Rare germline deleterious variants increase susceptibility for lung cancer.

Although multiple common susceptibility loci for lung cancer (LC) have been identified by genome-wide association studies, they can explain only a small portion of heritability. The etiological contribution of rare deleterious variants (RDVs) to LC risk is not fully characterized and may account for part of the missing heritability. Here, we sequenced the whole exomes of 2777 participants from the Environment and Genetics in Lung cancer Etiology study, a homogenous population including 1461 LC cases and 1316 controls. In single-variant analyses, we identified a new RDV, rs77187983 [EHBP1, odds ratio (OR) = 3.13, 95% confidence interval (CI) = 1.34-7.30, P = 0.008] and replicated two previously reported RDVs, rs11571833 (BRCA2, OR = 2.18; 95% CI = 1.25-3.81, P = 0.006) and rs752672077 (MPZL2, OR = 3.70, 95% CI = 1.04-13.15, P = 0.044). In gene-based analyses, we confirmed BRCA2 (P = 0.007) and ATM (P = 0.014) associations with LC risk and identified TRIB3 (P = 0.009), involved in maintaining genome stability and DNA repair, as a new candidate susceptibility gene. Furthermore, cases were enriched with RDVs in homologous recombination repair [carrier frequency (CF) = 22.9% versus 19.5%, P = 0.017] and Fanconi anemia (CF = 12.5% versus 10.2%, P = 0.036) pathways. Our results were not significant after multiple testing corrections but were enriched in cases versus controls from large scale public biobank resources, including The Cancer Genome Atlas, FinnGen and UK Biobank. Our study identifies novel candidate genes and highlights the importance of RDVs in DNA repair-related genes for LC susceptibility. These findings improve our understanding of LC heritability and may contribute to the development of risk stratification and prevention strategies.

Real-World Vehicle Emissions Characterization for the Shing Mun Tunnel in Hong Kong and Fort McHenry Tunnel in the United States.

