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Background: Variants within factor VIII (F8) are associated with sex-linked hemophilia A and thrombosis, with gene therapy approaches being available for pathogenic variants. Many variants within F8 remain variants of uncertain significance (VUS) or are under-explored as to their connections to phenotypic outcomes. Methods: We assessed data on F8 expression while screening the UniProt, ClinVar, Geno2MP, and gnomAD databases for F8 missense variants; these collectively represent the sequencing of more than a million individuals. Results: For the two F8 isoforms coding for different protein lengths (2351 and 216 amino acids), we observed noncoding variants influencing expression which are also associated with thrombosis risk, with uncertainty as to differences in females and males. Variant analysis identified a severe stratification of potential annotation issues for missense variants in subjects of non-European ancestry, suggesting a need for further defining the genetics of diverse populations. Additionally, few heterozygous female carriers of known pathogenic variants have sufficiently confident phenotyping data, leaving researchers unable to determine subtle, less defined phenotypes. Using structure movement correlations to known pathogenic variants for the VUS, we determined seven clusters of likely pathogenic variants based on screening work. Conclusions: This work highlights the need to define missense variants, especially those for VUS and from subjects of non-European ancestry, as well as the roles of these variants in women’s physiology. 

Atmospheric electrical discharges are now known to generate unexpectedly large amounts of the atmosphere’s primary oxidant, hydroxyl (OH), in thunderstorm anvils, where electrical discharges are caused by atmospheric charge separation. The question is “Do other electrical discharges also generate large amounts of oxidants?” In this paper, we demonstrate that corona formed on grounded metal objects under thunderstorms produce extreme amounts of OH, hydroperoxyl (HO 2 ), and ozone (O 3 ). Hundreds of parts per trillion to parts per billion of OH and HO 2 were measured during seven thunderstorms that passed over the rooftop site during an air quality study in Houston, TX in summer 2006. A combination of analysis of these field results and laboratory experiments shows that these extreme oxidant amounts were generated by corona on the inlet of the OH-measuring instrument and that corona are easier to generate on lightning rods than on the inlet. In the laboratory, increasing the electric field increased OH, HO 2 , and O 3 , with 14 times more O 3 generated than OH and HO 2 , which were equal. Calculations show that corona on lightning rods can annually generate OH that is 10–100 times ambient amounts within centimeters of the lightning rod and on high-voltage electrical power lines can generate OH that is 500 times ambient a meter away from the corona. Contrary to current thinking, previously unrecognized corona-generated OH, not corona-generated UV radiation, mostly likely initiates premature degradation of high-voltage polymer insulators. 

Abstract Reaction with the hydroxyl radical (OH) is often the first step in the removal of many atmospheric pollutants. The nitrogen oxides (NO_x) generated by lightning can increase the amount of HO_x(HO_x = OH + HO₂) present in the atmosphere, but direct HO_xproduction from lightning has never been quantitatively investigated in the laboratory. In this laboratory study, prodigious amounts of HO_xwere generated by both visible and subvisible electrical discharges over ranges of pressure and water vapor mixing ratios relevant to the troposphere. Also measured were NO, total nitrogen oxides (NO_x), ozone (O₃), and OH exposure, which is the integral of the hydroxyl radical concentration over time since the discharge. HO_xand OH exposure were approximately independent of pressure from 360 to 970 hPa and increased only slightly as water vapor increased from 1,000 to 8,000 parts per million volume (ppmv), while NO_xwas approximately independent of both pressure and water vapor over the same ranges. These laboratory measurements of excessive HO_xand OH exposure are similar to measurements of electrically generated HO_xdiscovered in electrified anvil clouds during a 2012 airborne study, thus demonstrating the relevance of these laboratory results to the atmosphere and the importance of understanding the electrically generated HO_xcontribution to atmospheric oxidation.