Genomic characterization of cervical lymph node metastases in papillary thyroid carcinoma following the Chornobyl accident.

Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.

Polygenic risk scores, radiation treatment exposures and subsequent cancer risk in childhood cancer survivors.

Survivors of childhood cancer are at increased risk for subsequent cancers attributable to the late effects of radiotherapy and other treatment exposures; thus, further understanding of the impact of genetic predisposition on risk is needed. Combining genotype data for 11,220 5-year survivors from the Childhood Cancer Survivor Study and the St Jude Lifetime Cohort, we found that cancer-specific polygenic risk scores (PRSs) derived from general population, genome-wide association study, cancer loci identified survivors of European ancestry at increased risk of subsequent basal cell carcinoma (odds ratio per s.d. of the PRS: OR = 1.37, 95% confidence interval (CI) = 1.29-1.46), female breast cancer (OR = 1.42, 95% CI = 1.27-1.58), thyroid cancer (OR = 1.48, 95% CI = 1.31-1.67), squamous cell carcinoma (OR = 1.20, 95% CI = 1.00-1.44) and melanoma (OR = 1.60, 95% CI = 1.31-1.96); however, the association for colorectal cancer was not significant (OR = 1.19, 95% CI = 0.94-1.52). An investigation of joint associations between PRSs and radiotherapy found more than additive increased risks of basal cell carcinoma, and breast and thyroid cancers. For survivors with radiotherapy exposure, the cumulative incidence of subsequent cancer by age 50 years was increased for those with high versus low PRS. These findings suggest a degree of shared genetic etiology for these malignancy types in the general population and survivors, which remains evident in the context of strong radiotherapy-related risk.

Inflated expectations: Rare-variant association analysis using public controls.

The use of publicly available sequencing datasets as controls (hereafter, "public controls") in studies of rare variant disease associations has great promise but can increase the risk of false-positive discovery. The specific factors that could contribute to inflated distribution of test statistics have not been systematically examined. Here, we leveraged both public controls, gnomAD v2.1 and several datasets sequenced in our laboratory to systematically investigate factors that could contribute to the false-positive discovery, as measured by λΔ95, a measure to quantify the degree of inflation in statistical significance. Analyses of datasets in this investigation found that 1) the significantly inflated distribution of test statistics decreased substantially when the same variant caller and filtering pipelines were employed, 2) differences in library prep kits and sequencers did not affect the false-positive discovery rate and, 3) joint vs. separate variant-calling of cases and controls did not contribute to the inflation of test statistics. Currently available methods do not adequately adjust for the high false-positive discovery. These results, especially if replicated, emphasize the risks of using public controls for rare-variant association tests in which individual-level data and the computational pipeline are not readily accessible, which prevents the use of the same variant-calling and filtering pipelines on both cases and controls. A plausible solution exists with the emergence of cloud-based computing, which can make it possible to bring containerized analytical pipelines to the data (rather than the data to the pipeline) and could avert or minimize these issues. It is suggested that future reports account for this issue and provide this as a limitation in reporting new findings based on studies that cannot practically analyze all data on a single pipeline.

Detection parameters for managing invasive rats in urban environments.

