Effects of Environmental Factors on Naturalistic Driving in Obstructive Sleep Apnea

Reduced visibility and other environmental factors can impair driver ability to respond to roadway hazards. We examined the effects of reduced visibility on naturalistic driving in 66 drivers, including 45 at-risk drivers with obstructive sleep apnea (OSA) and 21 controls. We analyzed three months of electronic data using “black box” recorder technology and assessed the extent to which driver speed, longitudinal acceleration, and lateral acceleration metrics depend on ambient visibility from web-based environmental data archives. We calculated summary driving metrics within 10-second intervals, and reduced these to within-subject means and tested for associations of interest. OSA drivers did not differ from controls with respect to electronic measures or visibility conditions in which they drove. On average, drivers drove slower when visibility was reduced. After controlling for speed, variations in lateral and longitudinal acceleration were positively associated with high-visibility conditions. These findings suggest that drivers exert greater vehicular control when visibility is limited, and that this association is not just due to slower speeds. Weaker relationships between visibility and driving measures in OSA suggest reduced adaptive strategies. Our methods provide a framework for analyzing the effects of other environmental factors on driving, and we provide an additional example using wind speed

Feedback from Naturalistic Driving Improves Treatment Compliance in Drivers with Obstructive Sleep Apnea

As part of a study in drivers with obstructive sleep apnea (OSA), we conducted a randomized clinical trial to assess whether individualized feedback can increase compliance with continuous positive airway pressure (CPAP) therapy. After completing 3.5 months of naturalistic driving monitoring, OSA drivers were randomized either to receive an intervention, which was feedback regarding their own naturalistic driving record and CPAP compliance, or to receive no such intervention. In the week immediately after the intervention date, drivers receiving feedback (n=30) improved their CPAP usage by an average of 35.8 minutes per night (p=0.008; 95% CI=9.6, 62.0) to a mean level of 296 minutes. By contrast, CPAP usage in the non-feedback group (n=36) decreased an average of 27.5 minutes per night (p=0.022; 95% CI=4.0, 51.0) to a mean level of 236 minutes. The mean group-specific changes were higher (better) in the feedback group than in the non-feedback group during the first, second, and third weeks of follow-up (p0.25 in all cases). Our study suggests that CPAP compliance can be increased using individualized feedback, but that follow-up feedback sessions or reminders may be necessary for sustained improvement

Linking GPS Data to GIS Databases in Naturalistic Studies: Examples from Drivers with Obstructive Sleep Apnea

In naturalistic studies, it is vital to give appropriate context when analyzing driving behaviors. Such contextualization can help address the hypotheses that explore a) how drivers perform within specific types of environment (e.g., road types, speed limits, etc.), and b) how often drivers are exposed to such specific environments. In order to perform this contextualization in an automated fashion, we are using Global Positioning System (GPS) data obtained at 1 Hz and merging this with Geographic Information Systems (GIS) databases maintained by the Iowa Department of Transportation (DOT). In this paper, we demonstrate our methods of doing this based on data from 43 drivers with obstructive sleep apnea (OSA). We also use maps from GIS software to illustrate how information can be displayed at the individual drive or day level, and we provide examples of some of the challenges that still need to be addressed

Triple-Negative Breast Cancer Risk Genes Identified by Multigene Hereditary Cancer Panel Testing

Background: Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor-negative, progesterone receptor-negative, human epidermal growth factor receptor-negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Methods: Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium(TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Results: Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. Conclusions: Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies.Peer reviewe

