Allelic variants of the estrogen receptor genes and frailty phenotype in postmenopausal women.

OBJECTIVE: The prevalence of frailty has been related to menopause. Our main objective was to investigate whether single nucleotide polymorphisms (SNPs) of the estrogen receptor (ER) ERα and ERß genes were related to the frailty phenotype in a population of community-dwelling postmenopausal women. METHODS: A cross-sectional study was performed in which we selected five SNPs, three in the ERα gene and two in the ERß. Linear regression was used to estimate the percentage of phenotypic variance after adjusting for confounding variables. RESULTS: A total of 470 women (mean ± standard deviation age 63.83 ± 8.16 years) were included, of whom 137 women were frail. The SNP rs3798577 of the ERα gene was the only variant associated with frailty, but this significance faded in the multivariant analysis. Body mass index (p = 0.012), number of comorbidities (0 vs. ≥2, p = 0.002) and two reproductive variables, number of miscarriages (none vs. ≥2, p = 0.036) and of childbirths (one vs. ≥3, p = 0.008), were independently related to frailty. CONCLUSION: The five SNPs of the ERα and ERß genes tested were not correlated with frailty. Other SNPs of the ER warrant analysis to clarify whether variance in the gene response affects frailty status.

Clinical performance and Willingness To Pay for soft toric contact lenses in low and moderate astigmats.

PURPOSE: To determine clinical performance and the 'Willingness To Pay' for toric vs. spherical soft contact lenses in an astigmatic population. METHODS: In the clinical study, subjects with binocular low to moderate astigmatism (-0.75DC to -1.50DC) wore pairs of soft toric (Biofinity toric) and spherical (Biofinity) contact lenses in random sequence. Visual acuity (high and low contrast, monocular and binocular), subjective comfort and subjective vision were recorded. In the economics study, first subjects who had participated in the clinical study were presented with a series of randomised economic scenarios in order to determine their Willingness To Pay a premium (i.e. an increase) for toric lenses. Then, a similar set of scenarios were presented to a much larger group of online respondents and again, Willingness To Pay was established. RESULTS: For the four measures of visual acuity, the Biofinity toric lens out-performed the Biofinity spherical lens by 0.6 to 1.1 lines.. Subjective vision performance was statistically significantly better with the toric lens for the distance task only. Comfort scores were not significantly different. Similar findings for Willingness To Pay were established for the clinical subjects and for the online respondents. The Willingness To Pay premium (additional fee) for a monthly supply of toric lenses (over spherical lenses) was between £13 and £16, if a toric lens provides better vision and similar comfort, as shown in the clinical study. CONCLUSION: Consumers are willing to pay a monthly premium of around 50% to benefit from the typical experience of better vision and similar comfort for toric vs. spherical lenses. The level of additional cost for toric lenses compared to their spherical equivalents is less than this in the market, so eye care professionals should consider that toric lenses are delivering a greater clinical return than anticipated by wearers for the relatively small increase in price.

DNA-m6A calling and integrated long-read epigenetic and genetic analysis with fibertools.

Long-read DNA sequencing has recently emerged as a powerful tool for studying both genetic and epigenetic architectures at single-molecule and single-nucleotide resolution. Long-read epigenetic studies encompass both the direct identification of native cytosine methylation as well as the identification of exogenously placed DNA N6-methyladenine (DNA-m6A). However, detecting DNA-m6A modifications using single-molecule sequencing, as well as co-processing single-molecule genetic and epigenetic architectures, is limited by computational demands and a lack of supporting tools. Here, we introduce fibertools, a state-of-the-art toolkit that features a semi-supervised convolutional neural network for fast and accurate identification of m6A-marked bases using PacBio single-molecule long-read sequencing, as well as the co-processing of long-read genetic and epigenetic data produced using either PacBio or Oxford Nanopore sequencing platforms. We demonstrate accurate DNA-m6A identification (>90% precision and recall) along >20 kilobase long DNA molecules with a ~1,000-fold improvement in speed. In addition, we demonstrate that fibertools can readily integrate genetic and epigenetic data at single-molecule resolution, including the seamless conversion between molecular and reference coordinate systems, allowing for accurate genetic and epigenetic analyses of long-read data within structurally and somatically variable genomic regions.

