Recurrent repeat expansions in human cancer genomes.

Expansion of a single repetitive DNA sequence, termed a tandem repeat (TR), is known to cause more than 50 diseases1,2. However, repeat expansions are often not explored beyond neurological and neurodegenerative disorders. In some cancers, mutations accumulate in short tracts of TRs, a phenomenon termed microsatellite instability; however, larger repeat expansions have not been systematically analysed in cancer3-8. Here we identified TR expansions in 2,622 cancer genomes spanning 29 cancer types. In seven cancer types, we found 160 recurrent repeat expansions (rREs), most of which (155/160) were subtype specific. We found that rREs were non-uniformly distributed in the genome with enrichment near candidate cis-regulatory elements, suggesting a potential role in gene regulation. One rRE, a GAAA-repeat expansion, located near a regulatory element in the first intron of UGT2B7 was detected in 34% of renal cell carcinoma samples and was validated by long-read DNA sequencing. Moreover, in preliminary experiments, treating cells that harbour this rRE with a GAAA-targeting molecule led to a dose-dependent decrease in cell proliferation. Overall, our results suggest that rREs may be an important but unexplored source of genetic variation in human cancer, and we provide a comprehensive catalogue for further study.

Population genetic structure and demographic history reconstruction of introduced flathead catfish (Pylodictis olivaris) in two US Mid-Atlantic rivers.

Population genetic analysis of invasive populations can provide valuable insights into the source of introductions, pathways for expansion, and their demographic histories. Flathead catfish (Pylodictis olivaris) are a prolific invasive species with high fecundity, long-distance dispersal, and piscivorous feeding habits that can lead to declines in native fish populations. In this study, we analyse the genetics of invasive P. olivaris in the Mid-Atlantic region to assess their connectivity and attempt to reconstruct the history of introduced populations. Based on an assessment across 13 microsatellite loci, P. olivaris from the Susquehanna River system (N = 537), Schuylkill River (N = 33), and Delaware River (N = 1) have low genetic diversity (global Hobs = 0.504), although we detected no evidence of substantial inbreeding (FIS = -0.083 to 0.022). P. olivaris from these different river systems were genetically distinct, suggesting separate introductions. However, population structure was much weaker within each river system and exhibited a pattern of high connectivity, with some evidence of isolation by distance. P. olivaris from the Susquehanna and Schuylkill rivers showed evidence for recent genetic bottlenecks, and demographic models were consistent with historical records, which suggest that populations were established by recent founder events consisting of a small number of individuals. Our results show the risk posed by small introductions of P. olivaris, which can spread widely once a population is established, and highlight the importance of prevention and sensitive early detection methods to prevent the spread of P. olivaris in the future.

One Year Into Dupilumab: Physician and Patient Experiences in Initiating Dupilumab for Pediatric Eosinophilic Esophagitis.

In 2022, the US Food and Drug Administration approved dupilumab for treatment of eosinophilic esophagitis (EoE). The aims of this study were to report physician and patient perspectives on initiating dupilumab. A 2-pronged approach was used: (1) data on physician prescribing practices was gathered via retrospective chart review of EoE patients prescribed dupilumab and (2) pediatric patients on dupilumab were approached to complete a questionnaire regarding reasons for initiation. During this time, 42 patients were prescribed dupilumab. From the physician's perspective, the primary reasons for dupilumab included nonresponse to topical corticosteroids (TCS) (52%), nonadherence (28%), adverse effects (10%), or to treat multiple atopic diseases (5%). The median dupilumab initiation time, from day prescribed to first injection, was 37 days [interquartile range (IQR) 37]. Almost all required prior authorization (PA) (98%), while 17% required letter of appeal and 2% required peer-to-peer. Fifteen patients (36%) completed the questionnaire portion of the study. From the patient's perspective, the primary reasons for dupilumab initiation included nonresponse to TCS (27%), nonadherence to TCS (27%), concern about adverse effects of TCS (7%), and treatment of multiple atopic diseases (33%). In conclusion, physicians are prescribing dupilumab primarily for nonresponse to TCS and almost all required PA with a long delay to starting dupilumab.

