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Background: Women have smaller coronary size than men independent of body surface area. Female to male heart transplantation demonstrates coronary lumen enlargement. Purpose: To investigate relationships between endogenous androgens and coronary luminal size in women with suspected ischemic heart disease (IHD). Methods: We analyzed 69 women with available androgen levels. Results: Group mean age was 54 ± 10 years with 64 % post-menopausal. Lumen cross-sectional area (CSA) and external elastic membrane (EEM) CSA positively correlated with free testosterone (FT) (r = 0.29, p = 0.049; r = 0.29, p = 0.01), respectively, and negatively correlated with SHBG (r = −0.26, p = 0.03; r = −0.29, p = 0.02), respectively. Atheroma CSA positively correlated with FT (r = 0.24. p = 0.05). These correlations became non-significant after adjusting for waist circumference. Conclusions: In women with suspected ischemic heart disease, endogenous androgens, coronary atheroma and luminal size are related, and may be moderated by waist circumference.

Background Cytochrome P450 2C19 (CYP2C19) intermediate and poor metabolizer patients exhibit diminished clopidogrel clinical effectiveness after percutaneous coronary intervention (PCI). However, outcome studies to date have lacked racial diversity. Thus, the impact of CYP2C19 genotype on cardiovascular outcomes in patients treated with clopidogrel who identify as Black or African American remains unclear. Methods and Results Adults among 5 institutions who self‐identified as Black or African American, underwent PCI and clinical CYP2C19 genotyping, and were treated with clopidogrel were included. Data were abstracted from health records. Major atherothrombotic (composite of death, myocardial infarction, ischemic stroke, stent thrombosis, or revascularization for unstable angina) and bleeding event rates within 1 year after PCI were compared across CYP2C19 metabolizer groups using multivariable Cox regression adjusted for potential confounders and baseline variables meeting a threshold of P

Type I diabetes is an autoimmune disease mediated by T-cell destruction of β cells in pancreatic islets. Currently, there is no known cure, and treatment consists of daily insulin injections. Genome-wide association studies and twin studies have indicated a strong genetic heritability for type I diabetes and implicated several genes. As most strongly associated variants are noncoding, there is still a lack of identification of functional and, therefore, likely causal variants. Given that many of these genetic variants reside in enhancer elements, we have tested 121 CD4+ T-cell enhancer variants associated with T1D. We found four to be functional through massively parallel reporter assays. Three of the enhancer variants weaken activity, while the fourth strengthens activity. We link these to their cognate genes using 3D genome architecture or eQTL data and validate them using CRISPR editing. Validated target genes include CLEC16A and SOCS1. While these genes have been previously implicated in type 1 diabetes and other autoimmune diseases, we show that enhancers controlling their expression harbor functional variants. These variants, therefore, may act as causal type 1 diabetic variants.

Objectives: Identifying the key factors associated with vaccine hesitancy remains a challenge as has been highlighted throughout the COVID-19 vaccine roll out and pandemic. The aim of this study was to determine characteristics associated with vaccine safety and compare perceived safety by vaccine. Our hypothesis is that vaccine safety perception will vary by vaccine with COVID-19 as ranked lowest for safety. Study design: Cross sectional. Methods: A statewide sample (n = 1024) responded to an online 28-point questionnaire via anonymous linked invitation. Results: Among the eight vaccines assessed, COVID-19 had the lowest perceived safety (53.13%) followed by human papillomavirus HPV (63.38%). A binomial logistic regression assessed COVID-19 vaccine safety beliefs (safe v not safe) finding age, political orientation, and perceived safety of certain vaccines as statistically significant. As age increased by year, vaccine safety beliefs increased. Persons who identified as conservative demonstrated less belief in vaccine safety than all other groups. Among persons who did not perceive the COVID-19 vaccine as safe, 65.8% believed chicken pox was safe, 63.3% and 61.1% perceived hepatitis A& B were safe. Conclusions: These findings demonstrate that vaccine safety beliefs differ by vaccine and that persons who do not believe in the safety of the COVID-19 are not exclusively against all vaccines. Understanding factors that increase vaccine safety by vaccine could assist in developing an intervention which could increase belief in safety for all vaccines.

Fronthaul data rates in case of millimeter wave (mmWave) wireless systems scale up to several Gbps in the currently deployed digitized radio over fiber solutions, resulting in large complexity remote radio heads (RRHs). We propose a promising solution involving optical frequency doubling and quadrupling, where all complex digital processing are moved to the centralized base band unit (BBU), thereby allowing placement of large number of low-complex RRHs at long distances. We experimentally demonstrate optical frequency doubling and quadrupling for the generation and transport of millimeter wave mmWave signals with OFDM containing QPSK, 16/64/256-QAM modulation formats over a distance of 2 km. These schemes enable the use of low-frequency RF signals at the BBU for the generation of mmWaves at the RRH. We evaluate the performance of the systems in terms of error vector magnitude (EVM) and out-of-band emissions of the upconverted data. Our results show that the proposed schemes achieve EVM values within the 3GPP 5G standard requirements. We also investigate the tunability and scalability of the proposed schemes across the n258 band (24.25 - 27.5 GHz) and discuss the feasibility of implementing dense wavelength division multiplexing (DWDM) for servicing multi-channel operation required for multisector antennas. The proposed schemes can support high data rate transmission for future wireless networks including 6G.

In this paper, we review the literature on economic approaches to providing value estimates of biodiversity. In most cases, the value estimates represent a lower estimate for a multitude of reasons, emanating from the complexity of definition and conceptualization of biodiversity as a capital stock and/or an ensuing flow of various ecosystem services. However, this exercise is important for accounting for these values in national income accounts, policy reforms, and raising funds for biodiversity financing. We discuss some of the theoretical and empirical challenges towards this valuation exercise along with providing estimates of biodiversity values.

