Auintus Horatius Flaccus, Epicurean Stoic

To fully appreciate the character and work of a great man, we must first visualize his life environ­ment and contemporary history. Such details may seem tiresome, as indeed they are, but that does not pre­vent them from having a tremendous influence upon such a character and such work. To the reader, dates and facts of history become very boring, so we will endeavor to eliminate them from our study, as much as possible. In Venusia, a small town of southern Italy, on December 8, 65 B.C. Quintus Horatius Flaccus was born. His parents, like all parents, must have entertained great hopes for the future of this little country child. But in their wildest dreams of fancy, they could scarcely have pictured to themselves the heights to which their son would rise. If the success of some millionaire or prominent statesman or humble origin makes us applaud, so much more should we approve the phenomenal success of Horace, who rose from a rustic village to immortal fame, not by barter or oratory, but by charming the hearts of men with winged words of song

On Wargaming

Wargames are as old as civilization—and perhaps older. In his informative and entertaining Public Broadcasting series Connections, James Burke argued that the first invention, the one that enabled all later inventions, was the plow. It allowed agriculture, and as agriculture permitted denser populations, the frequency of inventions increased, due either to “connecting” with new applications or combining with other inventions to create one that was greater than the sum of its parts.https://digital-commons.usnwc.edu/usnwc-newport-papers/1043/thumbnail.jp

Computational modeling of microRNA Biogenesis

Over the past few years it has been observed, thanks in no small part to high-throughput methods, that a large proportion of the human genome is transcribed in a tissue- and time-specific manner. Most of the detected transcripts are non-coding RNAs and their functional consequences are not yet fully understood. Among the different classes of non-coding transcripts, microRNAs (miRNAs) are small RNAs that post-transcriptionally regulate gene expression. Despite great progress in understanding the biological role of miRNAs, our understanding of how miRNAs are regulated and processed is still developing. High-throughput sequencing data have provided a robust platform for transcriptome-level, as well as gene-promoter analyses. In silico predictive models help shed light on the transcriptional and post-transcriptional regulation of miRNAs, including their role in gene regulatory networks. Here we discuss the advances in computational methods that model different aspects of miRNA biogeneis, from transcriptional regulation to post-transcriptional processing. In particular, we show how the predicted miRNA promoters from PROmiRNA, a miRNA promoter prediction tool, can be used to identify the most probable regulatory factors for a miRNA in a specific tissue. As differential miRNA post-transcriptional processing also affects gene-regulatory networks, especially in diseases like cancer, we also describe a statistical model proposed in the literature to predict efficient miRNA processing from sequence features

Toward three-dimensional in vitro models to study neurovascular unit functions in health and disease

The high metabolic demands of the brain require an efficient vascular system to be coupled with neural activity to supply adequate nutrients and oxygen. This supply is coordinated by the action of neurons, glial and vascular cells, known collectively as the neurovascular unit, which temporally and spatially regulate local cerebral blood flow through a process known as neurovascular coupling. In many neurodegenerative diseases, changes in functions of the neurovascular unit not only impair neurovascular coupling but also permeability of the blood-brain barrier, cerebral blood flow and clearance of waste from the brain. In order to study disease mechanisms, we need improved physiologically-relevant human models of the neurovascular unit. Advances towards modeling the cellular complexity of the neurovascular unit in vitro have been made using stem-cell derived organoids and more recently, vascularized organoids, enabling intricate studies of non-cell autonomous processes. Engineering and design innovations in microfluidic devices and tissue engineering are progressing our ability to interrogate the cerebrovasculature. These advanced models are being used to gain a better understanding of neurodegenerative disease processes and potential therapeutics. Continued innovation is required to build more physiologically-relevant models of the neurovascular unit encompassing both the cellular complexity and designed features to interrogate neurovascular unit functionality. Keywords: Alzheimer’s disease; cerebrovasculature; in vitro; model; neurodegeneration; neurovascular unit

Predictors of Mortality Among U.S. Veterans With \u3cem\u3eStreptococcus Pneumoniae\u3c/em\u3e Infections

Introduction Serious Streptococcus pneumoniae infections, encompassing pneumonia, bacteremia, and meningitis, are a major cause of mortality. However, literature regarding mortality is often limited to invasive pneumococcal disease, excluding pneumonia. This study sought to identify predictors of mortality among adults with serious pneumococcal disease, including pneumonia and invasive pneumococcal disease. Methods This was a nested case-control study of unvaccinated older Veterans with positive S. pneumoniae cultures (blood, cerebrospinal fluid, respiratory) admitted to Veterans Affairs medical centers nationally between 2002 and 2011. Patients vaccinated against pneumococcal disease were excluded. Using multivariable logistic regression, predictors of 30-day mortality were identified, including patient demographics, comorbidities during admission, and medical history within the previous year. Results Among 9,468 patients, there were 9,730 serious pneumococcal infections; 1,764 (18.6%) resulted in death within 30 days (cases), whereas 7,966 did not (controls). Pneumonia accounted for half (49.4%, n=871) of all deaths. Mortality predictors consistent with vaccine recommendations included dialysis (during hospitalization, OR=3.35, 95% CI=2.37, 4.72), moderate to severe liver disease (during hospitalization, OR=2.47, 95% CI=1.53, 3.99; within 1 year, OR=1.49, 95% CI=1.01, 2.20), and neutropenia (during hospitalization, OR=2.67, 95% CI=1.32, 5.42). Predictors not included in current recommendations included dementia (during hospitalization, OR=1.8, 95% CI=1.23, 2.61) and neurologic disorders (during hospitalization, OR=1.86, 95% CI=1.42, 2.45; within 1 year, OR=1.28, 95% CI=1.02, 1.59). Conclusions Several mortality predictors among unvaccinated Veterans with serious pneumococcal disease were consistent with pneumococcal vaccine recommendations, including organ or immune system dysfunction–related conditions. Other predictors, including neurologic disorders or dementia, may warrant expanded vaccination recommendations

