Empagliflozin in the Treatment of Type 2 Diabetes: Evidence to Date

In the last decade, researchers have gained a greater understanding of the pathophysiologic mechanisms of type 2 diabetes as a chronic and progressive disease. One of the more recent treatment targets is the kidney. The kidneys become maladaptive in diabetes by increasing the reabsorption of glucose above the normal physiologic renal threshold. This discovery has led to the development of the sodium/glucose cotransporter 2 inhibitors (SGLT2). These agents readjust the renal threshold for glucose reabsorption to a lower level and decrease glucose reabsorption, while increasing urinary glucose when the glucose is above the renal threshold and subsequently lowering plasma glucose. The mechanism of action of the SGLT2 inhibitors is insulin independent, which makes them a novel treatment of diabetes. At the time of preparation of this manuscript, there were three SGLT2 inhibitors available in the US. This manuscript focuses on empagliflozin, the newest SGLT2 inhibitor, the trials in its development, and the clinical data available to date. Further, the authors propose future applications of empagliflozin, including in the treatment of type 1 diabetes, and its potential role in renoprotection

The Information Content of Pore Fluid δ^(18)O and [CI^-]

Paleoceanographic proxies indicate that the ocean state during the Last Glacial Maximum (LGM) differed from the modern ocean state. Depth profiles of ocean sediment pore fluid δ^(18)O and [Cl^−] have been used to reconstruct the δ^(18)O and salinity at the LGM. Here, it is investigated whether pore fluid profiles can constrain ocean δ^(18)O and salinity at other times and, simultaneously, their ability to constrain the LGM δ^(18)O and salinity. An inverse framework is developed that relies on Bayesian parameter estimation, thus allowing formal separation of prior assumptions from the information in observations. Synthetic problems are used to explore the information about past ocean tracers that can be recovered from pore fluid profiles. It is concluded that prior knowledge of deep ocean mixing time scales is essential to an accurate inverse estimate of LGM ocean salinity and δ^(18)O from modern pore fluid profiles. The most recent 10 000 years of ocean salinity and δ^(18)O and the error in their estimates are better constrained by the pore fluid profiles than are the LGM values. The inverse estimate of salinity and δ^(18)O is strongly correlated with the estimate of diffusivity of oxygen isotopes and [Cl^−] in sediment pore fluids. Uncertainty on the diffusivity of oxygen isotopes and chloride in sediments is reduced through inversion of the pore fluid profiles, but simultaneous estimation of δ^(18)O or salinity and diffusivity increases the total uncertainty. The error reported in previous work may underestimate the true uncertainty of LGM deep ocean salinity and δ^(18)O

Thermal performance sensitivity studies in support of material modeling for extended storage of used nuclear fuel

The work reported here is an investigation of the sensitivity of component temperatures of a storage system, including fuel cladding temperatures, in response to age-related changes that could degrade the design-basis thermal behavior of the system. Three specific areas of interest were identified for this study. • degradation of the canister backfill gas from pure helium to a mixture of air and helium, resulting from postulated leakage due to stress corrosion cracking (SCC) of canister welds • changes in surface emissivity of system components, resulting from corrosion or other aging mechanisms, which could cause potentially significant changes in temperatures and temperature distributions, due to the effect on thermal radiation exchange between components • changes in fuel and basket temperatures due to changes in fuel assembly position within the basket cells in the canister The purpose of these sensitivity studies is to provide a realistic example of how changes in the physical properties or configuration of the storage system components can affect temperatures and temperature distributions. The magnitudes of these sensitivities can provide guidance for identifying appropriate modeling assumptions for thermal evaluations extending long term storage out beyond 50, 100, 200, and 300 years

Multiscale, multimodal analysis of tumor heterogeneity in IDH1 mutant vs wild-type diffuse gliomas.