Master lineage transcription factors anchor trans mega transcriptional complexes at highly accessible enhancer sites to promote long-range chromatin clustering and transcription of distal target genes.

The term 'super enhancers' (SE) has been widely used to describe stretches of closely localized enhancers that are occupied collectively by large numbers of transcription factors (TFs) and co-factors, and control the transcription of highly-expressed genes. Through integrated analysis of >600 DNase-seq, ChIP-seq, GRO-seq, STARR-seq, RNA-seq, Hi-C and ChIA-PET data in five human cancer cell lines, we identified a new class of autonomous SEs (aSEs) that are excluded from classic SE calls by the widely used Rank Ordering of Super-Enhancers (ROSE) method. TF footprint analysis revealed that compared to classic SEs and regular enhancers, aSEs are tightly bound by a dense array of master lineage TFs, which serve as anchors to recruit additional TFs and co-factors in trans. In addition, aSEs are preferentially enriched for Cohesins, which likely involve in stabilizing long-distance interactions between aSEs and their distal target genes. Finally, we showed that aSEs can be reliably predicted using a single DNase-seq data or combined with Mediator and/or P300 ChIP-seq. Overall, our study demonstrates that aSEs represent a unique class of functionally important enhancer elements that distally regulate the transcription of highly expressed genes.

Evaluating sources of bias in pedigree-based estimates of breeding population size.

Applications of genetic-based estimates of population size are expanding, especially for species for which traditional demographic estimation methods are intractable due to the rarity of adult encounters. Estimates of breeding population size (NS ) are particularly amenable to genetic-based approaches as the parameter can be estimated using pedigrees reconstructed from genetic data gathered from discrete juvenile cohorts, therefore eliminating the need to sample adults in the population. However, a critical evaluation of how genotyping and sampling effort influence bias in pedigree reconstruction, and how these biases subsequently influence estimates of NS , is needed to evaluate the efficacy of the approach under a range of scenarios. We simulated a model system to understand the interactive effects of genotyping and sampling effort on error in genetic pedigrees reconstructed from the program COLONY. We then evaluated how errors in pedigree reconstruction influenced bias and precision in estimates of NS using three different rarefaction estimators. Results indicated that pedigree error can be minimal when adequate genetic data are available, such as when juvenile sample sizes are large and/or individuals are genotyped at many informative loci. However, even in cases for which data are limited, using results of the simulation analysis to understand the magnitude and sources of bias in reconstructed pedigrees can still be informative when estimating NS . We applied results of the simulation analysis to evaluate N ̂ $$ \hat{N} $$ S for a population of federally endangered Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) in the Delaware River, USA. Our results indicated that NS is likely to be three orders of magnitude lower compared with historic breeding population sizes, which is a considerable advancement in our understanding of the population status of Atlantic sturgeon in the Delaware River. Our analyses are broadly applicable in the design and interpretation of studies seeking to estimate NS and can help to guide conservation decisions when ecological uncertainty is high. The utility of these results is expected to grow as rapid advances in genetic technologies increase the popularity of genetic population monitoring and estimation.

Cost benefit analysis of survey methods for assessing intertidal sediment disturbance: A bait collection case study.

Coastal management requires cost-effective, yet accurate, assessments of habitat condition, especially in areas protected by statutory conservation measures. Unmanned Aerial Vehicles (UAVs) provide alternatives to manned aircraft and walk-over (WO) surveys. To support coastal managers with method selection, we compare the costs and benefits of the three techniques using the extent of bait collection (sediment scarring from manual digging) on intertidal mudflats from three UK sites. UAV and WO surveys were conducted in parallel and aerial photography was downloaded from the Channel Coastal Observatory (CCO). Digging was digitised from estimations on foot (WO) or by manually labelling imagery with confidence assigned (UAV/CCO). Method efficacy is compared with respect to spatial coverage, control over survey time/location, spatial resolution, positioning accuracy, and area of digging detected. Personnel hours and up-front costs (e.g. training/equipment), costs for personnel time standardised by shore area, personnel risk, and environmental impact are also compared. Regarding efficacy, CCO imagery had extensive shore coverage compared to UAV and WO, however, assessments are restricted to times/locations with available imagery. Each method's resolution was sufficient to detect digging. WO achieved the highest resolution (on foot), but the lowest positioning accuracy, in contrast to accurate feature delineation on aerial imagery. An additive two-way ANOVA revealed a significantly higher percent area of 'dug' sediment (all confidence levels) recorded by UAV than WO. CCO was the most cost-effective with no fieldwork/equipment costs. UAV had the highest up-front costs, but WO was more costly for personnel hours/km2 for survey time and digitisation. For all methods, digitisation was the most time-consuming aspect. Compared to WO, UAV achieved rapid shore surveys and the CCO and UAV methods minimise personnel risks. UAV and WO both cause wildlife disturbance, with trampling an additional WO impact. With each method suited to sediment disturbance assessment, selection will depend on resources and objectives and will be aided by this holistic cost-benefit analysis. Cost-effectiveness will improve with evolving regulations that facilitate UAV use and technological developments (e.g. machine learning for disturbance detection) that could significantly expedite imagery analysis and enable broadscale assessments from CCO or satellite imagery.