Background Electronic health systems contain large amounts of unstructured data (UD) which are often unanalyzed due to the time and costs involved. Unanalyzed data creates missed opportunities to improve health outcomes. Natural language processing (NLP) is the foundation of generative artificial intelligence (GAI), which is the basis for large language models, such as ChatGPT. NLP and GAI are machine learning methods that analyze large amounts of data in a short time at minimal cost. The ability of NLP to conduct qualitative analyses is increasing, yet the results can lack context and nuance in their findings, requiring human intervention. Methods Our study compared outcomes, time, and costs of a previously published qualitative study. Our approach partnered an NLP model and a qualitative researcher (NLP+). UD from behavioral health patients were analyzed using NLP and a Latent Dirichlet allocation to identify the topics using probability of word coherence scores. The topics were then analyzed by a qualitative researcher, translated into themes, and compared with the original findings. Results The NLP + method results aligned with the original, qualitative derived themes. Our model also identified two additional themes which were not originally detected. The NLP + method required 6 hours of labor, 3 minutes for transcription, and a transcription cost of $1.17. The original, qualitative researcher only method required more than 36 hours ($2,250) of time and $1,100 for transcription. Conclusions While natural language processing analyzes voluminous amounts of data in seconds, context and nuance in human language are regularly missed. Combining a qualitative researcher with NLP + could be deployed in many settings, reducing time and costs, and improving context. Until large language models are more prevalent, a human interaction can help translate the patient experience by contextualizing data rich in social determinant indicators which may otherwise go unanalyzed.

Background The ADAPTABLE (Aspirin Dosing: A Patient‐Centric Trial Assessing Benefits and Long‐Term Effectiveness) was a large, pragmatic, randomized controlled trial that found no difference between high‐ versus low‐dose aspirin for secondary prevention of atherosclerotic cardiovascular disease. Whether concomitant P2Y12 inhibitor therapy modifies the effect of aspirin dose on clinical events remains unclear. Methods and Results Participants in ADAPTABLE were stratified according to baseline use of clopidogrel or prasugrel (P2Y12 group). The primary effectiveness end point was a composite of death, myocardial infarction, or stroke; and the primary safety end point was major bleeding requiring blood transfusions. We used multivariable Cox regression to compare the relative effectiveness and safety of aspirin dose within P2Y12 and non‐P2Y12 groups. Of 13 815 (91.6%) participants with available data, 3051 (22.1%) were receiving clopidogrel (2849 [93.4%]) or prasugrel (203 [6.7%]) at baseline. P2Y12 inhibitor use was associated with higher risk of the primary effectiveness end point (10.86% versus 6.31%; adjusted hazard ratio [HR], 1.40 [95% CI, 1.22–1.62]) but was not associated with bleeding (0.95% versus 0.53%; adjusted HR, 1.42 [95% CI, 0.91–2.22]). We found no interaction in the relative effectiveness and safety of high‐ versus low‐dose aspirin by P2Y12 inhibitor use. Overall, dose switching or discontinuation was more common in the high‐dose compared with low‐dose aspirin group, but the pattern was not modified by P2Y12 inhibitor use. Conclusions In this prespecified analysis of ADAPTABLE, we found that the relative effectiveness and safety of high‐ versus low‐dose aspirin was not modified by baseline P2Y12 inhibitor use. Registration https://www.clinical.trials.gov. Unique identifier: NCT02697916.

BackgroundWhile autoimmune rheumatic diseases (ARDs) have been linked with coronary microvascular dysfunction (CMD), the relationship between ARD and CMD in women with signs and symptoms of ischemia and no obstructive arteries (INOCA) are not well described. We hypothesized that among women with CMD, those with ARD history have greater angina, functional limitations, and myocardial perfusion compromise compared to those without ARD history.MethodsWomen with INOCA and confirmed CMD by invasive coronary function testing were included from the Women's Ischemia Syndrome Evaluation-Coronary Vascular Dysfunction (WISE-CVD) project (NCT00832702). Seattle Angina Questionnaire (SAQ), Duke Activity Status Index (DASI), and cardiac magnetic resonance myocardial perfusion reserve index (MPRI) were collected at baseline. Chart review was performed to confirm self-reported ARD diagnosis.ResultsOf the 207 women with CMD, 19 (9%) had a confirmed history of ARD. Compared to those without ARD, women with ARD were younger (p = 0.04). In addition, they had lower DASI-estimated metabolic equivalents (p = 0.03) and lower MPRI (p = 0.008) but similar SAQ scores. There was a trend towards increased nocturnal angina and stress-induced angina in those with ARD (p = 0.05 for both). Invasive coronary function variables were not significantly different between groups.ConclusionsAmong women with CMD, women with a history of ARD had lower functional status and worse myocardial perfusion reserve compared to women without ARD. Angina-related health status and invasive coronary function were not significantly different between groups. Further studies are warranted to understand mechanisms contributing to CMD among women with ARDs with INOCA.

We propose a blind joint equalization algorithm for M-QAM signals based on a widely linear filtering approach. The proposed scheme jointly compensates for receiver IQ imbalance, receiver IQ skew, polarization mixing, carrier recovery, followed by transmitter IQ imbalance and skew. We first investigate the proposed scheme’s tolerance to each of these impairments through numerical simulations for 32 GBd PM-16QAM and PM-64QAM signals and compare its performance with the conventional digital processing algorithms with and without IQ imbalance compensation. The proposed joint transceiver equalizer outperforms the conventional algorithms with a $Q^{2}$ improvement of greater than 1 dB, and with improved tolerance to IQ imbalance. Further, with the proposed algorithm, we experimentally demonstrate the improvement in $Q^{2}$ value with respect to conventional DSP for both PM-16QAM and PM-64QAM signals. We also show that the MSE convergence of the proposed joint equalizer is much faster than conventional DSP algorithms.