INTRODUCTION: Motor vehicle exhaust is an important source of air pollutants and greenhouse gases. Concerns over the health and climate effects of mobile-source emissions have prompted worldwide efforts to reduce vehicle emissions. Implementation of more stringent emission standards have driven advances in vehicle, engine, and exhaust after-treatment technologies as well as fuel formulations. On the other hand, vehicle numbers and travel distances have been increasing because of population and economic growth and changes in land use. These factors have resulted in changes to the amount and chemical composition of vehicle emissions.Roadway tunnel studies are a practical way to characterize real-world emissions from the on-road vehicle fleet in an environment isolated from other combustion pollution sources. Measurements in the same tunnel over time allow evaluation of vehicle emission changes and the effectiveness of emission reduction measures. Tunnel studies estimate the impacts of vehicle emissions on air quality and traffic-related exposures, generate source profile inputs for receptor-oriented source apportionment models, provide data to evaluate emission models, and serve as a baseline for future comparisons.The present study characterized motor vehicle emission factors and compositions in two roadway tunnels that were first studied over a decade ago. The specific aims were to (1) quantify current fleet air pollutant emission factors, (2) evaluate emission change over time, (3) establish source profiles for volatile organic compounds (VOCs) and particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5), (4) estimate contributions of fleet components and non-tailpipe emissions to VOCs and PM2.5, and (5) evaluate the performance of the latest versions of mobile-source emission models (i.e., the EMission FACtors vehicle emission model used in Hong Kong [EMFAC-HK] and the MOtor Vehicle Emission Simulator used in the United States [MOVES]). METHODS: Measurements were conducted in the Shing Mun Tunnel (SMT) in Hong Kong and the Fort McHenry Tunnel (FMT) in Baltimore, Maryland, in the United States, representing the different fleet compositions, emission controls, fuels, and near-road exposure levels found in Hong Kong and the United States. These tunnels have extensive databases acquired in 2003-2004 for the SMT and 1992 for the FMT. The SMT sampling was conducted during the period from 1/19/2015 to 3/31/2015, and the FMT sampling occurred during the periods from 2/8/2015 to 2/15/2015 (winter) and 7/31/2015 to 8/7/2015 (summer). Concentrations of criteria pollutants (e.g., carbon monoxide [CO], nitrogen oxides [NOx], and particulate matter [PM]) were measured in real time, and integrated samples of VOCs, carbonyls, polycyclic aromatic hydrocarbons (PAHs), and PM2.5 were collected in canisters and sampling media for off-line analyses. Emission factors were calculated from the tunnel measurements and compared with previous studies to evaluate emission changes over time. Emission contributions by different vehicle types were assessed by source apportionment modeling or linear regression. Vehicle emissions were modeled by EMFAC-HK version 3.3 and MOVES version 2014a for the SMT and the FMT, respectively, and compared with measured values. The influences of vehicle fleet composition and environmental parameters (i.e., temperature and relative humidity) on emissions were evaluated. RESULTS: In the SMT, emissions of PM2.5, sulfur dioxide (SO2), and total non-methane hydrocarbons (NMHCs) markedly decreased from 2003-2004 to 2015: SO2 and PM2.5 were reduced by ~80%, and total NMHCs was reduced by ~44%. Emission factors of ethene and propene, key tracers for diesel vehicle (DV) emissions, decreased by ~65%. These reductions demonstrate the effectiveness of control measures, such as the implementation of low-sulfur fuel regulations and the phasing out of older DVs. However, the emission factors of isobutane and n-butane, markers for liquefied petroleum gas (LPG), increased by 32% and 17% between 2003-2004 and 2015, respectively, because the number of LPG vehicles increased. Nitrogen dioxide (NO2) to NOx volume ratios increased between 2003-2004 and 2015, indicating an increased NO2 fraction in primary exhaust emissions. Although geological mineral concentrations were similar between the 2003-2004 and 2015 studies, the contribution of geological materials to PM2.5 increased from 2% in 2003-2004 to 5% in 2015, signifying the continuing importance of non-tailpipe PM emissions as tailpipe emissions decrease. Emissions of CO, ammonia (NH3), nitric oxide (NO), NO2, and NOx, as well as carbonyls and PAHs in the SMT did not show statistically significant (at P < 0.05 based on Student's t-test) decreases from 2003-2004 to 2015. The reason for this is not clear and requires further investigation.A steady decrease in emissions of all measured pollutants during the past 23 years has been observed from tunnel studies in the United States, reflecting the effect of emission standards and new technologies that were introduced during this period. Emission reductions were more pronounced for the light-duty (LD) fleet than for the heavy-duty (HD) fleet. In comparison with the 1992 FMT study, the 2015 FMT study demonstrated marked reductions in LD emissions for all pollutants: emission factors for naphthalene were reduced the most, by 98%; benzene, toluene, ethylbenzene, and xylene (BTEX), by 94%; CO, NMHCs, and NOx, by 87%; and aldehydes by about 71%. Smaller reductions were observed for HD emission factors: naphthalene emissions were reduced by 95%, carbonyl emissions decreased by about 75%, BTEX by 60%, and NOx 58%.The 2015 fleet-average emission factors were higher in the SMT for CO, NOx, and summer PM2.5 than those in the FMT. The higher CO emissions in the SMT were possibly attributable to a larger fraction of motorcycles and LPG vehicles in the Hong Kong fleet. DVs in Hong Kong and the United States had similar emission factors for NOx. However, the non-diesel vehicles (NDVs), particularly LPG vehicles, had higher emission factors than those of gasoline cars, contributing to higher NOx emissions in the SMT. The higher PM2.5 emission factors in the SMT were probably attributable to there being more double-deck buses in Hong Kong.In both tunnels, PAHs were predominantly in the gas phase, with larger (four and more aromatic rings) PAHs mostly in the particulate phase. Formaldehyde, acetaldehyde, crotonaldehyde, and acetone were the most abundant carbonyl compounds in the SMT. In the FMT, the most abundant carbonyls were formaldehyde, acetone, acetaldehyde, and propionaldehyde. HD vehicles emitted about threefold more carbonyl compounds than LD vehicles did. In the SMT, the NMHC species were enriched with marker species for LPG (e.g., n-butane, isobutane, and propane) and gasoline fuel vapor (e.g., toluene, isopentane, and m/p-xylene), indicating evaporative losses. Source contributions to SMT PM2.5 mass were diesel exhaust (51.5 ± 1.8%), gasoline exhaust (10.0 ± 0.8%), LPG exhaust (5.0 ± 0.5%), secondary sulfate (19.9 ± 1.0%), secondary nitrate (6.3 ± 0.9%), and road dust (7.3 ± 1.3%). In the FMT, total NMHC emissions were 14% and 8% higher in winter than in summer for LD and HD vehicles, respectively. Elemental carbon (EC) and organic carbon (OC) were the major constituents of tunnel PM2.5. De-icing salt contributions to PM2.5 were observed in the FMT in winter.Emission estimates by the EMFAC-HK agreed with SMT measurements for CO2; the modeled emission factors for CO, NOx, and NMHCs were 1.5, 1.6, and 2.2 times the measurements, respectively; and the modeled emission factor for PM2.5 was 61% of the measured value in 2003. The EMFAC-HK estimates and SMT measurements for 2015 differed by less than 35%. The MOVES2014a model generally overestimated emissions of most of the pollutants measured in the FMT. No pollutants were significantly underestimated. The largest overestimation was observed for emissions measured during HD-rich driving conditions in winter. CONCLUSIONS: Significant reductions in SO2 and PM2.5 emissions between 2003 and 2015 were observed in the SMT, indicating the effectiveness of control measures on these two pollutants. The total NMHC emissions in the SMT were reduced by 44%, although isobutane and n-butane emissions increased because of the increase in the size of the LPG fleet. No significant reductions were observed for CO and NOx, results that differed from those for roadside ambient concentrations, emission inventory estimates, and EMFAC-HK estimates. In contrast, there was a steady decrease in emissions of most pollutants in the tunnels in the United States.

