Smartphone-based pathogen diagnosis in urinary sepsis patients.

BackgroundThere is an urgent need for rapid, sensitive, and affordable diagnostics for microbial infections at the point-of-care. Although a number of innovative systems have been reported that transform mobile phones into potential diagnostic tools, the translational challenge to clinical diagnostics remains a significant hurdle to overcome.MethodsA smartphone-based real-time loop-mediated isothermal amplification (smaRT-LAMP) system was developed for pathogen ID in urinary sepsis patients. The free, custom-built mobile phone app allows the phone to serve as a stand-alone device for quantitative diagnostics, allowing the determination of genome copy-number of bacterial pathogens in real time.FindingsA head-to-head comparative bacterial analysis of urine from sepsis patients revealed that the performance of smaRT-LAMP matched that of clinical diagnostics at the admitting hospital in a fraction of the time (~1 h vs. 18-28 h). Among patients with bacteremic complications of their urinary sepsis, pathogen ID from the urine matched that from the blood - potentially allowing pathogen diagnosis shortly after hospital admission. Additionally, smaRT-LAMP did not exhibit false positives in sepsis patients with clinically negative urine cultures.InterpretationThe smaRT-LAMP system is effective against diverse Gram-negative and -positive pathogens and biological specimens, costs less than $100 US to fabricate (in addition to the smartphone), and is configurable for the simultaneous detection of multiple pathogens. SmaRT-LAMP thus offers the potential to deliver rapid diagnosis and treatment of urinary tract infections and urinary sepsis with a simple test that can be performed at low cost at the point-of-care. FUND: National Institutes of Health, Chan-Zuckerberg Biohub, Bill and Melinda Gates Foundation

Immunotherapy for Infarcts: In Vivo Postinfarction Macrophage Modulation Using Intramyocardial Microparticle Delivery of Map4k4 Small Interfering RNA

The myeloid cells infiltrating the heart early after acute myocardial infarction elaborate a secretome that largely orchestrates subsequent ventricular wall repair. Regulating this innate immune response could be a means to improve infarct healing. To pilot this concept, we utilized (beta1,3-d-) glucan-encapsulated small interfering RNA (siRNA)-containing particles (GeRPs), targeting mononuclear phagocytes, delivered to mice as a one-time intramyocardial injection immediately after acute infarction. Findings demonstrated that cardiac macrophages phagocytosed GeRPs in vivo and had little systemic dissemination, thus providing a means to deliver local therapeutics. Acute infarcts were then injected in vivo with phosphate-buffered saline (PBS; vehicle) or GeRPs loaded with siRNA to Map4k4, and excised hearts were examined at 3 and 7 days by quantitative polymerase chain reaction, flow cytometry, and histology. Compared with infarcted PBS-treated hearts, hearts with intrainfarct injections of siRNA-loaded GeRPs exhibited 69-89% reductions in transcripts for Map4k4 (mitogen-activated protein kinase kinase kinase kinase 4), interleukin (IL)-1beta, and tumor necrosis factor alpha at 3 days. Expression of other factors relevant to matrix remodeling-monocyte chemoattractant protein-1 (MCP-1), matrix metalloproteinases, hyaluronan synthases, matricellular proteins, and profibrotic factors transforming growth factor beta (TGF-beta), and connective tissue growth factor (CTGF)-were also decreased. Most effects peaked at 3 days, but, in some instances (Map4k4, IL-1beta, TGF-beta, CTGF, versican, and periostin), suppression persisted to 7 days. Thus, direct intramyocardial GeRP injection could serve as a novel and clinically translatable platform for in vivo RNA delivery to intracardiac macrophages for local and selective immunomodulation of the infarct microenvironment

Adam Smith and Colonialism

In the context of debates about liberalism and colonialism, the arguments of Adam Smith have been taken as illustrative of an important line of anti-colonial liberal thought. The reading of Smith presented here challenges this interpretation. It argues that Smith’s opposition to colonial rule derived largely from its impact on the metropole, rather than on its impact on the conquered and colonised; that Smith recognised colonialism had brought ‘improvement’ in conquered territories and that Smith struggled to balance recognition of moral diversity with a universal moral framework and a commitment to a particular interpretation of progress through history. These arguments have a wider significance as they point towards some of the issues at stake in liberal anti-colonial arguments more generally

