Analysis of Nanopore Detector Measurements using Machine Learning Methods, with Application to Single-Molecule Kinetics

At its core, a nanopore detector has a nanometer-scale biological membrane across which a voltage is applied. The voltage draws a DNA molecule into an á-hemolysin channel in the membrane. Consequently, a distinctive channel current blockade signal is created as the molecule flexes and interacts with the channel. This flexing of the molecule is characterized by different blockade levels in the channel current signal. Previous experiments have shown that a nanopore detector is sufficiently sensitive such that nearly identical DNA molecules were classified successfully using machine learning techniques such as Hidden Markov Models and Support Vector Machines in a channel current based signal analysis platform [4-9]. In this paper, methods for improving feature extraction are presented to improve both classification and to provide biologists and chemists with a better understanding of the physical properties of a given molecule

Associations between diet quality, vegetable availability and access, and food security in low-income children

Food insecurity is a pervasive problem in the United States, and has been previously associated with adverse health and wellbeing in children. The mechanism that underlies this association is assumed to be poor dietary intake, which is likely a result of lack of access to healthy, affordable foods. The purpose of this research was to examine associations between dietary quality, vegetable availability and access, and food insecurity within low-income children. Cross-sectional data from TX Sprouts, a school-based randomized controlled cooking, gardening, and nutrition intervention, were used. Public health and surveillance efforts rely on accurate measures of child food insecurity; however, research suggests that current efforts which utilize parent report of child-level food insecurity may be inaccurate or underestimate the true prevalence. The first aim was to compare child versus parent perceptions of child-level food security status via questionnaires within a large, ethnically diverse population. Previous approaches to alleviating food insecurity and providing nutritious foods, like vegetables, have focused on community or policy level barriers that these households may face. However, even when these barriers have been overcome, individual and interpersonal barriers to vegetable availability, access, and utilization may still persist. The second aim was to examine the relationship between individual and interpersonal barriers to availability, access and utilization of vegetables and household food insecurity. The third aim was to examine the relationship between self-reported food insecurity and dietary quality. Research in this area was needed as evidence linking food insecurity to child dietary intake has been largely unclear and has utilized parent’s perception of child-level food insecurity. The results of this research demonstrated the discordance that exists between child report and parent perceptions of child-level food insecurity and that additional research is needed in large, nationally representative samples. Further, within food-insecure households, significant barriers to access, availability, and utilization of vegetables were found. These barriers serve as ideal targets for future interventions seeking to improve vegetable consumption in low-income children. Lastly, food insecurity was associated with lower diet quality. Interventions targeting food insecure children are needed to improve dietary quality as this may alleviate some of the detrimental impacts of food insecurity on health and wellbeing.Nutritional Science

Data Mining and Privacy: An Initial Attempt at a Comprehensive Code of Conduct for Online Business

The prevalence of data mining by businesses and government organizations raises concerns among many individuals about the privacy of their personal data. We address this issue by offering a different perspective that reconciles the conflicting desires of businesses and consumers. We describe privacy, data mining, and their interaction in the larger context, identify the costs and benefits of the uses of data mining, and discuss potential stakeholders found at the intersection of the two subjects. To help synthesize our proposed code of ethical conduct, we examine existing codes of conduct and how they relate to the issue of privacy in the context of data mining with people, processes, and technology. Showing that a uniform code of ethical conduct for online privacy is feasible from both a managerial and ethical perspective, we provide an initial philosophical and principle synthesis that businesses and organizations can tailor for their own specific customers and needs. The developed code of ethical conduct respects consumers’ desire for privacy while allowing businesses to use data mining techniques to elicit information that benefits both the business and the consumer

Computational Vector Mechanics in Atmospheric and Climate Modeling

The mathematical underpinnings of vector analysis are reviewed as they are applied in the development of the ensemble of numeric statements for subsequent matrix solution. With the continued advances in computational power, there is increased interest in the field of atmospheric modelling to decrease the computational scale to a micro‐scale. This interest is partially motivated by the ability to solve large scale matrix systems in the number of occasions to enable a small‐scale time advancement to be approximated in a finite‐difference scheme. Solving entire large scale matrix systems several times a modelling second is now computationally feasible. Hence the motivation to increase computational detail by reducing modelling scale

High-resolution mapping of fluoroquinolones in TB rabbit lesions reveals specific distribution in immune cell types.

Understanding the distribution patterns of antibiotics at the site of infection is paramount to selecting adequate drug regimens and developing new antibiotics. Tuberculosis (TB) lung lesions are made of various immune cell types, some of which harbor persistent forms of the pathogen, Mycobacterium tuberculosis. By combining high resolution MALDI MSI with histology staining and quantitative image analysis in rabbits with active TB, we have mapped the distribution of a fluoroquinolone at high resolution, and identified the immune-pathological factors driving its heterogeneous penetration within TB lesions, in relation to where bacteria reside. We find that macrophage content, distance from lesion border and extent of necrosis drive the uneven fluoroquinolone penetration. Preferential uptake in macrophages and foamy macrophages, where persistent bacilli reside, compared to other immune cells present in TB granulomas, was recapitulated in vitro using primary human cells. A nonlinear modeling approach was developed to help predict the observed drug behavior in TB lesions. This work constitutes a methodological advance for the co-localization of drugs and infectious agents at high spatial resolution in diseased tissues, which can be applied to other diseases with complex immunopathology

Evidence for a Role of Endocannabinoids, Astrocytes and p38 Phosphorylation in the Resolution of Postoperative Pain