Background: Although a variety of standardized measurements have been described to evaluate acetabular dysplasia, no single measurement is without limitations. We describe the Sourcil Index (SI), a novel measure of the weight-bearing surface of the acetabulum on anteroposterior pelvis films. The SI is the angle formed by the medial and lateral margins of the sourcil and the center of rotation of the femoral head. Methods: Anteroposterior pelvis radiographs of skeletally mature patients from 2015 were reviewed. Studies with fractures or implants were excluded. Films were read by 2 orthopedic surgeons and a radiologist 3 times each, 8 weeks apart. The SI, Sharp's Angle (SA), and lateral center edge angle (LCEA) were recorded. Pearson intraclass correlation coefficients with 95% confidence intervals were calculated. The SI was then compared to the SA and LCEA to preliminarily assess diagnostic accuracy. Results: Five hundred thirty-five hips in 292 patients met inclusion. Intraobserver reliability is as follows: SI = 0.95 (0.93-0.98), LCEA = 0.89 (0.82 -0.96), and SA = 0.90 (0.85-0.96). Interobserver reliability is as follows: SI = 0.90 (0.84-0.94), SA = 0.78 (0.64-0.86), and LCEA = 0.73 (0.56-0.82). There were 51 dysplastic hips within this cohort. Conclusion: The SI is a reproducible measurement on plain radiographs. The SI is a two-dimensional representation of the size of the weight-bearing surface of the acetabulum and could provide an estimation of joint contact pressures. Used with existing measures, the SI may provide a more nuanced understanding of acetabular morphology.

Declining occupational therapy student mental health and well-being is well described in the literature. However, there is a lack of literature describing recommendations from the student perspective that could help academic programs as they develop and implement support programming. Involving students in the process can be beneficial as they are experts in their experiences. The purpose of this qualitative descriptive study was to describe recommendations current occupational therapy students had for their academic programs to best support them during their educational experience. The study sample consisted of 628 entry-level masters and doctoral occupational therapy students from 31 states. Participant responses to one open-ended question compromised the raw data. Data was analyzed line by line using a multi-tiered coding process. Five themes emerged from the data related to faculty/student interactions, in-classroom learning, out of classroom support, programmatic recommendations, and no recommendations. Many of the participants' recommendations were consistent with the general recommendations found in the literature. However, occupational therapy academic programs could incorporate the participants' recommendations into their local level programming while also highlighting occupational therapy's distinct values. To promote student well-being, consider all contexts and factors that impact their students' occupational performance and incorporating meaningful, occupation-based activities inside and outside of the classroom. As occupational therapy programs are successful in supporting their students, they could contribute to their university systems' wider campus efforts highlighting the profession's unique role in promoting health and well-being.

Abstract The challenges of Reproducibility and Replicability (R & R) in computer science experiments have become a focus of attention in the last decade, as efforts to adhere to good research practices have increased. However, experiments using Deep Learning (DL) remain difficult to reproduce due to the complexity of the techniques used. Challenges such as estimating poverty indicators (e.g., wealth index levels) from remote sensing imagery, requiring the use of huge volumes of data across different geographic locations, would be impossible without the use of DL technology. To test the reproducibility of DL experiments, we report a review of the reproducibility of three DL experiments which analyze visual indicators from satellite and street imagery. For each experiment, we identify the challenges found in the data sets, methods and workflows used. As a result of this assessment we propose a checklist incorporating relevant FAIR principles to screen an experiment for its reproducibility. Based on the lessons learned from this study, we recommend a set of actions aimed to improve the reproducibility of such experiments and reduce the likelihood of wasted effort. We believe that the target audience is broad, from researchers seeking to reproduce an experiment, authors reporting an experiment, or reviewers seeking to assess the work of others.

Reliable quantitative vegetation reconstructions for Europe during the Holocene are crucial to improving our understanding of landscape dynamics, making it possible to assess the past effects of environmental variables and land-use change on ecosystems and biodiversity, and mitigating their effects in the future. We present here the most spatially extensive and temporally continuous pollen-based reconstructions of plant cover in Europe (at a spatial resolution of 1° × 1°) over the Holocene (last 11.7 ka BP) using the ‘Regional Estimates of VEgetation Abundance from Large Sites’ (REVEALS) model. This study has three main aims. First, to present the most accurate and reliable generation of REVEALS reconstructions across Europe so far. This has been achieved by including a larger number of pollen records compared to former analyses, in particular from the Mediterranean area. Second, to discuss methodological issues in the quantification of past land cover by using alternative datasets of relative pollen productivities (RPPs), one of the key input parameters of REVEALS, to test model sensitivity. Finally, to validate our reconstructions with the global forest change dataset. The results suggest that the RPPs.st1 (31 taxa) dataset is best suited to producing regional vegetation cover estimates for Europe. These reconstructions offer a long-term perspective providing unique possibilities to explore spatial-temporal changes in past land cover and biodiversity.