Indexed Left Atrial Adipose Tissue Area Is Associated With Severity of Atrial Fibrillation and Atrial Fibrillation Recurrence Among Patients Undergoing Catheter Ablation

Background: Epicardial adipose tissue (EAT) has been associated with adverse left atrial (LA) remodeling and atrial fibrillation (AF) outcomes, possibly because of paracrine signaling. Objectives: We examined factors associated with a novel measure of EAT i.e., indexed LAEAT (iLAEAT) and its prognostic significance after catheter ablation (CA) of atrial fibrillation (AF). Methods: We performed a retrospective analysis of 274 participants with AF referred for CA. LAEAT area was measured from a single pre-ablation CT image and indexed to body surface area (BSA) to calculate iLAEAT. Clinical, echocardiographic data and 1-year AF recurrence rates after CA were compared across tertiles of iLAEAT. We performed logistic regression analysis adjusting for factors associated with AF to examine relations between iLAEAT and AF recurrence. Results: Mean age of participants was 61 +/- 10 years, 136 (49%) were women, mean BMI was 32 +/- 9 kg/m(2) and 85 (31%) had persistent AF. Mean iLAEAT was 0.82 +/- 0.53 cm(2)/m(2). Over 12-months, 109 (40%) had AF recurrence. Participants in the highest iLAEAT tertile were older, had higher CHA2DS2VASC scores, more likely to be male, have greater LA volume, and were more likely to have persistent (vs. paroxysmal) type AF than participants in the lowest iLAEAT tertile (p for all \u3c 0.05). In regression analyses, iLAEAT was associated with higher odds of AF recurrence (OR = 2.93; 95% CI 1.34-6.43). Conclusions: iLAEAT can quantify LA adipose tissue burden using standard CT images. It is strongly associated with AF risk factors and outcomes, supporting the hypothesis that EAT plays a role in the pathophysiology of AF

Feasibility of atrial fibrillation detection from a novel wearable armband device

BACKGROUND: Atrial fibrillation (AF) is the world’s most common heart rhythm disorder and even several minutes of AF episodes can contribute to risk for complications, including stroke. However, AF often goes undiagnosed owing to the fact that it can be paroxysmal, brief, and asymptomatic. OBJECTIVE: To facilitate better AF monitoring, we studied the feasibility of AF detection using a continuous electrocardiogram (ECG) signal recorded from a novel wearable armband device. METHODS: In our 2-step algorithm, we first calculate the R-R interval variability–based features to capture randomness that can indicate a segment of data possibly containing AF, and subsequently discriminate normal sinus rhythm from the possible AF episodes. Next, we use density Poincaré plot-derived image domain features along with a support vector machine to separate premature atrial/ventricular contraction episodes from any AF episodes. We trained and validated our model using the ECG data obtained from a subset of the MIMIC-III (Medical Information Mart for Intensive Care III) database containing 30 subjects. RESULTS: When we tested our model using the novel wearable armband ECG dataset containing 12 subjects, the proposed method achieved sensitivity, specificity, accuracy, and F1 score of 99.89%, 99.99%, 99.98%, and 0.9989, respectively. Moreover, when compared with several existing methods with the armband data, our proposed method outperformed the others, which shows its efficacy. CONCLUSION: Our study suggests that the novel wearable armband device and our algorithm can be used as a potential tool for continuous AF monitoring with high accuracy

Micro-RNAs Are Related to Epicardial Adipose Tissue in Participants With Atrial Fibrillation: Data From the MiRhythm Study

