Enhancing Syndromic Surveillance through Autonomic Health Grids

The Centers for Disease Control defines syndromic surveillance as, “an investigational approach where health department staff, assisted by automated data acquisition and generation of statistical alerts, monitor disease indicators in real-time or near real-time to detect outbreaks of disease earlier than would otherwise be possible with traditional public health methods” (CDC, 2004). While syndromic surveillance has traditionally been used in the context of detecting natural outbreaks, it is increasingly being used to develop systems to detect bioterrorism outbreaks. Timely response to a bioterrorism event requires accurate information exchange between clinicians and public health officials. This entails building highly complex surveillance systems that provide access to heterogeneous/distributed medical data, computational resources and collaborative services, for real-time decision making in a highly reliable and secure environment. In this paper we propose enhancing syndromic surveillance through grid and autonomic computing augmentations, and present our approach to a proof of concept modeling and simulation environment

Early Life Exposure to Unpredictable Parental Sensory Signals Shapes Cognitive Development Across Three Species

Exposure to early life adversity has long term consequences on cognitive function. Most research has focused on understanding components of early life adversities that contribute to later risk, including poverty, trauma, maltreatment, and neglect. Whereas these factors, in the aggregate, explain a significant proportion of emotional and cognitive problems, there are serious gaps in our ability to identify potential mechanisms by which early life adversities might promote vulnerability or resilience. Here we discuss early life exposure to unpredictable signals from the caretaker as an understudied type of adversity that is amenable to prevention and intervention. We employ a translational approach to discover underlying neurobiological mechanisms by which early life exposure to unpredictable signals sculpts the developing brain. First, we review evidence that exposure to unpredictable signals from the parent during sensitive periods impacts development of neural circuits. Second, we describe a method for characterizing early life patterns of sensory signals across species. Third, we present published and original data illustrating that patterns of maternal care predict memory function in humans, non-human primates, and rodents. Finally, implications are discussed for identifying individuals at risk so that early preventive-intervention can be provided

A novel Plasmodium falciparum rhoptry associated adhesin mediates erythrocyte invasion through the sialic-acid dependent pathway

Erythrocyte invasion by Plasmodium falciparum merozoites is central to blood-stage infection and malaria pathogenesis. This intricate process is coordinated by multiple parasite adhesins that bind erythrocyte receptors and mediate invasion through several alternate pathways. P. falciparum expresses 2700 genes during the blood-stages, of which the identity and function of many remains unknown. Here, we have identified and characterized a novel P. falciparum rhoptry associated adhesin (PfRA) that mediates erythrocyte invasion through the sialic-acid dependent pathway. PfRA appears to play a significant functional role as it is conserved across different Plasmodium species. It is localized in the rhoptries and further translocated to the merozoite surface. Both native and recombinant PfRA specifically bound erythrocytes in a sialic-acid dependent, chymotrypsin and trypsin resistant manner, which was abrogated by PfRA antibodies confirming a role in erythrocyte invasion. PfRA antibodies inhibited erythrocyte invasion and in combination with antibodies against other parasite ligands produced an additive inhibitory effect, thus validating its important role in erythrocyte invasion. We have thus identified a novel P. falciparum adhesin that binds with a sialic acid containing erythrocyte receptor. Our observations substantiate the strategy to block P. falciparum erythrocyte invasion by simultaneously targeting multiple conserved merozoite antigens involved in alternate invasion pathways

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Statistical Issues in Measurement with Applications in Forensics and Methylomics

The reliability of a measurement system is studied as a precursor to establishing the accuracy of the measurement system. Forensic science disciplines that rely on feature-based comparisons (e.g., handwriting analysis, fingerprint analysis) have been criticized for the absence of studies demonstrating reliability and accuracy. This has led to empirical evaluations through the use of "black-box" studies. Typically, data collected from inter-examiner (reproducibility) studies is analyzed separately from studies of intra-examiner (repeatability) studies. Motivated by these forensic studies, this dissertation develops methods to assess reliability for continuous, binary, and ordinal outcomes in forensics by combining inter-examiner and intra-examiner data for efficient estimation of reliability, while accounting for possible examiner-forensic sample interactions. Furthermore, we propose an exploratory method to cluster raters/ examiners to identify subpopulations that appear to apply similar decision-making approaches. The dissertation also includes the development of a statistical model to address measurement variability in methylomic studies

Lipid-Based Drug Delivery Systems

The principle objective of formulation of lipid-based drugs is to enhance their bioavailability. The use of lipids in drug delivery is no more a new trend now but is still the promising concept. Lipid-based drug delivery systems (LBDDS) are one of the emerging technologies designed to address challenges like the solubility and bioavailability of poorly water-soluble drugs. Lipid-based formulations can be tailored to meet a wide range of product requirements dictated by disease indication, route of administration, cost consideration, product stability, toxicity, and efficacy. These formulations are also a commercially viable strategy to formulate pharmaceuticals, for topical, oral, pulmonary, or parenteral delivery. In addition, lipid-based formulations have been shown to reduce the toxicity of various drugs by changing the biodistribution of the drug away from sensitive organs. However, the number of applications for lipid-based formulations has expanded as the nature and type of active drugs under investigation have become more varied. This paper mainly focuses on novel lipid-based formulations, namely, emulsions, vesicular systems, and lipid particulate systems and their subcategories as well as on their prominent applications in pharmaceutical drug delivery