We study the use of nonlinear semiconductor optical amplifier (SOA) for generating optical phase conjugate towards compensation of distortions in short distance optical fiber transmission due to Kerr nonlinearity and chromatic dispersion in coherent multi-carrier lightwave signals. We experimentally demonstrate the effectiveness of the SOA-based phase conjugator to improve the link budget with a 100 km standard single mode fiber link for 20 GHz coherent OFDM signals, with QPSK and 16QAM modulations and a corresponding net bit-rate of 40 Gbps and 80 Gbps respectively. Mid-span spectral inversion scheme is employed where the optical phase conjugate is generated through a partially degenerate four-wave mixing process in a nonlinear SOA. We demonstrate a bit error rate performance within $2\times 10^{-2}$ for an average launched power of up to 12 dBm (9 dBm) for QPSK (16QAM) coherent OFDM signals, in a 100 km fiber link. We also investigate the possible improvement in link budget using numerical simulation for 16QAM and 64QAM CO-OFDM signals with the proposed scheme.

NifB is a radical SAM enzyme involved in the biosynthesis of the Mo-nitrogenase cofactor, which is responsible for the ambient conversion of N2 to NH3. Here, the authors identify and uncover the function of a His43 residue as an essential nitrogen ligand of NifB in cofactor biosynthesis.

Identification of silencer elements by computational or experimental approaches in a genome-wide manner is still challenging. Here authors define uncharacterized cis-regulatory elements (CREs) in human and mouse genomes likely containing silencer elements, and test them in cells using massively parallel reporter assays to identify silencer elements that showed silencer activity.

We experimentally demonstrate the simultaneous compensation of both dispersion and nonlinear effects in a 100 km optical fiber link using optical phase conjugation of a 21 GB aud QPSK and 16QAM signal with nonlinear SOAs. Error-free performance is recorded for a launched power of up to 12 dBm, without any digital signal processing to compensate for distortions due to chromatic dispersion and nonlinear effects in fiber. The performance is verified for operation across the C-band.

Women with myocardial infarction with no obstructive coronary artery disease (MINOCA) are increasingly recognized. Women with MINOCA are at high risk for major adverse cardiovascular events. In this case, we focus on the importance of early identification and management of MINOCA to improve patients’ angina and related quality of life. (Level of Difficulty: Beginner.)

Background: The search of biomarkers in the field of depression requires easy implementable tests that are biologically rooted. Qualitative analysis of verbal fluency tests (VFT) are good candidates, but its cerebral correlates are unknown. Methods: We collected qualitative semantic and phonemic VFT scores along with grey and white matter anatomical MRI of depressed (n = 26) and healthy controls (HC, n = 25) women. Qualitative VFT variables are the “clustering score” (i.e. the ability to produce words within subcategories) and the “switching score” (i.e. the ability to switch between clusters). The clustering and switching scores were automatically calculated using a data-driven approach. Brain measures were cortical thickness (CT) and fractional anisotropy (FA). We tested for associations between CT, FA and qualitative VFT variables within each group. Results: Patients had reduced switching VFT scores compared to HC. Thicker cortex was associated with better switching score in semantic VFT bilaterally in the frontal (superior, rostral middle and inferior gyri), parietal (inferior parietal lobule including the supramarginal gyri), temporal (transverse and fusiform gyri) and occipital (lingual gyri) lobes in the depressed group. Positive association between FA and the switching score in semantic VFT was retrieved in depressed patients within the corpus callosum, right inferior fronto-occipital fasciculus, right superior longitudinal fasciculus extending to the anterior thalamic radiation (all p

Epigenetic mechanisms regulate osteogenic lineage differentiation of mesenchymal stromal cells. Histone methylation is controlled by multiple lysine demethylases and is an important step in controlling local chromatin structure and gene expression. Here, we show that the lysine-specific histone demethylase Kdm1A/Lsd1 is abundantly expressed in osteoblasts and that its suppression impairs osteoblast differentiation and bone nodule formation in vitro. Although Lsd1 knockdown did not affect global H3K4 methylation levels, genome-wide ChIP-Seq analysis revealed high levels of Lsd1 at gene promoters and its binding was associated with di- and tri-methylation of histone 3 at lysine 4 (H3K4me2 and H3K4me3). Lsd1 binding sites in osteoblastic cells were enriched for the Runx2 consensus motif suggesting a functional link between the two proteins. Importantly, inhibition of Lsd1 activity decreased osteoblast activity in vivo. In support, mesenchymal-targeted knockdown of Lsd1 led to decreased osteoblast activity and disrupted primary spongiosa ossification and reorganization in vivo. Together, our studies demonstrate that Lsd1 occupies Runx2-binding cites at H3K4me2 and H3K4me3 and its activity is required for proper bone formation.

American Muslims regularly encounter a tacit distinction between the civic and religious spheres of their daily lives. Islamic legal norms are not invoked incessantly to highlight the differences between Muslims and their fellow citizens, but instead are considered relevant for particular issues at particular times. Through examining examples of how Muslims engage with the American economic and legal system, it is shown that much of one’s engagement with the civic structures of American life is seen as unproblematic. Understanding this distinction helps Muslims participating in American life to properly conceptualize the relationship between their religious faith and their roles as citizens in the larger body politic.

The present study examined the effects of environmentally realistic exposure to atrazine (ATZ) on the behavior of sailfin mollies, Poecilia latipinna. ATZ is one of the most commonly used pesticides in the US and a known endocrine disrupting chemical (EDC). The behavior of sailfin mollies is well documented in the scientific literature. Moreover, they are ecologically important indicators of environmental health, widely distributed among the mangroves along the Gulf Coast of the Southeastern US where significant amounts of ATZ are introduced via runoff and storm water drainage from coastal households, businesses, and farms. Four sets of experiments designed to assess ATZ’s impact on various aspects of male and female reproductive behavior, aggression, anxiety, and boldness were conducted following 12 weeks of exposure to 1 or 15 ppb water-borne ATZ, along with a no-exposure control group. Results indicated that the behavior of ATZ-exposed individuals differed from those of controls: ATZ exposure affected which stimulus fish (a male vs. a female) subject females preferred to associate with while also affecting female strength of preference for males of larger body size and their sexual receptivity to conspecific males in general. ATZ-exposed males also showed reduced overall responsiveness to conspecific stimuli and directed significantly less aggression toward their mirror image compared with controls. Finally, ATZ exposure affected multiple aspects of male and female behavior that are often used as proxies for boldness and anxiety. Overall, ATZ exposure resulted in alterations across a variety of behaviors attributed to sexual receptivity, mate choice and motivation to mate, aggression, as well as boldness and anxiety. These ATZ-induced behavioral changes may adversely affect the long-term health of natural populations exposed to similar, environmentally realistic concentrations and add to a growing body of empirical data demonstrating substantial fitness consequences of exposure to sublethal concentrations of this known EDC.