Adsorption of mono- and multivalent cat- and anions on DNA molecules

Adsorption of monovalent and multivalent cat- and anions on a deoxyribose nucleic acid (DNA) molecule from a salt solution is investigated by computer simulation. The ions are modelled as charged hard spheres, the DNA molecule as a point charge pattern following the double-helical phosphate strands. The geometrical shape of the DNA molecules is modelled on different levels ranging from a simple cylindrical shape to structured models which include the major and minor grooves between the phosphate strands. The densities of the ions adsorbed on the phosphate strands, in the major and in the minor grooves are calculated. First, we find that the adsorption pattern on the DNA surface depends strongly on its geometrical shape: counterions adsorb preferentially along the phosphate strands for a cylindrical model shape, but in the minor groove for a geometrically structured model. Second, we find that an addition of monovalent salt ions results in an increase of the charge density in the minor groove while the total charge density of ions adsorbed in the major groove stays unchanged. The adsorbed ion densities are highly structured along the minor groove while they are almost smeared along the major groove. Furthermore, for a fixed amount of added salt, the major groove cationic charge is independent on the counterion valency. For increasing salt concentration the major groove is neutralized while the total charge adsorbed in the minor groove is constant. DNA overcharging is detected for multivalent salt. Simulations for a larger ion radii, which mimic the effect of the ion hydration, indicate an increased adsorbtion of cations in the major groove.Comment: 34 pages with 14 figure

Unexpected Role for Helicobacter pylori DNA Polymerase I As a Source of Genetic Variability

Helicobacter pylori, a human pathogen infecting about half of the world population, is characterised by its large intraspecies variability. Its genome plasticity has been invoked as the basis for its high adaptation capacity. Consistent with its small genome, H. pylori possesses only two bona fide DNA polymerases, Pol I and the replicative Pol III, lacking homologues of translesion synthesis DNA polymerases. Bacterial DNA polymerases I are implicated both in normal DNA replication and in DNA repair. We report that H. pylori DNA Pol I 5′- 3′ exonuclease domain is essential for viability, probably through its involvement in DNA replication. We show here that, despite the fact that it also plays crucial roles in DNA repair, Pol I contributes to genomic instability. Indeed, strains defective in the DNA polymerase activity of the protein, although sensitive to genotoxic agents, display reduced mutation frequencies. Conversely, overexpression of Pol I leads to a hypermutator phenotype. Although the purified protein displays an intrinsic fidelity during replication of undamaged DNA, it lacks a proofreading activity, allowing it to efficiently elongate mismatched primers and perform mutagenic translesion synthesis. In agreement with this finding, we show that the spontaneous mutator phenotype of a strain deficient in the removal of oxidised pyrimidines from the genome is in part dependent on the presence of an active DNA Pol I. This study provides evidence for an unexpected role of DNA polymerase I in generating genomic plasticity

Hematopoietic prostaglandin D synthase (HPGDS): A high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer

Intestinal tumors in ApcMin/+ mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D2 (PGD2). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37 °C, the wild-type enzyme lost 15% of its activity in one hour, whereas the Val187Ile form remained >95% active. At 50 °C, the half life of native HPGDS was 9 minutes, compared to 42 minutes for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75–1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model

Triple-negative breast cancer risk genes identified by multigene hereditary cancer panel testing

Background Germline genetic testing with hereditary cancer gene panels can identify women at increased risk of breast cancer. However, those at increased risk of triple-negative (estrogen receptor–negative, progesterone receptor–negative, human epidermal growth factor receptor–negative) breast cancer (TNBC) cannot be identified because predisposition genes for TNBC, other than BRCA1, have not been established. The aim of this study was to define the cancer panel genes associated with increased risk of TNBC. Methods Multigene panel testing for 21 genes in 8753 TNBC patients was performed by a clinical testing laboratory, and testing for 17 genes in 2148 patients was conducted by a Triple Negative Breast Cancer Consortium (TNBCC) of research studies. Associations between deleterious mutations in cancer predisposition genes and TNBC were evaluated using results from TNBC patients and reference controls. Results Germline pathogenic variants in BARD1, BRCA1, BRCA2, PALB2, and RAD51D were associated with high risk (odds ratio > 5.0) of TNBC and greater than 20% lifetime risk for overall breast cancer among Caucasians. Pathogenic variants in BRIP1, RAD51C, and TP53 were associated with moderate risk (odds ratio > 2) of TNBC. Similar trends were observed for the African American population. Pathogenic variants in these TNBC genes were detected in 12.0% (3.7% non-BRCA1/2) of all participants. Conclusions Multigene hereditary cancer panel testing can identify women with elevated risk of TNBC due to mutations in BARD1, BRCA1, BRCA2, PALB2, and RAD51D. These women can potentially benefit from improved screening, risk management, and cancer prevention strategies. Patients with mutations may also benefit from specific targeted therapeutic strategies