Clinical consequences of a miscalibrated digoxin immunoassay

A routine audit revealed that the analytical method used to measure digoxin concentrations by our statewide pathology provider in 2009 was underestimating digoxin concentrations by 10%. The assay was recalibrated by the manufacturer in 2010, but clinical outcomes of the underestimation were never measured. This is a pilot study to describe the prescribing behavior around out-of-range digoxin concentrations and to assess whether miscalibrated digoxin immunoassays contribute to clinically relevant effects, as measured by inappropriate alterations in digoxin doses.About 30,000 digoxin concentrations across the State Hospital system were obtained in 2 periods before and after recalibration of the digoxin assay. Digoxin concentration means were calculated and compared and were statistically significantly different. Subsequently, a single-centered retrospective review of 50 randomly chosen charts was undertaken to study the clinical implications of the underestimated concentrations.Mean digoxin concentrations for 2009 and 2011 were significantly different by 8.8% (confidence interval, 7.0%-10.6%). After recalculating the 2009 concentrations to their "corrected" values, there was a 16% increase in the number of concentrations within the range when compared with the 2011 concentrations (41.48% versus 48.04%). However, overall, this did not cause unnecessary dose changes in patients who were "borderline" or outside the therapeutic range when compared with controls (P = 0.10). The majority of decisions were based on the clinical impression rather than concentration alone (85.1% versus 14.9%), even when the concentration was outside the "therapeutic range."Although recalculating digoxin concentrations measured during 2009 to their corrected values produced a significant change in concentration and values inside and outside the range, this does not seem to have had an influence on patient treatment. Rather, clinicians tended to use the clinical impression to dose digoxin

Transient absorption and reshaping of ultrafast XUV light by laser-dressed helium

We present a theoretical study of transient absorption and reshaping of extreme ultraviolet (XUV) pulses by helium atoms dressed with a moderately strong infrared (IR) laser field. We formulate the atomic response using both the frequency-dependent absorption cross section and a time-frequency approach based on the time-dependent dipole induced by the light fields. The latter approach can be used in cases when an ultrafast dressing pulse induces transient effects, and/or when the atom exchanges energy with multiple frequency components of the XUV field. We first characterize the dressed atom response by calculating the frequency-dependent absorption cross section for XUV energies between 20 and 24 eV for several dressing wavelengths between 400 and 2000 nm and intensities up to 10^12 W/cm^2. We find that for dressing wavelengths near 1600 nm, there is an Autler-Townes splitting of the 1s ---> 2p transition that can potentially lead to transparency for absorption of XUV light tuned to this transition. We study the effect of this XUV transparency in a macroscopic helium gas by incorporating the time-frequency approach into a solution of the coupled Maxwell-Schr\"odinger equations. We find rich temporal reshaping dynamics when a 61 fs XUV pulse resonant with the 1s ---> 2p transition propagates through a helium gas dressed by an 11 fs, 1600 nm laser pulse.Comment: 13 pages, 8 figures, 1 table, RevTeX4, revise

Targeting triple-negative breast cancer cells with the histone deacetylase inhibitor panobinostat

INTRODUCTION: Of the more than one million global cases of breast cancer diagnosed each year, approximately fifteen percent are characterized as triple-negative, lacking the estrogen, progesterone, and Her2/neu receptors. Lack of effective therapies, younger age at onset, and early metastatic spread have contributed to the poor prognoses and outcomes associated with these malignancies. Here, we investigate the ability of the histone deacetylase inhibitor panobinostat (LBH589) to selectively target triple-negative breast cancer (TNBC) cell proliferation and survival in vitro and tumorigenesis in vivo. METHODS: TNBC cell lines MDA-MB-157, MDA-MB-231, MDA-MB-468, and BT-549 were treated with nanomolar (nM) quantities of panobinostat. Relevant histone acetylation was verified by flow cytometry and immunofluorescent imaging. Assays for trypan blue viability, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) proliferation, and DNA fragmentation were used to evaluate overall cellular toxicity. Changes in cell cycle progression were assessed with propidium iodide flow cytometry. Additionally, qPCR arrays were used to probe MDA-MB-231 cells for panobinostat-induced changes in cancer biomarkers and signaling pathways. Orthotopic MDA-MB-231 and BT-549 mouse xenograft models were used to assess the effects of panobinostat on tumorigenesis. Lastly, flow cytometry, ELISA, and immunohistochemical staining were applied to detect changes in cadherin-1, E-cadherin (CDH1) protein expression and the results paired with confocal microscopy in order to examine changes in cell morphology. RESULTS: Panobinostat treatment increased histone acetylation, decreased cell proliferation and survival, and blocked cell cycle progression at G2/M with a concurrent decrease in S phase in all TNBC cell lines. Treatment also resulted in apoptosis induction at 24 hours in all lines except the MDA-MB-468 cell line. MDA-MB-231 and BT-549 tumor formation was significantly inhibited by panobinostat (10 mg/kg/day) in mice. Additionally, panobinostat up-regulated CDH1 protein in vitro and in vivo and induced cell morphology changes in MDA-MB-231 cells consistent with reversal of the mesenchymal phenotype. CONCLUSIONS: This study revealed that panobinostat is overtly toxic to TNBC cells in vitro and decreases tumorigenesis in vivo. Additionally, treatment up-regulated anti-proliferative, tumor suppressor, and epithelial marker genes in MDA-MB-231 cells and initiated a partial reversal of the epithelial-to-mesenchymal transition. Our results demonstrate a potential therapeutic role of panobinostat in targeting aggressive triple-negative breast cancer cell types