Effective mitigation of the impacts of invasive ship rats (Rattus rattus) requires a good understanding of their ecology, but this knowledge is very sparse for urban and peri-urban areas. We radiomarked ship rats in Wellington, New Zealand, to estimate detection parameters (σ, ε0, θ, and g0) that describe the process of an animal encountering a device (bait stations, chew cards and WaxTags) from a distance, and then approaching it and deciding whether to interact with it. We used this information in simulation models to estimate optimal device spacing for eradicating ship rats from Wellington, and for confirming eradication. Mean σ was 25.37 m (SD = 11.63), which equates to a circular home range of 1.21 ha. The mean nightly probability of an individual encountering a device at its home range center (ε0) was 0.38 (SD = 0.11), whereas the probability of interacting with the encountered device (θ) was 0.34 (SD = 0.12). The derived mean nightly probability of an individual interacting with a device at its home range center (g0) was 0.13 (SD = 0.08). Importantly, σ and g0 are intrinsically linked through a negative relationship, thus g0 should be derived from σ using a predictive model including individual variability. Simulations using this approach showed that bait stations deployed for about 500 days using a 25 m × 25 m grid consistently achieved eradication, and that a surveillance network of 3.25 chew cards ha-1 or 3.75 WaxTags ha-1 active for 14 nights would be required to confidently declare eradication. This density could be halved if the surveillance network was deployed for 28 nights or if the prior confidence in eradication was high (0.85). These recommendations take no account of differences in detection parameters between habitats. Therefore, if surveillance suggests that individuals are not encountering devices in certain habitats, device density should be adaptively revised. This approach applies to initiatives globally that aim to optimise eradication with limited funding.

Invasive Urban Mammalian Predators: Distribution and Multi-Scale Habitat Selection.

A barrier to successful ecological restoration of urban green spaces in many cities is invasive mammalian predators. We determined the fine- and landscape-scale habitat characteristics associated with the presence of five urban predators (black and brown rats, European hedgehogs, house mice, and brushtail possums) in three New Zealand cities, in spring and autumn, in three green space types: forest fragments, amenity parks, and residential gardens. Season contributed to variations in detections for all five taxa. Rodents were detected least in residential gardens; mice were detected more often in amenity parks. Hedgehogs were detected least in forest fragments. Possums were detected most often in forest fragments and least often in residential gardens. Some of this variation was explained by our models. Proximity of amenity parks to forest patches was strongly associated with presence of possums (positively), hedgehogs (positively), and rats (negatively). Conversely, proximity of residential gardens to forest patches was positively associated with rat presence. Rats were associated with shrub and lower canopy cover and mice with herb layer cover. In residential gardens, rat detection was associated with compost heaps. Successful restoration of biodiversity in these cities needs extensive, coordinated predator control programmes that engage urban residents.

Extreme Precipitation and Flooding Contribute to Sudden Vegetation Dieback in a Coastal Salt Marsh.

Climate extremes are becoming more frequent with global climate change and have the potential to cause major ecological regime shifts. Along the northern Gulf of Mexico, a coastal wetland in Texas suffered sudden vegetation dieback following an extreme precipitation and flooding event associated with Hurricane Harvey in 2017. Historical salt marsh dieback events have been linked to climate extremes, such as extreme drought. However, to our knowledge, this is the first example of extreme precipitation and flooding leading to mass mortality of the salt marsh foundation species, Spartina alterniflora. Here, we investigated the relationships between baseline climate conditions, extreme climate conditions, and large-scale plant mortality to provide an indicator of ecosystem vulnerability to extreme precipitation events. We identified plant zonal boundaries along an elevation gradient with plant species tolerant of hypersaline conditions, including succulents and graminoids, at higher elevations, and flood-tolerant species, including S. alterniflora, at lower elevations. We quantified a flooding threshold for wetland collapse under baseline conditions characterized by incremental increases in flooding (i.e., sea level rise). We proposed that the sudden widespread dieback of S. alterniflora following Hurricane Harvey was the result of extreme precipitation and flooding that exceeded this threshold for S. alterniflora survival. Indeed, S. alterniflora dieback occurred at elevations above the wetland collapse threshold, illustrating a heightened vulnerability to flooding that could not be predicted from baseline climate conditions. Moreover, the spatial pattern of vegetation dieback indicated that underlying stressors may have also increased susceptibility to dieback in some S. alterniflora marshes.Collectively, our results highlight a new mechanism of sudden vegetation dieback in S. alterniflora marshes that is triggered by extreme precipitation and flooding. Furthermore, this work emphasizes the importance of considering interactions between multiple abiotic and biotic stressors that can lead to shifts in tolerance thresholds and incorporating climate extremes into climate vulnerability assessments to accurately characterize future climate threats.