A novel quantitative framework for riverscape genetics.

Riverscape genetics, which applies concepts in landscape genetics to riverine ecosystems, lack appropriate quantitative methods that address the spatial autocorrelation structure of linear stream networks and account for bidirectional geneflow. To address these challenges, we present a general framework for the design and analysis of riverscape genetic studies. Our framework starts with the estimation of pairwise genetic distance at sample sites and the development of a spatially structured ecological network (SSEN) on which riverscape covariates are measured. We then introduce the novel bidirectional geneflow in riverscapes (BGR) model that uses principles of isolation-by-resistance to quantify the effects of environmental covariates on genetic connectivity, with spatial covariance defined using simultaneous autoregressive models on the SSEN and the generalized Wishart distribution to model pairwise distance matrices arising through a random walk model of geneflow. We highlight the utility of this framework in an analysis of riverscape genetics for brook trout (Salvelinus fontinalis) in north central Pennsylvania, USA. Using the fixation index (FST ) as the measure of genetic distance, we estimated the effects of 12 riverscape covariates on geneflow by evaluating the relative support of eight competing BGR models. We then compared the performance of the top-ranked BGR model to results obtained from comparable analyses using multiple regression on distance matrices (MRM) and the program STRUCTURE. We found that the BGR model had more power to detect covariate effects, particularly for variables that were only partial barriers to geneflow and/or uncommon in the riverscape, making it more informative for assessing patterns of population connectivity and identifying threats to species conservation. This case study highlights the utility of our modeling framework over other quantitative methods in riverscape genetics, particularly the ability to rigorously test hypotheses about factors that influence geneflow and probabilistically estimate the effect of riverscape covariates, including stream flow direction. This framework is flexible across taxa and riverine networks, is easily executable, and provides intuitive results that can be used to investigate the likely outcomes of current and future management scenarios.

The Profile and Prognosis of Youth With Status Migrainosus: Results From an Observational Study.

