Challenging molecular dogmas in human sepsis using mathematical reasoning

Sepsis is defined as a dysregulated host-response to infection, across all ages and pathogens. What defines a dysregulated state remains intensively researched but incompletely understood. Here, we dissect the meaning of this definition and its importance for the diagnosis and management of sepsis. We deliberate on pathophysiological features and dogmas that range from cytokine storms and immune paralysis to dormancy and altered homeostasis setpoints. Mathematical reasoning, used to test for plausibility, reveals three interlinked cardinal rules governing host-response trajectories in sepsis. Rule one highlights that the amplitude of the immune response while important is not sufficient and is strictly dependent on rule two, specifying bioenergetic capacity and are together dynamically driven by rule three, delineating stability and alterations in setpoints. We consider these rules and associated pathophysiological parameters for guiding data-science and artificial intelligence mining of multi-omics and big-data for improving the precision of diagnostic and therapeutic approaches to sepsis

NEUROlogical Prognosis After Cardiac Arrest in Kids (NEUROPACK) study: protocol for a prospective multicentre clinical prediction model derivation and validation study in children after cardiac arrest

Introduction Currently, we are unable to accurately predict mortality or neurological morbidity following resuscitation after paediatric out of hospital (OHCA) or in-hospital (IHCA) cardiac arrest. A clinical prediction model may improve communication with parents and families and risk stratification of patients for appropriate postcardiac arrest care. This study aims to the derive and validate a clinical prediction model to predict, within 1 hour of admission to the paediatric intensive care unit (PICU), neurodevelopmental outcome at 3 months after paediatric cardiac arrest. Methods and analysis A prospective study of children (age: >24 hours and <16 years), admitted to 1 of the 24 participating PICUs in the UK and Ireland, following an OHCA or IHCA. Patients are included if requiring more than 1 min of cardiopulmonary resuscitation and mechanical ventilation at PICU admission Children who had cardiac arrests in PICU or neonatal intensive care unit will be excluded. Candidate variables will be identified from data submitted to the Paediatric Intensive Care Audit Network registry. Primary outcome is neurodevelopmental status, assessed at 3 months by telephone interview using the Vineland Adaptive Behavioural Score II questionnaire. A clinical prediction model will be derived using logistic regression with model performance and accuracy assessment. External validation will be performed using the Therapeutic Hypothermia After Paediatric Cardiac Arrest trial dataset. We aim to identify 370 patients, with successful consent and follow-up of 150 patients. Patient inclusion started 1 January 2018 and inclusion will continue over 18 months. Ethics and dissemination Ethical review of this protocol was completed by 27 September 2017 at the Wales Research Ethics Committee 5, 17/WA/0306. The results of this study will be published in peer-reviewed journals and presented in conferences. Trial registration number NCT03574025

nSeP: immune and metabolic biomarkers for early detection of neonatal sepsis-protocol for a prospective multicohort study

Introduction Diagnosing neonatal sepsis is heavily dependent on clinical phenotyping as culture-positive body fluid has poor sensitivity, and existing blood biomarkers have poor specificity. A combination of machine learning, statistical and deep pathway biology analyses led to the identification of a tripartite panel of biologically connected immune and metabolic markers that showed greater than 99% accuracy for detecting bacterial infection with 100% sensitivity. The cohort study described here is designed as a large-scale clinical validation of this previous work. Methods and analysis This multicentre observational study will prospectively recruit a total of 1445 newborn infants (all gestations)—1084 with suspected early—or late-onset sepsis, and 361 controls—over 4 years. A small volume of whole blood will be collected from infants with suspected sepsis at the time of presentation. This sample will be used for integrated transcriptomic, lipidomic and targeted proteomics profiling. In addition, a subset of samples will be subjected to cellular phenotype and proteomic analyses. A second sample from the same patient will be collected at 24 hours, with an opportunistic sampling for stool culture. For control infants, only one set of blood and stool sample will be collected to coincide with clinical blood sampling. Along with detailed clinical information, blood and stool samples will be analysed and the information will be used to identify and validate the efficacy of immune-metabolic networks in the diagnosis of bacterial neonatal sepsis and to identify new host biomarkers for viral sepsis

Synthesis and biological evaluation of mannose-6-phosphate-coated multivalent dendritic cluster glycosides

