Acute Pericarditis: Rapid Evidence Review.

Acute pericarditis is defined as inflammation of the pericardium and occurs in approximately 4.4% of patients who present to the emergency department for nonischemic chest pain, with a higher prevalence in men. Although there are numerous etiologies of pericarditis, most episodes are idiopathic and the cause is presumed to be viral. Diagnosis of pericarditis requires at least two of the following criteria: new or worsening pericardial effusion, characteristic pleuritic chest pain, pericardial friction rub, or electrocardiographic changes, including new, widespread ST elevations or PR depressions. Pericardial friction rubs are highly specific but transient, and they have been reported in 18% to 84% of patients with acute pericarditis. Classic electrocardiographic findings include PR-segment depressions; diffuse, concave, upward ST-segment elevations without reciprocal changes; and T-wave inversions. Transthoracic echocardiography should be performed in all patients with acute pericarditis to characterize the size of effusions and evaluate for complications. Nonsteroidal anti-inflammatory drugs are the first-line treatment option. Glucocorticoids should be reserved for patients with contraindications to first-line therapy and those who are pregnant beyond 20 weeks' gestation or have other systemic inflammatory conditions. Colchicine should be used in combination with first- or second-line treatments to reduce the risk of recurrence. Patients with a higher risk of complications should be admitted to the hospital for further workup and treatment.

Chronic Asthma Treatment: Common Questions and Answers.

Asthma affects more than 25 million people in the United States, and 62% of adults with asthma do not have adequately controlled symptoms. Asthma severity and level of control should be assessed at diagnosis and evaluated at subsequent visits using validated tools such as the Asthma Control Test or the asthma APGAR (activities, persistent, triggers, asthma medications, response to therapy) tools. Short-acting beta2 agonists are preferred asthma reliever medications. Controller medications consist of inhaled corticosteroids, long-acting beta2 agonists, long-acting muscarinic antagonists, and leukotriene receptor antagonists. Treatment typically begins with inhaled corticosteroids, and additional medications or dosage increases should be added in a stepwise fashion according to guideline-directed therapy recommendations from the National Asthma Education and Prevention Program or the Global Initiative for Asthma when symptoms are inadequately controlled. Single maintenance and reliever therapy combines an inhaled corticosteroid and long-acting beta2 agonist for controller and reliever treatments. This therapy is preferred for adults and adolescents because of its effectiveness in reducing severe exacerbations. Subcutaneous immunotherapy may be considered for those five years and older with mild to moderate allergic asthma; however, sublingual immunotherapy is not recommended. Patients with severe uncontrolled asthma despite appropriate treatment should be reassessed and considered for specialty referral. Biologic agents may be considered for patients with severe allergic and eosinophilic asthma.

Making Ventilator Associated Pneumonia Rate a Meaningful Quality Marker.

INTRODUCTION: Ventilator associated pneumonia (VAP) rate has been tracked as a comparable quality measure but there is significant variation between types of ICUs. We sought to understand variability and improve its utility as a marker of quality. METHODS: The National Trauma Database was surveyed to identify risk factors for VAP. Logistic regression, χ2, Student's T-test or Mann-Whitney U test were used. RESULTS: Risk factors associated with developing VAP were: injury severity score (ISS) (OR 1.03, 95% CI 1.03 -1.04), prehospital assisted respiration (PHAR) (OR 1.10, 1.03 -1.17), thoracic injuries (OR 2.28, 1.69-3.08), diabetes (OR 1.32, 1.20 -1.46), male gender (OR 1.38, 1.28 -1.60), care at a teaching hospital (OR 1.40, 1.29 -1.47) and unplanned intubation (OR 2.76, 2.52-3.03). DISCUSSION: ISS, PHAR, diabetes, male gender, care at a teaching hospital and unplanned intubation are risk factors for the development of VAP. These factors should be accounted for in order to make VAP an effective quality marker.

Discovery of Depression-Associated Factors From a Nationwide Population-Based Survey: Epidemiological Study Using Machine Learning and Network Analysis.