Risk stacking of pneumococcal vaccination indications increases mortality in unvaccinated adults with Streptococcus pneumoniae infections

Background Several chronic disease states have been identified as pneumococcal vaccination indications due to their ability to increase pneumococcal disease development and subsequent mortality. However, the risk of mortality according to the number of these disease states present is unknown. We sought to determine the impact of concomitant, multiple risk factors (stacked risks) for pneumococcal disease on 30-day mortality in adults. Methods This was a national case-control study of unvaccinated older Veterans (≥50 years of age) admitted to Veterans Affairs medical centers from 2002 to 2011 with serious pneumococcal infections (pneumonia, bacteremia, meningitis) based on positive S. pneumoniae blood, cerebrospinal fluid, or respiratory cultures, respectively. Cases were those not alive 30 days following culture, while controls were alive. Using logistic regression, we quantified risk of 30-day mortality among patients with stacked risk factors, including age ≥65 years, alcohol abuse, chronic heart disease, chronic liver disease, chronic respiratory disease, diabetes mellitus, immunodeficiency, and smoking. Results We identified 9730 serious pneumococcal infections, with an overall 30-day mortality rate of 18.6% (1764 cases, 7966 controls). Infection types included pneumonia (62%), bacteremia (26%), and bacteremic pneumonia (11%). Along with eight individual risk factors, we assessed 247 combinations of risk factors. Most cases (85%) and controls (74%) had at least two risk factors. Mortality increased as risks were stacked, up to six risk factors (one: OR 1.5, CI 1.08–2.07; two: OR 2.01, CI 1.47–2.75; three: OR 2.71, CI 1.99–3.69; four: OR 3.27, CI 2.39–4.47; five: OR 3.63, CI 2.60–5.07; six: OR 4.23, CI 2.69–6.65), with each additional risk factor increasing mortality an average of 55% (±13%). Conclusions Among adults ≥50 years with serious pneumococcal disease, mortality risk increased approximately 55% as vaccination indications present increased. Mortality with six stacked indications was double that of two indications

Intelligent subsystem interface for modular hardware system

A single chip application specific integrated circuit (ASIC) which provides a flexible, modular interface between a subsystem and a standard system bus. The ASIC includes a microcontroller/microprocessor, a serial interface for connection to the bus, and a variety of communications interface devices available for coupling to the subsystem. A three-bus architecture, utilizing arbitration, provides connectivity within the ASIC and between the ASIC and the subsystem. The communication interface devices include UART (serial), parallel, analog, and external device interface utilizing bus connections paired with device select signals. A low power (sleep) mode is provided as is a processor disable option

The Effect of Molecular Rapid Diagnostic Testing on Clinical Outcomes in Bloodstream Infections: A Systematic Review & Meta-analysis

Background. Previous reports on molecular rapid diagnostic testing (mRDT) do not consistently demonstrate improved clinical outcomes in bloodstream infections (BSIs). This meta-analysis seeks to evaluate the impact of mRDT in improving clinical outcomes in BSIs. Methods. We searched PubMed, CINAHL, Web of science, and EMBASE through May 2016 for BSI studies comparing clinical outcomes by mRDT and conventional microbiology methods. Results. Thirty-one studies were included with 5,920 patients. Risk of morality was significantly lower with mRDT as compared to conventional microbiology methods (OR 0.66, 95% CI 0.54-0.80) yielding a NNT of 20. The risk of mortality was slightly lower with mRDT in studies with antimicrobial stewardship programs (ASPs) (OR 0.64, 95% CI 0.51-0.79) and non-ASP studies failed to demonstrate a significant decrease in risk of mortality (OR 0.72, 95% CI 0.46-1.12). Significant decreases in mortality risk were observed with both Gram-positive (OR 0.73, 95% CI 0.55-0.97) and Gram-negative organisms (OR 0.51, 95% CI 0.33-0.78) but not yeast (OR 0.90, 95% CI 0.49-1.67). Time to effective therapy decreased by a weighted mean difference of -5.03 hours (95% CI -8.60 to -1.45) and length of stay decreased by -2.48 days (95% CI -3.90 to -1.06). Conclusions. For BSIs, mRDT was associated with significant decreases in risk of mortality in the presence of a ASP, but not in its absence. Additionally, mRDT decreased time to effective therapy and length of stay. mRDT should be considered as part of the standard of care in patients with BSIs