Introduction: Epicardial adipose tissue (EAT) has been linked to incidence and recurrence of atrial fibrillation (AF), but the underlying mechanisms that mediate this association remain unclear. Circulating microRNAs (miRNAs) contribute to the regulation of gene expression in cardiovascular diseases, including AF. Thus, we sought to test the hypothesis that circulating miRNAs relate to burden of EAT. Methods: We examined the plasma miRNA profiles of 91 participants from the miRhythm study, an ongoing study examining associations between miRNA and AF. We quantified plasma expression of 86 unique miRNAs commonly expressed in cardiomyocytes using quantitative reverse transcriptase polymerase chain reaction (qPCR). From computed tomography, we used validated methods to quantify the EAT area surrounding the left atrium (LA) and indexed it to body surface area (BSA) to calculate indexed LA EAT (iLAEAT). Participants were divided into tertiles of iLAEAT to identify associations with unique miRNAs. We performed logistic regression analyses adjusting for factors associated with AF to examine relations between iLAEAT and miRNA. We performed further bioinformatics analysis of miRNA predicted target genes to identify potential molecular pathways are regulated by the miRNAs. Results: The mean age of the participants was 59 +/- 9, 35% were women, and 97% were Caucasian. Participants in the highest tertile of iLAEAT were more likely to have hypertension, heart failure, and thick posterior walls. In regression analyses, we found that miRNAs 155-5p (p \u3c 0.001) and 302a-3p (p \u3c 0.001) were significantly associated with iLAEAT in patients with AF. The predicted targets of the miRNAs identified were implicated in the regulation of cardiac hypertrophy, adipogenesis, interleukin-8 (IL-8), and nerve growth factor (NGF) signaling. Conclusion: miRNA as well as EAT have previously been linked to AF. Our finding that iLAEAT and miRNAs 155-5p and 302a-3p are associated suggest a possible direct link to between these entities in the development and maintenance of AF. Further research is needed to study causal relationships between these biomarkers

Does shear wave ultrasound independently predict axillary lymph node metastasis in women with invasive breast cancer?

Shear wave elastography (SWE) shows promise as an adjunct to greyscale ultrasound examination in assessing breast masses. In breast cancer, higher lesion stiffness on SWE has been shown to be associated with features of poor prognosis. The purpose of this study was to assess whether lesion stiffness at SWE is an independent predictor of lymph node involvement. Patients with invasive breast cancer treated by primary surgery, who had undergone SWE examination were eligible. Data were retrospectively analysed from 396 consecutive patients. The mean stiffness values were obtained using the Aixplorer(®) ultrasound machine from SuperSonic Imagine Ltd. Measurements were taken from a region of interest positioned over the stiffest part of the abnormality. The average of the mean stiffness value obtained from each of two orthogonal image planes was used for analysis. Associations between lymph node involvement and mean lesion stiffness, invasive cancer size, histologic grade, tumour type, ER expression, HER-2 status and vascular invasion were assessed using univariate and multivariate logistic regression. At univariate analysis, invasive size, histologic grade, HER-2 status, vascular invasion, tumour type and mean stiffness were significantly associated with nodal involvement. Nodal involvement rates ranged from 7 % for tumours with mean stiffness <50 kPa to 41 % for tumours with a mean stiffness of >150 kPa. At multivariate analysis, invasive size, tumour type, vascular invasion, and mean stiffness maintained independent significance. Mean stiffness at SWE is an independent predictor of lymph node metastasis and thus can confer prognostic information additional to that provided by conventional preoperative tumour assessment and staging

Transactivation of EGFR by LPS induces COX-2 expression in enterocytes

Necrotizing enterocolitis (NEC) is the leading cause of gastrointestinal morbidity and mortality in preterm infants. NEC is characterized by an exaggerated inflammatory response to bacterial flora leading to bowel necrosis. Bacterial lipopolysaccharide (LPS) mediates inflammation through TLR4 activation and is a key molecule in the pathogenesis of NEC. However, LPS also induces cyclooxygenase-2 (COX-2), which promotes intestinal barrier restitution through stimulation of intestinal cell survival, proliferation, and migration. Epidermal growth factor receptor (EGFR) activation prevents experimental NEC and may play a critical role in LPS-stimulated COX-2 production. We hypothesized that EGFR is required for LPS induction of COX-2 expression. Our data show that inhibiting EGFR kinase activity blocks LPS-induced COX-2 expression in small intestinal epithelial cells. LPS induction of COX-2 requires Src-family kinase signaling while LPS transactivation of EGFR requires matrix metalloprotease (MMP) activity. EGFR tyrosine kinase inhibitors block LPS stimulation of mitogen-activated protein kinase ERK, suggesting an important role of the MAPK/ERK pathway in EGFR-mediated COX-2 expression. LPS stimulates proliferation of IEC-6 cells, but this stimulation is inhibited with either the EGFR kinase inhibitor AG1478, or the selective COX-2 inhibitor Celecoxib. Taken together, these data show that EGFR plays an important role in LPS-induction of COX-2 expression in enterocytes, which may be one mechanism for EGF in inhibition of NEC