BACKGROUND: In epidemiological studies, finding the best subset of factors is challenging when the number of explanatory variables is large. OBJECTIVE: Our study had two aims. First, we aimed to identify essential depression-associated factors using the extreme gradient boosting (XGBoost) machine learning algorithm from big survey data (the Korea National Health and Nutrition Examination Survey, 2012-2016). Second, we aimed to achieve a comprehensive understanding of multifactorial features in depression using network analysis. METHODS: An XGBoost model was trained and tested to classify "current depression" and "no lifetime depression" for a data set of 120 variables for 12,596 cases. The optimal XGBoost hyperparameters were set by an automated machine learning tool (TPOT), and a high-performance sparse model was obtained by feature selection using the feature importance value of XGBoost. We performed statistical tests on the model and nonmodel factors using survey-weighted multiple logistic regression and drew a correlation network among factors. We also adopted statistical tests for the confounder or interaction effect of selected risk factors when it was suspected on the network. RESULTS: The XGBoost-derived depression model consisted of 18 factors with an area under the weighted receiver operating characteristic curve of 0.86. Two nonmodel factors could be found using the model factors, and the factors were classified into direct (P<.05) and indirect (P≥.05), according to the statistical significance of the association with depression. Perceived stress and asthma were the most remarkable risk factors, and urine specific gravity was a novel protective factor. The depression-factor network showed clusters of socioeconomic status and quality of life factors and suggested that educational level and sex might be predisposing factors. Indirect factors (eg, diabetes, hypercholesterolemia, and smoking) were involved in confounding or interaction effects of direct factors. Triglyceride level was a confounder of hypercholesterolemia and diabetes, smoking had a significant risk in females, and weight gain was associated with depression involving diabetes. CONCLUSIONS: XGBoost and network analysis were useful to discover depression-related factors and their relationships and can be applied to epidemiological studies using big survey data.

Voltage-Controlled Antiferromagnetism in Magnetic Tunnel Junctions.

We demonstrate a voltage-controlled exchange bias effect in CoFeB/MgO/CoFeB magnetic tunnel junctions that is related to the interfacial Fe(Co)O_{x} formed between the CoFeB electrodes and the MgO barrier. The unique combination of interfacial antiferromagnetism, giant tunneling magnetoresistance, and sharp switching of the perpendicularly magnetized CoFeB allows sensitive detection of the exchange bias. We find that the exchange bias field can be isothermally controlled by magnetic fields at low temperatures. More importantly, the exchange bias can also be effectively manipulated by the electric field applied to the MgO barrier due to the voltage-controlled antiferromagnetic anisotropy in this system.

Observation of High Spin-to-Charge Conversion by Sputtered Bismuth Selenide Thin Films at Room Temperature.

We investigated spin-to-charge conversion in sputtered Bi43Se57/Co20Fe60B20 heterostructures with in-plane magnetization at room temperature. High spin-to-charge conversion voltage signals have been observed at room temperature. The transmission electron microscope images show that the sputtered bismuth selenide thin films are nanogranular in structure. The spin-pumping voltage decreases with an increase in the size of the grains. The inverse Edelstein effect length (λIEE) is estimated to be as large as 0.32 nm. The large λIEE is due to the spin-momentum locking and is further enhanced by quantum confinement in the nanosized grains of the sputtered bismuth selenide films. We also investigated the effect on spin-pumping voltage due to the insertion of layers of MgO and Ag. The MgO insertion layer has almost completely suppressed the spin-pumping voltage, whereas the Ag insertion layer has enhanced the λIEE by 43%.

Unusual Case of Penile Ecchymosis.

Hirudin is a potent anticoagulant found in the salivary glands of several species of leeches. We report a case of direct hirudin exposure after suspected leech bite causing significant penile ecchymosis. Diagnosis was not apparent on initial evaluation but made after a thorough history was obtained and the leech was found in the lining of his swim trunks, which he left at home. Although this presentation mimics several other potentially serious conditions, treatment is largely observational with anticipated rapid improvement over the course of hours without intervention.

Oncodomains: A protein domain-centric framework for analyzing rare variants in tumor samples.

The fight against cancer is hindered by its highly heterogeneous nature. Genome-wide sequencing studies have shown that individual malignancies contain many mutations that range from those commonly found in tumor genomes to rare somatic variants present only in a small fraction of lesions. Such rare somatic variants dominate the landscape of genomic mutations in cancer, yet efforts to correlate somatic mutations found in one or few individuals with functional roles have been largely unsuccessful. Traditional methods for identifying somatic variants that drive cancer are 'gene-centric' in that they consider only somatic variants within a particular gene and make no comparison to other similar genes in the same family that may play a similar role in cancer. In this work, we present oncodomain hotspots, a new 'domain-centric' method for identifying clusters of somatic mutations across entire gene families using protein domain models. Our analysis confirms that our approach creates a framework for leveraging structural and functional information encapsulated by protein domains into the analysis of somatic variants in cancer, enabling the assessment of even rare somatic variants by comparison to similar genes. Our results reveal a vast landscape of somatic variants that act at the level of domain families altering pathways known to be involved with cancer such as protein phosphorylation, signaling, gene regulation, and cell metabolism. Due to oncodomain hotspots' unique ability to assess rare variants, we expect our method to become an important tool for the analysis of sequenced tumor genomes, complementing existing methods.