Combining revealed and stated preference models for artificial reef siting: A study in the Florida Keys.

This paper investigates divers' preferences for artificial reef diving and willingness to pay (WTP) for large ship, artificial reef site attributes in the Florida Keys. We investigate diver demand for existing decommissioned ships that have been sunk off the Florida Keys as well as demand for four new vessels that are available for disposal from the U.S. Department of Transportation Maritime Administration inventory. Using survey data from divers, we compare revealed preference (RP) site choices, stated preference (SP) choices from a discrete choice experiment, and joint RP/SP choices. Our analysis also incorporates stated attribute non-attendance (ANA) at the choice-task level. Our results indicate that the joint RP/SP models with stated ANA are preferred, leading to decreases in marginal WTP as well as decreases in the variability of marginal WTP estimates in the 95% confidence intervals. Results provide a framework for directing more efficient future decision making regarding sinkings at locations that will enhance welfare for divers.

Cost-comparison study of reusable and disposable rhinolaryngoscopes in a large English teaching hospital.

OBJECTIVE: This study aimed to compare the cost per use of video-rhinolaryngoscopy using reusable and disposable devices in a tertiary referral centre. METHODS: A cost-comparison study was performed that utilised retrospective cost data and prospective utilisation data to compare the total costs of using reusable video-rhinolaryngoscopes versus a single-use alternative. RESULTS: It was estimated that 4776 and 1821 procedures were performed annually with reusable and disposable video-rhinolaryngoscopes, respectively. The cost per use was £66.61 for reusable devices versus £150.00 for disposable devices. The break-even point (i.e. when cost per use was equal, occurred at 1374 procedures per year). Thereafter, it was cheaper to use reusable devices. CONCLUSION: Disposable rhinolaryngoscopes may present a cheaper solution to services with low rates of rhinolaryngoscope utilisation. However, for larger services considering replacement of their reusable rhinolaryngoscopes with disposable units, it is likely that the recurring costs will be prohibitive in the medium to long term.

The regulatory landscape of Arabidopsis thaliana roots at single-cell resolution.

The scarcity of accessible sites that are dynamic or cell type-specific in plants may be due in part to tissue heterogeneity in bulk studies. To assess the effects of tissue heterogeneity, we apply single-cell ATAC-seq to Arabidopsis thaliana roots and identify thousands of differentially accessible sites, sufficient to resolve all major cell types of the root. We find that the entirety of a cell's regulatory landscape and its transcriptome independently capture cell type identity. We leverage this shared information on cell identity to integrate accessibility and transcriptome data to characterize developmental progression, endoreduplication and cell division. We further use the combined data to characterize cell type-specific motif enrichments of transcription factor families and link the expression of family members to changing accessibility at specific loci, resolving direct and indirect effects that shape expression. Our approach provides an analytical framework to infer the gene regulatory networks that execute plant development.

Performance of Risk Assessment Models for Prevalent or Undiagnosed Type 2 Diabetes Mellitus in a Multi-Ethnic Population-The Helius Study.

Background: Most risk assessment models for type 2 diabetes (T2DM) have been developed in Caucasians and Asians; little is known about their performance in other ethnic groups. Objectives: We aimed to identify existing models for the risk of prevalent or undiagnosed T2DM and externally validate them in a multi-ethnic population currently living in the Netherlands. Methods: A literature search to identify risk assessment models for prevalent or undiagnosed T2DM was performed in PubMed until December 2017. We validated these models in 4,547 Dutch, 3,035 South Asian Surinamese, 4,119 African Surinamese, 2,326 Ghanaian, 3,598 Turkish, and 3,894 Moroccan origin participants from the HELIUS (Healthy LIfe in an Urban Setting) cohort study performed in Amsterdam. Model performance was assessed in terms of discrimination (C-statistic) and calibration (Hosmer-Lemeshow test). We identified 25 studies containing 29 models for prevalent or undiagnosed T2DM. C-statistics varied between 0.77-0.92 in Dutch, 0.66-0.83 in South Asian Surinamese, 0.70-0.82 in African Surinamese, 0.61-0.81 in Ghanaian, 0.69-0.86 in Turkish, and 0.69-0.87 in the Moroccan populations. The C-statistics were generally lower among the South Asian Surinamese, African Surinamese, and Ghanaian populations and highest among the Dutch. Calibration was poor (Hosmer-Lemeshow p < 0.05) for all models except one. Conclusions: Generally, risk models for prevalent or undiagnosed T2DM show moderate to good discriminatory ability in different ethnic populations living in the Netherlands, but poor calibration. Therefore, these models should be recalibrated before use in clinical practice and should be adapted to the situation of the population they are intended to be used in.

