Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury

Introduction Acute kidney injury (AKI) can evolve quickly and clinical measures of function often fail to detect AKI at a time when interventions are likely to provide benefit. Identifying early markers of kidney damage has been difficult due to the complex nature of human AKI, in which multiple etiologies exist. The objective of this study was to identify and validate novel biomarkers of AKI. Methods We performed two multicenter observational studies in critically ill patients at risk for AKI - discovery and validation. The top two markers from discovery were validated in a second study (Sapphire) and compared to a number of previously described biomarkers. In the discovery phase, we enrolled 522 adults in three distinct cohorts including patients with sepsis, shock, major surgery, and trauma and examined over 300 markers. In the Sapphire validation study, we enrolled 744 adult subjects with critical illness and without evidence of AKI at enrollment; the final analysis cohort was a heterogeneous sample of 728 critically ill patients. The primary endpoint was moderate to severe AKI (KDIGO stage 2 to 3) within 12 hours of sample collection. Results Moderate to severe AKI occurred in 14% of Sapphire subjects. The two top biomarkers from discovery were validated. Urine insulin-like growth factor-binding protein 7 (IGFBP7) and tissue inhibitor of metalloproteinases-2 (TIMP-2), both inducers of G1 cell cycle arrest, a key mechanism implicated in AKI, together demonstrated an AUC of 0.80 (0.76 and 0.79 alone). Urine [TIMP-2]·[IGFBP7] was significantly superior to all previously described markers of AKI (P \u3c0.002), none of which achieved an AUC \u3e0.72. Furthermore, [TIMP-2]·[IGFBP7] significantly improved risk stratification when added to a nine-variable clinical model when analyzed using Cox proportional hazards model, generalized estimating equation, integrated discrimination improvement or net reclassification improvement. Finally, in sensitivity analyses [TIMP-2]·[IGFBP7] remained significant and superior to all other markers regardless of changes in reference creatinine method. Conclusions Two novel markers for AKI have been identified and validated in independent multicenter cohorts. Both markers are superior to existing markers, provide additional information over clinical variables and add mechanistic insight into AKI. Trial registration ClinicalTrials.gov number NCT01209169

Association of atrial fibrillation and obstructive sleep apnea.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with recurrent atrial fibrillation (AF) after electrocardioversion. OSA is highly prevalent in patients who are male, obese, and/or hypertensive, but its prevalence in patients with AF is unknown. METHODS AND RESULTS: We prospectively studied consecutive patients undergoing electrocardioversion for AF (n=151) and consecutive patients without past or current AF referred to a general cardiology practice (n=312). OSA was diagnosed with the Berlin questionnaire, which is validated to identify patients with OSA. We also assessed its accuracy compared with polysomnography in a sample of the study population. Groups were compared with the 2-tailed t, Wilcoxon, and chi2 tests. Logistic regression modeled the association of AF and OSA after adjustment for relevant covariates. Patients in each group had similar age, gender, body mass index, and rates of diabetes, hypertension, and congestive heart failure. The questionnaire performed with 0.86 sensitivity, 0.89 specificity, and 0.97 positive predictive value in our sample. The proportion of patients with OSA was significantly higher in the AF group than in the general cardiology group (49% versus 32%, P=0.0004). The adjusted odds ratio for the association between AF and OSA was 2.19 (95% CI 1.40 to 3.42, P=0.0006). CONCLUSIONS: The novel finding of this study is that a strong association exists between OSA and AF, such that OSA is strikingly more prevalent in patients with AF than in high-risk patients with multiple other cardiovascular diseases. The coinciding epidemics of obesity and AF underscore the clinical importance of these results

The use of non-uniform drowning terminology: a follow-up study

Background: In 2002, the World Congress on Drowning developed a uniform definition for drowning. The aim of this study is to determine the prevalence of “non-uniform drowning terminology� (NUDT) and “non-uniform drowning definitions� (NUDD) in peer-reviewed scientific literature from 2010 to 2016, and compare these findings with those from our unpublished study performing a similar analysis on literature from 2003 to 2010. Methods: A systematic review was performed using drowning-specific search terms in Pubmed and Web of Science. Titles and abstracts published between July 2010 and January 2016 were screened for relevance to the study focus. Articles meeting screening criteria were reviewed for exclusion criteria to produce the final group of studies. These articles were reviewed by four reviewers for NUDT and NUDD. The Fisher exact test was used to determine any statistically significant changes. Results: The final group of studies included 167 articles. A total of 53 articles (32%) utilized NUDT, with 100% of these including the term “near drowning�. The proportion of articles utilizing NUDT was significantly less than reported by our previous study (p < 0.05). In addition, 32% of the articles included a definition for drowning (uniform or non-uniform), with 15% of these utilizing NUDD. Discussion: Our study reveals a statistically significant improvement over the past thirteen years in the use of uniform drowning terminology in peer-reviewed scientific literature, although year-to-year variability over the current study period does not yield an obvious trend. Conclusions: Of the articles reviewed during the 2010-2016 study period, 32% included outdated and non-uniform drowning terminology and definitions. While this reveals an absolute decrease of 11% as compared with the previous study period (2003-2010), there is still significant room for improvement

