Upgrading antibiotic use within a class: Tradeoff between resistance and treatment success

Increasing resistance to antibiotics creates the need for prudent antibiotic use. When resistance to various antibiotics within a class is driven by stepwise accumulation of mutations, a dilemma may exist in regard to replacing an antibiotic that is losing effectiveness due to resistance with a new drug within the same class. Such replacement may enhance treatment success in the short term but promote the spread of highly resistant strains. We used mathematical models to quantify the tradeoff between minimizing treatment failures (by switching early) and minimizing the proliferation of the highly resistant strain (by delaying the switch). Numerical simulations were applied to investigate the cumulative prevalence of the highly resistant strain (Resistance) and the cumulative number of treatment failures (Failure) that resulted from following different antibiotic use policies. Whereas never switching to the new drug always minimizes Resistance and maximizes Failure, immediate switching usually maximizes Resistance and minimizes Failure. Thus, in most circumstances, there is a strict tradeoff in which early use of the new drug enhances treatment effectiveness while hastening the rise of high-level resistance. This tradeoff is most acute when acquired resistance is rare and the highly resistant strain is readily transmissible. However, exceptions occur when use of the new drug frequently leads to acquired resistance and when the highly resistant strain has substantial "fitness cost"; these circumstances tend to favor an immediate switch. We discuss the implications of these considerations in regard to antibiotic choices for Streptococcus pneumoniae

Prevalence of Masked Hypertension Among US Adults With Nonelevated Clinic Blood Pressure

Masked hypertension (MHT), defined as nonelevated blood pressure (BP) in the clinic setting and elevated BP assessed by ambulatory monitoring, is associated with increased risk of target organ damage, cardiovascular disease, and mortality. Currently, no estimate of MHT prevalence exists for the general US population. After pooling data from the Masked Hypertension Study (n = 811), a cross-sectional clinical investigation of systematic differences between clinic BP and ambulatory BP (ABP) in a community sample of employed adults in the New York City metropolitan area (2005-2012), and the National Health and Nutrition Examination Survey (NHANES; 2005-2010; n = 9,316), an ongoing nationally representative US survey, we used multiple imputation to impute ABP-defined hypertension status for NHANES participants and estimate MHT prevalence among the 139 million US adults with nonelevated clinic BP, no history of overt cardiovascular disease, and no use of antihypertensive medication. The estimated US prevalence of MHT in 2005-2010 was 12.3% of the adult population (95% confidence interval: 10.0, 14.5)-approximately 17.1 million persons aged ≥21 years. Consistent with prior research, estimated MHT prevalence was higher among older persons, males, and those with prehypertension or diabetes. To our knowledge, this study provides the first estimate of US MHT prevalence-nearly 1 in 8 adults with nonelevated clinic BP-and suggests that millions of US adults may be misclassified as not having hypertension

Health Benefits of Reducing Sugar-Sweetened Beverage Intake in High Risk Populations of California: Results from the Cardiovascular Disease (CVD) Policy Model

Background Consumption of sugar-sweetened beverage (SSB) has risen over the past two decades, with over 10 million Californians drinking one or more SSB per day. High SSB intake is associated with risk of type 2 diabetes, obesity, hypertension, and coronary heart disease (CHD). Reduction of SSB intake and the potential impact on health outcomes in California and among racial, ethnic, and low-income sub-groups has not been quantified. Methods We projected the impact of reduced SSB consumption on health outcomes among all Californians and California subpopulations from 2013 to 2022. We used the CVD Policy Model – CA, an established computer simulation of diabetes and heart disease adapted to California. We modeled a reduction in SSB intake by 10–20% as has been projected to result from proposed penny-per-ounce excise tax on SSB and modeled varying effects of this reduction on health parameters including body mass index, blood pressure, and diabetes risk. We projected avoided cases of diabetes and CHD, and associated health care cost savings in 2012 US dollars. Results Over the next decade, a 10–20% SSB consumption reduction is projected to result in a 1.8–3.4% decline in the new cases of diabetes and an additional drop of 0.5–1% in incident CHD cases and 0.5–0.9% in total myocardial infarctions. The greatest reductions are expected in African Americans, Mexican Americans, and those with limited income regardless of race and ethnicity. This reduction in SSB consumption is projected to yield $320–620 million in medical cost savings associated with diabetes cases averted and an additional savings of$14–27 million in diabetes-related CHD costs avoided. Conclusions A reduction of SSB consumption could yield substantial population health benefits and cost savings for California. In particular, racial, ethnic, and low-income subgroups of California could reap the greatest health benefits

The influence of feature selection methods on accuracy, stability and interpretability of molecular signatures

Motivation: Biomarker discovery from high-dimensional data is a crucial problem with enormous applications in biology and medicine. It is also extremely challenging from a statistical viewpoint, but surprisingly few studies have investigated the relative strengths and weaknesses of the plethora of existing feature selection methods. Methods: We compare 32 feature selection methods on 4 public gene expression datasets for breast cancer prognosis, in terms of predictive performance, stability and functional interpretability of the signatures they produce. Results: We observe that the feature selection method has a significant influence on the accuracy, stability and interpretability of signatures. Simple filter methods generally outperform more complex embedded or wrapper methods, and ensemble feature selection has generally no positive effect. Overall a simple Student's t-test seems to provide the best results. Availability: Code and data are publicly available at http://cbio.ensmp.fr/~ahaury/

Manipulation of flavour and aroma compound sequestration and release using a glycosyltransferase with specificity for terpene alcohols.

