Evaluation of potency and metabolic stability of diphyllin-derived Vacuolar-ATPase inhibitors.

Diphyllin is a naturally occurring lignan comprised of an aryl naphthalene lactone scaffold that demonstrates beneficial biological activities in disease models of cancer, obesity, and viral infection. A target of diphyllin and naturally occurring derivatives is the vacuolar ATPase (V-ATPase) complex. Although diphyllin-related natural products are active with in vitro models for viral entry, the potencies and unknown pharmacokinetic properties limit well-designed in vivo evaluations. Previous studies demonstrated that diphyllin derivatives have the utility of blocking the Ebola virus cell entry pathway. However, diphyllin shows limited potency and poor oral bioavailability in mice. An avenue to improve the potency was used in a new library of synthetic derivatives of diphyllin. Diphyllin derivatives exploiting ether linkages at the 4-position with one-to-three carbon spacers to an oxygen or nitrogen atom provided compounds with EC50 values ranging from 7 to 600 nM potency and selectivity up to >500 against Ebola virus in infection assays. These relative potencies are reflected in the Ebola virus infection of primary macrophages, a cell type involved in early pathogenesis. A target engagement study reveals that reducing the ATPV0a2 protein expression enhanced the potency of diphyllin derivatives to block EBOV entry, consistent with effects on the endosomal V-ATPase function. Despite the substantial enhancement of antiviral potencies, limitations were identified, including rapid clearance predicted by in vitro microsome stability assays. However, compounds with similar or improved half-lives relative to diphyllin demonstrated improved pharmacokinetic profiles in vivo. Importantly, these derivatives displayed suitable plasma levels using oral administration, establishing the feasibility of in vivo antiviral testing.

Niraparib maintenance therapy using an individualised starting dose in patients with platinum-sensitive recurrent ovarian cancer (NORA): final overall survival analysis of a phase 3 randomised, placebo-controlled trial.

Background: Niraparib significantly prolonged progression-free survival versus placebo in patients with platinum-sensitive, recurrent ovarian cancer (PSROC), regardless of germline BRCA mutation (gBRCAm) status, in NORA. This analysis reports final data on overall survival (OS). Methods: This randomised, double-blind, placebo-controlled, phase 3 trial enrolled patients across 30 centres in China between 26 September 2017 and 2 February 2019 (clinicaltrials.gov, NCT03705156). Eligible patients had histologically confirmed, recurrent, (predominantly) high-grade serous epithelial ovarian cancer, fallopian tube carcinoma, or primary peritoneal carcinoma (no histological restrictions for those with gBRCAm) and had received ≥2 prior lines of platinum-based chemotherapy. Patients were randomised (2:1) to receive niraparib or placebo, with stratification by gBRCAm status, time to recurrence following penultimate platinum-based chemotherapy, and response to last platinum-based chemotherapy. Following a protocol amendment, the starting dose was individualised: 200 mg/day for patients with bodyweight <77 kg and/or platelet count <150 × 103/µL at baseline and 300 mg/day otherwise. OS was a secondary endpoint. Findings: Totally, 265 patients were randomised to receive niraparib (n = 177) or placebo (n = 88), and 249 (94.0%) received an individualised starting dose. As of 14 August 2023, median follow-up for OS was 57.9 months (IQR, 54.8-61.6). Median OS (95% CI) with niraparib versus placebo was 51.5 (41.4-58.9) versus 47.6 (33.3-not evaluable [NE]) months, with hazard ratio [HR] of 0.86 (95% CI, 0.60-1.23), in the overall population; 56.0 (36.1-NE) versus 47.6 (31.6-NE) months, with HR of 0.86 (95% CI, 0.46-1.58), in patients with gBRCAm; and 46.5 (41.0-NE) versus 46.9 (31.8-NE) months, with HR of 0.87 (95% CI, 0.56-1.35), in those without. No new safety signals were identified, and myelodysplastic syndromes/acute myeloid leukaemia occurred in three (1.7%) niraparib-treated patients. Interpretation: Niraparib maintenance therapy with an individualised starting dose demonstrated a favourable OS trend versus placebo in PSROC patients, regardless of gBRCAm status. Funding: Zai Lab (Shanghai) Co., Ltd; National Major Scientific and Technological Special Project for "Significant New Drugs Development" in 2018, China [grant number 2018ZX09736019].