Frequency of Pathogenic Germline Variants in Cancer-Susceptibility Genes in the Childhood Cancer Survivor Study.

Background: Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study. Methods: Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons. Results: Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers. Conclusion: In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.

Radiation-related genomic profile of papillary thyroid carcinoma after the Chernobyl accident.

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid carcinoma (PTC) incidence in surrounding regions, particularly for radioactive iodine (131I)-exposed children. We analyzed genomic, transcriptomic, and epigenomic characteristics of 440 PTCs from Ukraine (from 359 individuals with estimated childhood 131I exposure and 81 unexposed children born after 1986). PTCs displayed radiation dose-dependent enrichment of fusion drivers, nearly all in the mitogen-activated protein kinase pathway, and increases in small deletions and simple/balanced structural variants that were clonal and bore hallmarks of nonhomologous end-joining repair. Radiation-related genomic alterations were more pronounced for individuals who were younger at exposure. Transcriptomic and epigenomic features were strongly associated with driver events but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth after environmental radiation exposure.

In-utero exposure to zidovudine-containing antiretroviral therapy and clonal hematopoiesis in HIV-exposed uninfected newborns.

OBJECTIVE: Zidovudine (ZDV) has been extensively used in pregnant women to prevent vertical transmission of HIV but few studies have evaluated potential mutagenic effects of ZDV during fetal development. DESIGN: Our study investigated clonal hematopoiesis in HIV-exposed uninfected (HEU) newborns, 94 of whom were ZDV-exposed and 91 antiretroviral therapy (ART)-unexposed and matched for potential confounding factors. METHODS: Utilizing high depth sequencing and genotyping arrays, we comprehensively examined blood samples collected during the first week after birth for potential clonal hematopoiesis associated with fetal ZDV exposure, including clonal single nucleotide variants (SNVs), small insertions and deletions (indels), and large structural copy number or copy neutral alterations. RESULTS: We observed no statistically significant difference in the number of SNVs and indels per person in ZDV-exposed children (adjusted ratio [95% confidence interval, CI] for expected number of mutations = 0.79 [0.50--1.22], P = 0.3), and no difference in the number of large structural alterations. Mutations in common clonal hematopoiesis driver genes were not found in the study population. Mutational signature analyses on SNVs detected no novel signatures unique to the ZDV-exposed children and the mutational profiles were similar between the two groups. CONCLUSION: Our results suggest that clonal hematopoiesis at levels detectable in our study is not strongly influenced by in-utero ZDV exposure; however, additional follow-up studies are needed to further evaluate the safety and potential long-term impacts of in-utero ZDV exposure in HEU children as well as better investigate genomic aberrations occurring late in pregnancy.

Responses of New Zealand forest birds to management of introduced mammals.

Over the past 1000 years New Zealand has lost 40-50% of its bird species, and over half of these extinctions are attributable to predation by introduced mammals. Populations of many extant forest bird species continue to be depredated by mammals, especially rats, possums, and mustelids. The management history of New Zealand's forests over the past 50 years presents a unique opportunity because a varied program of mammalian predator control has created a replicated management experiment. We conducted a meta-analysis of population-level responses of forest birds to different levels of mammal control recorded across New Zealand. We collected data from 32 uniquely treated sites and 20 extant bird species representing a total of 247 population responses to 3 intensities of invasive mammal control (zero, low, and high). The treatments varied from eradication of invasive mammals via ground-based techniques to periodic suppression of mammals via aerially sown toxin. We modeled population-level responses of birds according to key life history attributes to determine the biological processes that influence species' responses to management. Large endemic species, such as the Kaka (Nestor meridionalis) and New Zealand Pigeon (Hemiphaga novaeseelandiae), responded positively at the population level to mammal control in 61 of 77 cases for species ≥20 g compared with 31 positive responses from 78 cases for species <20 g. The Fantail (Rhipidura fuliginosa) and Grey Warbler (Gerygone igata), both shallow endemic species, and 4 nonendemic species (Blackbird [Turdus merula], Chaffinch [Fringilla coelebs], Dunnock [Prunella modularis], and Silvereye [Zosterops lateralis]) that arrived in New Zealand in the last 200 years tended to have slight negative or neutral responses to mammal control (59 of 77 cases). Our results suggest that large, deeply endemic forest birds, especially cavity nesters, are most at risk of further decline in the absence of mammal control and, conversely suggest that 6 species apparently tolerate the presence of invasive mammals and may be sensitive to competition from larger endemic birds.