While the chicken (Gallus gallus) is the most consumed agricultural animal worldwide, the chicken transcriptome remains understudied. We have characterized the transcriptome of 10 cell and tissue types from the chicken using RNA-seq, spanning intestinal tissues (ileum, jejunum, proximal cecum), immune cells (B cells, bursa, macrophages, monocytes, spleen T cells, thymus), and reproductive tissue (ovary). We detected 17,872 genes and 24,812 transcripts across all cell and tissue types, representing 73% and 63% of the current gene annotation, respectively. Further quantification of RNA transcript biotypes revealed protein-coding and lncRNAs specific to an individual cell/tissue type. Each cell/tissue type also has an average of around 1.2 isoforms per gene, however, they all have at least one gene with at least 11 isoforms. Differential expression analysis revealed a large number of differentially expressed genes between tissues of the same category (immune and intestinal). Many of these differentially expressed genes in immune cells were involved in cellular processes relating to differentiation and cell metabolism as well as basic functions of immune cells such as cell adhesion and signal transduction. The differential expressed genes of the different segments of the chicken intestine (jejunum, ileum, proximal cecum) correlated to the metabolic processes in nutrient digestion and absorption. These data should provide a valuable resource in understanding the chicken genome.

Standard cardiology practice often defers preventive strategies to primary care providers. We aimed to evaluate the effectiveness of a preventive cardiology clinic focused on lifestyle and nutrition counseling combined with guideline-directed medical therapy on reducing cardiovascular disease (CVD) risk. We queried the University of Florida-Health database for patients enrolled in the preventive cardiology clinic, and a general and interventional cardiology clinic from January 2016 to October 2019. Mean change in weight and blood cholesterol including LDL cholesterol (LDL-C), total cholesterol (TC) and triglycerides (TG) were compared in the three clinics in the initial cohort and stratified into primary and secondary prevention. A propensity score-matched analysis was done to adjust for CVD risk factors and statin use. Among a cohort of 239 patients, enrollment in the preventive clinic (n = 99) was associated with greater weight loss at 6 months compared to other clinics (n = 140) (mean −1.7 vs +0.1 kg, p 0.007). Preventive clinic was also associated with greater mean reduction in LDL-C (−24.8 vs −7.1 mg/dl, p 0.021), TC (−29.3 vs −2.0, p 0.003) and TG (−19.7 vs +13.3, p 0.002) at both initial and last follow-up (median time 6 and 16 months). The association with reduction in TG was observed in both primary and secondary prevention, but reduction in LDL-C and TC was only significant in secondary prevention. In a propensity-matched linear regression analysis, preventive clinic was independently associated with LDL-C reduction (b −14.7, r −0.3, p 0.038). A preventive cardiology clinic focused on patient education can be effective in reducing CVD risk.

Assisted reproductive technologies are known to alter the developmental environment of gametes and early embryos during the most dynamic period of establishing the epigenome. This may result in the introduction of errors during active DNA methylation reprogramming. Controlled ovarian hyperstimulation, or superovulation, is a ubiquitously used intervention which has been demonstrated to alter the methylation of certain imprinted genes. The objective of this study was to investigate whether ovarian hyperstimulation results in genome-wide DNA methylation changes in mouse early embryos. Ovarian hyperstimulation was induced by treating mice with either low doses (5 IU) or high doses (10 IU) of PMSG and hCG. Natural mating (NM) control mice received no treatment. Zygotes and 8-cell embryos were collected from each group and DNA methylomes were generated by whole-genome bisulfite sequencing. In the NM group, mean CpG methylation levels slightly decreased from zygote to 8-cell stage, whereas a large decrease in mean CpG methylation level was observed in both superovulated groups. A separate analysis of the mean CpG methylation levels within each developmental stage confirmed that significant genome-wide erasure of CpG methylation from the zygote to 8-cell stage only occurred in the superovulation groups. Our results suggest that superovulation alters the genome-wide DNA methylation erasure process in mouse early pre-implantation embryos. It is not clear whether these changes are transient or persistent. Further studies are ongoing to investigate the impact of ovarian hyperstimulation on DNA methylation re-establishment in later stages of embryo development.