OBJECTIVE: To characterize the clinical features of a large sample of children, adolescents, and young adults with a history of status migrainosus (SM) and to describe their short-term prognosis. BACKGROUND: Data on the clinical characteristics of children and adolescents with SM are sparse and little is known about the prognosis of this population. METHODS: This was a retrospective clinical cohort study that included patients from the Cincinnati Children's Headache Center if they had a diagnosis of migraine and data available for a 1-3 months follow-up interval. Data extracted from the initial interval visit (visit A) included: age, sex, race, migraine diagnosis, SM history, chronic migraine, medication overuse headache (MOH), body mass index (BMI), headache frequency, headache severity, disability, allodynia and lifestyle habits: caffeine intake, meal skipping, sleep duration, exercise frequency, and fluid intake. Data extracted from the initial consultation visit included: months with headache at initial consultation visit, patient endorsing "feeling depressed" and anxiety symptoms. Headache frequency and visit type were also measured at the second visit (visit B) in the follow-up interval. A multivariate logistic regression model with a backward elimination procedure was created to model the odds of having a diagnosis of SM using the cross-sectional predictor variables above. Second, chi-square tests were used to compare the proportion of patients with SM to the proportion of patients without SM who had each of the following outcomes in the short-term follow-up window: treatment response (50% or greater reduction in headache frequency), overall reduction in headache frequency (reduction of 1 or more headache days/month), minimal change in headache frequency (increase in 0-3 headache days/month), and clinical worsening (increase in 4 or more headache days/month). RESULTS: A total of 5316 youth with migraine were included and 559 (10.5%) had a history of SM. In the multivariate logistic regression model, predictors significantly associated with SM were: older age (OR = 1.13, 95% CI = 1.09-1.17, P < .0001), migraine with aura (MWA) (OR = 1.30, 95% CI = 1.03-1.65, P = .03), MOH (OR = 1.72, 95% CI = 1.30-2.28, P = .0001), headache frequency (OR = 0.99, 95% CI = 0.97-0.99, P = .030), higher headache severity (OR = 1.08, 95% CI = 1.02-1.15, P = .009), months with headache at initial consultation (OR = 1.00, 95% CI = 1.00-1.01, P = .042), and admission to infusion center at visit B (OR = 2.27, 95% CI = 1.38-3.72, P = .001). Patients with a history of SM were more likely to experience an increase in 4 or more headache days per month at follow-up: 15.2% as compared to 11.1% of those without SM, χ2 (1, n = 5316) = 8.172, P = .0043. CONCLUSIONS: Youth with SM represent a distinct subgroup of the migraine population and have an unfavorable short-term prognosis.

Predictors of Short-Term Prognosis While in Pediatric Headache Care: An Observational Study.

OBJECTIVES: To characterize the short-term prognosis of a clinical population of pediatric and young adult patients with migraine and explore predictors of clinical worsening while in care. METHODS: This was a retrospective study of all migraine patients seen at the Cincinnati Children's Hospital Headache Center from 09/01/2006 to 12/31/2017, who had at least 1 follow-up visit within 1-3 months of the index visit analyzed. Included data were: age, sex, race, primary ICHD diagnosis, chronic migraine, medication overuse, history of status migrainosus, BMI percentile, headache frequency, headache severity, PedMIDAS score, allodynia, preventive treatment type, lifestyle habits, disease duration, depressive and anxiety symptoms. Clinical worsening was defined as an increase in 4 or more headache days per month between the index visit and the follow-up visit. RESULTS: Data for 13,160 visit pairs (index and follow-up), from 5316 patients, were analyzed. Clinical worsening occurred in only 14.5% (1908/13,160), whereas a reduction in headache frequency was observed in 56.8% of visit intervals (7475/13,160), with 34.8% of the intervals (4580/13,160) showing a reduction of 50% or greater. The change in headache frequency was minimal (increase in 0-3 headaches/month) in 28.7% of intervals (3737/13,160). In the multivariable model, the odds of worsening were significantly higher with increasing age, female sex, chronic migraine, status migrainosus, depressive symptoms, higher PedMIDAS scores, and use of nutraceuticals, whereas the odds of worsening were lower for summer visits, caffeine drinkers, higher headache frequencies, and use of pharmaceuticals. CONCLUSIONS: The majority of pediatric patients who receive multimodal interdisciplinary care for migraine improve over time. Our findings highlight a set of clinical features that may help in identifying specific factors that may contribute to an unfavorable short-term prognosis.

Individual behaviour and resource use of thermally stressed brook trout Salvelinus fontinalis portend the conservation potential of thermal refugia.

Individual aggression and thermal refuge use were monitored in brook trout Salvelinus fontinalis in a controlled laboratory to determine how fish size and personality influence time spent in forage and thermal habitat patches during periods of thermal stress. On average, larger and more exploratory fish initiated more aggressive interactions and across all fish there was decreased aggression at warmer temperatures. Individual personality did not explain changes in aggression or habitat use with increased temperature; however, larger individuals initiated comparatively fewer aggressive interactions at warmer temperatures. Occupancy of forage patches generally declined as ambient stream temperatures approached critical maximum and fish increased thermal refuge use, with a steeper decline in forage patch occupancy observed in larger fish. These findings suggest that larger individuals may be more vulnerable to stream temperature rise. Importantly, even at thermally stressful temperatures, all fish periodically left the thermal refuge to forage. This indicates that the success of refugia at increasing population survival during periods of stream temperature rise may depend on the location of thermal refugia relative to forage locations within the larger habitat mosaic. These results provide insights into the potential for thermal refugia to improve population survival and can be used to inform predictions of population vulnerability to climate change.