In Vivo Biotransformation Rates of Organic Chemicals in Fish: Relationship with Bioconcentration and Biomagnification Factors.

In vivo dietary bioaccumulation experiments for 85 hydrophobic organic substances were conducted to derive the in vivo gastrointestinal biotransformation rates, somatic biotransformation rates, bioconcentration factors (BCF), and biomagnification factors (BMF) for improving methods for bioaccumulation assessment and to develop an in vivo biotransformation rate database for QSAR development and in vitro to in vivo biotransformation rate extrapolation. The capacity of chemicals to be biotransformed in fish was found to be highly dependent on the route of exposure. Somatic biotransformation was the dominant pathway for most chemicals absorbed via the respiratory route. Intestinal biotransformation was the dominant metabolic pathway for most chemicals absorbed via the diet. For substances not biotransformed or transformed exclusively in the body of the fish, the BCF and BMF appeared to be closely correlated. For substances subject to intestinal biotransformation, the same correlation did not apply. We conclude that intestinal biotransformation and bioavailability in water can modulate the relationship between the BCF and BMF. This study also supports a fairly simple rule of thumb that may be useful in the interpretation of dietary bioaccumulation tests; i.e., chemicals with a BMFL of <1 tend to exhibit BCFs based on either the freely dissolved (BCFWW,fd) or the total concentration (BCFWW,t) of the chemical in the water that is less than 5000.

Out-of-pocket spending on drugs and pharmaceutical products and cost-related prescription non-adherence among Canadians with chronic disease.