Wastewater-based epidemiology for comprehensive communitywide exposome surveillance: A gradient of metals exposure.

Community wastewater surveillance is an established means to measure health threats. Exposure to toxic metals as one of the key environmental contaminants has been attracting public health attention as exposure can be related to contamination across air, water, and soil as well as associated with individual factors. This research uses Jefferson County, Kentucky, as an urban exposome case study to analyze sub-county metal concentrations in wastewater as a possible indicator of community toxicant exposure risk, and to test the feasibility of using wastewater to identify potential community areas of elevated metals exposure. Variability in wastewater metal concentrations were observed across the county; 19 of the 26 sites had one or more metal results greater than one standard deviation above the mean and were designated areas of concern. Additionally, thirteen of the nineteen sites were of increased concern with levels greater than two standard deviations above the mean. This foundational research found variability in several instances between smaller nested upstream contributing neighborhood sewersheds when measured in the associated downstream treatment plant. Wastewater provides an opportunity to look at integrated toxicology to complement other toxicology data, looking at where people live and what toxicants need to be focused on to protect the health of people in that area.

Indoor coal ash and school and social competency among children aged 6-14 years.

BACKGROUND: A child's ability to succeed in social interactions and in a school setting are important for their development and growth. Exposure to environmental pollutants has been associated with poorer school performance and fewer social interaction in children. Fly ash, a waste product generated when burning coal for energy, is comprised of small glass spheres with neurotoxic heavy metal(loid)s found to be risk factors for learning and social problems in school. OBJECTIVE: The purpose of this novel study was to assess the association of fly ash in children's homes with school and social competency. METHODS: We recruited children aged 6-14 years old from communities located within 10 miles of two coal-burning power plants. In homes of the participants, fly ash was collected on polycarbonate filters using personal modular impactors. We measured school competency and social competency using the validated Child Behavioral Checklist. Using Tobit and linear regression we investigated the relationship of indoor fly ash with school and social competency. RESULTS: Forty-three percent of children in the study had fly ash in their homes. In covariate-adjusted Tobit models, children with fly ash in their homes scored on average 2.63 (95% CI: -4.98, -0.28) points lower on the school competency scale than peers without ash in their homes. We did not observe that fly ash in homes was related with lower social competency. SIGNIFICANCE: Results from this study suggest that children with fly ash in their homes had poorer performance in the school setting, compared to peers without fly ash in their homes. In the US, coal-fired power plants are being closed, however health concerns about pollution from coal ash storage facilities remains. Findings from this study can provide impetus for creating of public health policy and to highlight the need future research on children's exposure to fly ash. IMPACT: Children's growth and development are impacted by their social interactions and ability to perform in school settings. Environmental pollutants may impact these essential elements of development. Millions of children are exposed to fly ash which is a waste product generated from burning coal. Fly ash, an environmental health threat throughout the world, is comprised of small glass spheres with trace concentrations of neurotoxic metal(loid)s. Findings from this research show that children with fly ash in their homes are significantly more likely to have poorer school performance than children without fly ash in their homes.

Impact of Common Reflecting and Absorbing Building Materials on THz Multipath Channels.

THz band communication has the potential to meet the high data rate demands of many current and future applications. However, before these networks are realized, extensive channel measurements are needed in order to characterize the wireless channel at these frequencies, in order to inform system design and deployment. In the current paper, we present a set of double-directional channel measurements that are conducted in several relevant indoor and outdoor scenarios. Our aim is to see the effect of common building materials that might be particularly reflective or absorptive (such as energy-saving glass, window blinds, or metallic reflectors), and how their presence changes the channel characteristics. Among other effects we find that - depending on the considered dynamic range - presence/absence of these materials can increase the required equalizer length by an order of magnitude.

Exposure to coal ash and depression in children aged 6-14 years old.