Glycosides are an important potential source of aroma and flavour compounds for release as volatiles in flowers and fruit. The production of glycosides is catalysed by UDP-glycosyltransferases (UGTs) that mediate the transfer of an activated nucleotide sugar to acceptor aglycones. A screen of UGTs expressed in kiwifruit (Actinidia deliciosa) identified the gene AdGT4 which was highly expressed in floral tissues and whose expression increased during fruit ripening. Recombinant AdGT4 enzyme glycosylated a range of terpenes and primary alcohols found as glycosides in ripe kiwifruit. Two of the enzyme's preferred alcohol aglycones, hexanol and (Z)-hex-3-enol, contribute strongly to the 'grassy-green' aroma notes of ripe kiwifruit and other fruit including tomato and olive. Transient over-expression of AdGT4 in tobacco leaves showed that enzyme was able to glycosylate geraniol and octan-3-ol in planta whilst transient expression of an RNAi construct in Actinidia eriantha fruit reduced accumulation of a range of terpene glycosides. Stable over-expression of AdGT4 in transgenic petunia resulted in increased sequestration of hexanol and other alcohols in the flowers. Transgenic tomato fruit stably over-expressing AdGT4 showed changes in both the sequestration and release of a range of alcohols including 3-methylbutanol, hexanol and geraniol. Sequestration occurred at all stages of fruit ripening. Ripe fruit sequestering high levels of glycosides were identified as having a less intense, earthier aroma in a sensory trial. These results demonstrate the importance of UGTs in sequestering key volatile compounds in planta and suggest a future approach to enhancing aromas and flavours in flowers and during fruit ripening. Yauk YK1, Ged C, Wang MY, Matich AJ, Tessarotto L, Cooney JM, Chervin C, Atkinson RG

Manufacture of electrical and magnetic graded and anisotropic materials for novel manipulations of microwaves

Spatial transformations (ST) provide a design framework to generate a required spatial distribution of electrical and magnetic properties of materials to effect manipulations of electromagnetic waves. To obtain the electromagnetic properties required by these designs, the most common materials approach has involved periodic arrays of metal-containing subwavelength elements. While aspects of ST theory have been confirmed using these structures, they are often disadvantaged by narrowband operation, high losses and difficulties in implementation. An all-dielectric approach involves weaker interactions with applied fields, but may offer more flexibility for practical implementation. This paper investigates manufacturing approaches to produce composite materials that may be conveniently arranged spatially, according to ST-based designs. A key aim is to highlight the limitations and possibilities of various manufacturing approaches, to constrain designs to those that may be achievable. The article focuses on polymer-based nano- and microcomposites in which interactions with microwaves are achieved by loading the polymers with high-permittivity and high-permeability particles, and manufacturing approaches based on spray deposition, extrusion, casting and additive manufacture

New zebrafish models of neurodegeneration

In modern biomedicine, the increasing need to develop experimental models to further our understanding of disease conditions and delineate innovative treatments has found in the zebrafish (Danio rerio) an experimental model, and indeed a valuable asset, to close the gap between in vitro and in vivo assays. Translation of ideas at a faster pace is vital in the field of neurodegeneration, with the attempt to slow or prevent the dramatic impact on the society's welfare being an essential priority. Our research group has pioneered the use of zebrafish to contribute to the quest for faster and improved understanding and treatment of neurodegeneration in concert with, and inspired by, many others who have primed the study of the zebrafish to understand and search for a cure for disorders of the nervous system. Aware of the many advantages this vertebrate model holds, here, we present an update on the recent zebrafish models available to study neurodegeneration with the goal of stimulating further interest and increasing the number of diseases and applications for which they can be exploited. We shall do so by citing and commenting on recent breakthroughs made possible via zebrafish, highlighting their benefits for the testing of therapeutics and dissecting of disease mechanisms

Genome maps across 26 human populations reveal population-specific patterns of structural variation.

Large structural variants (SVs) in the human genome are difficult to detect and study by conventional sequencing technologies. With long-range genome analysis platforms, such as optical mapping, one can identify large SVs (>2 kb) across the genome in one experiment. Analyzing optical genome maps of 154 individuals from the 26 populations sequenced in the 1000 Genomes Project, we find that phylogenetic population patterns of large SVs are similar to those of single nucleotide variations in 86% of the human genome, while ~2% of the genome has high structural complexity. We are able to characterize SVs in many intractable regions of the genome, including segmental duplications and subtelomeric, pericentromeric, and acrocentric areas. In addition, we discover ~60 Mb of non-redundant genome content missing in the reference genome sequence assembly. Our results highlight the need for a comprehensive set of alternate haplotypes from different populations to represent SV patterns in the genome

A Defective mRNA Cleavage and Polyadenylation Complex Facilitates Expansions of Transcribed (GAA) n Repeats Associated with Friedreich’s Ataxia

Expansions of microsatellite repeats are responsible for numerous hereditary diseases in humans, including myotonic dystrophy and Friedreich's ataxia. Whereas the length of an expandable repeat is the main factor determining disease inheritance, recent data point to genomic trans modifiers that can impact the likelihood of expansions and disease progression. Detection of these modifiers may lead to understanding and treating repeat expansion diseases. Here, we describe a method for the rapid, genome-wide identification of trans modifiers for repeat expansion in a yeast experimental system. Using this method, we found that missense mutations in the endoribonuclease subunit (Ysh1) of the mRNA cleavage and polyadenylation complex dramatically increase the rate of (GAA) n repeat expansions but only when they are actively transcribed. These expansions correlate with slower transcription elongation caused by the ysh1 mutation. These results reveal an interplay between RNA processing and repeat-mediated genome instability, confirming the validity of our approach. Keywords: genome instability; repeat expansion; RNA polyadenylation; RNA processing; transcription-replication conflicts; Friedreich’s ataxia; DNA double-strand breaks; trans-modifiers of repeat expansions; genetic screen; whole-genome sequencin