Empirical null estimation using zero-inflated discrete mixture distributions and its application to protein domain data.

In recent mutation studies, analyses based on protein domain positions are gaining popularity over gene-centric approaches since the latter have limitations in considering the functional context that the position of the mutation provides. This presents a large-scale simultaneous inference problem, with hundreds of hypothesis tests to consider at the same time. This article aims to select significant mutation counts while controlling a given level of Type I error via False Discovery Rate (FDR) procedures. One main assumption is that the mutation counts follow a zero-inflated model in order to account for the true zeros in the count model and the excess zeros. The class of models considered is the Zero-inflated Generalized Poisson (ZIGP) distribution. Furthermore, we assumed that there exists a cut-off value such that smaller counts than this value are generated from the null distribution. We present several data-dependent methods to determine the cut-off value. We also consider a two-stage procedure based on screening process so that the number of mutations exceeding a certain value should be considered as significant mutations. Simulated and protein domain data sets are used to illustrate this procedure in estimation of the empirical null using a mixture of discrete distributions. Overall, while maintaining control of the FDR, the proposed two-stage testing procedure has superior empirical power.

Alternative Ac/Ds transposition induces major chromosomal rearrangements in maize.

Barbara McClintock reported that the Ac/Ds transposable element system can generate major chromosomal rearrangements (MCRs), but the underlying mechanism has not been determined. Here, we identified a series of chromosome rearrangements derived from maize lines containing pairs of closely linked Ac transposable element termini. Molecular and cytogenetic analyses showed that the MCRs in these lines comprised 17 reciprocal translocations and two large inversions. The breakpoints of all 19 MCRs are delineated by Ac termini and characteristic 8-base-pair target site duplications, indicating that the MCRs were generated by precise transposition reactions involving the Ac termini of two closely linked elements. This alternative transposition mechanism may have contributed to chromosome evolution and may also occur during V(D)J recombination resulting in oncogenic translocations.

Regulatory Single-Nucleotide Variant Predictor Increases Predictive Performance of Functional Regulatory Variants.

In silico methods for detecting functionally relevant genetic variants are important for identifying genetic markers of human inherited disease. Much research has focused on protein-coding variants since coding regions have well-defined physicochemical and functional properties. However, many bioinformatics tools are not applicable to variants outside coding regions. Here, we increase the classification performance of our regulatory single-nucleotide variant predictor (RSVP) for variants that cause regulatory abnormalities from an AUC of 0.90-0.97 by incorporating genomic regions identified by the ENCODE project into RSVP. RSVP is comparable to a recently published tool, Genome-Wide Annotation of Variants (GWAVA); both RSVP and GWAVA perform better on regulatory variants than a traditional variant predictor, combined annotation-dependent depletion (CADD). However, our method outperforms GWAVA on variants located at similar distances to the transcription start site as the positive set (AUC: 0.96) as compared with GWAVA (AUC: 0.71). Much of this disparity is due to RSVP's incorporation of features pertaining to the nearest gene (expression, GO terms, etc.), which are not included in GWAVA. Our findings hold out the promise of a framework for the assessment of all functional regulatory variants, providing a means to predict which rare or de novo variants are of pathogenic significance.

Computational and Experimental Studies of Regioselective SNAr Halide Exchange (Halex) Reactions of Pentachloropyridine.

The Halex reaction of pentachloropyridine with fluoride ion was studied experimentally and computationally with a modified ab initio G3MP2B3 method. The G3 procedure was altered, as the anionic transition state optimizations failed due to the lack of diffuse functions in the small 6-31G* basis set. Experimental Halex regioselectivities were consistent with kinetic control at the 4-position. The reverse Halex reaction of fluoropyridines with chloride sources was demonstrated using precipitation of LiF in DMSO as a driving force. Reverse Halex regioselectivity at the 4-position was predicted by computations and was consistent with kinetic control. Scrambling of halide ions between chlorofluoropyridines was catalyzed by n-Bu4PCl, and the products of these reactions were shown to result from a combination of kinetic and thermodynamic control. Comparison of the C-F and C-Cl homolytic bond dissociation energies suggests that an important thermodynamic factor which controls regioselectivity in this system is the weak C2-Cl bond. The differences between ΔH° values of chlorofluoropyridines can be explained by a combination of three factors: (1) the number of fluorine atoms in the molecule, (2) the number of fluorine atoms at the C2 and C6 positions, and (3) the number of pairs of fluorine atoms which are ortho to one another.

