Global diversity and balancing selection of 23 leading Plasmodium falciparum candidate vaccine antigens.

Investigation of the diversity of malaria parasite antigens can help prioritize and validate them as vaccine candidates and identify the most common variants for inclusion in vaccine formulations. Studies of vaccine candidates of the most virulent human malaria parasite, Plasmodium falciparum, have focused on a handful of well-known antigens, while several others have never been studied. Here we examine the global diversity and population structure of leading vaccine candidate antigens of P. falciparum using the MalariaGEN Pf3K (version 5.1) resource, comprising more than 2600 genomes from 15 malaria endemic countries. A stringent variant calling pipeline was used to extract high quality antigen gene 'haplotypes' from the global dataset and a new R-package named VaxPack was used to streamline population genetic analyses. In addition, a newly developed algorithm that enables spatial averaging of selection pressure on 3D protein structures was applied to the dataset. We analysed the genes encoding 23 leading and novel candidate malaria vaccine antigens including csp, trap, eba175, ama1, rh5, and CelTOS. Our analysis shows that current malaria vaccine formulations are based on rare haplotypes and thus may have limited efficacy against natural parasite populations. High levels of diversity with evidence of balancing selection was detected for most of the erythrocytic and pre-erythrocytic antigens. Measures of natural selection were then mapped to 3D protein structures to predict targets of functional antibodies. For some antigens, geographical variation in the intensity and distribution of these signals on the 3D structure suggests adaptation to different human host or mosquito vector populations. This study provides an essential framework for the diversity of P. falciparum antigens to be considered in the design of the next generation of malaria vaccines.

Investigation of a source model for a new electronic brachytherapy tandem by film measurement.

PURPOSE: To investigate the accuracy of a vendor-supplied source model for a new Xoft Axxent 0-degree titanium tandem by film measurement. METHODS: We measured the anisotropy factors at varying distances and angles from the tandem in water using radiochromic film (Gafchromic EBT3) and an Epson Perfection v750 desktop flatbed scanner (US Epson, Long Beach, CA). A 0-degree tandem was placed vertically in a water phantom. Four pieces of film, each at varying depths, were positioned orthogonal to the longitudinal axis of the tandem for azimuthal anisotropy measurements. Polar anisotropy measurements were taken with the film aligned parallel to the tandem. An absolute dose calibration for the film was verified with a PTW 34013 Soft X-Ray Chamber. The film measurements were analyzed using different color channels. The measured polar anisotropy for varying source positions was compared to the vendor's data. Azimuthal anisotropy was measured as a function of the radius and angle, and normalized to the mean value over all angles at the specified radius. RESULTS: The azimuthal anisotropy of the tandem and source was found to be consistent for different positions along the tandem's longitudinal axis and at varying distances from the tandem. Absolute dose using a calibrated parallel plate chamber showed agreement to within 2% of expected TPS values. The custom tandem, which has a thicker tip than the wall, was attenuating the 50 kV photons more than expected, at the angles where the photons had more wall material to traverse. This discrepancy was verified at different distances from the tandem and with different measurement techniques. As distance increased, anisotropy values had better agreement. CONCLUSIONS: We quantified the agreement between the measured and provided anisotropy factors for a new Xoft Axxent 0-degree titanium tandem. Radiochromic film response at low kV energy was also investigated. Our results showed that vendor-supplied TG-43 values were appropriate for clinical use at majority of the angles. A rigorous quality assurance method for new electronic brachytherapy sources and applicators, along with complete knowledge of all dosimetric measuring tools, should be implemented for all parts of the verification and commissioning process.

Opioid Epidemic in the United States: Empirical Trends, and A Literature Review of Social Determinants and Epidemiological, Pain Management, and Treatment Patterns.

OBJECTIVES: Dramatic increases in opioid and drug overdose mortality have occurred in the United States (US) over the past two decades. To address this national public health crisis and identify gaps in the literature, we analyzed recent empirical trends in US drug overdose mortality by key social determinants and conducted a selective review of the recent literature on the magnitude of the opioid crisis facing different racial/ethnic, socioeconomic, and rural-urban segments of the US population. METHODS: We used the 1999-2017 mortality data from the US National Vital Statistics System to analyze trends in drug overdose mortality by race/ethnicity, age, and geographic area. Log-linear regression was used to model mortality trends. Using various key words and their combinations, we searched PubMed and Google Scholar for select peer-reviewed journal articles and government reports published on the opioid epidemic between 2010 and 2018. RESULTS: Our original analysis and review indicate marked increases in drug overdose mortality overall and by race/ethnicity and geographic regions, with adolescents and young adults experiencing steep increases in mortality between 1999 and 2017. Our selective search yielded 405 articles, of which 39 publications were selected for detailed review. Suicide mortality from drug overdose among teens aged 12-19 increased consistently between 2009 and 2017, particularly among teen girls. The rise of efficient global supply chains has increased opioid prescription use and undoubtedly contributed to the opioid epidemic. Many other important contributing factors to the epidemic include lack of education and economic opportunities, poor working conditions, and low social capital in disadvantaged communities. CONCLUSIONS AND GLOBAL HEALTH IMPLICATIONS: Our analysis and review indicate substantial disparities in drug overdoses and related mortality, pain management, and treatment outcomes according to social determinants. Increases in drug overdoses and resultant mortality are not only unique to the US, but have also been observed in other industrialized countries. Healthcare systems, community leaders, and policymakers addressing the opioid epidemic should focus on upstream structural factors including education, economic opportunity, social cohesion, racial/ethnic disadvantage, geographic isolation, and life satisfaction.

