% higher personal BC concentrations (p=0.02) and 20% lower FeNO (p=0.04) compared to ‘non-active’ children. Among children with high personal BC (n=33), there was no relationship between activity and FeNO (p=1.00). The significant protective relationship between activity and airway inflammation was largely driven by children with lower personal BC (n=96, p=0.04). Conclusions Children that live in an urban environment and are physically active on a daily basis have higher personal exposure to BC. High BC offsets the protective relationship between physical activity and airway inflammation

Differences in Ambient Polycyclic Aromatic Hydrocarbon Concentrations between Streets and Alleys in New York City: Open Space vs. Semi-Closed Space

Background: Outdoor ambient polycyclic aromatic hydrocarbon (PAH) concentrations are variable throughout an urban environment. However, little is known about how variation in semivolatile and nonvolatile PAHs related to the built environment (open space vs. semi-closed space) contributes to differences in concentrations. Methods: We simultaneously collected 14, two-week samples of PAHs from the outside of windows facing the front (adjacent to the street) open side of a New York City apartment building and the alley, semi-closed side of the same apartment unit between 2007 and 2012. We also analyzed samples of PAHs measured from 35 homes across Northern Manhattan and the Bronx, 17 from street facing windows with a median floor level of 4 (range 2–26) and 18 from alley-facing windows with a median floor level of 4 (range 1–15). Results: Levels of nonvolatile ambient PAHs were significantly higher when measured from a window adjacent to a street (an open space), compared to a window 30 feet away, adjacent to an alley (a semi-closed space) (street geometric mean (GM) 1.32 ng/m3, arithmetic mean ± standard deviation (AM ± SD) 1.61 ± 1.04 ng/m3; alley GM 1.10 ng/m3, AM ± SD 1.37 ± 0.94 ng/m3). In the neighborhood-wide comparison, nonvolatile PAHs were also significantly higher when measured adjacent to streets compared with adjacent to alley sides of apartment buildings (street GM 1.10 ng/m3, AM ± SD 1.46 ± 1.24 ng/m3; alley GM 0.61 ng/m3, AM ± SD 0.81 ± 0.80 ng/m3), but not semivolatile PAHs. Conclusions: Ambient PAHs, nonvolatile PAHs in particular, are significantly higher when measured from a window adjacent to a street compared to a window adjacent to an alley, despite both locations being relatively close to street traffic. This study highlights small-scale spatial variations in ambient PAH concentrations that may be related to the built environment (open space vs. semi-closed space) from which the samples are measured, as well as the relative distance from street traffic, that could impact accurate personal exposure assessments

Short-term exposure to PM2.5 and vanadium and changes in asthma gene DNA methylation and lung function decrements among urban children

BACKGROUND: Both short and long-term exposure to traffic-related air pollutants have been associated with asthma and reduced lung function. We hypothesized that short-term indoor exposure to fine particulate matter <2.5 μm (PM2.5) and vanadium (V) would be associated with altered buccal cell DNA methylation of targeted asthma genes and decreased lung function among urban children in a nested subcohort of African American and Dominican children. METHODS: Six day integrated levels of air pollutants were measured from children's homes (age 9-14; n = 163), repeated 6 months later (n = 98). Buccal samples were collected repeatedly during visits. CpG promoter loci of asthma genes (i.e., interleukin 4 (IL4), interferon gamma (IFNγ), inducible nitric oxide synthase (NOS2A), arginase 2 (ARG2)) were pyrosequenced and lung function was assessed. RESULTS: Exposure to V, but not PM2.5, was associated with lower DNA methylation of IL4 and IFNγ. In exploratory analyses, V levels were associated with lower methylation of the proinflammatory NOS2A-CpG+5099 among asthmatic overweight or obese children but not nonasthmatics. Short-term exposure to PM2.5, but not V, appeared associated with lower lung function (i.e., reduced z-scores for forced expiratory volume in one second (FEV1, FEV1/ forced vital capacity [FEV1/FVC] and forced expiratory flow at 25-75% of FVC [FEF25-75]). CONCLUSIONS: Exposure to V was associated with altered DNA methylation of allergic and proinflammatory asthma genes implicated in air pollution related asthma. However, short-term exposure to PM2.5, but not V, appeared associated with decrements in lung function among urban children

Longitudinal data reveal strong genetic and weak non-genetic components of ethnicity-dependent blood DNA methylation levels

Epigenetic architecture is influenced by genetic and environmental factors, but little is known about their relative contributions or longitudinal dynamics. Here, we studied DNA methylation (DNAm) at over 750,000 CpG sites in mononuclear blood cells collected at birth and age 7 from 196 children of primarily self-reported Black and Hispanic ethnicities to study race-associated DNAm patterns. We developed a novel Bayesian method for high-dimensional longitudinal data and showed that race-associated DNAm patterns at birth and age 7 are nearly identical. Additionally, we estimated that up to 51% of all self-reported race-associated CpGs had race-dependent DNAm levels that were mediated through local genotype and, quite surprisingly, found that genetic factors explained an overwhelming majority of the variation in DNAm levels at other, previously identified, environmentally-associated CpGs. These results indicate that race-associated blood DNAm patterns in particular, and blood DNAm levels in general, are primarily driven by genetic factors, and are not as sensitive to environmental exposures as previously suggested, at least during the first 7 years of life