Altruistic and Private Values For Saving Lives With an Oyster Consumption Safety Program.

We use data from an Internet-based survey and estimate the benefits of an oyster consumption safety policy with the contingent valuation method. In addition to providing a context-specific estimate of willingness-to-pay for oyster safety, we consider an important issue in the contingent valuation mortality risk reduction literature. A number of studies find that willingness-to-pay for mortality risk reduction is not sensitive to the scope of the risk change. We present the scope test as a difference in the number of lives saved by the program, instead of small changes in risk, and find that referendum votes are responsive to scope. A third feature of this article is that we identify those at-risk respondents who would most benefit from the policy and decompose willingness-to-pay into use values and altruistic nonuse values. We find that willingness-to-pay per life saved ranges from $3.95 million to $7.69 million for the private good of lives saved when the respondent is at risk (i.e., use values). Willingness-to-pay per life saved including both use and altruistic nonuse values ranges from $6.89 million to $12.87 million.

FDG PET/CT for tumoral and systemic immune response monitoring of advanced melanoma during first-line combination ipilimumab and nivolumab treatment.

PURPOSE: We aimed to investigate the role of FDG-PET/CT in monitoring of response and immune-related adverse events (irAEs) following first-line combination-immune checkpoint inhibitor (combination-ICI) therapy for advanced melanoma. METHODS: We retrospectively reviewed outcomes in patients who had (1) first-line nivolumab plus ipilimumab; (2) pre- and post-treatment FDG-PET/CT scans (pre-FDG-PET/CT and post-FDG-PET/CT) within 2 and 4 months of starting ICI, respectively; and (3) at least one lesion assessable by PET response criteria in solid tumors (PERCIST). Extracranial response was monitored by 3 monthly FDG-PET/CT. Whole-body metabolic tumor volume (wbMTV) was measured pre- and post-treatment and correlated with outcome. FDG-PET/CT manifestations of irAE were defined as new increased non-tumoral uptake on post-FDG-PET/CT and were correlated with clinical presentation. RESULTS: Thirty-one consecutive patients, median age 60 years (range, 30-78), were identified from 2016 to 2018. The median number of combination-ICI cycles to the first post-FDG-PET/CT response assessment was 3 (interquartile range (IQR), 2-4). The best-overall responses were complete metabolic response (CMR) in 25 (80%), partial metabolic response (PMR) in 3 (10%), and progressive metabolic disease (PMD) in 3 (10%) patients. Patients with PMD had significantly higher pre-treatment wbMTV (p = 0.009). At a median follow-up of 21.5 months, 26 (84%) patients were alive with median progression-free and overall survival not reached. Secondary progression occurred in 9/31 (29%) patients at a median of 8.2 months (IQR, 6.9-15.5), of those majority (78%) was detected by FDG-PET/CT. Of 36 findings on post-FDG-PET/CT suggestive of irAE, 29 (80%) had clinical confirmation. In 3 (7%), the FDG-PET/CT findings preceded clinical presentation. The most common FDG-PET/CT detectable irAEs were endocrinopathies (36%) and enterocolitis (35%). CONCLUSION: FDG-PET/CT response evaluation predicts the long-term outcome of patients treated with first-line combination-ICIs. Long-term treatment response monitoring for detection of extracranial secondary progression is feasible by FDG-PET/CT. Beyond response assessment, FDG-PET/CT frequently detects clinically relevant irAEs, which may involve multiple systems contemporaneously or at various time-points and may precede clinical diagnosis.

Osteoarthritis in England: Incidence Trends From National Health Service Hospital Episode Statistics.