Summary: During mammalian embryogenesis, changes in morphology and gene expression are concurrent with epigenomic reprogramming. Using human embryonic stem cells representing the preimplantation blastocyst (naive) and postimplantation epiblast (primed), our data in 2iL/I/F naive cells demonstrate that a substantial portion of known human enhancers are premarked by H3K4me1, providing an enhanced open chromatin state in naive pluripotency. The 2iL/I/F enhancer repertoire occupies 9% of the genome, three times that of primed cells, and can exist in broad chromatin domains over 50 kb. Enhancer chromatin states are largely poised. Seventy-seven percent of 2iL/I/F enhancers are decommissioned in a stepwise manner as cells become primed. While primed topologically associating domains are largely unaltered upon differentiation, naive 2iL/I/F domains expand across primed boundaries, affecting three-dimensional genome architecture. Differential topologically associating domain edges coincide with 2iL/I/F H3K4me1 enrichment. Our results suggest that naive-derived 2iL/I/F cells have a unique chromatin landscape, which may reflect early embryogenesis. : Human ESCs grown in 2iL/I/F are useful for studying the transition from naive to primed pluripotency. Battle et al. show that the naive epigenome is globally enhanced for H3K4me1. Many of the H3K4me1 regions are putative enhancers and are lost, or decommissioned, during the transition to primed. Differential topologically associating domains (TADs) exist between states and contain H3K4me1 enrichment at TAD boundaries. Keywords: enhancers, 3D genome architecture, naive hESCs, embryogenesis

Abstract Background Catatonia is a neuropsychiatric syndrome characterized by diverse psychomotor abnormalities, including motor dysregulation and behavioral and affective disturbances. Once thought to occur primarily in the context of schizophrenia, recent data suggest most cases of catatonia develop in individuals with depressive or bipolar disorders. Moreover, catatonia may ensue in general medical and neurological conditions, as well as due to a variety of pharmaceuticals, drugs of abuse, and toxic agents. At one time considered rare in pediatric patients, evidence now suggests catatonia is both underrecognized and undertreated in this population, where it carries an elevated risk of morbidity and mortality. Here we present the case of a child with steroid-resistant nephrotic syndrome who developed catatonia due to cyclosporine A-related neurotoxicity. Case presentation A 9-year-old African-American boy with no psychiatric history and a 9-month history of nephrotic syndrome due to focal segmental glomerulosclerosis was admitted to the local children’s hospital for management of mutism, posturing, insomnia, gait abnormalities, and somatic delusions. Seven days prior to admission, his cyclosporine plasma concentration was elevated at 1224 ng/mL (therapeutic range: 100–200 ng/mL). Upon admission, cyclosporine was discontinued and psychiatry was consulted, diagnosing catatonia. The patient subsequently received propofol 80 mg IV resulting in a transient lysis of catatonia. Over a lengthy hospitalization, the patient’s catatonia was initially treated with lorazepam, quetiapine being added later to target psychosis. All signs and symptoms of catatonia resolved, and the patient was eventually tapered off both lorazepam and quetiapine with no return of symptoms more than 6 months later. Conclusions To our knowledge, this case represents the first reported instance of cyclosporine A-induced catatonia in a patient with steroid-resistant nephrotic syndrome. It illustrates the importance of maintaining vigilance for signs and symptoms of cyclosporine A-related neurotoxicity (including catatonia) in patients with steroid-resistant nephrotic syndrome. In addition, it highlights the challenges faced by clinicians in jurisdictions that prohibit the use of electroconvulsive therapy in pediatric patients.

Zinc oxide, an established inorganic metal oxide in nanoparticles form exhibits tremendous anti-bacterial activity. The present study focuses on determining the anti-bacterial activity of green synthesized zinc oxide nanoparticles (ZnO NPs). Results clearly validate the effective synthesis of spherical shaped nanoparticles with average size range of 60–80 nm. SEM and EDAX data buttresses the results obtained by XRD pattern in terms of size and purity. ZnO NPs exhibited dose-dependent anti-bacterial activity against Escherichia coli (E. coli) and the IC50 value was calculated to be around 20 μg/mL. Growth kinetics study was conducted in the presence of nanoparticles which demonstrated the bacteriostatic effect of ZnO NPs. The study recommends the potential use of ZnO NPs in industries like food, pharmaceutical, agriculture, cosmetic industries for its anti-bacterial activity. Keywords: Green synthesis, Zinc oxide nanoparticles, Anti-bacterial activity, E. coli, Growth kinetics

We propose an improved pilot free phase noise mitigation algorithm for COOFDM systems using weighted multi-level QPSK partitioning and Kalman filtering. Through extensive Monte Carlo simulations, we demonstrate an improvement in spectral efficiency of >6% in case of 200 Gbps single channel and 1 Tbps multi channel 16QAM CO-OFDM transmission with blind carrier phase estimation. We also experimentally demonstrate the performance of the proposed algorithm against the standard pilot aided algorithm for the transmission of 120 Gbps 16QAM CO-OFDM at different noise levels.

This commentary identifies the variability in definitions of agritourism that exists in a variety of different countries, discusses reasons why this variability might produce problems, and provides examples of efforts to harmonize these definitions, including an ongoing international dialogue on the topic.

Background: Qualitative methods analyze contextualized, unstructured data. These methods are time and cost intensive, often resulting in small sample sizes and yielding findings that are complicated to replicate. Integrating natural language processing (NLP) into a qualitative project can increase efficiency through time and cost savings; increase sample sizes; and allow for validation through replication. This study compared the findings, costs, and time spent between a traditional qualitative method (Investigator only) to a method pairing a qualitative investigator with an NLP function (Investigator +NLP). Methods: Using secondary data from a previously published study, the investigators designed an NLP process in Python to yield a corpus, keywords, keyword influence, and the primary topics. A qualitative researcher reviewed and interpreted the output. These findings were compared to the previous study results. Results: Using comparative review, our results closely matched the original findings. The NLP + Investigator method reduced the project time by a minimum of 120 hours and costs by $1,500. Discussion: Qualitative research can evolve by incorporating NLP methods. These methods can increase sample size, reduce project time, and significantly reduce costs. The results of an integrated NLP process create a corpus and code which can be reviewed and verified, thus allowing a replicable, qualitative study. New data can be added over time and analyzed using the same interpretation and identification. Off the shelf qualitative software may be easier to use, but it can be expensive and may not offer a tailored approach or easily interpretable outcomes which further benefits researchers.