Glioma is recognized to be a highly heterogeneous CNS malignancy, whose diverse cellular composition and cellular interactions have not been well characterized. To gain new clinical- and biological-insights into the genetically-bifurcated IDH1 mutant (mt) vs wildtype (wt) forms of glioma, we integrated data from protein, genomic and MR imaging from 20 treatment-naïve glioma cases and 16 recurrent GBM cases. Multiplexed immunofluorescence (MxIF) was used to generate single cell data for 43 protein markers representing all cancer hallmarks, Genomic sequencing (exome and RNA (normal and tumor) and magnetic resonance imaging (MRI) quantitative features (protocols were T1-post, FLAIR and ADC) from whole tumor, peritumoral edema and enhancing core vs equivalent normal region were also collected from patients. Based on MxIF analysis, 85,767 cells (glioma cases) and 56,304 cells (GBM cases) were used to generate cell-level data for 24 biomarkers. K-means clustering was used to generate 7 distinct groups of cells with divergent biomarker profiles and deconvolution was used to assign RNA data into three classes. Spatial and molecular heterogeneity metrics were generated for the cell data. All features were compared between IDH mt and IDHwt patients and were finally combined to provide a holistic/integrated comparison. Protein expression by hallmark was generally lower in the IDHmt vs wt patients. Molecular and spatial heterogeneity scores for angiogenesis and cell invasion also differed between IDHmt and wt gliomas irrespective of prior treatment and tumor grade; these differences also persisted in the MR imaging features of peritumoral edema and contrast enhancement volumes. A coherent picture of enhanced angiogenesis in IDHwt tumors was derived from multiple platforms (genomic, proteomic and imaging) and scales from individual proteins to cell clusters and heterogeneity, as well as bulk tumor RNA and imaging features. Longer overall survival for IDH1mt glioma patients may reflect mutation-driven alterations in cellular, molecular, and spatial heterogeneity which manifest in discernable radiological manifestations

Thermal Modeling of NUHOMS HSM-15 and HSM-1 Storage Modules at Calvert Cliffs Nuclear Power Station ISFSI

As part of the Used Fuel Disposition Campaign of the Department of Energy (DOE), visual inspections and temperature measurements were performed on two storage modules in the Calvert Cliffs Nuclear Power Station’s Independent Spent Fuel Storage Installation (ISFSI). Detailed thermal models models were developed to obtain realistic temperature predictions for actual storage systems, in contrast to conservative and bounding design basis calculations

Perceptions of Preparedness for Interprofessional Practice: A Survey of Health Professional Students at Three Universities

Objective: The purpose of this study was to evaluate health professions students’ understanding of their own and others’ roles on interprofessional (IP) teams, assess students’ perceptions of their preparedness to practice in an IP team, and determine differences by type of learning institution and participation in interprofessional education (IPE). Methods: Medical, nursing, and pharmacy students at three Ohio universities with unique IP learning models were surveyed. Descriptive statistics, analysis of variance (ANOVA), chi-square, and two sample t- tests were used to compare measures of knowledge, IPE participation, and preparedness. Results: Of the 981 invited students, 273 completed the survey (27.8% response). Overall, 70.7% of participants felt prepared to work on an IP team. Those who reported participation in IPE were more likely to feel prepared to practice on an IP team compared to those who did not (76.8% [149/194] vs. 55.3% [42/76], p=0.0005). Participation in IPE did not significantly affect knowledge scores (participators 79.6% vs. non-participators 81.0%, p=0.1731). Those who had higher profession-specific knowledge scores were more likely to feel prepared to work with that specific profession. Conclusions: Participation in IPE activities in the representative institutions was high, as was knowledge of professional roles. Both participation in IPE and increased knowledge of roles were associated with increased student-assessed preparedness. Advancement of skills and behaviors including knowledge of roles and other competencies may all be important. Pharmacy in particular should prioritize IPE as a means to elucidate our role on the patient care team.   Type: Original Researc

A large-scale genome-wide association study meta-analysis of cannabis use disorder