Ovarian hormones, age and pubertal development and their association with days of headache onset in girls with migraine: An observational cohort study.

Background Fifty-three percent of adolescent girls report headaches at the onset of menses, suggesting fluctuations of ovarian hormones trigger migraine during puberty. Aims To determine if urinary metabolites of estrogen and progesterone are associated with days of headache onset (HO) or severity in girls with migraine. Methods This was a pilot study and included 34 girls with migraine balanced across three age strata (pre-pubertal (8-11), pubertal (12-15), and post-pubertal (16-17) years of age). They collected daily urine samples and recorded the occurrence and severity of headache in a daily diary. Urine samples were assayed for estrone glucuronide (E1G) and pregnandiol glucuronide (PdG) and the daily change was calculated (ΔE1G, ΔPdG). Pubertal development was assessed by age, pubertal development score (PDS), and menstrual cycle variance. The primary outcome measures were HO days and headache severity. Generalized linear mixed models were used, and included the hormonal variables and three different representations of pubertal development as covariates. Results Models of HO days demonstrate a significant age*PdG interaction (OR 0.85 [95% CI 0.75, 0.97]) for a 1 standard deviation increase in PdG and three-year increase in age. A separate model showed a significant PDS*PdG interaction (OR -0.85 [95% CI; 0.76, 0.95]). ΔPDG was associated with headache severity in unadjusted models ( p < 0.017). Conclusion Age and pubertal development could moderate the effect of ovarian hormones on days of headache onset in girls with migraine.

Predictors of First-Line Treatment Success in Children and Adolescents Visiting an Infusion Center for Acute Migraine.

OBJECTIVES: To characterize a population of pediatric patients visiting an infusion center for acute migraine and determine predictors of first-line treatment success in this population. BACKGROUND: Though migraine is common in the pediatric emergency department and specialized infusion centers, little is known about this patient population and whether or not clinical data can be used to predict treatment response. METHODS: This was an observational study involving a retrospective analysis of data from visits to the Cincinnati Children's Hospital infusion center for treatment of an acute migraine. Data were extracted from a database and chart reviews were completed for missing or outlying data. Descriptive statistics were used to outline patient: sex, age, race, primary ICHD-III diagnosis, chronic migraine, medication overuse headache (MOH), headache frequency, month of treatment, headache severity, headache duration, use of acute medication at home in the past 24 hours and treatment received (metoclopramide vs prochlorperazine and dexamethasone vs no dexamethasone). The odds of success of first-line intervention were modeled using simple logistic regression with the above characteristics used as predictors. Predictors with a P value <.05 in the multiple logistic regression model with progressive backwards selection were entered into a final multiple logistic regression model controlling for age, sex and diagnosis, where a P value <.05 was considered statistically significant. RESULTS: Data from 837 visits (n = 837) were included in this analysis. Visits were significantly more frequent in the academic year as compared to the summer (Z = 10.716, P < .0001). In the multiple logistic regression model, the odds of first-line treatment success decreased as headache frequency increased (OR = 0.951, 95% CI = 0.934-0.969, P < .0001), were higher for patients without MOH (OR = 1.528, 95% CI = 1.097-3.714, P = .0469), and were higher for patients who did not receive dexamethasone (OR = 1.528, 95% CI = 1.097-3.714, P = .0469). CONCLUSIONS: Higher baseline headache frequency and presence of MOH may predict lower odds of treatment success after first-line intervention for pediatric migraine in the acute setting. These predictors may be useful in stratifying patients for treatment protocols and for planning future intervention studies.

Asynchrony among local communities stabilises ecosystem function of metacommunities.