BACKGROUND: Approximately one-third of Canadians' prescription medication costs are paid directly out-of-pocket. This study attempts to determine if out-of-pocket spending greater than 5% of household income on drugs and pharmaceutical products is associated with cost-related prescription non-adherence among people with cardiovascular-related chronic conditions. DATA AND METHODS: The data are from the survey on Barriers to Care for People with Chronic Health Conditions. Three categories of out-of-pocket spending on drugs and pharmaceutical products as a percentage of household income were identified: 0%, more than 0% to less than 5%, and 5% or more. Log-binomial regression was used to investigate associations between category of out-of-pocket spending and cost-related non-adherence. RESULTS: In 2012, about 80% of people aged 40 or older who lived in British Columbia, Alberta, Saskatchewan or Manitoba and had cardiovascular-related chronic conditions reported out-of-pocket spending on drugs and pharmaceutical products; 4.8% reported out-of-pocket spending of at least 5% of their household income. These individuals were significantly older, more often lived in households with incomes less than $30,000, and more often reported multiple morbidities than did people whose out-of-pocket spending on drugs and pharmaceutical products was less than 5% of household income. When the results were adjusted for age and sex, people whose spending amounted to 5% or more of household income were almost three times as likely (prevalence rate ratio = 2.6) to report cost-related prescription non-adherence than were those spending less than 5%. INTERPRETATION: Spending at least 5% of household income on drugs and pharmaceutical products was significantly associated with cost-related prescription non-adherence. Additional data are required to determine if even lower levels of spending put individuals at risk of cost related non-adherence.

Confidence intervals for ranks of age-adjusted rates across states or counties.

Health indices provide information to the general public on the health condition of the community. They can also be used to inform the government's policy making, to evaluate the effect of a current policy or healthcare program, or for program planning and priority setting. It is a common practice that the health indices across different geographic units are ranked and the ranks are reported as fixed values. We argue that the ranks should be viewed as random and hence should be accompanied by an indication of precision (i.e., the confidence intervals). A technical difficulty in doing so is how to account for the dependence among the ranks in the construction of confidence intervals. In this paper, we propose a novel Monte Carlo method for constructing the individual and simultaneous confidence intervals of ranks for age-adjusted rates. The proposed method uses as input age-specific counts (of cases of disease or deaths) and their associated populations. We have further extended it to the case in which only the age-adjusted rates and confidence intervals are available. Finally, we demonstrate the proposed method to analyze US age-adjusted cancer incidence rates and mortality rates for cancer and other diseases by states and counties within a state using a website that will be publicly available. The results show that for rare or relatively rare disease (especially at the county level), ranks are essentially meaningless because of their large variability, while for more common disease in larger geographic units, ranks can be effectively utilized.

Impact of emissions from natural gas production facilities on ambient air quality in the Barnett Shale area: a pilot study.

Rapid and extensive development of shale gas resources in the Barnett Shale region of Texas in recent years has created concerns about potential environmental impacts on water and air quality. The purpose of this study was to provide a better understanding of the potential contributions of emissions from gas production operations to population exposure to air toxics in the Barnett Shale region. This goal was approached using a combination of chemical characterization of the volatile organic compound (VOC) emissions from active wells, saturation monitoring for gaseous and particulate pollutants in a residential community located near active gas/oil extraction and processing facilities, source apportionment of VOCs measured in the community using the Chemical Mass Balance (CMB) receptor model, and direct measurements of the pollutant gradient downwind of a gas well with high VOC emissions. Overall, the study results indicate that air quality impacts due to individual gas wells and compressor stations are not likely to be discernible beyond a distance of approximately 100 m in the downwind direction. However, source apportionment results indicate a significant contribution to regional VOCs from gas production sources, particularly for lower-molecular-weight alkanes (< C6). Although measured ambient VOC concentrations were well below health-based safe exposure levels, the existence of urban-level mean concentrations of benzene and other mobile source air toxics combined with soot to total carbon ratios that were high for an area with little residential or commercial development may be indicative of the impact of increased heavy-duty vehicle traffic related to gas production. Implications: Rapid and extensive development of shale gas resources in recent years has created concerns about potential environmental impacts on water and air quality. This study focused on directly measuring the ambient air pollutant levels occurring at residential properties located near natural gas extraction and processing facilities, and estimating the relative contributions from gas production and motor vehicle emissions to ambient VOC concentrations. Although only a small-scale case study, the results may be useful for guidance in planning future ambient air quality studies and human exposure estimates in areas of intensive shale gas production.

Assessing racial, ethnic, and nativity disparities in US cancer mortality using a new integrated platform.