Summary Background Variation in liability to cannabis use disorder has a strong genetic component (estimated twin and family heritability about 50–70%) and is associated with negative outcomes, including increased risk of psychopathology. The aim of the study was to conduct a large genome-wide association study (GWAS) to identify novel genetic variants associated with cannabis use disorder. Methods To conduct this GWAS meta-analysis of cannabis use disorder and identify associations with genetic loci, we used samples from the Psychiatric Genomics Consortium Substance Use Disorders working group, iPSYCH, and deCODE (20 916 case samples, 363 116 control samples in total), contrasting cannabis use disorder cases with controls. To examine the genetic overlap between cannabis use disorder and 22 traits of interest (chosen because of previously published phenotypic correlations [eg, psychiatric disorders] or hypothesised associations [eg, chronotype] with cannabis use disorder), we used linkage disequilibrium score regression to calculate genetic correlations. Findings We identified two genome-wide significant loci: a novel chromosome 7 locus (FOXP2, lead single-nucleotide polymorphism [SNP] rs7783012; odds ratio [OR] 1·11, 95% CI 1·07–1·15, p=1·84 × 10−9) and the previously identified chromosome 8 locus (near CHRNA2 and EPHX2, lead SNP rs4732724; OR 0·89, 95% CI 0·86–0·93, p=6·46 × 10−9). Cannabis use disorder and cannabis use were genetically correlated (rg 0·50, p=1·50 × 10−21), but they showed significantly different genetic correlations with 12 of the 22 traits we tested, suggesting at least partially different genetic underpinnings of cannabis use and cannabis use disorder. Cannabis use disorder was positively genetically correlated with other psychopathology, including ADHD, major depression, and schizophrenia. Interpretation These findings support the theory that cannabis use disorder has shared genetic liability with other psychopathology, and there is a distinction between genetic liability to cannabis use and cannabis use disorder. Funding National Institute of Mental Health; National Institute on Alcohol Abuse and Alcoholism; National Institute on Drug Abuse; Center for Genomics and Personalized Medicine and the Centre for Integrative Sequencing; The European Commission, Horizon 2020; National Institute of Child Health and Human Development; Health Research Council of New Zealand; National Institute on Aging; Wellcome Trust Case Control Consortium; UK Research and Innovation Medical Research Council (UKRI MRC); The Brain & Behavior Research Foundation; National Institute on Deafness and Other Communication Disorders; Substance Abuse and Mental Health Services Administration (SAMHSA); National Institute of Biomedical Imaging and Bioengineering; National Health and Medical Research Council (NHMRC) Australia; Tobacco-Related Disease Research Program of the University of California; Families for Borderline Personality Disorder Research (Beth and Rob Elliott) 2018 NARSAD Young Investigator Grant; The National Child Health Research Foundation (Cure Kids); The Canterbury Medical Research Foundation; The New Zealand Lottery Grants Board; The University of Otago; The Carney Centre for Pharmacogenomics; The James Hume Bequest Fund; National Institutes of Health: Genes, Environment and Health Initiative; National Institutes of Health; National Cancer Institute; The William T Grant Foundation; Australian Research Council; The Virginia Tobacco Settlement Foundation; The VISN 1 and VISN 4 Mental Illness Research, Education, and Clinical Centers of the US Department of Veterans Affairs; The 5th Framework Programme (FP-5) GenomEUtwin Project; The Lundbeck Foundation; NIH-funded Shared Instrumentation Grant S10RR025141; Clinical Translational Sciences Award grants; National Institute of Neurological Disorders and Stroke; National Heart, Lung, and Blood Institute; National Institute of General Medical Sciences.Peer reviewe

Neural expression and post-transcriptional dosage compensation of the steroid metabolic enzyme 17β-HSD type 4

<p>Abstract</p> <p>Background</p> <p>Steroids affect many tissues, including the brain. In the zebra finch, the estrogenic steroid estradiol (E₂) is especially effective at promoting growth of the neural circuit specialized for song. In this species, only the males sing and they have a much larger and more interconnected song circuit than females. Thus, it was surprising that the gene for 17β-hydroxysteroid dehydrogenase type 4 (HSD17B4), an enzyme that converts E₂to a less potent estrogen, had been mapped to the Z sex chromosome. As a consequence, it was likely that HSD17B4 was differentially expressed in males (ZZ) and females (ZW) because dosage compensation of Z chromosome genes is incomplete in birds. If a higher abundance of HSD17B4 mRNA in males than females was translated into functional enzyme in the brain, then contrary to expectation, males could produce less E₂in their brains than females.</p> <p>Results</p> <p>Here, we used molecular and biochemical techniques to confirm the HSD17B4 Z chromosome location in the zebra finch and to determine that HSD17B4 mRNA and activity were detectable in the early developing and adult brain. As expected, HSD17B4 mRNA expression levels were higher in males compared to females. This provides further evidence of the incomplete Z chromosome inactivation mechanisms in birds. We detected HSD17B4 mRNA in regions that suggested a role for this enzyme in the early organization and adult function of song nuclei. We did not, however, detect significant sex differences in HSD17B4 activity levels in the adult brain.</p> <p>Conclusions</p> <p>Our results demonstrate that the HSD17B4 gene is expressed and active in the zebra finch brain as an E₂metabolizing enzyme, but that dosage compensation of this Z-linked gene may occur via post-transcriptional mechanisms.</p