Respuestas de Aves Habitantes de Bosques Neozelandeses al Manejo de Mamíferos Introducidos Resumen En los últimos 1000 años, Nueva Zelanda ha perdido entre el 40% y 50% de las especies de aves. De estas extinciones, más de la mitad se puede atribuir a la depredación por mamíferos introducidos. Las poblaciones existentes de aves de bosque todavía están siendo depredadas por mamíferos, principalmente ratas, zarigüeyas y mustélidos. La historia de manejo de los bosques en Nueva Zelanda durante los recientes 50 años representa una oportunidad única porque un programa variado de control de mamíferos depredadores ha creado un experimento de manejo replicado. Realizamos un metaanálisis de las respuestas a nivel poblacional de las aves de bosque ante diferentes niveles de control de mamíferos registrados en toda Nueva Zelanda. Recolectamos datos de 32 sitios tratados de manera única y de 20 especies existentes de aves que representan un total de 247 respuestas poblacionales a tres intensidades de control de mamíferos invasores (cero, bajo y alto). Los tratamientos variaron desde la erradicación de los mamíferos invasores por vía de técnicas terrestres hasta la eliminación periódica de los mamíferos por medio de toxinas dispersadas por vía aérea. Modelamos las respuestas a nivel poblacional de las aves de acuerdo con los atributos de historia de vida importantes para determinar los procesos biológicos que influyen sobre las respuestas de las especies al manejo. Las especies endémicas grandes, como la kaka (Nestor meridionalis) y la paloma de Nueva Zelanda (Hemiphaga novaeseelandiae), respondieron positivamente a nivel poblacional al control de mamíferos en 61 de los 77 casos para especies con un peso ≥20 g comparado con 31 respuestas positivas de 78 casos para especies con un peso <20 g. El ave cola de abanico (Rhipidura fuliginosa) y la curruca gris (Gerygone igata), ambas especies endémicas someras, junto con cuatro especies no endémicas (el mirlo [Turdus merula], el pinzón [Fringilla coelebs], el acentor [Prunella modularis] y el pájaro de anteojos [Zosterops lateralis]) que arribaron a Nueva Zelanda en los últimos 200 años presentaron una tendencia hacia las respuestas negativas o neutrales al control de mamíferos (59 de 77 casos). Nuestros resultados sugieren que las aves endémicas grandes y que habitan en las profundidades del bosque, especialmente aquellas que anidan en cavidades, tienen el mayor riesgo de vivir una declinación en el futuro si el control de mamíferos se ausenta. A la inversa, nuestros resultados también sugieren que seis especies aparentemente toleran la presencia de mamíferos invasores y podrían ser vulnerables a la competencia generada por aves endémicas de mayor tamaño.

Subsequent Neoplasm Risk Associated With Rare Variants in DNA Damage Response and Clinical Radiation Sensitivity Syndrome Genes in the Childhood Cancer Survivor Study.

PURPOSE: Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown. PATIENTS AND METHODS: We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10-5. RESULTS: Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10-5), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10-5). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10-5), another gene implicated in DNA double-strand break repair. CONCLUSION: In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.

Quantifying hydrologic controls on local- and landscape-scale indicators of coastal wetland loss.

