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Background: Internationally, 20% to 50% of cancer is diagnosed through emergency presentation, which is associated with lower survival, poor patient experience, and socioeconomic disparities, but population-based evidence about emergency diagnosis in the United States is limited. We estimated emergency department (ED) involvement in the diagnosis of cancer in a nationally representative population of older US adults, and its association with sociodemographic, clinical, and tumor characteristics., Methods: We analyzed Surveillance, Epidemiology, and End Results Program-Medicare data for Medicare beneficiaries (≥66 years old) with a diagnosis of female breast, colorectal, lung, and prostate cancers (2008-2017), defining their earliest cancer-related claim as their index date, and patients who visited the ED 0 to 30 days before their index date to have "ED involvement" in their diagnosis, with stratification as 0 to 7 or 8 to 30 days. We estimated covariate-adjusted associations of patient age, sex, race and ethnicity, marital status, comorbidity score, tumor stage, year of diagnosis, rurality, and census-tract poverty with ED involvement using modified Poisson regression., Results: Among 614 748 patients, 23% had ED involvement, with 18% visiting the ED in the 0 to 7 days before their index date. This rate varied greatly by tumor site, with breast cancer at 8%, colorectal cancer at 39%, lung cancer at 40%, and prostate cancer at 7%. In adjusted models, older age, female sex, non-Hispanic Black and Native Hawaiian or Other Pacific Islander race, being unmarried, recent year of diagnosis, later-stage disease, comorbidities, and poverty were associated with ED involvement., Conclusions: The ED may be involved in the initial identification of cancer for 1 in 5 patients. Earlier, system-level identification of cancer in non-ED settings should be prioritized, especially among underserved populations., (© The Author(s) 2024. Published by Oxford University Press.)

Cryo-soft X-ray tomography is the unique technology that can image whole intact cells in 3D under normal and pathological conditions without labelling or fixation, at high throughput and spatial resolution. The sample preparation is relatively straightforward; requiring just fast freezing of the specimen before transfer to the microscope for imaging. It is also possible to image chemically fixed samples where necessary. The technique can be correlated with cryo fluorescence microscopy to localize fluorescent proteins to organelles within the whole cell volume. Cryo-correlated light and soft X-ray tomography is particularly useful for the study of gross morphological changes brought about by disease or drugs. For example, viral fluorescent tags can be co-localized to sites of viral replication in the soft X-ray volume. In general this approach is extremely useful in the study of complex 3D organelle structure, nanoparticle uptake or in the detection of rare events in the context of whole cell structure. The main challenge of soft X-ray tomography is that the soft X-ray illumination required for imaging has heretofore only been available at a small number of synchrotron labs worldwide. Recently, a compact device with a footprint small enough to fit in a standard laboratory setting has been deployed ("the SXT-100") and is routinely imaging cryo prepared samples addressing a variety of disease and drug research applications. The SXT-100 facilitates greater access to this powerful technique and greatly increases the scope and throughput of potential research projects. Furthermore, the availability of cryo-soft X-ray tomography in the laboratory will accelerate the development of novel correlative and multimodal workflows by integration with light and electron microscope based approaches. It also allows for co-location of this powerful imaging modality at BSL3 labs or other facilities where safety or intellectual property considerations are paramount. Here we describe the compact SXT-100 microscope along with its novel integrated cryo-fluorescence imaging capability., (Copyright © 2024 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Immortal time bias is a well-recognized bias in clinical epidemiology but is rarely discussed in environmental epidemiology. Under the target trial framework, this bias is formally conceptualized as a misalignment between the start of study follow-up (time 0) and treatment assignment. This misalignment can occur when attained duration of follow-up is encoded into treatment assignment using minimums, maximums, or averages. The bias can be exacerbated in the presence of time trends commonly found in environmental exposures. Using lung cancer cases from the California Cancer Registry (2000-2010) linked with estimated concentrations of particulate matter less than or equal to 2.5 μm in aerodynamic diameter (PM2.5), we replicated previous studies that averaged PM2.5 exposure over follow-up in a time-to-event model. We compared this approach with one that ensures alignment between time 0 and treatment assignment, a discrete-time approach. In the former approach, the estimated overall hazard ratio for a 5-μg/m3 increase in PM2.5 was 1.38 (95% confidence interval: 1.36, 1.40). Under the discrete-time approach, the estimated pooled odds ratio was 0.99 (95% confidence interval: 0.98, 1.00). We conclude that the strong estimated effect in the former approach was likely driven by immortal time bias, due to misalignment at time 0. Our findings highlight the importance of appropriately conceptualizing a time-varying environmental exposure under the target trial framework to avoid introducing preventable systematic errors., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Soft X-ray tomography (SXT) is an imaging technique to visualise whole cells without fixation, staining, and sectioning. For SXT imaging, cells are cryopreserved and imaged at cryogenic conditions. Such 'near-to-native' state imaging is in high demand and initiated the development of the laboratory table-top SXT microscope. As many laboratories do not have access to cryogenic equipment, we asked ourselves whether SXT imaging is feasible on dry specimens. This paper shows how the dehydration of cells can be used as an alternative sample preparation to obtain ultrastructure information. We compare different dehydration processes on mouse embryonic fibroblasts in terms of ultrastructural preservation and shrinkage. Based on this analysis, we chose critical point (CPD) dried cells for SXT imaging. In comparison to cryopreserved and air-dried cells, CPD dehydrated cells show high structural integrity although with about 3-7 times higher X-ray absorption for cellular organelles. As the difference in X-ray absorption values between organelles is preserved, 3D anatomy of CPD-dried cells can be segmented and analysed, demonstrating the applicability of CPD-dried sample preparation for SXT imaging. LAY DESCRIPTION: Soft X-ray tomography (SXT) is an imaging technique that allows to see the internal structures of cells without the need for special treatments like fixation or staining. Typically, SXT imaging involves freezing and imaging cells at very low temperatures. However, since many labs lack the necessary equipment, we explored whether SXT imaging could be done on dry samples instead. We compared different dehydration methods and found that critical point drying (CPD) was the most promising for SXT imaging. CPD-dried cells showed high structural integrity, although they absorbed more X-rays than hydrated cells, demonstrating that CPD-dried sample preparation is a viable alternative for SXT imaging., (© 2023 The Authors. Journal of Microscopy published by John Wiley & Sons Ltd on behalf of Royal Microscopical Society.)