Neutral Effect of Exenatide on Serum Testosterone in Men with Type 2 Diabetes Mellitus: A Prospective Cohort

BACKGROUND: Endogenous testosterone increases with weight loss from diet, exercise, and bariatric surgery. However, little is known about testosterone levels after weight loss from medication. OBJECTIVES: Uncover the effects of Glucagon-Like Peptide-1 receptor agonist (GLP-1 RA) therapy on serum testosterone. MATERIAL AND METHODS: Prospective cohort study of men starting GLP-1 RA therapy for type 2 diabetes mellitus. RESULTS: 51 men lost 2.27 kg (p = 0.00162) and their HbA1c values improved by 0.7% (p = 0.000503) after 6 months of GLP-1 RA therapy. There was no significant change in testosterone for the group as a whole. However, in subgroup analyses, there was a significant difference in total testosterone change between men starting with baseline total testosterone/dL (238.5 ± 56.5 ng/dL to 272.2 ± 82.3 ng/dL) compared to higher values (438 ± 98.2 ng/dL to 412 ± 141.2 ng/dL) (p = 0.0172);free testosterone increased if the baseline total testosterone was/dL (55.2 ± 12.8 pg/mL to 57.2 ± 17.6 pg/mL) and decreased if \u3e320 ng/dL (74.7 ± 16.3 pg/mL to 64.2 ± 17.7 pg/mL) (p = 0.00807). Additionally, there were significant differences in testosterone change between men with HbA1c improvements ≥1% (351.6 ± 123.9 ng/dL to 394.4 ± 136.5 ng/dL) compared to men with HbA1c changes CONCLUSION: GLP-1 RA therapy improves weight and HbA1c without adverse effects on testosterone. Those starting with lower testosterone values or attaining greater improvement in HbA1c may see additional benefits

The Personality and Cognitive Traits Associated with Adolescents’ Sensitivity to Social Norms

Little is known about the personality and cognitive traits that shape adolescents’ sensitivity to social norms. Further, few studies have harnessed novel empirical tools to elicit sensitivity to social norms among adolescent populations. This paper examines the association between sensitivity to norms and various personality and cognitive traits using an incentivised rule-following task grounded in Game Theory. Cross-sectional data were obtained from 1274 adolescents. Self-administered questionnaires were used to measure personality traits as well as other psychosocial characteristics. Incentivised rule-following experiments gauged sensitivity to social norms. A series of multilevel mixed effects ordered logistic regression models were employed to assess the association between sensitivity to norms and the personality and cognitive traits. The results highlighted statistically significant univariate associations between the personality and cognitive traits and sensitivity to norms. However, in the multivariate adjusted model, the only factor associated with sensitivity to norms was gender. The gender-stratified analyses revealed differences in the personality and cognitive traits associated with sensitivity to norms across genders. For males need to belong was significantly negatively associated with sensitivity to norms in the multivariate model. By comparison, emotional stability was negatively associated with sensitivity to norms for females. This study reinforced the findings from an earlier study and suggested female adolescents had higher levels of sensitivity to norms. The results indicated no consistent pattern between sensitivity to norms and the personality and cognitive traits. Our findings provide a basis for further empirical research on a relatively nascent construct, and bring a fresh perspective to the question of norm-following preferences among this age group