Background Recurrent hospitalization is prevalent in women with signs and symptoms of ischemia and no obstructive coronary artery disease. We hypothesized that rates of angina hospitalization might have changed over time, given advances in diagnostic and therapeutic approaches. Methods and Results We evaluated 551 women enrolled in the WISE (Women's Ischemia Syndrome Evaluation) study with no obstructive coronary artery disease (CAD) for a follow‐up period of 9.1 years. We analyzed angina hospitalization rates using the Kaplan‐Meier method. Univariate analysis and multivariable Cox proportional hazard models were developed for prediction of angina hospitalization in women with signs and symptoms of angina and no CAD. A total of 223 women had nonobstructive CAD (>20–50%

Abstract Background Gender distribution varies across neurodegenerative disorders, with, traditionally, a higher female frequency reported in Alzheimer’s disease (AD) and a higher male frequency in Parkinson’s disease (PD). Conflicting results on gender distribution are reported concerning dementia with Lewy bodies (DLB), usually considered as an intermediate disease between AD and PD. The aim of the present study was to investigate gender differences in DLB in French specialized memory settings using data from the French national database spanning from 2010 to 2015 and to compare sex ratio in DLB with that in AD, Parkinson’s disease dementia (PDD), and PD. Our hypothesis was that there is a balanced sex ratio in DLB, different from that found in AD and PD. Methods We conducted a repeated cross-sectional study. The study population comprised individuals with a DLB, AD, PDD, or PD diagnosis according to the International Classification of Diseases, Tenth Revision, in the French National Alzheimer Database between 2010 and 2015. Sex ratio and demographic data were compared using multinomial logistic regression and a Bayesian statistical model. Results From 2010 to 2015 in French specialized memory settings, sex ratios (female percent/male percent) were found as follows: 1.21 (54.7%/45.3%) for DLB (n = 10,309), 2.34 (70.1%/29.9%) for AD (n = 135,664), 0.76 (43.1%/56.9%) for PD (n = 8744), and 0.83 (45.4%/54.6%) for PDD (n = 3198). Significant differences were found between each group, but not between PDD and PD, which had a similar sex ratio. Conclusions This large-sample prevalence study confirms the balanced gender distribution in the DLB population compared with AD and PD-PDD. Gender distribution and general demographic characteristics differed between DLB and PDD. This is consistent with the hypothesis that DLB is a distinct disease with characteristics intermediate between AD and PD, as well as with the hypothesis that DLB could have at least partially distinct neuropathological correlates.

NifB is a key enzyme in the biosynthesis pathway of the nitrogenase FeMo cofactor. Here, the authors investigate the maturation of its iron-sulfur clusters by EPR and biochemical analyses, showing how individual precursor clusters participate in the formation of the final iron-sulfur cluster.

Abstract Objective To determine the likelihood that head injured patients on Warfarin with a negative initial head CT will have a positive repeat head CT. A retrospective chart review of our institution’s trauma registry was performed for all patients admitted for blunt head trauma and on Warfarin anti-coagulation from January 2009 to April 2014. Inclusion criteria included patients over 18 years of age with initial GCS ≥ 13, INR greater than 1.5 and negative initial head CT. Initial CT findings, repeat CT findings and INR were recorded. Interventions performed on patients with a delayed bleed were also investigated. Results 394 patients met the study inclusion criteria. 121 (31%) of these patients did not receive a second CT while 273 patients (69%) underwent a second CT. The mean INR was 2.74. Six patients developed a delayed bleed, of which two were clinically significant. No patients had any neurosurgical intervention. Our results demonstrate a low rate of delayed bleeding. The utility of repeat head CT in the neurologically stable patient is thus questioned. Patients who have an abnormal baseline neurological status and those with INR >3 may represent a subgroup of patients in whom repeat head CT should be performed.

Introduction: Substance use disorders (SUD) are a significant threat to both individual and public health. To date, SUD pharmacotherapy has focused primarily on agonist medications (i.e. nicotine replacement therapy for tobacco use disorder; methadone and buprenorphine for opioid use disorder), antagonist medications (i.e. naltrexone for opioid use disorder), and aversive therapy (i.e. disulfiram for alcohol use disorder). Pharmacotherapeutic approaches utilizing an immunological framework for medication development represent an important focus of study for treatment of these illnesses. Areas covered: This review discusses vaccines for treatment of substance use disorders. Using PubMed (https://www.ncbi.nlm.nih.gov/pubmed/), we searched both preclinical and human clinical trials of vaccines for treatment of nicotine, cocaine, methamphetamine, and opioid use disorders. In addition, we searched for recently developed strategies for enhancement of the immunologic response through alteration of conjugate molecules and adjuvants. Expert commentary: Despite challenges in human clinical trials of SUD vaccines, a number of strategies have been introduced which may ultimately improve efficacy. These challenges, as well as their implications for vaccine development, are discussed. Additionally, the optimal conditions for research study and treatment are considered.

Human bone marrow stromal cells, or mesenchymal stem cells (BM-MSCs), need expansion prior to use as cell-based therapies in immunological and tissue repair applications. Aging and expansion of BM-MSCs induce epigenetic changes that can impact therapeutic outcomes. By applying sequencing-based methods, we reveal that the breadth of DNA methylation dynamics associated with aging and expansion is greater than previously reported. Methylation changes are enriched at known distal transcription factor binding sites such as enhancer elements, instead of CpG-rich regions, and are associated with changes in gene expression. From this, we constructed hypo- and hypermethylation-specific regulatory networks, including a sub-network of BM-MSC master regulators and their predicted target genes, and identified putatively disrupted signaling pathways. Our genome-wide analyses provide a broader overview of age- and expansion-induced DNA methylation changes and a better understanding of the extent to which these changes alter gene expression and functionality of human BM-MSCs.