Generation of tandem direct duplications by reversed-ends transposition of maize ac elements.

Tandem direct duplications are a common feature of the genomes of eukaryotes ranging from yeast to human, where they comprise a significant fraction of copy number variations. The prevailing model for the formation of tandem direct duplications is non-allelic homologous recombination (NAHR). Here we report the isolation of a series of duplications and reciprocal deletions isolated de novo from a maize allele containing two Class II Ac/Ds transposons. The duplication/deletion structures suggest that they were generated by alternative transposition reactions involving the termini of two nearby transposable elements. The deletion/duplication breakpoint junctions contain 8 bp target site duplications characteristic of Ac/Ds transposition events, confirming their formation directly by an alternative transposition mechanism. Tandem direct duplications and reciprocal deletions were generated at a relatively high frequency (~0.5 to 1%) in the materials examined here in which transposons are positioned nearby each other in appropriate orientation; frequencies would likely be much lower in other genotypes. To test whether this mechanism may have contributed to maize genome evolution, we analyzed sequences flanking Ac/Ds and other hAT family transposons and identified three small tandem direct duplications with the structural features predicted by the alternative transposition mechanism. Together these results show that some class II transposons are capable of directly inducing tandem sequence duplications, and that this activity has contributed to the evolution of the maize genome.

Crosstalk between the circadian clock and innate immunity in Arabidopsis.

The circadian clock integrates temporal information with environmental cues in regulating plant development and physiology. Recently, the circadian clock has been shown to affect plant responses to biotic cues. To further examine this role of the circadian clock, we tested disease resistance in mutants disrupted in CCA1 and LHY, which act synergistically to regulate clock activity. We found that cca1 and lhy mutants also synergistically affect basal and resistance gene-mediated defense against Pseudomonas syringae and Hyaloperonospora arabidopsidis. Disrupting the circadian clock caused by overexpression of CCA1 or LHY also resulted in severe susceptibility to P. syringae. We identified a downstream target of CCA1 and LHY, GRP7, a key constituent of a slave oscillator regulated by the circadian clock and previously shown to influence plant defense and stomatal activity. We show that the defense role of CCA1 and LHY against P. syringae is at least partially through circadian control of stomatal aperture but is independent of defense mediated by salicylic acid. Furthermore, we found defense activation by P. syringae infection and treatment with the elicitor flg22 can feedback-regulate clock activity. Together this data strongly supports a direct role of the circadian clock in defense control and reveal for the first time crosstalk between the circadian clock and plant innate immunity.

Changes in weather and climate extremes: state of knowledge relevant to air and water quality in the United States.

Air and water quality are impacted by extreme weather and climate events on time scales ranging from minutes to many months. This review paper discusses the state of knowledge of how and why extreme events are changing and are projected to change in the future. These events include heat waves, cold waves, floods, droughts, hurricanes, strong extratropical cyclones such as nor'easters, heavy rain, and major snowfalls. Some of these events, such as heat waves, are projected to increase, while others, with cold waves being a good example, will decrease in intensity in our warming world. Each extreme's impact on air or water quality can be complex and can even vary over the course of the event.

Transcribed enhancer sequences are required for maize p1 paramutation.

Paramutation is a transfer of heritable silencing states between interacting endogenous alleles or between endogenous alleles and homologous transgenes. Prior results demonstrated that paramutation occurs at the P1-rr (red pericarp and red cob) allele of the maize p1 (pericarp color 1) gene when exposed to a transgene containing a 1.2-kb enhancer fragment (P1.2) of P1-rr. The paramutable P1-rr allele undergoes transcriptional silencing resulting in a paramutant light-pigmented P1-rr' state. To define more precisely the sequences required to elicit paramutation, the P1.2 fragment was further subdivided, and the fragments transformed into maize plants and crossed with P1-rr. Analysis of the progeny plants showed that the sequences required for paramutation are located within a ∼600-bp segment of P1.2 and that this segment overlaps with a previously identified enhancer that is present in 4 direct repeats in P1-rr. The paramutagenic segment is transcribed in both the expressed P1-rr and the silenced P1-rr'. Transcription is sensitive to α-amanitin, indicating that RNA polymerase II mediates most of the transcription of this sequence. Although transcription within the paramutagenic sequence was similar in all tested genotypes, small RNAs were more abundant in the silenced P1-rr' epiallele relative to the expressed P1-rr allele. In agreement with prior results indicating the association of RNA-mediated DNA methylation in p1 paramutation, DNA blot analyses detected increased cytosine methylation of the paramutant P1-rr' sequences homologous to the transgenic P1.2 subfragments. Together these results demonstrate that the P1-rr enhancer repeats mediate p1 paramutation.