Design and Construction of Absorption Cells for Precision Radial Velocities in the K Band using Methane Isotopologues

We present a method to optimize absorption cells for precise wavelength calibration in the near-infrared. We apply it to design and optimize methane isotopologue cells for precision radial velocity measurements in the K band. We also describe the construction and installation of two such cells for the CSHELL spectrograph at NASA's IRTF. We have obtained their high-resolution laboratory spectra, which we can then use in precision radial velocity measurements and which can also have other applications. In terms of obtainable RV precision methane should out-perform other proposed cells, such as the ammonia cell ($^{14}$NH$_{3}$) recently demonstrated on CRIRES/VLT. The laboratory spectra of Ammonia and the Methane cells show strong absorption features in the H band that could also be exploited for precision Doppler measurements. We present spectra and preliminary radial velocity measurements obtained during our first-light run. These initial results show that a precision down to 20-30 m s$^{-1}$ can be obtained using a wavelength interval of only 5 nm in the K band and S/N$\sim$150. This supports the prediction that a precision down to a few m s$^{-1}$ can be achieved on late M dwarfs using the new generation of NIR spectrographs, thus enabling the detection of terrestrial planets in their habitable zones. Doppler measurements in the NIR can also be used to mitigate the radial velocity jitter due to stellar activity enabling more efficient surveys on young active stars.Comment: accepted PASP, Apr 2012 (in press). Preprint version with 36 pages, 9 Figures, 2 Table

Heart Failure Therapeutics on the Basis of a Biased Ligand of the Angiotensin-2 Type 1 Receptor Rationale and Design of the BLAST-AHF Study (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure)

The BLAST-AHF (Biased Ligand of the Angiotensin Receptor Study in Acute Heart Failure) study is designed to test the efficacy and safety of TRV027, a novel biased ligand of the angiotensin-2 type 1 receptor, in patients with acute heart failure (AHF). AHF remains a major public health problem, and no currently-available therapies have been shown to favorably affect outcomes. TRV027 is a novel biased ligand of the angiotensin-2 type 1 receptor that antagonizes angiotensin-stimulated G-protein activation while stimulating beta-arrestin. In animal models, these effects reduce afterload while increasing cardiac performance and maintaining stroke volume. In initial human studies, TRV027 appears to be hemodynamically active primarily in patients with activation of the renin-angiotensin-aldosterone system, a potentially attractive profile for an AHF therapeutic. BLAST-AHF is an international prospective, randomized, phase IIb, dose-ranging study that will randomize up to 500 AHF patients with systolic blood pressure &gt;= 120 mm Hg and</p

Genome-scale resources for Thermoanaerobacterium saccharolyticum

Background Thermoanaerobacterium saccharolyticum is a hemicellulose-degrading thermophilic anaerobe that was previously engineered to produce ethanol at high yield. A major project was undertaken to develop this organism into an industrial biocatalyst, but the lack of genome information and resources were recognized early on as a key limitation. Results Here we present a set of genome-scale resources to enable the systems level investigation and development of this potentially important industrial organism. Resources include a complete genome sequence for strain JW/SL-YS485, a genome-scale reconstruction of metabolism, tiled microarray data showing transcription units, mRNA expression data from 71 different growth conditions or timepoints and GC/MS-based metabolite analysis data from 42 different conditions or timepoints. Growth conditions include hemicellulose hydrolysate, the inhibitors HMF, furfural, diamide, and ethanol, as well as high levels of cellulose, xylose, cellobiose or maltodextrin. The genome consists of a 2.7 Mbp chromosome and a 110 Kbp megaplasmid. An active prophage was also detected, and the expression levels of CRISPR genes were observed to increase in association with those of the phage. Hemicellulose hydrolysate elicited a response of carbohydrate transport and catabolism genes, as well as poorly characterized genes suggesting a redox challenge. In some conditions, a time series of combined transcription and metabolite measurements were made to allow careful study of microbial physiology under process conditions. As a demonstration of the potential utility of the metabolic reconstruction, the OptKnock algorithm was used to predict a set of gene knockouts that maximize growth-coupled ethanol production. The predictions validated intuitive strain designs and matched previous experimental results. Conclusion These data will be a useful asset for efforts to develop T. saccharolyticum for efficient industrial production of biofuels. The resources presented herein may also be useful on a comparative basis for development of other lignocellulose degrading microbes, such as Clostridium thermocellum. Electronic supplementary material The online version of this article (doi:10.1186/s12918-015-0159-x) contains supplementary material, which is available to authorized users