BACKGROUND: When coal is burned for energy, coal ash, a hazardous waste product, is generated. Throughout the world, over 1 billion tons of coal ash is produced yearly. In the United States, over 78 million tons of coal ash was produced in 2019. Fly ash, the main component of coal ash contains neurotoxic metal (loid)s that may affect children's neurodevelopment and mental health. The objective of this study was to investigate the association between fly ash and depressive problems in children aged 6-14 years old. METHODS: Children and their parents/guardians were recruited from 2015 to 2020. Tobit regression and logistic regression were used to assess the association between coal fly ash and depressive problems. To determine fly ash presence, Scanning Electron Microscopy was conducted on polycarbonate filters containing PM10 from the homes of the study participants. Depressive problems in children were measured using the Depressive Problems DSM and withdrawn/depressed syndromic problem scales of the Child Behavior Checklist. RESULTS: In covariate-adjusted Tobit regression models, children with fly ash on the filter had higher scores on the DSM Depressive Problems (3.13 points; 95% CI = 0.39, 5.88) compared with children who did not have fly ash on the filter. Logistic regression supported these findings. CONCLUSION: Coal ash is one of the largest waste streams in the U.S, but it is not classified as a hazardous waste by the Environmental Protection Agency. To our knowledge, no studies have assessed the impact of coal ash on children's mental health. This study highlights the need for further research into the effects of coal ash exposure on children's mental health, and improved regulations on release and storage of coal ash.

Use of fetal tele-echo at small regional hospitals increases the rate of prenatal diagnosis of congenital heart disease.

BACKGROUND: To improve the rate of prenatal diagnosis of Congenital heart disease (CHD) in Kentucky, four fetal tele-echocardiography sites were established at regional hospitals in Kentucky: Ashland in 2011, Paducah in 2014, Lexington in 2014, and Owensboro in 2016. METHODS: A 13-year retrospective review of medical records at Norton Children's Hospital was performed to identify patients with CHD who had cardiac surgery or intervention prior to one year of age. The rate of prenatal diagnosis prior to establishing any fetal tele-echocardiography sites was compared to the rate of prenatal diagnosis after the sites were established. Independent t-tests were used to determine if there was a statistically significant increase in the rate of prenatal diagnosis. RESULTS: 1287 patients had cardiac surgery or cath lab intervention prior to one year of age at our institution from June 2005 to December 2018 and were included in the analysis. Seventeen patients were excluded due to incomplete medical records. The rate of prenatal diagnosis prior to the implementation of the first fetal tele-echocardiography site was 13.8% and after the sites were established, the prenatal diagnosis rate was 39.7% (p < 0.01). CONCLUSION: Increasing the number of fetal tele-echocardiography sites at small regional hospitals in Kentucky was associated with a statistically significant increase in the rate of prenatal diagnosis for patients less than 1 year of age who had cardiac surgery or cath lab intervention at Norton Children's Hospital in Louisville. Fetal tele-echocardiography is an effective method to improve the rate of prenatal diagnosis in regions served by small regional hospitals with limited access to fetal echocardiography.

Proximity to coal-fired power plants and neurobehavioral symptoms in children.

BACKGROUND: Coal-fired power plants are a major source of air pollution that can impact children's health. Limited research has explored if proximity to coal-fired power plants contributes to children's neurobehavioral disorders. OBJECTIVE: This community-based study collected primary data to investigate the relationships of residential proximity to power plants and neurobehavioral problems in children. METHODS: 235 participants aged 6-14 years who lived within 10 miles of two power plants were recruited. Exposure to particulate matter ≤10 µm (PM10) was measured in children's homes using personal modular impactors. Neurobehavioral symptoms were assessed using the Child Behavior Checklist (CBCL). Multiple regression models were performed to test the hypothesized associations between proximity/exposure and neurobehavioral symptoms. Geospatial statistical methods were used to map the spatial patterns of exposure and neurobehavioral symptoms. RESULTS: A small proportion of the variations of neurobehavioral problems (social problems, affective problems, and anxiety problems) were explained by the regression models in which distance to power plants, traffic proximity, and neighborhood poverty was statistically associated with the neurobehavioral health outcomes. Statistically significant hot spots of participants who had elevated levels of attention deficit hyperactivity disorder, anxiety, and social problems were observed in the vicinity of the two power plants. SIGNIFICANCE: Results of this study suggest an adverse impact of proximity to power plants on children's neurobehavioral health. Although coal-fired power plants are being phased out in the US, health concern about exposure from coal ash storage facilities remains. Furthermore, other countries in the world are increasing coal use and generating millions of tons of pollutants and coal ash. Findings from this study can inform public health policies to reduce children's risk of neurobehavioral symptoms in relation to proximity to power plants.