An alarming portion of patients develop persistent or chronic pain following surgical procedures, but the mechanisms underlying the transition from acute to chronic pain states are not fully understood. In general, endocannabinoids (ECBs) inhibit nociceptive processing by stimulating cannabinoid receptors type 1 (CB(1)) and type 2 (CB(2)). We have previously shown that intrathecal administration of a CB(2) receptor agonist reverses both surgical incision-induced behavioral hypersensitivity and associated over-expression of spinal glial markers. We therefore hypothesized that endocannabinoid signaling promotes the resolution of acute postoperative pain by modulating pro-inflammatory signaling in spinal cord glial cells.To test this hypothesis, rats receiving paw incision surgery were used as a model of acute postoperative pain that spontaneously resolves. We first characterized the concentration of ECBs and localization of CB(1) and CB(2) receptors in the spinal cord following paw incision. We then administered concomitant CB(1) and CB(2) receptor antagonists/inverse agonists (AM281 and AM630, 1 mg x kg(-1) each, i.p.) during the acute phase of paw incision-induced mechanical allodynia and evaluated the expression of glial cell markers and phosphorylated p38 (a MAPK associated with inflammation) in the lumbar dorsal horn. Dual blockade of CB(1) and CB(2) receptor signaling prevented the resolution of postoperative allodynia and resulted in persistent over-expression of spinal Glial Fibrillary Acidic Protein (GFAP, an astrocytic marker) and phospho-p38 in astrocytes. We provide evidence for the functional significance of these astrocytic changes by demonstrating that intrathecal administration of propentofylline (50 microg, i.t.) attenuated both persistent behavioral hypersensitivity and over-expression of GFAP and phospho-p38 in antagonist-treated animals.Our results demonstrate that endocannabinoid signaling via CB(1) and CB(2) receptors is necessary for the resolution of paw incision-induced behavioral hypersensitivity and for the limitation of pro-inflammatory signaling in astrocytes following surgical insult. Our findings suggest that therapeutic strategies designed to enhance endocannabinoid signaling may prevent patients from developing persistent or chronic pain states following surgery

Early Health Economic Modeling of Novel Therapeutics in Age-Related Hearing Loss

Background: Health systems face challenges to accelerate access to innovations that add value and avoid those unlikely to do so. This is very timely to the field of age-related sensorineural hearing loss (ARHL), where a significant unmet market need has been identified and sizeable investments made to promote the development of novel hearing therapeutics (NT). This study aims to apply health economic modeling to inform the development of cost-effective NT. Methods: We developed a decision-analytic model to assess the potential costs and effects of using regenerative NT in patients ≥50 with ARHL. This was compared to the current standard of care including hearing aids and cochlear implants. Input data was collected from systematic literature searches and expert opinion. A UK NHS healthcare perspective was adopted. Three different but related analyses were performed using probabilistic modeling: (1) headroom analysis, (2) scenario analyses, and (3) threshold analyses. Results: The headroom analysis shows an incremental net monetary benefit (iNMB) of £20,017[£11,299–£28,737] compared to the standard of care due to quality-adjusted life-years (QALY) gains and cost savings. Higher therapeutic efficacy and access for patients with all degrees of hearing loss yields higher iNMBs. Threshold analyses shows that the ceiling price of the therapeutic increases with more severe degrees of hearing loss. Conclusion: NT for ARHL are potentially cost-effective under current willingness-to-pay (WTP) thresholds with considerable room for improvement in the current standard of care pathway. Our model can be used to help decision makers decide which therapeutics represent value for money and are worth commissioning, thereby paving the way for urgently needed NT

Fluoroquinolone Efficacy against Tuberculosis Is Driven by Penetration into Lesions and Activity against Resident Bacterial Populations.

Fluoroquinolones represent the pillar of multidrug-resistant tuberculosis (MDR-TB) treatment, with moxifloxacin, levofloxacin, or gatifloxacin being prescribed to MDR-TB patients. Recently, several clinical trials of "universal" drug regimens, aiming to treat drug-susceptible and drug-resistant TB, have included a fluoroquinolone. In the absence of clinical data comparing their side-by-side efficacies in controlled MDR-TB trials, a pharmacological rationale is needed to guide the selection of the most efficacious fluoroquinolone. The present studies were designed to test the hypothesis that fluoroquinolone concentrations (pharmacokinetics) and activity (pharmacodynamics) at the site of infection are better predictors of efficacy than the plasma concentrations and potency measured in standard growth inhibition assays and are better suited to determinations of whether one of the fluoroquinolones outperforms the others in rabbits with active TB. We first measured the penetration of these fluoroquinolones in lung lesion compartments, and their potency against bacterial populations that reside in each compartment, to compute lesion-centric pharmacokinetic-pharmacodynamic (PK/PD) parameters. PK modeling methods were used to quantify drug penetration from plasma to tissues at human-equivalent doses. On the basis of these metrics, moxifloxacin emerged with a clear advantage, whereas plasma-based PK/PD favored levofloxacin (the ranges of the plasma AUC/MIC ratio [i.e., the area under the concentration-time curve over 24 h in the steady state divided by the MIC] are 46 to 86 for moxifloxacin and 74 to 258 for levofloxacin). A comparative efficacy trial in the rabbit model of active TB demonstrated the superiority of moxifloxacin in reducing bacterial burden at the lesion level and in sterilizing cellular and necrotic lesions. Collectively, these results show that PK/PD data obtained at the site of infection represent an adequate predictor of drug efficacy against TB and constitute the baseline required to explore synergies, antagonism, and drug-drug interactions in fluoroquinolone-containing regimens