Women's gambling behaviour, product preferences, and perceptions of product harm: Differences by age and gambling risk status

Background: Women's participation in, and harm from gambling, is steadily increasing. There has been very limited research to investigate how gambling behaviour, product preferences, and perceptions of gambling harm may vary across subgroups of women. Methods: This study surveyed a convenience sample of 509 women from Victoria and New South Wales, Australia. Women were asked a range of questions about their socio-demographic characteristics and gambling behaviour. Focusing on four gambling products in Australia-casino gambling, electronic gambling machines (EGMs), horse betting, and sports betting-women were asked about their frequency of participation, their product preferences, and perceptions of product harms. The sample was segmented a priori according to age and gambling risk status, and differences between groups were identified using Chi-square tests and ANOVAs. Thematic analysis was used to interpret qualitative data. Results: Almost two thirds (n=324, 63.7%) of women had engaged with one of the four products in the previous 12 months. Compared to other age groups, younger women aged 16-34 years exhibited a higher proportion of problem gambling, gambled more frequently, and across more products. While EGMs were the product gambled on most frequently by women overall, younger women were significantly more likely to bet on sports and gamble at casinos relative to older women. Qualitative data indicated that younger women engaged with gambling products as part of a 'night out', 'with friends', due to their 'ease of access' and perceived 'chance of winning big'. There were significant differences in the perceptions of the harms associated with horse and sports betting according to age and gambling risk status, with younger women and gamblers perceiving these products as less harmful. Conclusions: This study highlights that there are clear differences in the gambling behaviour, product preferences, and perceptions of product harms between subgroups of women. A gendered approach will enable public health researchers and policymakers to ensure that the unique factors associated with women's gambling are taken into consideration in a comprehensive public health approach to reducing and preventing gambling harm

Worldwide population differentiation at disease-associated SNPs

<p>Abstract</p> <p>Background</p> <p>Recent genome-wide association (GWA) studies have provided compelling evidence of association between genetic variants and common complex diseases. These studies have made use of cases and controls almost exclusively from populations of European ancestry and little is known about the frequency of risk alleles in other populations. The present study addresses the transferability of disease associations across human populations by examining levels of population differentiation at disease-associated single nucleotide polymorphisms (SNPs).</p> <p>Methods</p> <p>We genotyped ~1000 individuals from 53 populations worldwide at 25 SNPs which show robust association with 6 complex human diseases (Crohn's disease, type 1 diabetes, type 2 diabetes, rheumatoid arthritis, coronary artery disease and obesity). Allele frequency differences between populations for these SNPs were measured using Fst. The Fst values for the disease-associated SNPs were compared to Fst values from 2750 random SNPs typed in the same set of individuals.</p> <p>Results</p> <p>On average, disease SNPs are not significantly more differentiated between populations than random SNPs in the genome. Risk allele frequencies, however, do show substantial variation across human populations and may contribute to differences in disease prevalence between populations. We demonstrate that, in some cases, risk allele frequency differences are unusually high compared to random SNPs and may be due to the action of local (i.e. geographically-restricted) positive natural selection. Moreover, some risk alleles were absent or fixed in a population, which implies that risk alleles identified in one population do not necessarily account for disease prevalence in all human populations.</p> <p>Conclusion</p> <p>Although differences in risk allele frequencies between human populations are not unusually large and are thus likely not due to positive local selection, there is substantial variation in risk allele frequencies between populations which may account for differences in disease prevalence between human populations.</p

A high-precision near-infrared survey for radial velocity variable low-mass stars using CSHELL and a methane gas cell

We present the results of a precise near-infrared (NIR) radial velocity (RV) survey of 32 low-mass stars with spectral types K2-M4 using CSHELL at the NASA InfraRed Telescope Facility in the K band with an isotopologue methane gas cell to achieve wavelength calibration and a novel, iterative RV extraction method. We surveyed 14 members of young (≈25-150 Myr) moving groups, the young field star ϵ Eridani, and 18 nearby (&lt;25 pc) low-mass stars and achieved typical single-measurement precisions of 8-15 m s-1with a long-term stability of 15-50 m s-1 over longer baselines. We obtain the best NIR RV constraints to date on 27 targets in our sample, 19 of which were never followed by high-precision RV surveys. Our results indicate that very active stars can display long-term RV variations as low as ∼25-50 m s-1 at ≈2.3125 μm, thus constraining the effect of jitter at these wavelengths. We provide the first multiwavelength confirmation of GJ 876 bc and independently retrieve orbital parameters consistent with previous studies. We recovered RV variabilities for HD 160934 AB and GJ 725 AB that are consistent with their known binary orbits, and nine other targets are candidate RV variables with a statistical significance of 3σ-5σ. Our method, combined with the new iSHELL spectrograph, will yield long-term RV precisions of ≲5 m s-1 in the NIR, which will allow the detection of super-Earths near the habitable zone of mid-M dwarfs