A real-time ppg peak detection method for accurate determination of heart rate during sinus rhythm and cardiac arrhythmia

Objective: We have developed a peak detection algorithm for accurate determination of heart rate, using photoplethysmographic (PPG) signals from a smartwatch, even in the presence of various cardiac rhythms, including normal sinus rhythm (NSR), premature atrial contraction (PAC), premature ventricle contraction (PVC), and atrial fibrillation (AF). Given the clinical need for accurate heart rate estimation in patients with AF, we developed a novel approach that reduces heart rate estimation errors when compared to peak detection algorithms designed for NSR. Methods: Our peak detection method is composed of a sequential series of algorithms that are combined to discriminate the various arrhythmias described above. Moreover, a novel Poincaré plot scheme is used to discriminate between basal heart rate AF and rapid ventricular response (RVR) AF, and to differentiate PAC/PVC from NSR and AF. Training of the algorithm was performed only with Samsung Simband smartwatch data, whereas independent testing data which had more samples than did the training data were obtained from Samsung’s Gear S3 and Galaxy Watch 3. Results: The new PPG peak detection algorithm provides significantly lower average heart rate and interbeat interval beat-to-beat estimation errors—30% and 66% lower—and mean heart rate and mean interbeat interval estimation errors—60% and 77% lower—when compared to the best of the seven other traditional peak detection algorithms that are known to be accurate for NSR. Our new PPG peak detection algorithm was the overall best performers for other arrhythmias. Conclusion: The proposed method for PPG peak detection automatically detects and discriminates between various arrhythmias among different waveforms of PPG data, delivers significantly lower heart rate estimation errors for participants with AF, and reduces the number of false negative peaks. Significance: By enabling accurate determination of heart rate despite the presence of AF with rapid ventricular response or PAC/PVCs, we enable clinicians to make more accurate recommendations for heart rate control from PPG data

Joint analysis of left ventricular expression and circulating plasma levels of Omentin after myocardial ischemia

BACKGROUND: Omentin-1, also known as Intelectin-1 (ITLN1), is an adipokine with plasma levels associated with diabetes, obesity, and coronary artery disease. Recent studies suggest that ITLN1 can mitigate myocardial ischemic injury but the expression of ITLN1 in the heart itself has not been well characterized. The purpose of this study is to discern the relationship between the expression pattern of ITLN1 RNA in the human heart and the level of circulating ITLN1 protein in plasma from the same patients following myocardial ischemia. METHODS: A large cohort of patients (n = 140) undergoing elective cardiac surgery for aortic valve replacement were enrolled in this study. Plasma and left ventricular biopsy samples were taken at the beginning of cardiopulmonary bypass and after an average of 82 min of ischemic cross clamp time. The localization of ITLN1 in epicardial adipose tissue (EAT) was also further characterized with immunoassays and cell fate transition studies. RESULTS: mRNA expression of ITLN1 decreases in left ventricular tissue after acute ischemia in human patients (mean difference 280.48, p = 0.001) whereas plasma protein levels of ITLN1 increase (mean difference 5.24, p \u3c 0.001). Immunohistochemistry localized ITLN1 to the mesothelium or visceral pericardium of EAT. Epithelial to mesenchymal transition in mesothelial cells leads to a downregulation of ITLN1 expression. CONCLUSIONS: Myocardial injury leads to a decrease in ITLN1 expression in the heart and a corresponding increase in plasma levels. These changes may in part be due to an epithelial to mesenchymal transition of the cells that express ITLN1 following ischemia. Trial Registration Clinicaltrials.gov ID: NCT00985049