Background: Androgen deprivation therapy (ADT) is frequently utilized in conjunction with radiotherapy (RT) in the definitive management of prostate cancer. Prior studies have suggested an association between ADT use and acute kidney injury (AKI), however, these included heterogeneous populations undergoing a variety of treatments and relied on billing codes to ascertain the incidence of AKI., Methods: We analyzed a cohort of 27,868 veterans undergoing definitive RT + /- ADT for prostate cancer between 2001 and 2015 using the Veterans Affairs Informatics and Computing Infrastructure (VINCI). Exposure was defined as use of ADT within one year of diagnosis. The primary outcome was AKI, defined by an increase in serum creatinine to at least 1.5 times the baseline value. AKIs were classified as mild, moderate, or severe in accordance with international guidelines. A multivariate competing risks model was used to account for demographic and oncologic factors as well as medications and procedures known to influence the risk of AKI., Results: Most (n = 18,754) men received RT alone; 9,114 men received RT + ADT. The incidence of AKI at two years after diagnosis was 10.5% in the RT + ADT group and 7.9% in the RT group (Gray's test p < 0.01). Multivariate analysis confirmed ADT usage was associated with an increased risk for any AKI (SHR = 1.24, 95% CI = 1.14-1.36, p < 0.01). ADT was also associated with an increased risk of mild AKI (SHR = 1.13, 95% CI = 1.01-1.27, p = 0.04) and moderate AKI (SHR = 1.45, 95% CI = 1.20-1.76, p < 0.01), though not severe AKI (SHR = 1.33, 95% CI = 0.93-1.91, p = 0.11)., Conclusions: Our findings confirm that use of ADT is associated with an increased risk of AKI in patients undergoing definitive RT for prostate cancer. Clinicians should be alert to the potential for renal dysfunction in this population., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Bromodomain-containing protein 8 (BRD8) is a subunit of the NuA4/TIP60-histone acetyltransferase complex. Although BRD8 has been considered to act as a co-activator of the complex, its biological role remains to be elucidated. Here, we uncovered that BRD8 accumulates in colorectal cancer cells through the inhibition of ubiquitin-dependent protein degradation by the interaction with MRG domain binding protein. Transcriptome analysis coupled with genome-wide mapping of BRD8-binding sites disclosed that BRD8 transactivates a set of genes independently of TIP60, and that BRD8 regulates the expression of multiple subunits of the pre-replicative complex in concert with the activator protein-1. Depletion of BRD8 induced cell-cycle arrest at the G1 phase and suppressed cell proliferation. We have also shown that the bromodomain of BRD8 is indispensable for not only the interaction with histone H4 or transcriptional regulation but also its own protein stability. These findings highlight the importance of bromodomain as a therapeutic target., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Background: Traditional epidemiologic approaches such as time-series or case-crossover designs are often used to estimate the effects of extreme weather events but can be limited by unmeasured confounding. Quasi-experimental methods are a family of methods that leverage natural experiments to adjust for unmeasured confounding indirectly. The recently developed generalized synthetic control method that exploits the timing of an exposure is well suited to estimate the impact of acute environmental events on health outcomes. To demonstrate how this method can be used to study extreme weather events, we examined the impact of the 20-26 October 2007 Southern California wildfire storm on respiratory hospitalizations., Methods: We used generalized synthetic control to compare the average number of ZIP code-level respiratory hospitalizations during the wildfire storm between ZIP codes that were classified as exposed versus unexposed to wildfire smoke. We considered wildfire exposure eligibility for each ZIP code using fire perimeters and satellite-based smoke plume data. We retrieved respiratory hospitalization discharge data from the Office of Statewide Health Planning and Development. R code to implement the generalized synthetic control method is included for reproducibility., Results: The analysis included 172 exposed and 578 unexposed ZIP codes. We estimated that the average effect of the wildfire storm among the exposed ZIP codes was an 18% (95% confidence interval: 10% to 29%) increase in respiratory hospitalizations., Conclusions: We illustrate the use of generalized synthetic control to leverage natural experiments to quantify the health impacts of extreme weather events when traditional approaches are unavailable or limited by assumptions., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: To report key findings associated with an outbreak of SARS-CoV-2 following a teenage disco in Northern Ireland., Study Design: Observational case series., Methods: A case was defined as an individual who attended the event with a positive SARS-CoV-2 result between 6th and 20th November 2021. Demographic and clinical information, including symptom status, date of onset and school attended, were recorded during contact tracing. Vaccination status was derived from the COVID-19 Vaccine Management System. Forty-five samples associated with the outbreak were sequenced as part of the NI Whole Genome Sequencing (WGS) programme., Results: Only 2.4% (5/205) of cases received a COVID-19 vaccine more than 14 days before the event. 84.9% (174/205) had received no vaccine at the time of the event and 12.7% (26/205) had been vaccinated within 14 days, offering only limited disease protection. The AY4.2.2 lineage of two cases who attended the event after symptom onset was found in 69% of sequenced outbreak cases., Conclusions: This study demonstrates extensive COVID-19 transmission in largely unvaccinated teenagers in an indoor venue with limited social distancing, close social contact and mixing, limited ventilation and singing and shouting. Public Health authorities developing COVID-19 entertainment regulations should consider congregations of teenagers in these settings, especially if vaccination rates are low in this group or they are not eligible for vaccination at that time. Public communications should be developed to ensure young people with COVID-19 symptoms follow public guidance regarding self-isolation and in particular avoid indoor events with larger numbers., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

The US Food and Drug Administration (FDA) has concluded that the efficacy of drugs approved for the treatment of partial onset seizures (POS) in adults can be extrapolated to pediatric patients 1 month of age and above and that independent efficacy trials in this pediatric population are no longer needed. This paper focuses on the dosing, pharmacokinetic (PK), exposure-response, and clinical information that were leveraged from the approved drugs for the treatment of POS to conduct analyses that supported extrapolation of efficacy in pediatric patients. Clinical data from trials for eight drugs (levetiracetam, oxcarbazepine, topiramate, lamotrigine, gabapentin, perampanel, tiagabine, and vigabatrin) approved in both adults and pediatric patients for the treatment of POS were analyzed. Comparisons of exposures at approved doses, placebo response, and model-based exposure-response relationships were performed. Based on disease similarity, similar response to intervention, and similar exposure-response relationships in adults and pediatric patients, it was concluded that extrapolation of efficacy in pediatric patients aged 1 month and above is acceptable. PK analysis to determine pediatric dose and regimens that provide drug exposure similar to that known to be effective in adult patients with POS will be required, along with long-term open-label safety data in pediatric patients., (Published 2022. This article is a U.S. Government work and is in the public domain in the USA.)

Background Patients with symptomatic severe aortic stenosis (ssAS) have a high mortality risk and compromised quality of life. Surgical/transcatheter aortic valve replacement (AVR) is a Class I recommendation, but it is unclear if this recommendation is uniformly applied. We determined the impact of managing cardiologists on the likelihood of ssAS treatment. Methods and Results Using natural language processing of Optum electronic health records, we identified 26 438 patients with newly diagnosed ssAS (2011-2016). Multilevel, multivariable Fine-Gray competing risk models clustered by cardiologists were used to determine the impact of cardiologists on the likelihood of 1-year AVR treatment. Within 1 year of diagnosis, 35.6% of patients with ssAS received an AVR; however, rates varied widely among managing cardiologists (0%, lowest quartile; 100%, highest quartile [median, 29.6%; 25th-75th percentiles, 13.3%-47.0%]). The odds of receiving AVR varied >2-fold depending on the cardiologist (median odds ratio for AVR, 2.25; 95% CI, 2.14-2.36). Compared with patients with ssAS of cardiologists with the highest treatment rates, those treated by cardiologists with the lowest AVR rates experienced significantly higher 1-year mortality (lowest quartile, adjusted hazard ratio, 1.22, 95% CI, 1.13-1.33). Conclusions Overall AVR rates for ssAS were low, highlighting a potential challenge for ssAS management in the United States. Cardiologist AVR use varied substantially; patients treated by cardiologists with lower AVR rates had higher mortality rates than those treated by cardiologists with higher AVR rates.

Background/aims: To examine how measuring adherence at 3 weeks by self-report and pill counts compares to measurements at 7 weeks in a pre-randomization run-in period., Methods: Study within a trial of an international parallel group randomized controlled trial (RCT) that compares spironolactone to placebo. Adults receiving dialysis enter an 8-week active run-in period with spironolactone. Adherence was assessed by both self-report and pill counts in a subgroup of participants at both 3 weeks and 7 weeks., Results: 332 participants entered the run-in period of which 166 had complete data. By self-report, 146/166 (94.0%) and 153/166 (92.2%) had at least 80% adherence at 3 and 7 weeks respectively (kappa = 0.27 (95% C.I. 0.16 to 0.38). By pill counts, the mean (SD) adherence was 96.5% (16.1%) and 92.4% (18.2%) at 3 and 7 weeks respectively (r = 0.32) with a mean (SD) difference of 3.1% (17.8%) and a 95% limit of agreement from -31.7% to +37.9%. The proportion of adherent participants by self-report and pill counts at 3 weeks agreed in 87.4% of participants (McNemar's p-value 0.58, kappa 0.11, p = 0.02) and at 7 weeks agreed in 92.2% (McNemar's p-value 0.82, kappa 0.47, p < 0.001)., Conclusions: Three and seven-week run-in periods and both self-reported and pill count assessments performed similarly., Trial Registration: ClinicalTrials.gov Identifier: NCT03020303., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: We evaluated whether there is equitable distribution across sexes of treatment and outcomes for aortic valve replacement (AVR), via surgical (SAVR) or transcatheter (TAVR) methods, in symptomatic severe aortic stenosis (ssAS) patients., Methods: Using de-identified data, we identified 43,822 patients with ssAS (2008-2016). Multivariate competing risk models were used to determine the likelihood of any AVR, while accounting for the competing risk of death. Association between sex and 1-year mortality, stratified by AVR status, was evaluated using multivariate Cox regression models with AVR as a time-dependent variable., Results: Among patients with ssAS, 20,986 (47.9%) were female. Females were older (median age 81 vs. 78, P<0.001), more likely to have body mass index <20 (8.5% vs. 3.5%), and home oxygen use (4.4% vs. 3.4%, P<0001 for all). Overall, 12,129 (27.7%) patients underwent AVR for ssAS. Females were less likely to undergo AVR compared with males (24.1% vs. 31.0%, adjusted hazard ratio [HR] 0.80, 95% confidence interval [CI] 0.77-0.83), but when treated, were more likely to undergo TAVR (37.9% vs. 30.9%, adjusted HR 1.21, 95% CI 1.15-1.27). Untreated females and males had similarly high rates of mortality at 1 year (31.1% vs. 31.3%, adjusted HR 0.98, 95% CI 0.94-1.03). Among those undergoing AVR, females had significantly higher mortality (10.2% vs. 9.4%, adjusted HR 1.24, 95% CI 1.10-1.41), driven by increased SAVR-associated mortality (9.0% vs. 7.6%, adjusted HR 1.43, 95% CI 1.21-1.69)., Conclusions: Treatment rates for ssAS patients remain suboptimal with disparities in female treatment., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