Abstract Genome compaction is a universal feature of cells and has emerged as a global regulator of gene expression. Compaction is maintained by a multitude of architectural proteins, long non-coding RNAs (lncRNAs), and regulatory DNA. Each component comprises interlinked regulatory circuits that organize the genome in three-dimensional (3D) space to manage gene expression. In this review, we update the current state of 3D genome catalogues and focus on how recent technological advances in 3D genomics are leading to an enhanced understanding of disease mechanisms. We highlight the use of genome-wide chromatin conformation capture (Hi-C) coupled with oligonucleotide capture technology (capture Hi-C) to map interactions between gene promoters and distal regulatory elements such as enhancers that are enriched for disease variants from genome-wide association studies (GWASs). We discuss how aberrations in architectural units are associated with various pathological outcomes, and explore how recent advances in genome and epigenome editing show great promise for a systematic understanding of complex genetic disorders. Our growing understanding of 3D genome architecture—coupled with the ability to engineer changes in it—may create novel therapeutic opportunities.

We currently lack a comprehensive understanding of the mechanisms underlying neural tube formation and their contributions to neural tube defects (NTDs). Developing a model to study such a complex morphogenetic process, especially one that models human-specific aspects, is critical. Three-dimensional, human embryonic stem cell (hESC)-derived neural rosettes (NRs) provide a powerful resource for in vitro modeling of human neural tube formation. Epigenomic maps reveal enhancer elements unique to NRs relative to 2D systems. A master regulatory network illustrates that key NR properties are related to their epigenomic landscapes. We found that folate-associated DNA methylation changes were enriched within NR regulatory elements near genes involved in neural tube formation and metabolism. Our comprehensive regulatory maps offer insights into the mechanisms by which folate may prevent NTDs. Lastly, our distal regulatory maps provide a better understanding of the potential role of neurological-disorder-associated SNPs.

The establishment of DNA methylation patterns in oocytes is a highly dynamic process marking gene-regulatory events during fertilization, embryonic development, and adulthood. However, after epigenetic reprogramming in primordial germ cells, how and when DNA methylation is re-established in developing human oocytes remains to be characterized. Here, using single-cell whole-genome bisulfite sequencing, we describe DNA methylation patterns in three different maturation stages of human oocytes. We found that while broad-scale patterns of CpG methylation have been largely established by the immature germinal vesicle stage, localized changes continue into later development. Non-CpG methylation, on the other hand, undergoes a large-scale, generalized remodeling through the final stage of maturation, with the net overall result being the accumulation of methylation as oocytes mature. The role of the genome-wide, non-CpG methylation remodeling in the final stage of oocyte maturation deserves further investigation.

Summary: Activating germline mutations in STAT3 were recently identified as a cause of neonatal diabetes mellitus associated with beta-cell autoimmunity. We have investigated the effect of an activating mutation, STAT3K392R, on pancreatic development using induced pluripotent stem cells (iPSCs) derived from a patient with neonatal diabetes and pancreatic hypoplasia. Early pancreatic endoderm differentiated similarly from STAT3K392R and healthy-control cells, but in later stages, NEUROG3 expression was upregulated prematurely in STAT3K392R cells together with insulin (INS) and glucagon (GCG). RNA sequencing (RNA-seq) showed robust NEUROG3 downstream targets upregulation. STAT3 mutation correction with CRISPR/Cas9 reversed completely the disease phenotype. STAT3K392R-activating properties were not explained fully by altered DNA-binding affinity or increased phosphorylation. Instead, reporter assays demonstrated NEUROG3 promoter activation by STAT3 in pancreatic cells. Furthermore, proteomic and immunocytochemical analyses revealed increased nuclear translocation of STAT3K392R. Collectively, our results demonstrate that the STAT3K392R mutation causes premature endocrine differentiation through direct induction of NEUROG3 expression. : Saarimäki-Vire et al. use iPSCs derived from a patient with permanent neonatal diabetes to demonstrate that an activating STAT3 mutation leads to premature NEUROG3 expression and concomitant differentiation of pancreatic progenitors through increased nuclear shuttling of the mutant protein. Keywords: monogenic diabetes, STAT3, NEUROG3, iPSC, stem cells, CRISPR, genome editing, pancreatic differentiation, beta cell, endocrine cells

CRISPR/Cas9-mediated gene editing is an emerging strategy to treat Duchenne muscular dystrophy. Here the authors develop multiple CRISPR/Cas9-based approaches to correct different dystrophin gene mutations, and show significant restoration of dystrophin expression in skeletal and cardiac muscle in mice.

Objective. In a separate, contemporary cohort, we sought to confirm findings of the original Women’s Ischemia Syndrome Evaluation (WISE). Background. The original WISE observed a high prevalence of both invasively determined coronary endothelial and coronary microvascular dysfunction (CMD) that predicted adverse events in follow-up. Methods. We comparatively studied the WISE-Coronary Vascular Dysfunction (CVD) cohort (2009-2011), with signs and symptoms of ischemia but without significant CAD, to the original WISE (1997-2001) cohort. CMD was defined as coronary flow reserve (CFR) ≤2.5, or endothelial dysfunction as epicardial coronary artery constriction to acetylcholine (ACH), or

The incidence of type 1 diabetes is increasing, potentially implicating non-genetic factors. Here the authors conduct an epigenome-wide association study in disease-discordant twins and find increased DNA methylation variability at genes associated with immune cell metabolism and the cell cycle.