BACKGROUND AND AIMS: Coastal wetlands have evolved to withstand stressful abiotic conditions through the maintenance of hydrologic feedbacks between vegetation production and flooding. However, disruption of these feedbacks can lead to ecosystem collapse, or a regime shift from vegetated wetland to open water. To prevent the loss of critical coastal wetland habitat, we must improve understanding of the abiotic-biotic linkages among flooding and wetland stability. The aim of this research was to identify characteristic landscape patterns and thresholds of wetland degradation that can be used to identify areas of vulnerability, reduce flooding threats and improve habitat quality. METHODS: We measured local- and landscape-scale responses of coastal wetland vegetation to flooding stress in healthy and degrading coastal wetlands. We hypothesized that conversion of Spartina patens wetlands to open water could be defined by a distinct change in landscape configuration pattern, and that this change would occur at a discrete elevation threshold. KEY RESULTS: Despite similarities in total land and water cover, we observed differences in the landscape configuration of vegetated and open water pixels in healthy and degrading wetlands. Healthy wetlands were more aggregated, and degrading wetlands were more fragmented. Generally, greater aggregation was associated with higher wetland elevation and better drainage, compared with fragmented wetlands, which had lower elevation and poor drainage. The relationship between vegetation cover and elevation was non-linear, and the conversion from vegetated wetland to open water occurred beyond an elevation threshold of hydrologic stress. CONCLUSIONS: The elevation threshold defined a transition zone where healthy, aggregated, wetland converted to a degrading, fragmented, wetland beyond an elevation threshold of 0.09 m [1988 North American Vertical Datum (NAVD88)] [0.27 m mean sea level (MSL)], and complete conversion to open water occurred beyond 0.03 m NAVD88 (0.21 m MSL). This work illustrates that changes in landscape configuration can be used as an indicator of wetland loss. Furthermore, in conjunction with specific elevation thresholds, these data can inform restoration and conservation planning to maximize wetland stability in anticipation of flooding threats.

Behaviourally specialized foragers are less efficient and live shorter lives than generalists in wasp colonies.

A widely held assumption in ecology is that specialists are more efficient than generalists. However, empirical evidence for this fundamental assumption is surprisingly scarce and often contradictory. Theoretically, the evolution of alternative life history strategies is underpinned by a trade-off between activity levels and survival. We investigated the consequences of specialization in a foraging context, by comparing the performance and longevity of closely related individuals in a social insect, the common wasp (Vespula vulgaris). Using radio-frequency identification technology, we monitored the lifetime foraging activity of individual wasps from three colonies kept under natural foraging conditions. Returning foragers were video-recorded as they passed the nest entrance so that their foraging load could be assessed. There were substantial differences in foraging activity and survival within and between colonies. At the colony level, foraging specialization was weak. Yet, workers within each nest demonstrated a remarkable range of foraging specialization levels (defined as the degree of overlap between individual and colony-level task allocation) and efficiencies (defined by the number of successful trips and trip duration). We found that specialist foragers were less efficient than generalist siblings within the same colony. Behavioural specialists accomplished fewer successful trips per foraging day, and their trips were typically relatively longer. Specialized foragers also showed reduced life expectancy. The mortality risk was higher for individuals spending relatively more time in the field, yet we found no link between the level of specialization and relative field exposure. Our extensive dataset of unprecedented detail provides strong empirical evidence that behavioural specialization is not associated with a better lifetime performance, on the contrary, the opposite appears true for the common wasp. We also show that the survival of genetically similar individuals can be linked to life-long differences in behaviour according to classical life-history theory predictions.

The Impact of a Heart Failure Management Program in a Medicare Advantage Population.

Heart failure (HF) is currently among the most prevalent and costly chronic diseases among older adults, who are at increased risk because of other chronic conditions and the aging process. HF has a significant impact on the health care system, patient outcomes, and the unsustainable rising costs of care. The primary objectives were to: (1) determine cost savings differences in medical expenditures between engaged and non-engaged members referred to a HF management program; (2) examine differences in length of stay and time to first post-engagement acute inpatient admission; and (3) examine the impact of using a remote weight monitoring scale on medical expenditures and inpatient admissions. Generalized linear modeling was used to compare key outcomes among individuals who engaged in the program and a propensity-matched cohort of those who were eligible but did not engage. Key outcomes included post-engagement acute inpatient medical service utilization, all-cause per-member-per-month medical expenses, and acute inpatient length of stay. When paired with regular use of a remote weight monitoring scale, engagement in this HF management program appears to be associated with decreased risk for acute inpatient admission and lower all-cause medical expenditures. Participation in a clinically based HF management program may improve health-related and financial outcomes among older individuals. However, further development and evaluation of disease management programs could help to improve their effectiveness and thus patient outcomes.