As global pig health diseases, porcine respiratory disease complex (PRDC) and porcine circovirus-associated disease (PCVAD) generate substantial economic losses despite pigs been vaccinated against the primary causative virus, highlighting the importance of understanding virome interactions and specifically co-factor infections. Established primary endemic pathogens for PRDC include porcine circovirus 2 (PCV2), porcine reproductive and respiratory syndrome virus (PRRSv) and swine influenza virus (SIV), and PCV2 aetiology in interaction with other co-infecting viruses can result in PCVAD. Porcine parvovirus (PPV) 1 is a well-characterized virus with an available vaccine preventing reproductive failure in sows. However, whilst novel PPV 2 to 7 viruses have been identified since 2001, their viral pathogenic potential in clinical and subclinical disease remains to be determined. Therefore, this study has sought to develop a better understanding of their potential role as associated co-infections in PRDC and PCVAD by examining archival samples for the presence of PCV2 and the novel parvoviruses PPV2-4 from clinically diseased pigs across production age stages. Epidemiologically, the novel PPV2 was found to be the most prevalent within the fattener age group with PPV2-4 statistically associated with pig respiratory disease and enteric ulcers. Additionally, statistical modelling by latent class analysis (LCA) on veterinary pathology scored pigs found a clustering co-factor association between PPV2 and PCV2, suggesting the novel PPV may be involved in PRDC and PCVAD. Phylogenetic analysis of novel PPVs revealed the PPV2 capsid evolution to be diverged from the original strains with a low nucleotide homology of 88%-96% between two distinct clades. These findings determine that novel PPV 2-4 viruses are statistically associated as co-infectors in a diseased pig population, and significantly detected PPV2 clustering co-infection frequency with PCV2 in PRDC and PCVAD diseased pigs through LCA analysis., (© 2020 Crown copyright. Transboundary and Emerging Diseases published by Wiley-VCH GmbH.)

Understanding the activation properties of aerosol particles as cloud condensation nuclei (CCN) is important for the climate and hydrological cycle, but their properties are not fully understood. In this study, the CCN activation properties of aerosols are investigated at two different sites in southern Spain: an urban background station in Granada and a high altitude mountain station in the Sierra Nevada National Park, with a horizontal separation of 21 km and vertical separation of 1820 m. CCN activity at the urban environment is driven by primary sources, mainly road traffic. Maximum CCN concentrations occurred during traffic rush hours, although this is also when the activation fraction is lowest. This is due to the characteristics of the rush hour aerosol consisting of ultrafine and less hygroscopic particles. In contrast, the mountain site exhibited larger and more hygroscopic particles, with CCN activity driven by the joint effect of new particle formation (NPF) and vertical transport of anthropogenic particles from Granada urban area by orographic buoyant upward flow. This led to the maximum concentrations of CCN and aerosol particles occurring at midday at the mountain site. Clear differences in the diurnal evolution of CCN between NPF events and non-event days were observed at the Sierra Nevada station, demonstrating the large contribution of NPF to CCN concentrations, especially at high supersaturations. The isolated contribution of NPF to CCN concentration has been estimated to be 175% higher at SS = 0.5% relative to what it would be without NPF. We conclude that NPF could be the major source of CCN at this mountain site. Finally, two empirical models were used to parameterize CCN concentration in terms of aerosol optical or physical parameters. The models can explain measurements satisfactorily at the urban station. At the mountain site both models cannot reproduce satisfactorily the observations at low SS., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

The purpose of electronic health record (EHR) abstraction includes collection of data related to administrative coding functions, quality improvement, clinical registry functions and clinical research. This article examines the different abstraction methods, such as manual abstraction, simple query, and natural language processing (NLP). It also discusses the advantages and disadvantages of each of those methods. The process used for successful EHR abstraction is also discussed and includes the scope and resources needed (time, budget, type of healthcare professionals RHIA, RHIT, etc.). The relationship between EHRs and the clinical registry is also examined with a focus on validity of the data extracted. Future research in this area to examine abstraction methods across hospitals who do data abstraction are being finalized for a future publication., (Copyright © 2021 by the American Health Information Management Association.)

Objective: We aimed to compare cardiovascular (CV) events, all-cause mortality, and CV mortality rates among adults with and without diabetes in countries with differing levels of income., Research Design and Methods: The Prospective Urban Rural Epidemiology (PURE) study enrolled 143,567 adults aged 35-70 years from 4 high-income countries (HIC), 12 middle-income countries (MIC), and 5 low-income countries (LIC). The mean follow-up was 9.0 ± 3.0 years., Results: Among those with diabetes, CVD rates (LIC 10.3, MIC 9.2, HIC 8.3 per 1,000 person-years, P < 0.001), all-cause mortality (LIC 13.8, MIC 7.2, HIC 4.2 per 1,000 person-years, P < 0.001), and CV mortality (LIC 5.7, MIC 2.2, HIC 1.0 per 1,000 person-years, P < 0.001) were considerably higher in LIC compared with MIC and HIC. Within LIC, mortality was higher in those in the lowest tertile of wealth index (low 14.7%, middle 10.8%, and high 6.5%). In contrast to HIC and MIC, the increased CV mortality in those with diabetes in LIC remained unchanged even after adjustment for behavioral risk factors and treatments (hazard ratio [95% CI] 1.89 [1.58-2.27] to 1.78 [1.36-2.34])., Conclusions: CVD rates, all-cause mortality, and CV mortality were markedly higher among those with diabetes in LIC compared with MIC and HIC with mortality risk remaining unchanged even after adjustment for risk factors and treatments. There is an urgent need to improve access to care to those with diabetes in LIC to reduce the excess mortality rates, particularly among those in the poorer strata of society., (© 2020 by the American Diabetes Association.)

Objective: Previous prospective studies on the association of white rice intake with incident diabetes have shown contradictory results but were conducted in single countries and predominantly in Asia. We report on the association of white rice with risk of diabetes in the multinational Prospective Urban Rural Epidemiology (PURE) study., Research Design and Methods: Data on 132,373 individuals aged 35-70 years from 21 countries were analyzed. White rice consumption (cooked) was categorized as <150, ≥150 to <300, ≥300 to <450, and ≥450 g/day, based on one cup of cooked rice = 150 g. The primary outcome was incident diabetes. Hazard ratios (HRs) were calculated using a multivariable Cox frailty model., Results: During a mean follow-up period of 9.5 years, 6,129 individuals without baseline diabetes developed incident diabetes. In the overall cohort, higher intake of white rice (≥450 g/day compared with <150 g/day) was associated with increased risk of diabetes (HR 1.20; 95% CI 1.02-1.40; P for trend = 0.003). However, the highest risk was seen in South Asia (HR 1.61; 95% CI 1.13-2.30; P for trend = 0.02), followed by other regions of the world (which included South East Asia, Middle East, South America, North America, Europe, and Africa) (HR 1.41; 95% CI 1.08-1.86; P for trend = 0.01), while in China there was no significant association (HR 1.04; 95% CI 0.77-1.40; P for trend = 0.38)., Conclusions: Higher consumption of white rice is associated with an increased risk of incident diabetes with the strongest association being observed in South Asia, while in other regions, a modest, nonsignificant association was seen., (© 2020 by the American Diabetes Association.)