BACKGROUND: Foreign-born populations in the United States have markedly increased, yet cancer trends remain unexplored. Survey-based Population-Adjusted Rate Calculator (SPARC) is a new tool for evaluating nativity differences in cancer mortality. METHODS: Using SPARC, we calculated 3-year (2016-2018) age-adjusted mortality rates and rate ratios for common cancers by sex, age group, race and ethnicity, and nativity. Trends by nativity were examined for the first time for 2006-2018. Traditional cancer statistics draw populations from decennial censuses. However, nativity-stratified populations are from the American Community Surveys, thus involve sampling errors. To rectify this, SPARC employed bias-corrected estimators. Death counts came from the National Vital Statistics System. RESULTS: Age-adjusted mortality rates were higher among US-born populations across nearly all cancer types, with the largest US-born, foreign-born difference observed in lung cancer among Black women (rate ratio = 3.67, 95% confidence interval [CI] = 3.37 to 4.00). The well-documented White-Black differences in breast cancer mortality existed mainly among US-born women. For all cancers combined, descending trends were more accelerated for US-born compared with foreign-born individuals in all race and ethnicity groups with changes ranging from -2.6% per year in US-born Black men to stable (statistically nonsignificant) among foreign-born Black women. Pancreas and liver cancers were exceptions with increasing, stable, or decreasing trends depending on nativity and race and ethnicity. Notably, foreign-born Black men and foreign-born Hispanic men did not show a favorable decline in colorectal cancer mortality. CONCLUSIONS: Although all groups show beneficial cancer mortality trends, those with higher rates in 2006 have experienced sharper declines. Persistent disparities between US-born and foreign-born individuals, especially among Black people, necessitate further investigation.

Evaluation of passive samplers as a cost-effective method to predict the impact of wildfire smoke in grapes and wines.

Wildfire smoke exposure alters grape composition, potentially resulting in "smoke tainted" wines. This has been correlated with elevated levels of smoke-derived volatile phenols (VPs) in grapes and wines. This work sought to create a predictive tool that could correlate levels of VPs in smoke with concentrations in grapes and wines. Therefore, passive samplers and Cabernet Sauvignon grapes were intentionally exposed to various smoke intensities, and wines were made thereafter. As expected, concentrations of VPs in grapes and wines were positively associated with the intensity of smoke exposure. Interestingly, levels of guaiacol in the passive samplers had a strong positive correlation with concentrations in grapes (R2 = 0.9999) and wines (R2 = 0.9998). The passive samplers were able to accurately predict guaiacol levels in smoke exposed grapes and wines with percent errors ranging from 0.08 to 11.3 %. These results suggest the capability of passive samplers to act as a monitoring system in vineyards during smoke events.

Healthcare Providers and Parents Highlight Challenges of Pediatric Hand Fracture Care.

Pediatric hand fractures are common, and many are referred to hand surgeons despite less than 10% of referrals requiring surgical intervention. We explored healthcare provider and parent perspectives to inform a new care pathway. Methods: We conducted a qualitative descriptive study using virtual focus groups. Emergency physicians, hand therapists, plastic surgeons, and parents of children treated for hand fractures were asked to discuss their experiences with existing care for pediatric hand fractures, and perceptions surrounding the implementation of a new care pathway. Data were analyzed using directed content analysis with an inductive approach. Results: Four focus groups included 24 participants: 18 healthcare providers and six parents. Four themes were identified: educating parents throughout the hand fracture journey, streamlining the referral process for simple hand fractures, identifying the most appropriate care provider for simple hand fractures, and maintaining strong multidisciplinary connections to facilitate care. Participants described gaps in the current care, including a need to better inform parents, and elucidated the motivations behind emergency medicine physicians' existing referral practices. Participants also generally agreed on the need for more efficient management of simple hand fractures that do not require surgical care. Healthcare providers believed the strong preexisting relationship between surgeons and hand therapists would facilitate the changes brought forward by the new care pathway. Conclusion: These findings highlighted shortcomings of existing care for pediatric hand fractures and will inform the co-development and implementation of a new care pathway to enable more efficient management while preserving good patient outcomes.

An integrated, directed mass spectrometric approach for in-depth characterization of complex peptide mixtures.