Climate and plant controls on soil organic matter in coastal wetlands.

Coastal wetlands are among the most productive and carbon-rich ecosystems on Earth. Long-term carbon storage in coastal wetlands occurs primarily belowground as soil organic matter (SOM). In addition to serving as a carbon sink, SOM influences wetland ecosystem structure, function, and stability. To anticipate and mitigate the effects of climate change, there is a need to advance understanding of environmental controls on wetland SOM. Here, we investigated the influence of four soil formation factors: climate, biota, parent materials, and topography. Along the northern Gulf of Mexico, we collected wetland plant and soil data across elevation and zonation gradients within 10 estuaries that span broad temperature and precipitation gradients. Our results highlight the importance of climate-plant controls and indicate that the influence of elevation is scale and location dependent. Coastal wetland plants are sensitive to climate change; small changes in temperature or precipitation can transform coastal wetland plant communities. Across the region, SOM was greatest in mangrove forests and in salt marshes dominated by graminoid plants. SOM was lower in salt flats that lacked vascular plants and in salt marshes dominated by succulent plants. We quantified strong relationships between precipitation, salinity, plant productivity, and SOM. Low precipitation leads to high salinity, which limits plant productivity and appears to constrain SOM accumulation. Our analyses use data from the Gulf of Mexico, but our results can be related to coastal wetlands across the globe and provide a foundation for predicting the ecological effects of future reductions in precipitation and freshwater availability. Coastal wetlands provide many ecosystem services that are SOM dependent and highly vulnerable to climate change. Collectively, our results indicate that future changes in SOM and plant productivity, regulated by cascading effects of precipitation on freshwater availability and salinity, could impact wetland stability and affect the supply of some wetland ecosystem services.

Alternative Isoform Analysis of Ttc8 Expression in the Rat Pineal Gland Using a Multi-Platform Sequencing Approach Reveals Neural Regulation.

Alternative isoform regulation (AIR) vastly increases transcriptome diversity and plays an important role in numerous biological processes and pathologies. However, the detection and analysis of isoform-level differential regulation is difficult, particularly in the face of complex and incompletely-annotated transcriptomes. Here we have used Illumina short-read/high-throughput RNA-Seq to identify 55 genes that exhibit neurally-regulated AIR in the pineal gland, and then used two other complementary experimental platforms to further study and characterize the Ttc8 gene, which is involved in Bardet-Biedl syndrome and non-syndromic retinitis pigmentosa. Use of the JunctionSeq analysis tool led to the detection of several novel exons and splice junctions in this gene, including two novel alternative transcription start sites which were found to display disproportionately strong neurally-regulated differential expression in several independent experiments. These high-throughput sequencing results were validated and augmented via targeted qPCR and long-read Pacific Biosciences SMRT sequencing. We confirmed the existence of numerous novel splice junctions and the selective upregulation of the two novel start sites. In addition, we identified more than 20 novel isoforms of the Ttc8 gene that are co-expressed in this tissue. By using information from multiple independent platforms we not only greatly reduce the risk of errors, biases, and artifacts influencing our results, we also are able to characterize the regulation and splicing of the Ttc8 gene more deeply and more precisely than would be possible via any single platform. The hybrid method outlined here represents a powerful strategy in the study of the transcriptome.

The Association Between Health Program Participation and Employee Retention.