High resolution magnetic field measurements in hydrogen and helium plasmas using active laser spectroscopy.

Passive spectroscopic measurements of Zeeman splitting have been used reliably to measure magnetic fields in plasmas for decades. However, a requirement is that the field magnitude must be sufficiently strong to be resolved over Doppler and instrument broadening (typically >10 000 G). A diagnostic for measuring magnetic fields spectroscopically well below this limit (>20 G) with high sensitivity has been developed at the Oak Ridge National Laboratory. The diagnostic relies on measuring a high resolution spectral profile using Doppler-free saturation spectroscopy (DFSS) and then fitting the spectrum to a quantum mechanical model. DFSS is an active, laser based technique that greatly reduces the influence of Doppler broadening and eliminates instrument broadening. To date, the diagnostic has been successfully employed to measure the magnetic field in magnetized (550-900 G), low-temperature (5-10 eV), low-density (1010-1012 cm-3), hydrogen and helium plasmas in the 5-200 mTorr pressure range using a low power (25 mW) diode laser. Implementing an approximate crossover resonance model, the measurements are shown to be accurate within 5 G for helium and 83 G for hydrogen. The accuracy in hydrogen can be improved to 39 G if the crossover resonances are neglected. A more robust crossover model can decrease this error to <1 G.

Social Determinants of Health in the United States: Addressing Major Health Inequality Trends for the Nation, 1935-2016.

OBJECTIVES: This study describes key population health concepts and examines major empirical trends in US health and healthcare inequalities from 1935 to 2016 according to important social determinants such as race/ethnicity, education, income, poverty, area deprivation, unemployment, housing, rural-urban residence, and geographic location. METHODS: Long-term trend data from the National Vital Statistics System, National Health Interview Survey, National Survey of Children's Health, American Community Survey, and Behavioral Risk Factor Surveillance System were used to examine racial/ethnic, socioeconomic, rural-urban, and geographic inequalities in health and health care. Life tables, age-adjusted rates, prevalence, and risk ratios were used to examine health differentials, which were tested for statistical significance at the 0.05 level. RESULTS: Life expectancy of Americans increased from 69.7 years in 1950 to 78.8 years in 2015. However, despite the overall improvement, substantial gender and racial/ethnic disparities remained. In 2015, life expectancy was highest for Asian/Pacific Islanders (87.7 years) and lowest for African-Americans (75.7 years). Life expectancy was lower in rural areas and varied from 74.5 years for men in rural areas to 82.4 years for women in large metro areas, with rural-urban disparities increasing during the 1990-2014 time period. Infant mortality rates declined dramatically during the past eight decades. However, racial disparities widened over time; in 2015, black infants had 2.3 times higher mortality than white infants (11.4 vs. 4.9 per 1,000 live births). Infant and child mortality was markedly higher in rural areas and poor communities. Black infants and children in poor, rural communities had nearly three times higher mortality rate compared to those in affluent, rural areas. Racial/ethnic, socioeconomic, and geographic disparities were particularly marked in mortality and/or morbidity from cardiovascular disease, cancer, diabetes, COPD, HIV/AIDS, homicide, psychological distress, hypertension, smoking, obesity, and access to quality health care. CONCLUSIONS AND GLOBAL HEALTH IMPLICATIONS: Despite the overall health improvement, significant social disparities remain in a number of health indicators, most notably in life expectancy and infant mortality. Marked disparities in various health outcomes indicate the underlying significance of social determinants in disease prevention and health promotion and necessitate systematic and continued monitoring of health inequalities according to social factors. A multi-sectoral approach is needed to tackle persistent and widening health inequalities among Americans.

Clinical, molecular, and cellular features of non-Puerto Rican Hermansky-Pudlak syndrome patients of Hispanic descent.

Hermansky-Pudlak syndrome (HPS) is an autosomal recessive condition characterized by a bleeding diathesis and hypopigmentation of the skin, hair, and eyes. Some HPS patients develop other complications such as granulomatous colitis and/or fatal pulmonary fibrosis. Eight genes have been associated with this condition, resulting in subtypes HPS-1 through HPS-8. The HPS gene products are involved in the biogenesis of specialized lysosome-related organelles such as melanosomes and platelet delta granules. HPS1 and HPS4 form a stable complex named biogenesis of lysosome-related organelles complex (BLOC)-3, and patients with BLOC-3 or AP-3 deficiency develop pulmonary fibrosis. Therefore, it is important to subtype each HPS patient. HPS type 1 (HPS-1) occurs frequently on the island of Puerto Rico because of a founder mutation. Here, we describe seven mutations, six of which, to our knowledge, are previously unreported in the HPS1, HPS4, and HPS5 genes among patients of Mexican, Uruguayan, Honduran, Cuban, Venezuelan, and Salvadoran ancestries. Our findings demonstrate that the diagnosis of HPS should be considered in Hispanic patients with oculocutaneous albinism and bleeding symptoms. Moreover, such patients should not be assumed to have the HPS-1 subtype typical of northwest Puerto Rican patients. We recommend molecular HPS subtyping in such cases, as it may have significant implications for prognosis and intervention.