Rfam: updates to the RNA families database

Rfam is a collection of RNA sequence families, represented by multiple sequence alignments and covariance models (CMs). The primary aim of Rfam is to annotate new members of known RNA families on nucleotide sequences, particularly complete genomes, using sensitive BLAST filters in combination with CMs. A minority of families with a very broad taxonomic range (e.g. tRNA and rRNA) provide the majority of the sequence annotations, whilst the majority of Rfam families (e.g. snoRNAs and miRNAs) have a limited taxonomic range and provide a limited number of annotations. Recent improvements to the website, methodologies and data used by Rfam are discussed. Rfam is freely available on the Web at http://rfam.sanger.ac.uk/and http://rfam.janelia.org/

VUV frequency combs from below-threshold harmonics

Recent demonstrations of high-harmonic generation (HHG) at very high repetition frequencies (~100 MHz) may allow for the revolutionary transfer of frequency combs to the vacuum ultraviolet (VUV). This advance necessitates unifying optical frequency comb technology with strong-field atomic physics. While strong-field studies of HHG have often focused on above-threshold harmonic generation (photon energy above the ionization potential), for VUV frequency combs an understanding of below-threshold harmonic orders and their generation process is crucial. Here we present a new and quantitative study of the harmonics 7-13 generated below and near the ionization threshold in xenon gas. We show multiple generation pathways for these harmonics that are manifested as on-axis interference in the harmonic yield. This discovery provides a new understanding of the strong-field, below-threshold dynamics under the influence of an atomic potential and allows us to quantitatively assess the achievable coherence of a VUV frequency comb generated through below threshold harmonics. We find that under reasonable experimental conditions temporal coherence is maintained. As evidence we present the first explicit VUV frequency comb structure beyond the 3rd harmonic.Comment: 16 pages, 4 figures, 1 tabl

Intimate partner violence, substance use, and health comorbidities among women: A narrative review

Exposure to intimate partner violence (IPV), including physical, sexual, and psychological violence, aggression, and/or stalking, impacts overall health and can have lasting mental and physical health consequences. Substance misuse is common among individuals exposed to IPV, and IPV-exposed women (IPV-EW) are at-risk for transitioning from substance misuse to substance use disorder (SUD) and demonstrate greater SUD symptom severity; this too can have lasting mental and physical health consequences. Moreover, brain injury is highly prevalent in IPV-EW and is also associated with risk of substance misuse and SUD. Substance misuse, mental health diagnoses, and brain injury, which are highly comorbid, can increase risk of revictimization. Determining the interaction between these factors on the health outcomes and quality of life of IPV-EW remains a critical need. This narrative review uses a multidisciplinary perspective to foster further discussion and research in this area by examining how substance use patterns can cloud identification of and treatment for brain injury and IPV. We draw on past research and the knowledge of our multidisciplinary team of researchers to provide recommendations to facilitate access to resources and treatment strategies and highlight intervention strategies capable of addressing the varied and complex needs of IPV-EW

Pre-notification letter type and response rate to a postal survey among women who have recently given birth

Background: Surveys are commonly used in health research to assess patient satisfaction with hospital care. Achieving an adequate response rate, in the face of declining trends over time, threatens the quality and reliability of survey results. This paper reports on a postal satisfaction survey conducted with women who had recently given birth, and explores the effect of two strategies on response rates. Methods: A sample of 2048 Australian women who had recently given birth were invited to participate in a postal survey about their recent experiences with maternity care. The study design included two different strategies intended to increase response rates: a randomised controlled trial testing two types of pre-notification letter (with or without the option of opting out of the survey), and a request for consent to link survey data with existing routinely collected health data (omitting the latter data items from the survey reduced survey length and participant burden). Results: The survey had an overall response rate of 46%. Women receiving the pre-notification letter with the option of opting out of the survey were more likely to actively decline to participate than women receiving the letter without this option, although the overall numbers of women were small (27 versus 12). Letter type was not significantly associated with the return of a completed survey. Among women who completed the survey, 97% gave consent to link their survey data with existing health data. Conclusions: Seeking consent for record linkage was highly acceptable to women who completed the survey, and represents an important strategy to add to the arsenal for designing and implementing effective surveys. In addition to aspects of survey design, future research should explore how to more effectively influence personal constructs that contribute to the decision to participate in surveys.NHMR