Heavy Metal(loid) Body Burden in Environmentally Exposed Children With and Without Internalizing Behavior Problems.

The prevalence of internalizing behavior disorders in children is increasing. Reasons for increasing anxiety and depression include several factors with a less studied consideration being the potential neurotoxic effects of environmental exposures. One group at risk for environmental exposures is children living near coal-burning power plants with coal ash storage facilities. Multivariate logistic regression was used to assess the relationship between metal(loid) exposures and internalizing behaviors in children aged 6-14 years. Metal(loid)s in nail samples were determined by Proton-Induced X-ray Emission and internalizing behavior problems were obtained from the parent ratings on the Child Behavior Checklist. Results indicated that concentrations of metal(loid)s in nails differ between children with internalizing behaviors and without internalizing behaviors. Logistic regression models suggested that exposure to zinc and imputed zirconium were associated with internalizing behaviors in children. However, when a sex-metal(loid) interaction term was included, none of the metal(loid)s were associated with internalizing behaviors indicating a role of sex differences in neurotoxicity with zinc and copper showing effects only for males. In all models, greater exposure to traffic was associated with internalizing behaviors. Zinc has previously been shown to increase risk for mental health problems, while zirconium has received less attention. Out findings indicate that environmental exposures of zinc and zirconium deserve further attention in studies of childhood internalizing disorders.

Manganese body burden in children is associated with reduced visual motor and attention skills.

Manganese (Mn) is an essential element, however, children with moderate to high Mn exposure can exhibit neurobehavioral impairments. One way Mn appears to affect brain function is through altering dopaminergic systems involved with motor and cognitive control including frontal - striatal brain systems. Based on the risk for motor and attention problems, we evaluated neurobehavioral function in 255 children at risk for Mn exposure due to living in proximity to coal ash storage sites. Proton Induced X-ray Emissions (PIXE) analysis was conducted on finger and toenails samples. Multiple neuropsychological tests were completed with the children. Fifty-five children had Mn concentrations above the limit of detection (LOD) (median concentration = 3.95 ppm). Children with detectable Mn concentrations had reduced visual motor skills (ß = -5.62, CI: -9.11, -2.12, p = 0.008) and more problems with sustained attention, based on incorrect responses on a computerized attention test, (ß = 0.40, CI: 0.21, 0.59, p < 0.001) compared with children who had Mn concentrations below the LOD. Findings suggest that Mn exposure impacts attention and motor control possibly due to neurotoxicity involving basal ganglia and forebrain regions. Visual-motor and attention tests may provide a sensitive measure of Mn neurotoxicity, useful for evaluating the effects of exposure in children and leading to better treatment options.

Nail Samples of Children Living near Coal Ash Storage Facilities Suggest Fly Ash Exposure and Elevated Concentrations of Metal(loid)s.

Children who live near coal-fired power plants are exposed to coal fly ash, which is stored in landfills and surface impoundments near residential communities. Fly ash has the potential to be released as fugitive dust. Using data collected from 263 children living within 10 miles of coal ash storage facilities in Jefferson and Bullitt Counties, Kentucky, USA, we quantified the elements found in nail samples. Furthermore, using principal component analysis (PCA), we investigated whether metal(loid)s that are predominately found in fly ash loaded together to indicate potential exposure to fly ash. Concentrations of several neurotoxic metal(loid)s, such as chromium, manganese, and zinc, were higher than concentrations reported in other studies of both healthy and environmentally exposed children. From PCA, it was determined that iron, aluminum, and silicon in fly ash were found to load together in the nails of children living near coal ash storage facilities. These metal(loid)s were also highly correlated with each other. Last, results of geospatial analyses partially validated our hypothesis that children's proximity to power plants was associated with elevated levels of concentrations of fly ash metal(loid)s in nails. Taken together, nail samples may be a powerful tool in detecting exposure to fly ash.