Wildfire smoke adversely impacts respiratory health as fine particles can penetrate deeply into the lungs. Epidemiological studies of differential impacts typically target population subgroups in terms of vulnerability to wildfire smoke. Such information is useful to customize smoke warnings and mitigation actions for specific groups of individuals. In addition to individual vulnerability, it is also important to assess spatial patterns of health impacts to identify vulnerable communities and tailor public health actions during wildfire smoke events., Methods: We assess the spatiotemporal variation in respiratory hospitalizations in San Diego County during a set of major wildfires in 2007, which led to a substantial public health burden. We propose a spatial within-community matched design analysis, adapted to the study of wildfire impacts, coupled with a Bayesian Hierarchical Model, that explicitly considers the spatial variation of respiratory health associated with smoke exposure, compared to reference periods before and after wildfires. We estimate the signal-to-noise ratio to ultimately gauge the precision of the Bayesian model output., Results: We find the highest excess hospitalizations in areas covered by smoke, mainly ZIP codes contained by and immediately downwind of wildfire perimeters, and that excess hospitalizations tend to follow the distribution of smoke plumes across space (ZIP codes) and time (days)., Conclusions: Analyzing the spatiotemporal evolution of exposure to wildfire smoke is necessary due to variations in smoke plume extent, particularly in this region where the most damaging wildfires are associated with strong wind conditions., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report.Sponsorships or competing interests that may be relevant to content are disclosed at the end of the article., (Copyright © 2020 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Background: Recent studies have reported inconsistent associations between maternal residential green space and preterm birth (PTB, born < 37 completed gestational weeks). In addition, windows of susceptibility during pregnancy have not been explored and potential interactions of green space with air pollution exposures during pregnancy are still unclear., Objectives: To evaluate the relationships between green space and PTB, identify windows of susceptibility, and explore potential interactions between green space and air pollution., Methods: Birth certificate records for all births in California (2001-2008) were obtained. The Normalized Difference Vegetation Index (NDVI) was used to characterized green space exposure. Gestational age was treated as a time-to-event outcome; Cox proportional hazard models were applied to estimate the association between green space exposure and PTB, moderately PTB (MPTB, gestational age < 35 weeks), and very PTB (VPTB, gestational age < 30 weeks), after controlling for maternal age, race/ethnicity, education, and median household income. Month-specific green space exposure was used to identify potential windows of susceptibility. Potential interactions between green space and air pollution [fine particulate matter < 2.5 µm (PM 2.5 ), nitrogen dioxide (NO 2 ), and ozone (O 3 )] were examined on both additive and multiplicative scales., Results: In total, 3,753,799 eligible births were identified, including 341,123 (9.09%) PTBs, 124,631 (3.32%) MPTBs, and 22,313 (0.59%) VPTBs. A reduced risk of PTB was associated with increases in residential NDVI exposure in 250 m, 500 m, 1000 m, and 2000 m buffers. In the 2000 m buffer, the association was strongest for VPTB [adjusted hazard ratio (HR) per interquartile range increase in NDVI: 0.959, 95% confidence interval (CI): 0.942-0.976)], followed by MPTB (HR = 0.970, 95% CI: 0.962-0.978) and overall PTB (HR = 0.972, 95% CI: 0.966-0.978). For PTB, green space during the 3rd - 5th gestational months had stronger associations than those in the other time periods, especially during the 4th gestational month (NDVI 2000 m: HR = 0.970, 95% CI: 0.965-0.975). We identified consistent positive additive and multiplicative interactions between decreasing green space and higher air pollution., Conclusion: This large study found that maternal exposure to residential green space was associated with decreased risk of PTB, MPTB, and VPTB, especially in the second trimester. There is a synergistic effect between low green space and high air pollution levels on PTB, indicating that increasing exposure to green space may be more beneficial for women with higher air pollution exposures during pregnancy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background Aortic valve replacement (AVR) is a life-saving treatment for patients with symptomatic severe aortic valve stenosis. We sought to determine whether transcatheter AVR has resulted in a more equitable treatment rate by race in the United States. Methods and Results A total of 32 853 patients with symptomatic severe aortic valve stenosis were retrospectively identified via Optum's deidentified electronic health records database (2007-2017). AVR rates in non-Hispanic Black and White patients were assessed in the year after diagnosis. Multivariate Fine-Gray hazards models were used to evaluate the likelihood of AVR by race, with adjustment for patient factors and the managing cardiologist. Time-trend and 1-year symptomatic severe aortic valve stenosis survival analyses were also performed. From 2011 to 2016, the rate of AVR increased from 20.1% to 37.1%. Overall, Black individuals were less likely than Whites to receive AVR (22.9% versus 31.0%; unadjusted hazard ratio [HR], 0.70; 95% CI, 0.62-0.79; fully adjusted HR, 0.76; 95% CI, 0.67-0.85). Yet, during 2015 to 2016, AVR racial differences were attenuated (29.5% versus 35.2%; adjusted HR, 0.86; 95% CI, 0.74-1.02) because of greater uptake of transcatheter AVR in Blacks than Whites (53.4% of AVRs versus 47.3%; P =0.128). Untreated patients had significantly higher 1-year mortality than those treated (adjusted HR, 0.57; 95% CI, 0.53-0.61), which was consistent by race (interaction P value=0.52). Conclusions Although transcatheter AVR has increased the use of AVR in the United States, treatment rates remain low. Black patients with symptomatic severe aortic valve stenosis were less likely than White patients to receive AVR, yet these differences have recently narrowed.

Background: Hematologic toxicity is a critical problem limiting treatment delivery in cancer patients undergoing concurrent chemoradiotherapy. However, the extent to which anatomic variations in radiation dose limit chemotherapy delivery is poorly understood. A unique natural experiment arises in patients with head and neck and cervical cancer, who frequently undergo identical chemotherapy but receive radiation to different regions of the body. Comparing these cohorts can help elucidate to what extent hematologic toxicity is attributable to marrow radiation as opposed to chemotherapy. Methods: In this longitudinal cohort study, we compared hematologic toxicity and bone marrow compensatory response in 148 patients (90 cervix, 58 head/neck) undergoing chemoradiotherapy with concurrent weekly cisplatin 40 mg/m 2 . We used linear mixed effect models to compare baseline and time-varying peripheral cell counts and hemoglobin levels between cohorts. To assess bone marrow compensatory response, we measured the change in metabolically active bone marrow (ABM) volume on 18 F-fluorodeoxyglucose positron emission tomography/computed tomography. Results: We observed greater reductions in log-transformed lymphocyte, platelet, and absolute neutrophil counts (ANC) for cervix compared to head/neck cancer patients (fixed effects for time-cohort interaction [95% CI]: lymphocytes, -0.06 [-0.09, -0.031]; platelets,-0.028 [-0.051, -0.0047]; ANC, -0.043 [-0.075, -0.011]). Mean ANC nadirs were also lower for cervical vs. head/neck cancer cohorts (2.20 vs. 2.85 × 10 3 per μL, p < 0.01). Both cohorts exhibited reductions in ABM volume within the radiation field, and increases in ABM volume in out-of-field areas, indicating varying compensatory response to radiation injury. Conclusions: Cervical cancer patients had faster decreases in ANC, lymphocyte, and platelet counts, and lower ANC nadirs, indicating a significant effect of pelvic irradiation on acute peripheral blood cell counts. Both cohorts exhibited a compensatory response with increased out-of-field bone marrow activity., (Copyright © 2020 Vitzthum, Heide, Park, Williamson, Sheridan, Huynh-Le, Sirak, Wei, Tarnawski, Mahantshetty, Nguyen, Mayadev, Yashar, Sacco and Mell.)

The objective of this study is to assess the impact of the California 1995 Smoke-Free Workplace Act (SFWA) on cigarette smoking prevalence in the population. We used survey responses related to cigarette smoking from the Behavioral Risk Factor Surveillance System (BRFSS) from 1990 to 2000. We utilize a synthetic control method which creates a weighted combination of control states to produce a single 'synthetic' control group to best approximate the counterfactual trend in California in the absence of the SFWA. Variables known to be associated with smoking were included to weight each state in the pre-intervention period as medians by state and included: distribution of race/ethnicity (White, Black, Asian, Hispanic), sex (Male/Female), marital status (married/unmarried), high school education (yes/no) and employment status (yes/no). We find evidence that there was a small decrease in population smoking prevalence in California in the year immediately following the SFWA, but this effect was not sustained beyond 1995. We hypothesize that one potential explanation for the lack of prolonged impact on population smoking prevalence is that there are sustained effects from the passage of 1989 California Proposition 99, which enacted an excise tax on tobacco products. Understanding how workplace smoking ban legislation affects population smoking behaviors is necessary to better inform policy development in other states and counties and to improve existing policies. Future work should consider the impact of smoking legislation impacts subgroups of the population by socioeconomic status, occupation or race/ethnicity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 Published by Elsevier Inc.)

Background: Although opioids play a critical role in the management of cancer pain, the ongoing opioid epidemic has raised concerns regarding their persistent use and abuse. We lack data-driven tools in oncology to understand the risk of adverse opioid-related outcomes. This project seeks to identify clinical risk factors and create a risk score to help identify patients at risk of persistent opioid use and abuse., Methods: Within a cohort of 106 732 military veteran cancer survivors diagnosed between 2000 and 2015, we determined rates of persistent posttreatment opioid use, diagnoses of opioid abuse or dependence, and admissions for opioid toxicity. A multivariable logistic regression model was used to identify patient, cancer, and treatment risk factors associated with adverse opioid-related outcomes. Predictive risk models were developed and validated using a least absolute shrinkage and selection operator regression technique., Results: The rate of persistent opioid use in cancer survivors was 8.3% (95% CI = 8.1% to 8.4%); the rate of opioid abuse or dependence was 2.9% (95% CI = 2.8% to 3.0%); and the rate of opioid-related admissions was 2.1% (95% CI = 2.0% to 2.2%). On multivariable analysis, several patient, demographic, and cancer and treatment factors were associated with risk of persistent opioid use. Predictive models showed a high level of discrimination when identifying individuals at risk of adverse opioid-related outcomes including persistent opioid use (area under the curve [AUC] = 0.85), future diagnoses of opioid abuse or dependence (AUC = 0.87), and admission for opioid abuse or toxicity (AUC = 0.78)., Conclusion: This study demonstrates the potential to predict adverse opioid-related outcomes among cancer survivors. With further validation, personalized risk-stratification approaches could guide management when prescribing opioids in cancer patients., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Importance: Researchers often analyze cancer registry data to assess for differences in survival among cancer treatments. However, the retrospective, nonrandomized design of these analyses raises questions about study validity., Objective: To examine the extent to which comparative effectiveness analyses using observational cancer registry data produce results concordant with those of randomized clinical trials., Design, Setting, and Participants: In this comparative effectiveness study, a total of 141 randomized clinical trials referenced in the National Comprehensive Cancer Network Clinical Practice Guidelines for 8 common solid tumor types were identified. Data on participants within the National Cancer Database (NCDB) diagnosed between 2004 and 2014, matching the eligibility criteria of the randomized clinical trial, were obtained. The present study was conducted from August 1, 2017, to September 10, 2019. The trials included 85 118 patients, and the corresponding NCDB analyses included 1 344 536 patients. Three Cox proportional hazards regression models were used to determine hazard ratios (HRs) for overall survival, including univariable, multivariable, and propensity score-adjusted models. Multivariable and propensity score analyses controlled for potential confounders, including demographic, comorbidity, clinical, treatment, and tumor-related variables., Main Outcomes and Measures: The main outcome was concordance between the results of randomized clinical trials and observational cancer registry data. Hazard ratios with an NCDB analysis were considered concordant if the NDCB HR fell within the 95% CI of the randomized clinical trial HR. An NCDB analysis was considered concordant if both the NCDB and clinical trial P values for survival were nonsignificant (P ≥ .05) or if they were both significant (P < .05) with survival favoring the same treatment arm in the NCDB and in the randomized clinical trial., Results: Analyses using the NCDB-produced HRs for survival were concordant with those of 141 randomized clinical trials in 79 univariable analyses (56%), 98 multivariable analyses (70%), and 90 propensity score models (64%). The NCDB analyses produced P values concordant with randomized clinical trials in 58 univariable analyses (41%), 65 multivariable analyses (46%), and 63 propensity score models (45%). No clinical trial characteristics were associated with concordance between NCDB analyses and randomized clinical trials, including disease site, type of clinical intervention, or severity of cancer., Conclusions and Relevance: The findings of this study suggest that comparative effectiveness research using cancer registry data often produces survival outcomes discordant with those of randomized clinical trial data. These findings may help provide context for clinicians and policy makers interpreting observational comparative effectiveness research in oncology.