OBJECTIVE: It is typical in epidemiological research of osteoarthritis (OA) to collect data for the hand, hip, and knee. However, little population-based data exist for this disease in the foot. Thus, we addressed patterns of OA for the foot compared with the hand, hip, and knee spanning 2000/2001 to 2017/2018 in England. METHODS: Secondary-care data from 3 143 928 patients with OA of the foot, hand, hip, and knee were derived from the National Health Service (NHS) Hospital Episode Statistics (HES) database. Distribution, population prevalence, and incidence of joint-specific OA were stratified by age and sex. RESULTS: OA incidence increased significantly at the foot [3.8% (95% confidence interval [CI] 3.0, 4.6)], hand [10.9% (10.1, 11.7)], hip [3.8% (2.9, 4.7)], and knee [2.9% (2.2, 3.6)] per year from 2000/2001 to 2017/2018. A higher proportion of women were diagnosed with OA, whereas greater incidence in men was estimated for the hand and hip. Foot OA presented comparable diagnosis numbers to the hand. More recently during 2012/2013 to 2017/2018, a significant rise in hip OA was estimated among younger adults, whereas knee OA decreased across all age groups. Incidence of OA in the foot and hand were particularly significant among the 75 or older age group, though bimodal age distributions were observed for both sites. CONCLUSION: The significant increase in secondary care records for OA in England underscores the importance of exploring possible causative factors and identifying groups most at risk. Further detailed data may be particularly important for the hip, which represents significant incidence among younger adults. Greater incidence of OA in the foot compared with the knee emphasizes the need for well-conducted epidemiological research in this area. Monitoring the performance of surgical outcomes at the population-level for this frequently affected yet understudied site could have substantial potential to reduce the socioeconomic burden it represents to the NHS.

Accelerating structure-function mapping using the ViVa webtool to mine natural variation.

Thousands of sequenced genomes are now publicly available capturing a significant amount of natural variation within plant species; yet, much of these data remain inaccessible to researchers without significant bioinformatics experience. Here, we present a webtool called ViVa (Visualizing Variation) which aims to empower any researcher to take advantage of the amazing genetic resource collected in the Arabidopsis thaliana 1001 Genomes Project (http://1001genomes.org). ViVa facilitates data mining on the gene, gene family, or gene network level. To test the utility and accessibility of ViVa, we assembled a team with a range of expertise within biology and bioinformatics to analyze the natural variation within the well-studied nuclear auxin signaling pathway. Our analysis has provided further confirmation of existing knowledge and has also helped generate new hypotheses regarding this well-studied pathway. These results highlight how natural variation could be used to generate and test hypotheses about less-studied gene families and networks, especially when paired with biochemical and genetic characterization. ViVa is also readily extensible to databases of interspecific genetic variation in plants as well as other organisms, such as the 3,000 Rice Genomes Project ( http://snp-seek.irri.org/) and human genetic variation ( https://www.ncbi.nlm.nih.gov/clinvar/).

Cross-strand disulfides in the hydrogen bonding site of antiparallel ß-sheet (aCSDhs): Forbidden disulfides that are highly strained, easily broken.

Some disulfide bonds perform important structural roles in proteins, but another group has functional roles via redox reactions. Forbidden disulfides are stressed disulfides found in recognizable protein contexts, which currently constitute more than 10% of all disulfides in the PDB. They likely have functional redox roles and constitute a major subset of all redox-active disulfides. The torsional strain of forbidden disulfides is typically higher than for structural disulfides, but not so high as to render them immediately susceptible to reduction under physionormal conditions. Previously we characterized the most abundant forbidden disulfide in the Protein Data Bank, the aCSDn: a canonical motif in which disulfide-bonded cysteine residues are positioned directly opposite each other on adjacent anti-parallel ß-strands such that the backbone hydrogen-bonded moieties are directed away from each other. Here we perform a similar analysis for the aCSDh, a less common motif in which the opposed cysteine residues are backbone hydrogen bonded. Oxidation of two Cys in this context places significant strain on the protein system, with the ß-chains tilting toward each other to allow disulfide formation. Only left-handed aCSDh conformations are compatible with the inherent right-handed twist of ß-sheets. aCSDhs tend to be more highly strained than aCSDns, particularly when both hydrogen bonds are formed. We discuss characterized roles of aCSDh motifs in proteins of the dataset, which include catalytic disulfides in ribonucleotide reductase and ahpC peroxidase as well as a redox-active disulfide in P1 lysozyme, involved in a major conformation change. The dataset also includes many binding proteins.