County-level demographic, social, economic, and lifestyle correlates of COVID-19 infection and death trajectories during the first wave of the pandemic in the United States.

BACKGROUND: The US COVID-19 epidemic impacted counties differently across space and time, though large-scale transmission dynamics are unclear. The study's objective was to group counties with similar trajectories of COVID-19 cases and deaths and identify county-level correlates of the distinct trajectory groups. METHODS: Daily COVID-19 cases and deaths were obtained from 3141 US counties from January through June 2020. Clusters of epidemic curve trajectories of COVID-19 cases and deaths per 100,000 people were identified with Proc Traj. We utilized polytomous logistic regression to estimate Odds Ratios for trajectory group membership in relation to county-level demographics, socioeconomic factors, school enrollment, employment and lifestyle data. RESULTS: Six COVID-19 case trajectory groups and five death trajectory groups were identified. Younger counties, counties with a greater proportion of females, Black and Hispanic populations, and greater employment in private sectors had higher odds of being in worse case and death trajectories. Percentage of counties enrolled in grades 1-8 was associated with earlier-start case trajectories. Counties with more educated adult populations had lower odds of being in worse case trajectories but were generally not associated with worse death trajectories. Counties with higher poverty rates, higher uninsured, and more living in non-family households had lower odds of being in worse case and death trajectories. Counties with higher smoking rates had higher odds of being in worse death trajectory counties. DISCUSSION: In the absence of clear guidelines and personal protection, smoking, racial and ethnic groups, younger populations, social, and economic factors were correlated with worse COVID-19 epidemics that may reflect population transmission dynamics during January-June 2020. After vaccination of high-risk individuals, communities with higher proportions of youth, communities of color, smokers, and workers in healthcare, service and goods industries can reduce viral spread by targeting vaccination programs to these populations and increasing access and education on non-pharmaceutical interventions.

Protocol for measuring indoor exposure to coal fly ash and heavy metals, and neurobehavioural symptoms in children aged 6 to 14 years old.

INTRODUCTION: Fly ash is a waste product generated from burning coal for electricity. It is comprised of spherical particles ranging in size from 0.1 µm to over 100 µm in diameter that contain trace levels of heavy metals. Large countries such as China and India generate over 100 million tons per year while smaller countries like Italy and France generate 2 to 3 million tons per year. The USA generates over 36 million tons of ash, making it one of the largest industrial waste streams in the nation. Fly ash is stored in landfills and surface impoundments exposing communities to fugitive dust and heavy metals that leach into the groundwater. Limited information exists on the health impact of exposure to fly ash. This protocol represents the first research to assess children's exposure to coal fly ash and neurobehavioural outcomes. METHODS: We measure indoor exposure to fly ash and heavy metals, and neurobehavioural symptoms in children aged 6 to 14 years old. Using air pollution samplers and lift tape samples, we collect particulate matter ≤10 µm that is analysed for fly ash and heavy metals. Toenails and fingernails are collected to assess body burden for 72 chemical elements. Using the Behavioural Assessment and Research System and the Child Behaviour Checklist, we collect information on neurobehavioural outcomes. Data collection began in September 2015 and will continue until February 2021. ETHICS AND DISSEMINATION: This study was approved by the Institutional Review Boards of the University of Louisville (#14.1069) and the University of Alabama at Birmingham (#300003807). We have collected data from 267 children who live within 10 miles of two power plants. Children are at a greater risk for environmental exposure which justifies the rationale for this study. Results of this study will be distributed at conferences, in peer-reviewed journals and to the participants of the study.

Spatial Disparities in Coronavirus Incidence and Mortality in the United States: An Ecological Analysis as of May 2020.