OBJECTIVE: Using health plan membership as a proxy for employee retention, the objective of this study was to examine whether use of health promotion programs was associated with employee retention. METHODS: Propensity score weighted generalized linear regression models were used to estimate the association between telephonic programs or health risk surveys and retention. Analyses were conducted with six study samples based on type of program participation. RESULTS: Retention rates were highest for employees with either telephonic program activity or health risk surveys and lowest for employees who did not participate in any interventions. Participants ranged from 71% more likely to 5% less likely to remain with their employers compared with nonparticipants, depending on the sample used in analyses. CONCLUSIONS: Using health promotion programs in combination with health risk surveys may lead to improvements in employee retention.

Detection and visualization of differential splicing in RNA-Seq data with JunctionSeq.

Although RNA-Seq data provide unprecedented isoform-level expression information, detection of alternative isoform regulation (AIR) remains difficult, particularly when working with an incomplete transcript annotation. We introduce JunctionSeq, a new method that builds on the statistical techniques used by the well-established DEXSeq package to detect differential usage of both exonic regions and splice junctions. In particular, JunctionSeq is capable of detecting differential usage of novel splice junctions without the need for an additional isoform assembly step, greatly improving performance when the available transcript annotation is flawed or incomplete. JunctionSeq also provides a powerful and streamlined visualization toolset that allows bioinformaticians to quickly and intuitively interpret their results. We tested our method on publicly available data from several experiments performed on the rat pineal gland and Toxoplasma gondii, successfully detecting known and previously validated AIR genes in 19 out of 19 gene-level hypothesis tests. Due to its ability to query novel splice sites, JunctionSeq is still able to detect these differences even when all alternative isoforms for these genes were not included in the transcript annotation. JunctionSeq thus provides a powerful method for detecting alternative isoform regulation even with low-quality annotations. An implementation of JunctionSeq is available as an R/Bioconductor package.

Using Propensity to Succeed Modeling to Increase Utilization and Adherence in a Nurse HealthLine Telephone Triage Program.

Propensity to succeed modeling was used to identify characteristics associated with higher utilization of a telephone triage program and adherence to nurse recommendations among callers. Characteristics significantly associated with calling the telephone triage service and engaging in triage services were being female and having an elevated health risk score. Callers most likely to adhere to nurse recommendations were younger than 85 years of age, had called on a weekday, and had received a recommendation to seek care at an emergency department or a doctor's office visit. Additional analyses suggest the propensity to succeed modeling is stable and valid.

Frequency of Participation in an Employee Fitness Program and Health Care Expenditures.

Regular physical activity is strongly linked to prevention of costly chronic health conditions. However, there has been limited examination of the impact that level of participation in physical activity promotion programs has on health care costs. This study examined a fitness reimbursement program (FRP) offered to small employers. FRP participants received $20 reimbursement every month they visited their fitness center ≥12 days. Visits were recorded electronically. Participants were assigned to 4 mutually exclusive cohorts by mean monthly fitness center visits: low (<4 visits); low-moderate (≥4 and <8 visits), high-moderate (≥8 and <12 visits), and high (≥12 visits, which qualified for reimbursement). Cohorts were matched by inverse propensity score weighting on demographic, health status, health care supply, and socioeconomic characteristics. Between-cohort differences in propensity score-weighted health care costs, starting from FRP program sign-up, were examined with a generalized linear model. Analyses were conducted with and without high-cost outliers during the pre- and post-FRP period. A total of 8723 participants (mean follow-up: 11.1 months) were identified during October 2010-June 2013. With high-cost outliers removed (n = 226), a pattern of lower per-member-per-month health care costs was observed with increasing participation: compared with the low cohort, monthly savings were: $6.14 (2.6%) for low-moderate (P = 0.60), $16.40 (6.9%) for moderate-high (P = 0.16), and $20.01 (8.4%) for high (P = 0.08). With high-cost outliers included, significant monthly cost savings were observed for the moderate-high ($43.52, P < 0.01) and high ($52.66, P < 0.001) cohorts. These results indicate directionally positive cost outcomes associated with increasing level of fitness center participation.