The predisposition to neuropsychiatric disease involves a complex, polygenic, and pleiotropic genetic architecture. However, little is known about how genetic variants impart brain dysfunction or ...pathology. We used transcriptomic profiling as a quantitative readout of molecular brain-based phenotypes across five major psychiatric disorders-autism, schizophrenia, bipolar disorder, depression, and alcoholism-compared with matched controls. We identified patterns of shared and distinct gene-expression perturbations across these conditions. The degree of sharing of transcriptional dysregulation is related to polygenic (single-nucleotide polymorphism-based) overlap across disorders, suggesting a substantial causal genetic component. This comprehensive systems-level view of the neurobiological architecture of major neuropsychiatric illness demonstrates pathways of molecular convergence and specificity.
Although tricuspid valve operations remain associated with high mortality (approximately 8% to 10%), no robust prediction models exist to support clinical decision making. We developed a preoperative ...clinical risk model with an easily calculable clinical risk score (CRS) to predict mortality and major morbidity after isolated tricuspid valve surgery.
The Society of Thoracic Surgeons database records were evaluated for 2,050 isolated TV repair and replacement operations for any etiology performed at 50 hospitals (2002 to 2014) in a number of states. Parsimonious preoperative risk prediction models were developed using multiple-level mixed effects regression to estimate mortality and composite major morbidity risk. Model results were utilized to establish a novel CRS for patients undergoing tricuspid valve operations. Models were evaluated for discrimination and calibration.
Operative mortality and composite major morbidity rates were 9% and 42%, respectively. Final regression models performed well (both p < 0.001; areas under the receiver-operating characteristics curve 0.74 and 0.76) and included preoperative factors: age, sex, stroke, hemodialysis, ejection fraction, lung disease, New York Heart Association class, reoperation, and urgent or emergency status (all p < 0.05). A simple CRS from 0 to 10+ was highly associated (p < 0.001) with incremental increases in predicted mortality and major morbidity. Predicted mortality risk ranged from 2% to 34% across CRS categories, and predicted major morbidity risk ranged from 13% to 71%.
Mortality and major morbidity after isolated tricuspid valve surgery can be predicted using preoperative patient data from The Society of Thoracic Surgeons National Adult Cardiac Database. A simple clinical risk score predicts mortality and major morbidity after isolated tricuspid valve surgery. This score may facilitate perioperative counseling and identification of suitable patients for tricuspid valve surgery.
Physicians diagnose subjectively the etiology of inaccessible infections where sampling is not feasible (such as, pneumonia, sinusitis, cholecystitis, peritonitis), as bacterial or viral. The ...diagnosis is based on their experience with some medical markers like blood counts and medical symptoms since it is harder to obtain swabs and reliable laboratory results for most cases. In this study, infrared spectroscopy with machine learning algorithms was used for the rapid and objective diagnosis of the etiology of inaccessible infections and enables an assessment of the error for the subjective diagnosis of the etiology of these infections by physicians. Our approach allows for diagnoses of the etiology of both accessible and inaccessible infections as based on an analysis of the innate immune system response through infrared spectroscopy measurements of white blood cell (WBC) samples. In the present study, we examined 343 individuals involving 113 controls, 89 inaccessible bacterial infections, 54 accessible bacterial infections, 60 inaccessible viral infections, and 27 accessible viral infections. Using our approach, the results show that it is possible to differentiate between controls and infections (combined bacterial and viral) with 95% accuracy, and enabling the diagnosis of the etiology of accessible infections as bacterial or viral with >94% sensitivity and > 90% specificity within one hour after the collection of the blood sample with error rate <6%. Based on our approach, the error rate of the physicians' subjective diagnosis of the etiology of inaccessible infections was found to be >23%.
Rapid and objective diagnosis of the etiology of inaccessible infections by analyzing WBCs spectra, measured by FTIR spectroscopy, using machine-learning.
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome associated with multiple pathophysiologic abnormalities, including left ventricular (LV) diastolic dysfunction, ...longitudinal LV systolic dysfunction, abnormal ventricular-arterial coupling, pulmonary hypertension, and right ventricular (RV) remodeling/dysfunction. However, the relative prognostic significance of each of these pathophysiologic abnormalities in HFpEF is unknown.