PURPOSE: This ecological analysis investigates the spatial patterns of the COVID-19 epidemic in the United States in relation to socioeconomic variables that characterize US counties. METHODS: Data on confirmed cases and deaths from COVID-19 for 2,814 US counties were obtained from Johns Hopkins University. We used Geographic Information Systems (GIS) to map the spatial aspects of this pandemic and investigate the disparities between metropolitan and nonmetropolitan communities. Multiple regression models were used to explore the contextual risk factors of infections and death across US counties. We included population density, percent of population aged 65+, percent population in poverty, percent minority population, and percent of the uninsured as independent variables. A state-level measure of the percent of the population that has been tested for COVID-19 was used to control for the impact of testing. FINDINGS: The impact of COVID-19 in the United States has been extremely uneven. Although densely populated large cities and their surrounding metropolitan areas are hotspots of the pandemic, it is counterintuitive that incidence and mortality rates in some small cities and nonmetropolitan counties approximate those in epicenters such as New York City. Regression analyses support the hypotheses of positive correlations between COVID-19 incidence and mortality rates and socioeconomic factors including population density, proportions of elderly residents, poverty, and percent population tested. CONCLUSIONS: Knowledge about the spatial aspects of the COVID-19 epidemic and its socioeconomic correlates can inform first responders and government efforts. Directives for social distancing and to "shelter-in-place" should continue to stem the spread of COVID-19.

Biomechanics during cross-body lunging in individuals with and without painful cam and/or pincer morphology.

BACKGROUND: Femoroacetabular impingement is a patho-mechanical hip condition that can lead to restrictions in hip motion, particularly in end-range hip flexion, adduction and/or internal rotation. Radiographic evidence of femoroacetabular impingement - cam and/or pincer morphology - is prevalent in the general and athletic populations. There is, however, a lack of studies that have analyzed the performance of sport-specific movements in people possessing these morphologies. Therefore, the purpose of this study was to compare cross-body lunge biomechanics between individuals with and without painful cam and/or pincer morphology. METHODS: This was an exploratory, cross-sectional study where nine participants with cam and/or pincer morphology and symptoms, thirteen participants with asymptomatic cam and/or pincer morphology, and eleven pain-free controls performed the cross-body lunge during a single session. Trunk, pelvis, hip, knee and ankle kinematics, as well as hip, knee and ankle kinetics and vertical ground reaction forces were examined. FINDINGS: Overall, the groups performed the movement similarly, with most variables statistically similar between groups. However, pelvis sagittal plane excursion throughout the entire cross-body lunge was significantly larger in those with cam and/or pincer morphology and symptoms compared to those with asymptomatic cam and/or pincer morphology (P = .046, effect size = 0.98). INTERPRETATION: The results of this study show that cross-body lunge performance is similar across individuals with and without painful cam and/or pincer morphology. However, future research should aim to better understand pelvis biomechanics during sporting activities, as pelvis sagittal plane excursion may have important implications in rehabilitation and sport performance.

Prevalence of Femoroacetabular Impingement Syndrome among Young and Middle-aged White Adults.

OBJECTIVE: The purpose of the study was to determine the prevalence of femoroacetabular impingement syndrome (FAIS) in white adults 20 to 49 years of age. METHODS: Participants were white men and women aged 20-49 years, recruited through random digit dialing from the population of Metro Vancouver, British Columbia, Canada. Participants filled out a self-administered questionnaire and underwent a physical examination and radiographs of both hips. FAIS was defined as a combination of hip symptoms, physical signs of impingement, and radiological findings of cam or pincer morphology as recommended by the Warwick Agreement. All analyses were weighted to reflect the population from which the sample was drawn. RESULTS: Data were obtained for 500 participants. In the study population, 48.9% were males and the age distribution was 32.2%, 31.4%, and 36.4% in the groups 20-29, 30-39, and 40-49 years, respectively. The physical signs of impingement correlated significantly with symptoms, but there was no significant association between either symptoms or physical examination with radiographic findings. FAIS on either side was found in 3.0% (95% CI 1.5-4.5) of the population. CONCLUSION: In this study, FAIS was present in 3% of whites aged 20-49 years. Further research is needed to develop consistent criteria for assessing hip symptoms, physical signs, and hip joint morphology, and to better understand the relationships between them.

Biological intratumoral therapy for the high-grade glioma part II: vector- and cell-based therapies and radioimmunotherapy.