The synthesis of multivalent dendritic cluster glycosides of mannopyranosyl-6-phosphate is presented. Poly(amido amine)-based dendrimers of 0.5-3.5 generations, containing carboxylic acid peripheral functionalities, were utilized so as to install 4, 8, 16 and 32 mannopyranosyl-6-phosphate residues at the peripheries of the dendrimers. Amide bond formation between an amine-tethered mannopyranosyl-6-phosphate monomer unit and carboxylic acid-functionalized dendrimers was conducted to synthesize the dendritic cluster glycosides. The constitutions of the Man-6-P-containing dendrimers were assessed by <SUP>1</SUP>H, <SUP>13</SUP>C and <SUP>31</SUP>P NMR spectroscopies and the sugar content analysis by a resorcinol assay. Preliminary biological studies with few newly synthesized Man-6-P-containing dendrimers showed that these compounds could bind the purified goat liver mannose 6-phopshate receptor (MPR 300) protein

Scalable Single-Phase Multi-Functional Inverter for Integration of Rooftop Solar-PV to Low-Voltage Ideal and Weak Utility Grid

Integration of rooftop solar-PV (RTSPV) systems and extensive use of nonlinear loads in the low-voltage distribution system (LVDS) leads to poor power quality (PQ). Therefore, it is necessary to address the issues leading to poor PQ at the point of common coupling of the LVDS. In this article, a multi-band hysteresis current control (MB-HCC) for the multi-functional inverter (MFI) is proposed which improves the efficiency of the MFI and also enhances the PQ of the LVDS. The MB-HCC uses simple switching logic and outperforms in its multi-functional tasks such as active power injection and power conditioning. MB-HCC offers better efficiency over variable double-band HCC (VDB-HCC) as it operates at a lower switching frequency. The performance of the proposed system is simulated by using MATLAB/Simulink and validated by OPAL-RT based real-time simulation studies. During the variation of solar irradiation, the proposed MFI has an average efficiency of 98.5% under the ideal grid and 97.34% under the distorted grid. Moreover, the percentage of Total Harmonic Distortion under ideal and distorted grid conditions is brought down to below 5%, and also, reactive power compensation maintains unity power factor operation complying with the IEEE-519-2014 and 1547 standards. These results substantiate the hypothesis of scalability of the single-phase MB-HCC-based MFI for an LVDS contributing to economy and ecology

Enhanced Dual-Spectrum Line Interpolated FFT with Four-Term Minimal Sidelobe Cosine Window for Real-Time Harmonic Estimation in Synchrophasor Smart-Grid Technology

The proliferation of nonlinear loads and integration of renewable energy sources require attention for accurate harmonic estimation along with estimation of fundamental amplitude, phase, and frequency for protection, improving power quality, and managing power effectively in a smart distribution grid. There are currently different Windowed Interpolated Fast Fourier Transform (WIFFT) algorithms for harmonic voltage estimation, but estimation of current harmonics using WIFFT is not explored sufficiently. The existing WIFFT algorithms, when used for current harmonic estimation result in low accuracy due to spectral leakage and picket fence effect. On the other hand, Interpolated Discrete Fourier Transform (DFT) is used for synchrophasor quality metrics, but it is effective only when there are no harmonics and the fundamental frequency is constant. This paper proposes a unified solution, comprising of peak location index search (PLIS)-based Dual-Spectrum Line Interpolated Fast Fourier Transform (DSLIFFT) algorithm with 4-Term Minimal Sidelobe Cosine Window (4MSCW) for estimating both low-amplitude voltage or current harmonics and synchrophasor under variable frequency conditions for high-penetration renewable energy utility grids. The effectiveness of the proposed algorithm is validated by simulation studies and real-time experimentation using the National Instruments reconfigurable embedded system under nonlinear loading conditions

sj-pdf-1-jcb-10.1177_0271678X231212961 - Supplemental material for Acute severe hypoglycemia alters mouse brain microvascular proteome

Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231212961 for Acute severe hypoglycemia alters mouse brain microvascular proteome by Siva SVP Sakamuri, Venkata N Sure, Lokanatha Oruganti, William Wisen, Partha K Chandra, Ning Liu, Vivian A Fonseca, Xiaoying Wang, Jennifer Klein and Prasad VG Katakam in Journal of Cerebral Blood Flow & Metabolism</p