Temporal stability of ecosystem functioning increases the predictability and reliability of ecosystem services, and understanding the drivers of stability across spatial scales is important for land management and policy decisions. We used species-level abundance data from 62 plant communities across five continents to assess mechanisms of temporal stability across spatial scales. We assessed how asynchrony (i.e. different units responding dissimilarly through time) of species and local communities stabilised metacommunity ecosystem function. Asynchrony of species increased stability of local communities, and asynchrony among local communities enhanced metacommunity stability by a wide range of magnitudes (1-315%); this range was positively correlated with the size of the metacommunity. Additionally, asynchronous responses among local communities were linked with species' populations fluctuating asynchronously across space, perhaps stemming from physical and/or competitive differences among local communities. Accordingly, we suggest spatial heterogeneity should be a major focus for maintaining the stability of ecosystem services at larger spatial scales.

Asymmetric responses of primary productivity to precipitation extremes: A synthesis of grassland precipitation manipulation experiments.

Climatic changes are altering Earth's hydrological cycle, resulting in altered precipitation amounts, increased interannual variability of precipitation, and more frequent extreme precipitation events. These trends will likely continue into the future, having substantial impacts on net primary productivity (NPP) and associated ecosystem services such as food production and carbon sequestration. Frequently, experimental manipulations of precipitation have linked altered precipitation regimes to changes in NPP. Yet, findings have been diverse and substantial uncertainty still surrounds generalities describing patterns of ecosystem sensitivity to altered precipitation. Additionally, we do not know whether previously observed correlations between NPP and precipitation remain accurate when precipitation changes become extreme. We synthesized results from 83 case studies of experimental precipitation manipulations in grasslands worldwide. We used meta-analytical techniques to search for generalities and asymmetries of aboveground NPP (ANPP) and belowground NPP (BNPP) responses to both the direction and magnitude of precipitation change. Sensitivity (i.e., productivity response standardized by the amount of precipitation change) of BNPP was similar under precipitation additions and reductions, but ANPP was more sensitive to precipitation additions than reductions; this was especially evident in drier ecosystems. Additionally, overall relationships between the magnitude of productivity responses and the magnitude of precipitation change were saturating in form. The saturating form of this relationship was likely driven by ANPP responses to very extreme precipitation increases, although there were limited studies imposing extreme precipitation change, and there was considerable variation among experiments. This highlights the importance of incorporating gradients of manipulations, ranging from extreme drought to extreme precipitation increases into future climate change experiments. Additionally, policy and land management decisions related to global change scenarios should consider how ANPP and BNPP responses may differ, and that ecosystem responses to extreme events might not be predicted from relationships found under moderate environmental changes.

Improving actions to control high blood pressure in Hispanic communities - Racial and Ethnic Approaches to Community Health Across the U.S. Project, 2009-2012.

BACKGROUND: Compared with the general population in the United States (U.S.), Hispanics with hypertension are less likely to be aware of their condition, to take antihypertensive medication, and to adopt healthy lifestyles to control high blood pressure. We examined whether a multi-community intervention successfully increased the prevalence of actions to control hypertension among Hispanics. METHODS: Annual survey from 2009-2012 was conducted in six Hispanic communities in the Racial and Ethnic Approaches to Community Health (REACH) Across the U.S. PROJECT: The survey used address based sampling design that matched the geographies of intervention program. RESULTS: Age- and sex-standardized prevalences of taking hypertensive medication, changing eating habits, cutting down on salt, and reducing alcohol use significantly increased among Hispanics with self-reported hypertension in REACH communities. The 3-year relative percent increases were 5.8, 6.8, 7.9, and 35.2% for the four indicators, respectively. These favorable (healthier) trends occurred in both foreign-born and U.S.-born Hispanics. CONCLUSION: This large community-based participatory intervention resulted in more Hispanic residents in the communities taking actions to control high blood pressure.

Factors Influencing Migraine Recurrence After Infusion and Inpatient Migraine Treatment in Children and Adolescents.