Management of high-grade gliomas (HGGs) remains a complex challenge with an overall poor prognosis despite aggressive multimodal treatment. New translational research has focused on maximizing tumor cell eradication through improved tumor cell targeting while minimizing collateral systemic side effects. In particular, biological intratumoral therapies have been the focus of novel translational research efforts due to their inherent potential to be both dynamically adaptive and target specific. This two part review will provide an overview of biological intratumoral therapies that have been evaluated in human clinical trials in HGGs, and summarize key advances and remaining challenges in the development of these therapies as a potential new paradigm in the management of HGGs. Part II discusses vector-based therapies, cell-based therapies and radioimmunotherapy.

Biological intratumoral therapy for the high-grade glioma part I: intratumoral delivery and immunotoxins.

Management of high-grade gliomas remains a complex challenge. Standard of care consists of microsurgical resection, chemotherapy and radiation, but despite these aggressive multimodality therapies the overall prognosis remains poor. A major focus of ongoing translational research studies is to develop novel therapeutic strategies that can maximize tumor cell eradication while minimizing collateral side effects. Particularly, biological intratumoral therapies have been the focus of new translational research efforts due to their inherent potential to be both dynamically adaptive and target specific. This two-part review will provide an overview of biological intratumoral therapies and summarize key advances and remaining challenges in intratumoral biological therapies for high-grade glioma. Part I focuses on discussion of the concepts of intratumoral delivery and immunotoxin therapies.

Relationship Between Hip Morphology and Hip-Related Patient-Reported Outcomes in Young and Middle-Aged Individuals: A Population-Based Study.

OBJECTIVE: Radiographic measurements of the alpha angle and the lateral center edge (LCE) angle in the hip joint are important for the diagnosis of femoroacetabular syndrome, a potential risk factor for hip osteoarthritis. Our objective was to determine whether these measurements are associated with hip-related patient-reported outcomes in young and middle-aged individuals. METHODS: A stratified random sample of white men and women ages 20-49 years, with and without hip pain, was selected using random digit dialing from the population of metro Vancouver, Canada. The alpha and LCE angles were measured bilaterally on radiographs using Dunn and anteroposterior views, respectively. Patient-reported outcomes were measured by the Copenhagen Hip And Groin Outcome Score (HAGOS), which has scales for symptoms, pain, daily activities, sports, physical activity, and quality of life (QoL). We performed descriptive analyses and a regression analysis with restricted cubic splines, adjusted for age and sex and weighted for the sampling design. RESULTS: Data were obtained for 500 subjects. The alpha angle distribution was strongly skewed, with a mean of 54°. The LCE angle distribution was symmetric, with a mean of 34°. In the restricted cubic splines analysis, the relationship between the alpha angle and HAGOS scores was nonlinear, with higher alpha angles generally associated with worse HAGOS scores for alpha >60°. The associations were statistically significant for symptoms, sports, and QoL. No association was found between the LCE angle and HAGOS scales. CONCLUSION: In a general population sample ages 20-49 years, we have found an association between the alpha angle and hip-related patient-reported outcomes.

Ovarian Cancer Incidence in the U.S. and Toxic Emissions from Pulp and Paper Plants: A Geospatial Analysis.

Ovarian cancer is the fifth leading cause of female cancer mortality in the U.S. and accounts for five percent of all cancer deaths among women. No environmental risk factors for ovarian cancer have been confirmed. We previously reported that ovarian cancer incidence rates at the state level were significantly correlated with the extent of pulp and paper manufacturing. We evaluated that association using county-level data and advanced geospatial methods. Specifically, we investigated the relationship of spatial patterns of ovarian cancer incidence rates with toxic emissions from pulp and paper facilities using data from the Environmental Protection Agency's Toxic Release Inventory (TRI). Geospatial analysis identified clusters of counties with high ovarian cancer incidence rates in south-central Iowa, Wisconsin, New York, Pennsylvania, Alabama, and Georgia. A bivariate local indicator of spatial autocorrelation (LISA) analysis confirmed that counties with high ovarian cancer rates were associated with counties with large numbers of pulp and paper mills. Regression analysis of state level data indicated a positive correlation between ovarian cancer and water pollutant emissions. A similar relationship was identified from the analysis of county-level data. These data support a possible role of water-borne pollutants from pulp and paper mills in the etiology of ovarian cancer.