Novel zebrafish behavioral assay to identify modifiers of the rapid, nongenomic stress response.

When vertebrates face acute stressors, their bodies rapidly undergo a repertoire of physiological and behavioral adaptations, which is termed the stress response. Rapid changes in heart rate and blood glucose levels occur via the interaction of glucocorticoids and their cognate receptors following hypothalamic-pituitary-adrenal axis activation. These physiological changes are observed within minutes of encountering a stressor and the rapid time domain rules out genomic responses that require gene expression changes. Although behavioral changes corresponding to physiological changes are commonly observed, it is not clearly understood to what extent hypothalamic-pituitary-adrenal axis activation dictates adaptive behavior. We hypothesized that rapid locomotor response to acute stressors in zebrafish requires hypothalamic-pituitary-interrenal (HPI) axis activation. In teleost fish, interrenal cells are functionally homologous to the adrenocortical layer. We derived eight frameshift mutants in genes involved in HPI axis function: two mutants in exon 2 of mc2r (adrenocorticotropic hormone receptor), five in exon 2 or 5 of nr3c1 (glucocorticoid receptor [GR]) and two in exon 2 of nr3c2 (mineralocorticoid receptor [MR]). Exposing larval zebrafish to mild environmental stressors, acute changes in salinity or light illumination, results in a rapid locomotor response. We show that this locomotor response requires a functioning HPI axis via the action of mc2r and the canonical GR encoded by nr3c1 gene, but not MR (nr3c2). Our rapid behavioral assay paradigm based on HPI axis biology can be used to screen for genetic and environmental modifiers of the hypothalamic-pituitary-adrenal axis and to investigate the effects of corticosteroids and their cognate receptor interactions on behavior.

The endocannabinoid gene faah2a modulates stress-associated behavior in zebrafish.

The ability to orchestrate appropriate physiological and behavioral responses to stress is important for survival, and is often dysfunctional in neuropsychiatric disorders that account for leading causes of global disability burden. Numerous studies have shown that the endocannabinoid neurotransmitter system is able to regulate stress responses and could serve as a therapeutic target for the management of these disorders. We used quantitative reverse transcriptase-polymerase chain reactions to show that genes encoding enzymes that synthesize (abhd4, gde1, napepld), enzymes that degrade (faah, faah2a, faah2b), and receptors that bind (cnr1, cnr2, gpr55-like) endocannabinoids are expressed in zebrafish (Danio rerio). These genes are conserved in many other vertebrates, including humans, but fatty acid amide hydrolase 2 has been lost in mice and rats. We engineered transcription activator-like effector nucleases to create zebrafish with mutations in cnr1 and faah2a to test the role of these genes in modulating stress-associated behavior. We showed that disruption of cnr1 potentiated locomotor responses to hyperosmotic stress. The increased response to stress was consistent with rodent literature and served to validate the use of zebrafish in this field. Moreover, we showed for the first time that disruption of faah2a attenuated the locomotor responses to hyperosmotic stress. This later finding suggests that FAAH2 may be an important mediator of stress responses in non-rodent vertebrates. Accordingly, FAAH and FAAH2 modulators could provide distinct therapeutic options for stress-aggravated disorders.

Automated low-contrast pattern recognition algorithm for magnetic resonance image quality assessment.