LC-MS/MS has emerged as the method of choice for the identification and quantification of protein sample mixtures. For very complex samples such as complete proteomes, the most commonly used LC-MS/MS method, data-dependent acquisition (DDA) precursor selection, is of limited utility. The limited scan speed of current mass spectrometers along with the highly redundant selection of the most intense precursor ions generates a bias in the pool of identified proteins toward those of higher abundance. A directed LC-MS/MS approach that alleviates the limitations of DDA precursor ion selection by decoupling peak detection and sequencing of selected precursor ions is presented. In the first stage of the strategy, all detectable peptide ion signals are extracted from high resolution LC-MS feature maps or aligned sets of feature maps. The selected features or a subset thereof are subsequently sequenced in sequential, non-redundant directed LC-MS/MS experiments, and the MS/MS data are mapped back to the original LC-MS feature map in a fully automated manner. The strategy, implemented on an LTQ-FT MS platform, allowed the specific sequencing of 2,000 features per analysis and enabled the identification of more than 1,600 phosphorylation sites using a single reversed phase separation dimension without the need for time-consuming prefractionation steps. Compared with conventional DDA LC-MS/MS experiments, a substantially higher number of peptides could be identified from a sample, and this increase was more pronounced for low intensity precursor ions.

Assessment of Oncology Practice Billing Claims for Supplementing Chemotherapy: A Pilot Study in the Georgia SEER Cancer Registry.

BACKGROUND: Chemotherapy information in the population-based cancer registries is underascertained and lacks detail. We conducted a pilot study in the Georgia SEER Cancer Registry (GCR) to investigate the feasibility of supplementing chemotherapy information using billing claims from six private oncology practices (OP). METHODS: To assess cancer patients' representativeness from OP, we compared individuals with invasive first primary cancers diagnosed during 2013-2015 in the GCR (cohort 1) with those who had at least one OP claim in the 12 months after diagnosis (cohort 2). To assess completeness of OP claims to capture chemotherapy (yes or no), we further restricted cohort 2 to patients ages 65 years and older enrolled in fee-for-service Medicare Part A and B from the diagnosis date through 12 months follow-up or to the date of death. With Medicare data serving as the gold standard, sensitivity, specificity, and kappa statistics for the receipt of chemotherapy per OP claims were calculated by demographic and clinical characteristics. RESULTS: Cancer patients seeking care in the OP included in our analysis were not representative of the underlying patient population in the GCR. The practices underrepresented minorities and uninsured while overrepresenting females, persons with high socioeconomic status, patients residing outside the metropolitan Atlanta area, and persons with advance staged disease. The ability of practice claims to identify chemotherapy receipt was moderate (76.1% sensitivity) but varied by demographic and clinical characteristics (76.1-83.0%). CONCLUSIONS: Given the limited ability of OP claims to identify chemotherapy receipt, we suggest analyzing these data for hypothesis generation, but inference should be limited to this patient cohort.

Dominant volatile organic compounds (VOCs) measured at four Cannabis growing facilities: Pilot study results.

In recent years, sale of recreational marijuana products has been permitted in several states and countries resulting in rapid growth of the commercial cannabis cultivation and processing industry. As previous research has shown, biogenic volatile organic compounds (BVOCs) emitted from plants can react with other urban air constituents (e.g., NOx, HO radical) and thus negatively affect regional air quality. In this pilot study, BVOC emissions from Cannabis plants were analyzed at four grow facilities. The concentrations of measured BVOCs inside the facilities were between 110 and 5,500 µg m-3. One adult Cannabis plant emits hundreds of micrograms of BVOCs per day and thus can trigger the formation of tropospheric ozone (approximately 2.6 g day-1 plant-1) and other toxic air pollutants. In addition, high concentrations of butane (1,080- 43,000 µg m-3), another reactive VOC, were observed at the facilities equipped with Cannabis oil extraction stations. Implications: High concentrations of VOCs emitted from Cannabis grow facilities can lead to the formation of ozone, secondary VOCs (e.g., formaldehyde and acrolein), and particulate matter. Our results highlight that further assessment of VOC emissions from Cannabis facilities is needed, and this assessment is one of the key factors for developing policies for optimal air pollution control.