Acceptability, feasibility, drug safety, and effectiveness of a pilot mass drug administration with a single round of sulfadoxine-pyrimethamine plus primaquine and indoor residual spraying in communities with malaria transmission in Haiti, 2018

For a malaria elimination strategy, Haiti's National Malaria Control Program piloted a mass drug administration (MDA) with indoor residual spraying (IRS) in 12 high-transmission areas across five communes after implementing community case management and strengthened surveillance. The MDA distributed sulfadoxine-pyrimethamine and single low-dose primaquine to eligible residents during house visits. The IRS campaign applied pirimiphos-methyl insecticide on walls of eligible houses. Pre- and post-campaign cross-sectional surveys were conducted to assess acceptability, feasibility, drug safety, and effectiveness of the combined interventions. Stated acceptability for MDA before the campaign was 99.2%; MDA coverage estimated at 10 weeks post-campaign was 89.6%. Similarly, stated acceptability of IRS at baseline was 99.9%; however, household IRS coverage was 48.9% because of the high number of ineligible houses. Effectiveness measured by Plasmodium falciparum prevalence at baseline and 10 weeks post-campaign were similar: 1.31% versus 1.43%, respectively. Prevalence of serological markers were similar at 10 weeks post-campaign compared with baseline, and increased at 6 months. No severe adverse events associated with the MDA were identified in the pilot; there were severe adverse events in a separate, subsequent campaign. Both MDA and IRS are acceptable and feasible interventions in Haiti. Although a significant impact of a single round of MDA/IRS on malaria transmission was not found using a standard pre- and post-intervention comparison, it is possible there was blunting of the peak transmission. Seasonal malaria transmission patterns, suboptimal IRS coverage, and low baseline parasitemia may have limited the effectiveness or the ability to measure effectiveness

An AI-powered patient triage platform for future viral outbreaks using COVID-19 as a disease model

Over the last century, outbreaks and pandemics have occurred with disturbing regularity, necessitating advance preparation and large-scale, coordinated response. Here, we developed a machine learning predictive model of disease severity and length of hospitalization for COVID-19, which can be utilized as a platform for future unknown viral outbreaks. We combined untargeted metabolomics on plasma data obtained from COVID-19 patients (n = 111) during hospitalization and healthy controls (n = 342), clinical and comorbidity data (n = 508) to build this patient triage platform, which consists of three parts: (i) the clinical decision tree, which amongst other biomarkers showed that patients with increased eosinophils have worse disease prognosis and can serve as a new potential biomarker with high accuracy (AUC = 0.974), (ii) the estimation of patient hospitalization length with ± 5 days error (R2 = 0.9765) and (iii) the prediction of the disease severity and the need of patient transfer to the intensive care unit. We report a significant decrease in serotonin levels in patients who needed positive airway pressure oxygen and/or were intubated. Furthermore, 5-hydroxy tryptophan, allantoin, and glucuronic acid metabolites were increased in COVID-19 patients and collectively they can serve as biomarkers to predict disease progression. The ability to quickly identify which patients will develop life-threatening illness would allow the efficient allocation of medical resources and implementation of the most effective medical interventions. We would advocate that the same approach could be utilized in future viral outbreaks to help hospitals triage patients more effectively and improve patient outcomes while optimizing healthcare resources

Physical activity, black carbon exposure and airway inflammation in an urban adolescent cohort.

Objective: Regular physical activity can improve cardiopulmonary health; however, increased respiratory rates and tidal volumes during activity may increase the effective internal dose of air pollution exposure. Our objective was to investigate the impact of black carbon (BC) measured by personal sampler on the relationship between physical activity and fractional exhaled nitric oxide (FeNO), a marker of airway inflammation. We hypothesized that higher personal BC would attenuate the protective effect of physical activity on airway inflammation. Methods: We performed a cross-sectional study nested in a birth cohort of African American and Dominican children living in the Bronx and Northern Manhattan, New York City. Children were recruited based on age (target 9-14 year olds) and presence (n=70) or absence (n=59) of current asthma. Children wore wrist mounted accelerometers for 6 days and were classified as 'active' if they had ≥60min of moderate-to-vigorous activity (MVA) each day and 'non-active' if they had <60min of MVA on any given day, based on CDC guidelines. Personal BC measured using a MicroAeth, was assessed during two 24-h periods, at the beginning and end of physical activity assessment. High BC was defined as the upper tertile of BC measured with personal sampler. FeNO measurements were sampled at the beginning and end of the of physical activity assessment. Results: In multivariable linear regression models, 'active' children had 25% higher personal BC concentrations (p=0.02) and 20% lower FeNO (p=0.04) compared to 'non-active' children. Among children with high personal BC (n=33), there was no relationship between activity and FeNO (p=1.00). The significant protective relationship between activity and airway inflammation was largely driven by children with lower personal BC (n=96, p=0.04). Conclusions: Children that live in an urban environment and are physically active on a daily basis have higher personal exposure to BC. High BC offsets the protective relationship between physical activity and airway inflammation.VoRSUNY DownstateEnvironmental and Occupational Health SciencesN/