OBJECTIVE: To evaluate factors that influence migraine recurrence after outpatient infusion or inpatient treatment for intractable migraine. BACKGROUND: Recurrence of migraine after acute treatment in an infusion center or an inpatient setting is not well documented in children and adolescents. Given the multifactorial pathogenesis of migraines, multiple factors may influence migraine recurrence. It has been reported that treatment with steroids may reduce the risk of migraine recurrence. The efficacy of steroids as a therapeutic adjunct has not been established. Studies in the adult population have yielded conflicting results. METHODS: This study is a retrospective chart review of patients presenting for treatment of an intractable migraine to the outpatient infusion unit or inpatient unit at Cincinnati Children's Hospital Medical Center (CCHMC). Data collected included: age, gender, location of treatment (outpatient, inpatient), migraine duration, diagnosis, severity, the addition of steroids to treatment protocols, and recurrence of migraine at 48 and 72 hours after discharge. Data were analyzed using Fisher's exact tests, logistic regression with backward elimination for variable selection, and least squares means slicing with associated odds ratios. RESULTS: Charts from 207 pediatric patients were analyzed. Using logistic regression analysis: location, gender, diagnosis, and age were all found to be significant predictors of migraine recurrence (P < .05). Patients treated in the inpatient setting were significantly less likely to experience recurrence compared to patients treated in an outpatient infusion unit (OR = 0.32; 95% CI 0.17-0.61, P = .0002). Male patients with a diagnosis of episodic migraine were significantly less likely to experience recurrence than male patients with chronic migraine (OR 0.17; 95% CI 0.04-0.73; P = .0074). The inclusion of steroids in this study population showed no significant reduction in migraine recurrence. The probability of recurrence decreased with age for episodic migraine patients, while the probability increased with age for chronic migraine patients. CONCLUSIONS: Recurrence is an important consideration when treating intractable migraines. Age, gender, diagnosis, and location of treatment correlate with migraine recurrence, but the inclusion of steroids does not. Considering these factors in the management of migraines may improve the outcome of these patients and reduce the risk of recurrence.

Cardiovascular risk, social vigilance, and stress profiles of male law enforcement officers versus civilians.

This study examined the cardiovascular disease (CVD) risk profiles of male law enforcement officers (LEOs) and civilians. CVD risk profiles were based on data collected using traditional objective (e.g., resting BP, cholesterol), novel objective (e.g., ambulatory BP) and self-report measures (e.g., EMA social vigilance). A subset of male LEOs (n = 30, M age = 41.47, SD = 8.03) and male civilians (n = 120, M age = 40.73, SD = 13.52) from a larger study were included in analyses. Results indicated LEOs had significantly higher body mass index [BMI], 31.17 kg/m2 versus 28.87 kg/m2, and exhibited significantly higher trait and state social vigilance across multiple measures, whereas perceived stress was higher among civilians. Findings highlight the need for future research examining CVD risk associated with occupational health disparities, including attributes of individuals entering certain professions as well as experiential and environmental demands of the work.

Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis.

Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression.

Least explored factors associated with prenatal smoking.

Poor pregnancy and birth outcomes are major problems in the United States, and maternal smoking during pregnancy has been identified as one of the most preventable risk factors associated with these outcomes. This study examines less explored risk factors of smoking among underserved African American pregnant women. A cross-sectional survey was conducted at an outpatient obstetrics-gynecology clinic of an inner-city university hospital in Virginia from March 2009 through January 2011 in which pregnant women (N = 902) were interviewed at their first prenatal care visit. Survey questions included items related to women's sociodemographic characteristics as well as their pregnancy history; criminal history; receipt of social services; child protective services involvement; insurance status; and history of substance abuse, domestic violence, and depression. Multiple logistic regression was conducted to calculate odds ratios and 95 % confidence intervals depicting the relationship between these factors and smoking during pregnancy. The analysis reported that maternal age [OR = 1.08, 95 % CI = 1.05-1.12], less than high school education [OR = 4.30, 95 % CI = 2.27-8.14], unemployed [OR = 2.33, 95 % CI = 1.35-4.04], criminal history [OR = 1.66, 95 % CI = 1.05-2.63], receipt of social services [OR = 2.26, 95 % CI = 1.35-3.79] alcohol use [OR = 2.73, 95 % CI = 1.65-4.51] and illicit drug use [OR = 1.97, 95 % CI = 1.04-3.74] during pregnancy were statistically significant risk factors associated with smoking during pregnancy. In addition to the well known risk factors, public health professionals should be aware that criminal history and receipt of social services are important factors associated with smoking during pregnancy. Social service providers such as WIC and prisons and jails may offer a unique opportunity for education and cessation interventions during the preconception or interconception period.