Background and Purpose- Patients with transient ischemic attack (TIA) and minor ischemic stroke are at risk for early recurrent cerebral ischemia. Anticoagulants are associated with reduced recurrence but also increased hemorrhagic transformation (HT). The safety of the novel oral anticoagulant dabigatran in acute stroke has not been evaluated. Methods- DATAS II (Dabigatran Treatment of Acute Stroke II) was a phase II prospective, randomized open label, blinded end point trial. Patients with noncardioembolic stroke/transient ischemic attack (National Institutes of Health Stroke Scale score, ≤9; infarct volume, ≤25 mL) were randomized to dabigatran or aspirin. Magnetic resonance imaging was performed before randomization and repeated at day 30. Imaging end points were ascertained centrally by readers blinded to treatment. The primary end point was symptomatic HT within 37 days of randomization. Results- A total of 305 patients, mean age 66.59±13.21 years, were randomized to dabigatran or aspirin a mean of 42.00±17.31 hours after symptom onset. The qualifying event was a transient ischemic attack in 21%, and ischemic stroke in 79% of patients. Median National Institutes of Health Stroke Scale (interquartile range) was 1 (0-2), and mean infarct volume 3.2±6.5 mL. No symptomatic HT occurred. Asymptomatic petechial HT developed in 11/142 (7.8%) of dabigatran-assigned patients and 5/142 (3.5%) of aspirin-assigned patients (relative risk, 2.301 [95% CI, 0.778-6.802]). Baseline infarct volume predicted incident HT (odds ratio, 1.07 [95% CI, 1.03-1.12]; P =0.0026). Incident covert infarcts on day 30 imaging occurred in 9/142 (6.3%) of dabigatran-assigned and 14/142 (9.8%) of aspirin-assigned patients (relative risk, 0.62 [95% CI, 0.26, 1.48]). Conclusions- Dabigatran was associated with a risk of HT similar to aspirin in acute minor noncardioembolic ischemic stroke/transient ischemic attack. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02295826.

Objective: Our aims were to assess the association of dairy intake with prevalence of metabolic syndrome (MetS) (cross-sectionally) and with incident hypertension and incident diabetes (prospectively) in a large multinational cohort study., Methods: The Prospective Urban Rural Epidemiology (PURE) study is a prospective epidemiological study of individuals aged 35 and 70 years from 21 countries on five continents, with a median follow-up of 9.1 years. In the cross-sectional analyses , we assessed the association of dairy intake with prevalent MetS and its components among individuals with information on the five MetS components (n=112 922). For the prospective analyses , we examined the association of dairy with incident hypertension (in 57 547 individuals free of hypertension) and diabetes (in 131 481 individuals free of diabetes)., Results: In cross-sectional analysis, higher intake of total dairy (at least two servings/day compared with zero intake; OR 0.76, 95% CI 0.71 to 0.80, p-trend<0.0001) was associated with a lower prevalence of MetS after multivariable adjustment. Higher intakes of whole fat dairy consumed alone (OR 0.72, 95% CI 0.66 to 0.78, p-trend<0.0001), or consumed jointly with low fat dairy (OR 0.89, 95% CI 0.80 to 0.98, p-trend=0.0005), were associated with a lower MetS prevalence. Low fat dairy consumed alone was not associated with MetS (OR 1.03, 95% CI 0.77 to 1.38, p-trend=0.13). In prospective analysis, 13 640 people with incident hypertension and 5351 people with incident diabetes were recorded. Higher intake of total dairy (at least two servings/day vs zero serving/day) was associated with a lower incidence of hypertension (HR 0.89, 95% CI 0.82 to 0.97, p-trend=0.02) and diabetes (HR 0.88, 95% CI 0.76 to 1.02, p-trend=0.01). Directionally similar associations were found for whole fat dairy versus each outcome., Conclusions: Higher intake of whole fat (but not low fat) dairy was associated with a lower prevalence of MetS and most of its component factors, and with a lower incidence of hypertension and diabetes. Our findings should be evaluated in large randomized trials of the effects of whole fat dairy on the risks of MetS, hypertension, and diabetes., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Preterm birth is a leading cause of infant morbidity and mortality. Identifying potentially modifiable triggers toward the end of gestation, such as extreme heat, can improve understanding of the role of acute stress on early deliveries and inform warning systems. In this study we examined the association between extreme heat, variously defined during the last week of gestation, and risk of preterm birth among mothers in California., Methods: We created a population-based cohort comprised of 1,967,300 mothers who had live, singleton births in California, from May through September 2005-2013. Daily temperature data estimated at the maternal zip code of residence was used to create 12 definitions of extreme heat with varying relative temperatures (75th, 90th, 95th, and 98th percentiles) and durations (at least 2, 3, or 4 consecutive days). We estimated risk of preterm birth (<37 gestational weeks) in relation to exposure to extreme heat during the last week of gestation with multi-level Cox proportional hazard regression models, adjusting for maternal characteristics, sex of neonate, and seasonality. We also included randomly generated data, SAS code, and estimates for reproducibility purposes., Results: Approximately 7% of the cohort had a preterm birth. For all definitions of extreme heat, the risk of preterm birth was consistently higher among mothers who experienced an extreme heat episode during their last week of gestation. Hazard ratios ranged from 1.008 (95% CI: 0.997, 1.021) to 1.128 (95% CI: 1.052, 1.210), with increasing associations as the relative temperature and duration of extreme heat episode increased., Conclusion: This study adds to the previous literature by considering multiple definitions of extreme heat and applying a time-to-event framework. Findings suggest that acute exposure to extreme heat during the last week of gestation may trigger an earlier delivery. Implementing heat warning systems targeted toward pregnant women may improve birth outcomes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Ltd.)

Background: Eggs are a rich source of essential nutrients, but they are also a source of dietary cholesterol. Therefore, some guidelines recommend limiting egg consumption. However, there is contradictory evidence on the impact of eggs on diseases, largely based on studies conducted in high-income countries., Objectives: Our aim was to assess the association of egg consumption with blood lipids, cardiovascular disease (CVD), and mortality in large global studies involving populations from low-, middle-, and high-income countries., Methods: We studied 146,011 individuals from 21 countries in the Prospective Urban Rural Epidemiology (PURE) study. Egg consumption was recorded using country-specific validated FFQs. We also studied 31,544 patients with vascular disease in 2 multinational prospective studies: ONTARGET (Ongoing Telmisartan Alone and in Combination with Ramipril Global End Point Trial) and TRANSCEND (Telmisartan Randomized Assessment Study in ACEI Intolerant Subjects with Cardiovascular Disease). We calculated HRs using multivariable Cox frailty models with random intercepts to account for clustering by study center separately within each study., Results: In the PURE study, we recorded 14,700 composite events (8932 deaths and 8477 CVD events). In the PURE study, after excluding those with history of CVD, higher intake of egg (≥7 egg/wk compared with <1 egg/wk intake) was not significantly associated with blood lipids, composite outcome (HR: 0.96; 95% CI: 0.89, 1.04; P-trend = 0.74), total mortality (HR: 1.04; 95% CI: 0.94, 1.15; P-trend = 0.38), or major CVD (HR: 0.92; 95% CI: 0.83, 1.01; P-trend = 0.20). Similar results were observed in ONTARGET/TRANSCEND studies for composite outcome (HR 0.97; 95% CI: 0.76, 1.25; P-trend = 0.09), total mortality (HR: 0.88; 95% CI: 0.62, 1.24; P-trend = 0.55), and major CVD (HR: 0.97; 95% CI: 0.73, 1.29; P-trend = 0.12)., Conclusions: In 3 large international prospective studies including ∼177,000 individuals, 12,701 deaths, and 13,658 CVD events from 50 countries in 6 continents, we did not find significant associations between egg intake and blood lipids, mortality, or major CVD events. The ONTARGET and TRANSCEND trials were registered at clinicaltrials.gov as NCT00153101. The PURE trial was registered at clinicaltrials.gov as NCT03225586., (Copyright © The Author(s) 2020.)