Machine Learning Models for Low Back Pain Detection and Factor Identification: Insights From a 6-Year Nationwide Survey.

This study aimed to enhance performance, identify additional predictors, and improve the interpretability of biopsychosocial machine learning models for low back pain (LBP). Using survey data from a 6-year nationwide study involving 17,609 adults aged ≥50 years (Korea National Health and Nutrition Examination Survey), we explored 119 factors to detect LBP in individuals who reported experiencing LBP for at least 30 days within the previous 3 months. Our primary model, model 1, employed eXtreme Gradient Boosting (XGBoost) and selected primary factors (PFs) based on their feature importance scores. To extend this, we introduced additional factors, such as lumbar X-ray findings, physical activity, sitting time, and nutrient intake levels, which were available only during specific survey periods, into models 2 to 4. Model performance was evaluated using the area under the curve, with predicted probabilities explained by SHapley Additive exPlanations. Eleven PFs were identified, and model 1 exhibited an enhanced area under the curve .8 (.77-.84, 95% confidence interval). The factors had varying impacts across individuals, underscoring the need for personalized assessment. Hip and knee joint pain were the most significant PFs. High levels of physical activity were found to have a negative association with LBP, whereas a high intake of omega-6 was found to have a positive association. Notably, we identified factor clusters, including hip joint pain and female sex, potentially linked to osteoarthritis. In summary, this study successfully developed effective XGBoost models for LBP detection, thereby providing valuable insight into LBP-related factors. Comprehensive LBP management, particularly in women with osteoarthritis, is crucial given the presence of multiple factors. PERSPECTIVE: This article introduces XGBoost models designed to detect LBP and explores the multifactorial aspects of LBP through the application of SHapley Additive exPlanations and network analysis on the 4 developed models. The utilization of this analytical system has the potential to aid in devising personalized management strategies to address LBP.

Predictors of response in PROMIS-global in a chronic low back pain specialty clinic: STarTBack and chronic overlapping pain conditions.

BACKGROUND: Tools, such as the STarTBack Screening Tool (SBT), have been developed to identify risks of progressing to chronic disability in low back pain (LBP) patients in the primary care population. However, less is known about predictors of change in function after treatment in the specialty care population. OBJECTIVE: We pursued a retrospective observational cohort study involving LBP patients seen in a multidisciplinary specialty clinic to assess which features can predict change in function at follow-up. METHODS: The SBT was administered at initial visit, and a variety of patient characteristics were available in the chart including the presence of chronic overlapping pain conditions (COPCs). Patient Reported Outcomes Measurement Information System-10 (PROMIS-10) global physical health (PH) and global mental health (MH) were measured at baseline and at pragmatic time points during follow-up. Linear regression was used to estimate adjusted associations between available features and changes in PROMIS scores. RESULTS: 241 patients were followed for a mean of 17.0 ± 7.5 months. Mean baseline pain was 6.7 (SD 2.1), PROMIS-10 global MH score was 44.8 (SD 9.3), and PH score was 39.4 (SD 8.6). 29.7% were low-risk on the SBT, 41.8% were medium-risk, and 28.5% were high-risk. Mean change in MH and PH scores from baseline to the follow-up questionnaire were 0.86 (SD 8.11) and 2.39 (SD 7.52), respectively. Compared to low-risk patients, high-risk patients had a mean 4.35 points greater improvement in their MH score (p= 0.004) and a mean 3.54 points greater improvement in PH score (p= 0.006). Fewer COPCs also predicted greater improvement in MH and PH. CONCLUSIONS: SBT and the presence of COPC, which can be assessed at initial presentation to a specialty clinic, can predict change in PROMIS following treatment. Effort is needed to identify other factors that can help predict change in function after treatment in the specialty care setting.