Analysis of the Basidiomycete Coprinopsis cinerea Reveals Conservation of the Core Meiotic Expression Program over Half a Billion Years of Evolution

Coprinopsis cinerea (also known as Coprinus cinereus) is a multicellular basidiomycete mushroom particularly suited to the study of meiosis due to its synchronous meiotic development and prolonged prophase. We examined the 15-hour meiotic transcriptional program of C. cinerea, encompassing time points prior to haploid nuclear fusion though tetrad formation, using a 70-mer oligonucleotide microarray. As with other organisms, a large proportion (∼20%) of genes are differentially regulated during this developmental process, with successive waves of transcription apparent in nine transcriptional clusters, including one enriched for meiotic functions. C. cinerea and the fungi Saccharomyces cerevisiae and Schizosaccharomyces pombe diverged ∼500–900 million years ago, permitting a comparison of transcriptional programs across a broad evolutionary time scale. Previous studies of S. cerevisiae and S. pombe compared genes that were induced upon entry into meiosis; inclusion of C. cinerea data indicates that meiotic genes are more conserved in their patterns of induction across species than genes not known to be meiotic. In addition, we found that meiotic genes are significantly more conserved in their transcript profiles than genes not known to be meiotic, which indicates a remarkable conservation of the meiotic process across evolutionarily distant organisms. Overall, meiotic function genes are more conserved in both induction and transcript profile than genes not known to be meiotic. However, of 50 meiotic function genes that were co-induced in all three species, 41 transcript profiles were well-correlated in at least two of the three species, but only a single gene (rad50) exhibited coordinated induction and well-correlated transcript profiles in all three species, indicating that co-induction does not necessarily predict correlated expression or vice versa. Differences may reflect differences in meiotic mechanisms or new roles for paralogs. Similarities in induction, transcript profiles, or both, should contribute to gene discovery for orthologs without currently characterized meiotic roles

Leveraging genome-wide data to investigate differences between opioid use vs. opioid dependence in 41,176 individuals from the Psychiatric Genomics Consortium

To provide insights into the biology of opioid dependence (OD) and opioid use (i.e., exposure, OE), we completed a genome-wide analysis comparing 4503 OD cases, 4173 opioid-exposed controls, and 32,500 opioid-unexposed controls, including participants of European and African descent (EUR and AFR, respectively). Among the variants identified, rs9291211 was associated with OE (exposed vs. unexposed controls; EUR z = -5.39, p = 7.2 × 10-8). This variant regulates the transcriptomic profiles of SLC30A9 and BEND4 in multiple brain tissues and was previously associated with depression, alcohol consumption, and neuroticism. A phenome-wide scan of rs9291211 in the UK Biobank (N > 360,000) found association of this variant with propensity to use dietary supplements (p = 1.68 × 10-8). With respect to the same OE phenotype in the gene-based analysis, we identified SDCCAG8 (EUR + AFR z = 4.69, p = 10-6), which was previously associated with educational attainment, risk-taking behaviors, and schizophrenia. In addition, rs201123820 showed a genome-wide significant difference between OD cases and unexposed controls (AFR z = 5.55, p = 2.9 × 10-8) and a significant association with musculoskeletal disorders in the UK Biobank (p = 4.88 × 10-7). A polygenic risk score (PRS) based on a GWAS of risk-tolerance (n = 466,571) was positively associated with OD (OD vs. unexposed controls, p = 8.1 × 10-5; OD cases vs. exposed controls, p = 0.054) and OE (exposed vs. unexposed controls, p = 3.6 × 10-5). A PRS based on a GWAS of neuroticism (n = 390,278) was positively associated with OD (OD vs. unexposed controls, p = 3.2 × 10-5; OD vs. exposed controls, p = 0.002) but not with OE (p = 0.67). Our analyses highlight the difference between dependence and exposure and the importance of considering the definition of controls in studies of addiction