Fungi are ubiquitous and often abundant components of virtually all ecosystems on Earth, serving a diversity of functions. While there is clear evidence that fungal-mediated processes can influence environmental conditions, and in turn select for specific fungi, it is less clear how fungi respond to environmental fluxes over relatively long time frames. Here we set out to examine changes in airborne fungi collected over the course of 13 y, which is the longest sampling time to date. Air filter samples were collected from the Mauna Loa Observatory (MLO) on Hawaii Island, and analyzed using Illumina amplicon sequencing. As a study site, MLO is unique because of its geographic isolation and high elevation, making it an ideal place to capture global trends in climate and aerobiota. We found that the fungal aerobiota sampled at MLO had high species turnover, but compositional similarity did not decrease as a function of time between samples. We attribute these patterns to neutral processes such as idiosyncratic dispersal timing and trajectories. Furthermore, the composition of fungi at any given point was not significantly influenced by any local or global environmental variables we examined. This, and our additional finding of a core set of persistent fungi during our entire sampling period, indicates some degree of stability among fungi in the face of natural environmental fluctuations and human-associated global change. We conclude that the movement of fungi through the atmosphere is a relatively stochastic process., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Exposure to ambient fine particulate matter (particulate matter ≤2.5 μm in aerodynamic diameter (PM2.5)) during pregnancy is associated with preterm birth (PTB), a leading cause of infant morbidity and mortality. Results from studies attempting to identify etiologically relevant exposure periods of vulnerability have been inconsistent, possibly because of failure to consider the time-to-event nature of the outcome and lagged exposure effects of PM2.5. In this study, we aimed to identify critical exposure windows for weekly PM2.5 exposure and PTB in California using California birth cohort data from 2005-2010. Associations were assessed using distributed-lag Cox proportional hazards models. We assessed effect-measure modification by race/ethnicity by calculating the weekly relative excess risk due to interaction. For a 10-μg/m3 increase in PM2.5 exposure over the entire period of gestation, PTB risk increased by 11% (hazard ratio = 1.11, 95% confidence interval: 1.09, 1.14). Gestational weeks 17-24 and 36 were associated with increased vulnerability to PM2.5 exposure. We find that non-Hispanic black mothers may be more susceptible to effects of PM2.5 exposure than non-Hispanic white mothers, particularly at the end of pregnancy. These findings extend our knowledge about the existence of specific exposure periods during pregnancy that have the greatest impact on preterm birth., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Embolic stroke of undetermined source (ESUS) identifies patients with cryptogenic ischemic stroke presumed due to embolism from several unidentified sources. Among patients with recent ESUS, we sought to determine independent predictors of recurrent ischemic stroke during treatment with aspirin or rivaroxaban and to assess the relative effects of these treatments according to risk., Methods: Exploratory analyses of 7213 participants in the NAVIGATE ESUS international trial who were randomized to aspirin 100 mg/day or rivaroxaban 15 mg/day and followed for a median of 11 months, during which time there were 309 first recurrent ischemic strokes (4.6% per year). Baseline features were correlated with recurrent stroke by multivariate analysis., Results: The 7 independent predictors of recurrent stroke were stroke or transient ischemic attack (TIA) prior to the qualifying stroke (hazard ratio [HR] 2.03 95% confidence internal [CI] 1.58-2.60), current tobacco user (HR 1.62, 95% CI 1.24-2.12), age (HR 1.02 per year increase, 95%CI 1.01-1.03), diabetes (HR 1.28, 95% CI 1.01-1.64), multiple acute infarcts on neuroimaging (HR 1.49, 95% CI 1.09-2.02), aspirin use prior to qualifying stroke (HR 1.34, 95% CI 1.02-1.70), and time from qualifying stroke to randomization (HR .98, 95% CI .97-.99). The rate of recurrent stroke rate was 2.6% per year for participants without any of these risk factors, and increased by an average of 45% for each independent predictor (P < .001). There were no significant interactions between treatment effects and independent stroke predictors or stroke risk status., Conclusions: In this large cohort of ESUS patients, several features including prior stroke or TIA, advanced age, current tobacco user, multiple acute infarcts on neuroimaging, and diabetes independently identified those with an increased risk of ischemic stroke recurrence. The relative effects of rivaroxaban and aspirin were similar across the spectrum of independent stroke predictors and recurrent stroke risk status., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Exposure to fine particulate matter (PM 2.5 ) during pregnancy has been shown to be associated with reduced birth weight and racial/ethnic minorities have been found to be more vulnerable. Previous studies have focused on the mean value of birth weight associated with PM 2.5 , which may mask meaningful differences. We applied a quantile regression approach to investigate the variation by percentile of birth weight and compared non-Hispanic (NH) Black, NH White, and Hispanic mothers., Methods: Data for singleton births in California from October 24, 2005 to February 27, 2010 were collected from the birth records accessed from the California Department of Public Health. Air pollution monitoring data collected by the California Air Resources Board and interpolated for each zip code using an inverse-distance weighting approach, and linked to maternal zip code of residence reported on the birth certificate. Multilevel linear regression models were conducted with mother's residential zip code tabulation area as a random effect. Multilevel quantile regression models were used to analyze the association at different percentiles of birth weight (5th, 10th, 25th, 50th, 75th, 90th, 95th), as well as examine the heterogeneity in this association between racial/ethnic groups., Results: Linear regression revealed that a 10 μg/m 3 increase in PM 2.5 exposure during pregnancy is associated with a mean birth weight decrease of 7.31 g [95% confidence interval (CI): 8.10, 6.51] and NH Black mothers are the most vulnerable. Results of the quantile regression are not constant across quantiles. For NH Black mothers whose infants had the lowest birthweight of less than 2673 g (5th percentile), a 10 μg/m 3 increase in PM 2.5 exposure is associated with a decrease of 18.57 g [95% CI: 22.23, 14.91], while it is associated with a decrease of 7.77 g [95% CI: 8.73, 6.79] for NH White mothers and 7.76 [8.52, 7.00] decrease for Hispanic mothers at the same quantile., Conclusion: Results of the quantile regression revealed greater disparities, particularly for infants with the lowest birth weight. By identifying vulnerable populations, we can promote and implement policies to confront these health disparities., (Copyright © 2019 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of Environmental Epidemiology. All rights reserved.)

Aims and Objectives: To report the development, testing and validation of an instrument to assess the stressors experienced by student nurses during their older adult clinical placements., Background: The world's population of older adults is accelerating rapidly, with associated increased healthcare demands and a growing need for skilled nursing staff. However, this sector fails to attract adequate numbers of nursing graduates which is leading to a significant gap between nursing supply and demand. Older adult care is considered to be less attractive than other specialties and accompanied by more sources of stress., Design: A quantitative design was used., Methods: Data were collected from a cohort of Irish student nurses (n = 242) completing older adult clinical placements as part of their undergraduate degree. Exploratory and confirmatory factor analysis examined the instrument's underlying latent structure. Discriminant validity was investigated using a confirmatory factor analysis model with covariates. STROBE guidelines for cross-sectional studies informed reporting of this paper's research., Results: Factor analyses identified two factors relating to "Knowledge and Workload" and "Resources," which were assessed by nine and six items, respectively. Discriminant validity analyses found a significant relationship between age and the workload and knowledge factor, and between year of programme and the resources factor. The new instrument was labelled the Student Nurse Stressor-15 (SNS-15) Scale., Conclusions: The SNS-15 contained some overlap with stressors from extant general student nurse stress instruments and a number of unique stressors encountered in older adult care. Future research directions are discussed., Relevance to Clinical Practice: The SNS-15 may assist stakeholders in nurse education and practice with the development of undergraduate degree programmes and clinical placements, and ultimately, in improving patient care and student retention., (© 2018 John Wiley & Sons Ltd.)