We prospectively studied 419 patients with HFpEF using echocardiography and sphygmomanometry to assess HFpEF pathophysiologic markers. Cox proportional hazards analyses were used to determine the associations between pathophysiologic markers and outcomes. Mean age was 65±12 years; 62% were women; 39% were black; comorbidities were common; and study participants met published criteria for HFpEF. RV abnormalities were frequent: 28% had abnormal tricuspid annular plane systolic excursion, 15% had reduced RV fractional area change, and 34% had RV hypertrophy. During a median follow-up time of 18 months, 102 (24%) were hospitalized for HF and 175 (42%) experienced the composite end point of cardiovascular hospitalization or death. Decreased LV compliance, measured as reduced LV end-diastolic volume at an idealized LV end-diastolic pressure of 20 mm Hg (EDV20), and RV remodeling, as indicated by increased RV wall thickness, were the 2 pathophysiologic markers most predictive of worse outcomes: adjusted hazard ratio per 1 SD decrease in EDV20=1.39 (95% confidence interval CI, 1.10-1.75; P=0.006), and hazard ratio per 1 SD increase in RV wall thickness=1.37 (95% CI, 1.16-1.61; P<0.001). These associations persisted after additional adjustment for markers of HF severity. By contrast, markers of LV relaxation, longitudinal LV systolic dysfunction, and ventricular-arterial coupling were not significantly associated with adverse outcomes.
In patients with HFpEF, reduced LV compliance and RV remodeling are the strongest pathophysiologic predictors of adverse outcomes.
Interleukin-7 (IL-7) is required for lymphocyte development and homeostasis although the actual sites of IL-7 production have never been clearly identified. We produced a bacterial artificial ...chromosome (BAC) transgenic mouse expressing ECFP in the Il7 locus. The construct lacked a signal peptide and ECFP (enhanced cyan fluorescent protein) accumulated inside IL-7-producing stromal cells in thoracic thymus, cervical thymus and bone marrow. In thymus, an extensive reticular network of IL-7-containing processes extended from cortical and medullary epithelial cells, closely contacting thymocytes. Central memory CD8 T cells, which require IL-7 and home to bone marrow, physically associated with IL-7-producing cells as we demonstrate by intravital imaging.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human viral and bacterial infections are responsible for a variety of diseases that are still the main causes of death and economic burden for society across the globe. Despite the different ...responses of the immune system to these infections, some of them have similar symptoms, such as fever, sneezing, inflammation, vomiting, diarrhea, and fatigue. Thus, physicians usually encounter difficulties in distinguishing between viral and bacterial infections on the basis of these symptoms. Rapid identification of the etiology of infection is highly important for effective treatment and can save lives in some cases. The current methods used for the identification of the nature of the infection are mainly based on growing the infective agent in culture, which is a time-consuming (over 24 h) and usually expensive process. The main objective of this study was to evaluate the potential of the mid-infrared spectroscopic method for rapid and reliable identification of bacterial and viral infections based on simple peripheral blood samples. For this purpose, white blood cells (WBCs) and plasma were isolated from the peripheral blood samples of patients with confirmed viral or bacterial infections. The obtained spectra were analyzed by multivariate analysis: principle component analysis (PCA) followed by linear discriminant analysis (LDA), to identify the infectious agent type as bacterial or viral in a time span of about 1 h after the collection of the blood sample. Our preliminary results showed that it is possible to determine the infectious agent with high success rates of 82% for sensitivity and 80% for specificity, based on the WBC data.
Correction for 'Diagnosis of inaccessible infections using infrared microscopy of white blood cells and machine learning algorithms' by Adam H. Agbaria
et al.
,
Analyst
, 2020, DOI:
...10.1039/D0AN00752H
.
Nontargeted metabolomics methods have increased potential to identify new disease biomarkers, but assessments of the additive information provided in large human cohorts by these less biased ...techniques are limited. To diversify our knowledge of diabetes-associated metabolites, we leveraged a method that measures 305 targeted or "known" and 2,342 nontargeted or "unknown" compounds in fasting plasma samples from 2,750 participants (315 incident cases) in the Jackson Heart Study (JHS)-a community cohort of self-identified African Americans-who are underrepresented in omics studies. We found 307 unique compounds (82 known) associated with diabetes after adjusting for age and sex at a false discovery rate of <0.05 and 124 compounds (35 known, including 11 not previously associated) after further adjustments for BMI and fasting plasma glucose. Of these, 144 and 68 associations, respectively, replicated in a multiethnic cohort. Among these is an apparently novel isomer of the 1-deoxyceramide Cer(m18:1/24:0) with functional geonomics and high-resolution mass spectrometry. Overall, known and unknown metabolites provided complementary information (median correlation ρ = 0.29), and their inclusion with clinical risk factors improved diabetes prediction modeling. Our findings highlight the importance of including nontargeted metabolomics methods to provide new insights into diabetes development in ethnically diverse cohorts.
Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate ...causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.
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