PURPOSE: Low contrast (LC) detectability is a common test criterion for diagnostic radiologic quality control (QC) programs. Automation of this test is desirable in order to reduce human variability and to speed up analysis. However, automation is challenging due to the complexity of the human visual perception system and the ability to create algorithms that mimic this response. This paper describes the development and testing of an automated LC detection algorithm for use in the analysis of magnetic resonance (MR) images of the American College of Radiology (ACR) QC phantom. METHODS: The detection algorithm includes fuzzy logic decision processes and various edge detection methods to quantify LC detectability. Algorithm performance was first evaluated using a single LC phantom MR image with the addition of incremental zero mean Gaussian noise resulting in a total of 200 images. A c-statistic was calculated to determine the role of CNR to indicate when the algorithm would detect ten spokes. To evaluate inter-rater agreement between experienced observers and the algorithm, a blinded observer study was performed on 196 LC phantom images acquired from nine clinical MR scanners. The nine scanners included two MR manufacturers and two field strengths (1.5 T, 3.0 T). Inter-rater and algorithm-rater agreement was quantified using Krippendorff's alpha. RESULTS: For the Gaussian noise added data, CNR ranged from 0.519 to 11.7 with CNR being considered an excellent discriminator of algorithm performance (c-statistic = 0.9777). Reviewer scoring of the clinical phantom data resulted in an inter-rater agreement of 0.673 with the agreement between observers and algorithm equal to 0.652, both of which indicate significant agreement. CONCLUSIONS: This study demonstrates that the detection of LC test patterns for MR imaging QC programs can be successfully developed and that their response can model the human visual detection system of expert MR QC readers.

Cost-Effectiveness of Treatment Sequences of Chemotherapies and Targeted Biologics for Elderly Metastatic Colorectal Cancer Patients.

BACKGROUND: Treatment patterns for metastatic colorectal cancer (mCRC) patients have changed considerably over the last decade with the introduction of new chemotherapies and targeted biologics. These treatments are often administered in various sequences with limited evidence regarding their cost-effectiveness. OBJECTIVE: To conduct a pharmacoeconomic evaluation of commonly administered treatment sequences among elderly mCRC patients. METHODS: A probabilistic discrete event simulation model assuming Weibull distribution was developed to evaluate the cost-effectiveness of the following common treatment sequences: (a) first-line oxaliplatin/irinotecan followed by second-line oxaliplatin/irinotecan + bevacizumab (OI-OIB); (b) first-line oxaliplatin/irinotecan + bevacizumab followed by second-line oxaliplatin/irinotecan + bevacizumab (OIB-OIB); (c) OI-OIB followed by a third-line targeted biologic (OI-OIB-TB); and (d) OIB-OIB followed by a third-line targeted biologic (OIB-OIB-TB). Input parameters for the model were primarily obtained from the Surveillance, Epidemiology, and End Results-Medicare linked dataset for incident mCRC patients aged 65 years and older diagnosed from January 2004 through December 2009. A probabilistic sensitivity analysis was performed to account for parameter uncertainty. Costs (2014 U.S. dollars) and effectiveness were discounted at an annual rate of 3%. RESULTS: In the base case analyses, at the willingness-to-pay (WTP) threshold of $100,000/quality-adjusted life-year (QALY) gained, the treatment sequence OIB-OIB (vs. OI-OIB) was not cost-effective with an incremental cost-effectiveness ratio (ICER) per patient of $119,007/QALY; OI-OIB-TB (vs. OIB-OIB) was dominated; and OIB-OIB-TB (vs. OIB-OIB) was not cost-effective with an ICER of $405,857/QALY. Results similar to the base case analysis were obtained assuming log-normal distribution. Cost-effectiveness acceptability curves derived from a probabilistic sensitivity analysis showed that at a WTP of $100,000/QALY gained, sequence OI-OIB was 34% cost-effective, followed by OIB-OIB (31%), OI-OIB-TB (20%), and OIB-OIB-TB (15%). CONCLUSIONS: Overall, survival increases marginally with the addition of targeted biologics, such as bevacizumab, at first line and third line at substantial costs. Treatment sequences with bevacizumab at first line and targeted biologics at third line may not be cost-effective at the commonly used threshold of $100,000/QALY gained, but a marginal decrease in the cost of bevacizumab may make treatment sequences with first-line bevacizumab cost-effective. Future economic evaluations should validate the study results using parameters from ongoing clinical trials. DISCLOSURES: This study was supported in part by a grant from the Agency for Healthcare Research and Quality (R01-HS018956) and in part by a grant from the Cancer Prevention and Research Institute of Texas (RP130051), which were obtained by Du. The authors report no conflicts of interest. Study concept and design were primarily contributed by Parikh, along with the other authors. All authors participated in data collection, and Parikh took the lead in data interpretation and analysis, along with Lairson and Morgan, with assistance from Du. The manuscript was written primarily by Parikh, along with Lairson, Morgan, and Du, and revised by Parikh.