The U.S. Environmental Protection Agency (EPA) is involved in the discovery, evaluation, and application of low-cost air quality (AQ) sensors to support citizen scientists by directly engaging with them in the pursuit of community-based interests. The emergence of low-cost (<$2500) sensors have allowed a wide range of stakeholders to better understand local AQ conditions. Here we present results from the deployment of the EPA developed Citizen Science Air Monitor (CSAM) used to conduct approximately five months (October 2016⁻February 2017) of intensive AQ monitoring in an area of Puerto Rico (Tallaboa-Encarnación, Peñuelas) with little historical data on pollutant spatial variability. The CSAMs were constructed by combining low-cost particulate matter size fraction 2.5 micron (PM 2.5 ) and nitrogen dioxide (NO₂) sensors and distributed across eight locations with four collocated weather stations to measure local meteorological parameters. During this deployment 1 h average concentrations of PM 2.5 and NO₂ ranged between 0.3 to 33.6 µg/m³ and 1.3 to 50.6 ppb, respectively. Peak concentrations were observed for both PM 2.5 and NO₂ when conditions were dominated by coastal-originated winds. These results advanced the community's understanding of pollutant concentrations and trends while improving our understanding of the limitations and necessary procedures to properly interpret measurements produced by low-cost sensors.

Maternal exposure to ambient air pollution has been associated with preterm birth (PTB), however, entire pregnancy or trimester-specific associations were generally reported, which may not sufficiently identify windows of susceptibility. Using birth registry data from Guangzhou, a megacity of southern China (population ~14.5 million), including 469,975 singleton live births between January 2015 and July 2017, we assessed the association between weekly air pollution exposure and PTB in a retrospective cohort study. Daily average concentrations of PM 2.5 , PM 10 , NO 2 , SO 2 , and O 3 from 11 monitoring stations were used to estimate district-specific exposures for each participant based on their district residency during pregnancy. Distributed lag models (DLMs) incorporating Cox proportional hazard models were applied to estimate the association between weekly maternal exposure to air pollutant and PTB risk (as a time-to-event outcome), after controlling for temperature, seasonality, and individual-level covariates. We also considered moderate PTB (32-36 gestational weeks) and very PTB (28-31 gestational weeks) as outcomes of interest. Hazard ratios (HRs) and 95% confidential intervals (95% CIs) were calculated for an interquartile range (IQR) increase in air pollutants during the study period. An IQR increase in PM 2.5 exposure during the 20th to 28th gestational weeks (27.0 μg/m 3 ) was significantly associated with PTB risk, with the strongest effect in the 25th week (HR = 1.034, 95% CI:1.010-1.059). The significant exposure windows were the 19th-28th weeks for PM 10 , the 18th-31st weeks for NO 2 , and the 23rd-31st weeks for O 3 , respectively. The strongest associations were observed in the 25th week for PM 10 (IQR = 37.0 μg/m 3 ; HR = 1.048, 95% CI:1.034-1.062), the 26th week for NO 2 (IQR = 29.0 μg/m 3 ; HR = 1.060, 95% CI:1.028-1.094), and in the 28th week for O 3 (IQR = 90.0 μg/m 3 ; HR = 1.063, 95% CI:1.046-1.081). Similar patterns were observed for moderate PTB (32-36 gestational weeks) and very PTB (28-31 gestational weeks) for PM 2.5 , PM 10 , NO 2 exposure, but the effects were greater for very PTB. We did not observe any association between pregnancy SO 2 exposure and the risk of PTB. Our results suggest that middle to late pregnancy is the most susceptible air pollution exposure window for air pollution and PTB among women in Guangzhou, China., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Dietary guidelines recommend minimising consumption of whole-fat dairy products, as they are a source of saturated fats and presumed to adversely affect blood lipids and increase cardiovascular disease and mortality. Evidence for this contention is sparse and few data for the effects of dairy consumption on health are available from low-income and middle-income countries. Therefore, we aimed to assess the associations between total dairy and specific types of dairy products with mortality and major cardiovascular disease., Methods: The Prospective Urban Rural Epidemiology (PURE) study is a large multinational cohort study of individuals aged 35-70 years enrolled from 21 countries in five continents. Dietary intakes of dairy products for 136 384 individuals were recorded using country-specific validated food frequency questionnaires. Dairy products comprised milk, yoghurt, and cheese. We further grouped these foods into whole-fat and low-fat dairy. The primary outcome was the composite of mortality or major cardiovascular events (defined as death from cardiovascular causes, non-fatal myocardial infarction, stroke, or heart failure). Hazard ratios (HRs) were calculated using multivariable Cox frailty models with random intercepts to account for clustering of participants by centre., Findings: Between Jan 1, 2003, and July 14, 2018, we recorded 10 567 composite events (deaths [n=6796] or major cardiovascular events [n=5855]) during the 9·1 years of follow-up. Higher intake of total dairy (>2 servings per day compared with no intake) was associated with a lower risk of the composite outcome (HR 0·84, 95% CI 0·75-0·94; p trend =0·0004), total mortality (0·83, 0·72-0·96; p trend =0·0052), non-cardiovascular mortality (0·86, 0·72-1·02; p trend =0·046), cardiovascular mortality (0·77, 0·58-1·01; p trend =0·029), major cardiovascular disease (0·78, 0·67-0·90; p trend =0·0001), and stroke (0·66, 0·53-0·82; p trend =0·0003). No significant association with myocardial infarction was observed (HR 0·89, 95% CI 0·71-1·11; p trend =0·163). Higher intake (>1 serving vs no intake) of milk (HR 0·90, 95% CI 0·82-0·99; p trend =0·0529) and yogurt (0·86, 0·75-0·99; p trend =0·0051) was associated with lower risk of the composite outcome, whereas cheese intake was not significantly associated with the composite outcome (0·88, 0·76-1·02; p trend =0·1399). Butter intake was low and was not significantly associated with clinical outcomes (HR 1·09, 95% CI 0·90-1·33; p trend =0·4113)., Interpretation: Dairy consumption was associated with lower risk of mortality and major cardiovascular disease events in a diverse multinational cohort., Funding: Full funding sources are listed at the end of the paper (see Acknowledgments)., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

The human brain is an important site of HIV replication and persistence during antiretroviral therapy (ART). Direct evaluation of HIV infection in the brains of otherwise healthy individuals is not feasible; therefore, we performed a large-scale study of bone marrow/liver/thymus (BLT) humanized mice as an in vivo model to study HIV infection in the brain. Human immune cells, including CD4+ T cells and macrophages, were present throughout the BLT mouse brain. HIV DNA, HIV RNA, and/or p24+ cells were observed in the brains of HIV-infected animals, regardless of the HIV isolate used. HIV infection resulted in decreased numbers of CD4+ T cells, increased numbers of CD8+ T cells, and a decreased CD4+/CD8+ T cell ratio in the brain. Using humanized T cell-only mice (ToM), we demonstrated that T cells establish and maintain HIV infection of the brain in the complete absence of human myeloid cells. HIV infection of ToM resulted in CD4+ T cell depletion and a reduced CD4+/CD8+ T cell ratio. ART significantly reduced HIV levels in the BLT mouse brain, and the immune cell populations present were indistinguishable from those of uninfected controls, which demonstrated the effectiveness of ART in controlling HIV replication in the CNS and returning cellular homeostasis to a pre-HIV state.

Background: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin., Methods: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding., Results: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001)., Conclusions: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).

ASXL1 plays key roles in epigenetic regulation of gene expression through methylation of histone H3K27, and disruption of ASXL1 drives myeloid malignancies, at least in part, via derepression of posterior HOXA loci. However, little is known about the identity of proteins that interact with ASXL1 and about the functions of ASXL1 in modulation of the active histone mark, such as H3K4 methylation. In this study, we demonstrate that ASXL1 is a part of a protein complex containing HCFC1 and OGT; OGT directly stabilizes ASXL1 by O-GlcNAcylation. Disruption of this novel axis inhibited myeloid differentiation and H3K4 methylation as well as H2B glycosylation and impaired transcription of genes involved in myeloid differentiation, splicing, and ribosomal functions; this has implications for myelodysplastic syndrome (MDS) pathogenesis, as each of these processes are perturbed in the disease. This axis is responsible for tumor suppression in the myeloid compartment, as reactivation of OGT induced myeloid differentiation and reduced leukemogenecity both in vivo and in vitro. Our data also suggest that MLL5, a known HCFC1/OGT-interacting protein, is responsible for gene activation by the ASXL1-OGT axis. These data shed light on the novel roles of the ASXL1-OGT axis in H3K4 methylation and activation of transcription.

Every network scientist knows that preferential attachment combines with growth to produce networks with power-law in-degree distributions. How, then, is it possible for the network of American Physical Society journal collection citations to enjoy a log-normal citation distribution when it was found to have grown in accordance with preferential attachment? This anomalous result, which we exalt as the preferential attachment paradox, has remained unexplained since the physicist Sidney Redner first made light of it over a decade ago. Here we propose a resolution. The chief source of the mischief, we contend, lies in Redner having relied on a measurement procedure bereft of the accuracy required to distinguish preferential attachment from another form of attachment that is consistent with a log-normal in-degree distribution. There was a high-accuracy measurement procedure in use at the time, but it would have have been difficult to use it to shed light on the paradox, due to the presence of a systematic error inducing design flaw. In recent years the design flaw had been recognised and corrected. We show that the bringing of the newly corrected measurement procedure to bear on the data leads to a resolution of the paradox.