Transcriptomes of human prostate cells.

BACKGROUND: The gene expression profiles of most human tissues have been studied by determining the transcriptome of whole tissue homogenates. Due to the solid composition of tissues it is difficult to study the transcriptomes of individual cell types that compose a tissue. To overcome the problem of heterogeneity we have developed a method to isolate individual cell types from whole tissue that are a source of RNA suitable for transcriptome profiling. RESULTS: Using monoclonal antibodies specific for basal (integrin beta4), luminal secretory (dipeptidyl peptidase IV), stromal fibromuscular (integrin alpha 1), and endothelial (PECAM-1) cells, respectively, we separated the cell types of the prostate with magnetic cell sorting (MACS). Gene expression of MACS-sorted cell populations was assessed with Affymetrix GeneChips. Analysis of the data provided insight into gene expression patterns at the level of individual cell populations in the prostate. CONCLUSION: In this study, we have determined the transcriptome profile of a solid tissue at the level of individual cell types. Our data will be useful for studying prostate development and cancer progression in the context of single cell populations within the organ.

Hybridization and introgression in two ecologically dissimilar Fundulus hybrid zones.

Hybridization and introgression appear more common in rapidly evolving groups, suggesting an important role in the evolutionary process. Detailed studies of how extrinsic or intrinsic forces regulate hybridization and introgression have the potential for broadening our understanding of mechanisms generating diversity. Species in the Fundulus notatus species complex have broad overlapping ranges and occur in replicated hybrid zones along predictable stream gradients. Typical hybrid zone structure has Fundulus olivaceus in headwaters, F. notatus downstream, and hybrid zones near confluences or abrupt shifts in habitat. Rarely, the typical upstream-downstream orientation is reversed raising questions as to how hybrid zones are formed and maintained. We used next-generation sequencing data to study hybridization and introgression in hybrid zones in neighboring drainages that differ in orientation (typical and reversed). We predicted extrinsic forces linked to stream gradients would result in noticeable differences between the two. Contrary to predictions, the data indicate the hybrid zones are remarkably similar. We used individual-based simulations to explore the potential role of intrinsic and extrinsic forces in generating and maintaining typical and reversed hybrid zones. Simulation results were consistent with reversed hybrid zones being formed from stochastic processes combined with strong intrinsic forces and weak extrinsic forces.

Assessment of the relationship between Contegra conduit size and early valvar insufficiency.

BACKGROUND: Contegra bovine jugular vein (BJV) conduit results vary widely, and little attention has been directed at assessment of early conduit insufficiency. Conduit insufficiency is graded subjectively, and criteria vary. Several studies have used branch pulmonary artery flow reversal (BPAFR) to define severe conduit insufficiency. BJV valves are larger than human pulmonary valves of similar diameter. We hypothesize that anatomic differences between BJV and human pulmonary valves limit the use of BPAFR in the evaluation of BJV competence. Our purposes were to (1) assess the prevalence of early and 6-month BJV conduit insufficiency in our patients, (2) determine if conduit size affects BJV competence, and (3) determine if BPAFR is a specific discriminator of severe conduit insufficiency. METHODS: We reviewed 135 BJV conduits. One cardiologist blinded to original reports reviewed postoperative and 6-month echocardiograms. Conduits were grouped by size: group 1, 12 to 14 mm (n=51), and group 2, 16 to 22 mm (n=84). Moderate or greater insufficiency was considered clinically significant. RESULTS: Early conduit insufficiency was common in group 1 (37%) and rare in group 2 (5%, p<0.0001). After excluding conduits with significant insufficiency, BPAFR occurred in 18% (group 1, 27%; group 2, 13%; p=0.02). At follow-up, insufficiency worsened in group 1 but was stable in group 2. CONCLUSIONS: Early conduit insufficiency is common and worsens with follow-up in small BJVs. Conduit insufficiency is limited in larger sizes and remains stable. BJV exhibits BPAFR commonly in the absence of significant conduit insufficiency. BPAFR should not be used as a primary criterion for grading insufficiency in BJV conduits.