High-throughput screens allow for the identification of specific biomolecules with characteristics of interest. In barcoded screens, DNA barcodes are linked to target biomolecules in a manner allowing for the target molecules making up a library to be identified by sequencing the DNA barcodes using Next Generation Sequencing. To be useful in experimental settings, the DNA barcodes in a library must satisfy certain constraints related to GC content, homopolymer length, Hamming distance, and blacklisted subsequences. Here we report a novel framework to quickly generate large-scale libraries of DNA barcodes for use in high-throughput screens. We show that our framework dramatically reduces the computation time required to generate large-scale DNA barcode libraries, compared with a naїve approach to DNA barcode library generation. As a proof of concept, we demonstrate that our framework is able to generate a library consisting of one million DNA barcodes for use in a fragment antibody phage display screening experiment. We also report generating a general purpose one billion DNA barcode library, the largest such library yet reported in literature. Our results demonstrate the value of our novel large-scale DNA barcode library generation framework for use in high-throughput screening applications.

Memristors have been considered as a leading candidate for a number of critical applications ranging from nonvolatile memory to non-Von Neumann computing systems. Feature extraction, which aims to transform input data from a high-dimensional space to a space with fewer dimensions, is an important technique widely used in machine learning and pattern recognition applications. Here, we experimentally demonstrate that memristor arrays can be used to perform principal component analysis, one of the most commonly used feature extraction techniques, through online, unsupervised learning. Using Sanger's rule, that is, the generalized Hebbian algorithm, the principal components were obtained as the memristor conductances in the network after training. The network was then used to analyze sensory data from a standard breast cancer screening database with high classification success rate (97.1%).

Background: Middle-aged and older Americans from underrepresented racial and ethnic backgrounds are at risk for greater chronic disease morbidity than their white counterparts. Cigarette smoking increases the severity of chronic illness, worsens physical functioning, and impairs the successful management of symptoms. As a result, it is important to understand whether smoking behaviors change after the onset of a chronic condition. We assessed the racial/ethnic differences in smoking behavior change after onset of chronic diseases among middle-aged and older adults in the US., Methods: We use longitudinal data from the Health and Retirement Study (HRS 1992-2010) to examine changes in smoking status and quantity of cigarettes smoked after a new heart disease, diabetes, cancer, stroke, or lung disease diagnosis among smokers., Results: The percentage of middle-aged and older smokers who quit after a new diagnosis varied by racial/ethnic group and disease: for white smokers, the percentage ranged from 14% after diabetes diagnosis to 32% after cancer diagnosis; for black smokers, the percentage ranged from 15% after lung disease diagnosis to 40% after heart disease diagnosis; the percentage of Latino smokers who quit was only statistically significant after stoke, where 38% quit. In logistic models, black (OR = 0.43, 95% CI: 0.19-0.99) and Latino (OR = 0.26, 95% CI: 0.11-0.65) older adults were less likely to continue smoking relative to white older adults after a stroke, and Latinos were more likely to continue smoking relative to black older adults after heart disease onset (OR = 2.69, 95% CI [1.05-6.95]). In models evaluating changes in the number of cigarettes smoked after a new diagnosis, black older adults smoked significantly fewer cigarettes than whites after a new diagnosis of diabetes, heart disease, stroke or cancer, and Latino older adults smoked significantly fewer cigarettes compared to white older adults after newly diagnosed diabetes and heart disease. Relative to black older adults, Latinos smoked significantly fewer cigarettes after newly diagnosed diabetes., Conclusions: A large majority of middle-aged and older smokers continued to smoke after diagnosis with a major chronic disease. Black participants demonstrated the largest reductions in smoking behavior. These findings have important implications for tailoring secondary prevention efforts for older adults.

The U.S. Environmental Protection Agency (EPA) is actively involved in supporting citizen science projects and providing communities with information and assistance for conducting their own air pollution monitoring. As part of a Regional Applied Research Effort (RARE) project, EPA's Office of Research and Development (ORD) worked collaboratively with EPA Region 2 and the Ironbound Community Corporation (ICC) in Newark, New Jersey, to develop and test the "Air Sensor Toolbox for Citizen Scientists." In this collaboration, citizen scientists measured local gaseous and particulate air pollution levels by using a customized low-cost sensor pod designed and fabricated by EPA. This citizen science air quality measurement project provided an excellent opportunity for EPA to evaluate and improve the Toolbox resources available to communities. The Air Sensor Toolbox, developed in coordination with the ICC, can serve as a template for communities across the country to use in developing their own air pollution monitoring programs in areas where air pollution is a concern. This pilot project provided an opportunity for a highly motivated citizen science organization and the EPA to work together directly to address environmental concerns within the community. Useful lessons were learned about how to improve coordination between the government and communities and the types of tools and technologies needed for conducting an effective citizen science project that can be applied to future efforts., Competing Interests: AUTHOR DISCLOSURE STATEMENT No competing financial interests exist.

Complex network growth across diverse fields of science is hypothesized to be driven in the main by a combination of preferential attachment and node fitness processes. For measuring the respective influences of these processes, previous approaches make strong and untested assumptions on the functional forms of either the preferential attachment function or fitness function or both. We introduce a Bayesian statistical method called PAFit to estimate preferential attachment and node fitness without imposing such functional constraints that works by maximizing a log-likelihood function with suitably added regularization terms. We use PAFit to investigate the interplay between preferential attachment and node fitness processes in a Facebook wall-post network. While we uncover evidence for both preferential attachment and node fitness, thus validating the hypothesis that these processes together drive complex network evolution, we also find that node fitness plays the bigger role in determining the degree of a node. This is the first validation of its kind on real-world network data. But surprisingly the rate of preferential attachment is found to deviate from the conventional log-linear form when node fitness is taken into account. The proposed method is implemented in the R package PAFit.

Transposon-based insertional mutagenesis is a valuable method for conducting unbiased forward genetic screens to identify cancer genes in mice. We used this system to elucidate factors involved in the malignant transformation of neural stem cells into glioma-initiating cells. We identified an RNA-binding protein, La-related protein 4b (LARP4B), as a candidate tumor-suppressor gene in glioma. LARP4B expression was consistently decreased in human glioma stem cells and cell lines compared with normal neural stem cells. Moreover, heterozygous deletion of LARP4B was detected in nearly 80% of glioblastomas in The Cancer Genome Atlas database. LARP4B loss was also associated with low expression and poor patient survival. Overexpression of LARP4B in glioma cell lines strongly inhibited proliferation by inducing mitotic arrest and apoptosis in four of six lines as well as in two patient-derived glioma stem cell populations. The expression levels of CDKN1A and BAX were also upregulated upon LARP4B overexpression, and the growth-inhibitory effects were partially dependent on p53 (TP53) activity in cells expressing wild-type, but not mutant, p53. We further found that the La module, which is responsible for the RNA chaperone activity of LARP4B, was important for the growth-suppressive effect and was associated with BAX mRNA. Finally, LARP4B depletion in p53 and Nf1-deficient mouse primary astrocytes promoted cell proliferation and led to increased tumor size and invasiveness in xenograft and orthotopic models. These data provide strong evidence that LARP4B serves as a tumor-suppressor gene in glioma, encouraging further exploration of the RNA targets potentially involved in LARP4B-mediatd growth inhibition. Cancer Res; 76(8); 2254-64. ©2016 AACR., (©2016 American Association for Cancer Research.)

This paper proposes a two-dimensional velocity model (2DVM) of the primary visual cortex (V1). The model's novel aspect is that it specifies a particular pattern of long-range cortical temporal connections, via the Connection Algorithm, and shows how the addition of these connections to well-known spatial properties of V1 transforms V1 into a velocity map. The map implies a number of organizational properties of V1: (1) the singularity of each orientation pinwheel contributes to the detection of slow-moving spots across the visual field; (2) the speed component of neuronal velocity selectivity decreases monotonically across each joint orientation contour line for parallel motion and increases monotonically for orthogonal motion; (3) the cells that are direction selective to slow-moving objects are situated in the periphery of V1; and (4) neurons in distinct pinwheels tend to be connected to neurons with similar tuning preferences in other pinwheels. The model accounts for various types of known illusionary perceptions of human vision: perceptual filling-in, illusionary orientation and visual crowding. The three distinguishing features of 2DVM are: (1) it unifies the functional properties of the conventional energy model of V1; (2) it directly relates the functional properties to the known structure of the upper layers of V1; and (3) it implies that the spatial selectivity features of V1 are side effects of its more important role as a velocity map of the visual field., (Copyright © 2015 Elsevier Ltd. All rights reserved.)