The Use of Putative Dialysis Initiation Time in Comparative Outcomes of Patients with Advanced Chronic Kidney Disease: Methodological Aspects

The latest data from the United States Renal Data Systems show over 134,000 individuals with end-stage kidney disease (ESKD) starting dialysis in the year 2019. ESKD patients on dialysis, the default treatment strategy, have high mortality and hospitalization, especially in the first year of dialysis. An alternative treatment strategy is (non-dialysis) conservative management (CM). The relative effectiveness of CM with respect to various patient outcomes, including survival, hospitalization, and health-related quality of life among others, especially in elderly ESKD or advanced chronic kidney disease patients with serious comorbidities, is an active area of research. A technical challenge inherent in comparing patient outcomes between CM and dialysis patient groups is that the start of follow-up time is “not defined” for patients on CM because they do not initiate dialysis. One solution is the use of putative dialysis initiation (PDI) time. In this work, we examine the validity of the use of PDI time to determine the start of follow-up for longitudinal retrospective and prospective cohort studies involving CM. We propose and assess the efficacy of estimating PDI time using linear mixed effects model of kidney function decline over time via simulation studies. We also illustrate how the estimated PDI time can be used to effectively estimate the survival distribution

High-Dimensional Fixed Effects Profiling Models and Applications in End-Stage Kidney Disease Patients: Current State and Future Directions

Profiling analysis aims to evaluate health care providers, including hospitals, nursing homes, or dialysis facilities among others with respect to a patient outcome, such as 30-day unplanned hospital readmission or mortality. Fixed effects (FE) profiling models have been developed over the last decade, motivated by the overall need to (a) improve accurate identification or “flagging” of under-performing providers, (b) relax assumptions inherent in random effects (RE) profiling models, and (c) take into consideration the unique disease characteristics and care/treatment processes of end-stage kidney disease (ESKD) patients on dialysis. In this paper, we review the current state of FE methodologies and their rationale in the ESKD population and illustrate applications in four key areas: profiling dialysis facilities for (1) patient hospitalizations over time (longitudinally) using standardized dynamic readmission ratio (SDRR), (2) identification of dialysis facility characteristics (e.g., staffing level) that contribute to hospital readmission, and (3) adverse recurrent events using standardized event ratio (SER). Also, we examine the operating characteristics with a focus on FE profiling models. Throughout these areas of applications to the ESKD population, we identify challenges for future research in both methodology and clinical studies

Exploratory time varying lagged regression: Modeling association of cognitive and functional trajectories with expected clinic visits in older adults

Motivated by a longitudinal study on factors affecting the frequency of clinic visits of older adults, an exploratory time varying lagged regression analysis is proposed to relate a longitudinal response to multiple cross-sectional and longitudinal predictors from time varying lags. Regression relations are allowed to vary with time through smooth varying coefficient functions. The main goal of the proposal is to detect deviations from a concurrent varying coefficient model potentially in a subset of the longitudinal predictors with nonzero estimated lags. The proposed methodology is geared towards irregular and infrequent data where different longitudinal variables may be observed at different frequencies, possibly at unsynchronized time points and contaminated with additive measurement error. Furthermore, to cope with the curse of dimensionality which limits related current modeling approaches, a sequential model building procedure is proposed to explore and select the time varying lags of the longitudinal predictors. The estimation procedure is based on estimation of the moments of the predictor and response trajectories by pooling information from all subjects. The finite sample properties of the proposed estimation algorithm are studied under various lag structures and correlation levels among the predictor processes in simulation studies. Application to the clinic visits data show the effect of cognitive and functional impairment scores from varying lags on the frequency of the clinic visits throughout the study

Design of a Gd-DOTA-Phthalocyanine Conjugate Combining MRI Contrast Imaging and Photosensitization Properties as a Potential Molecular Theranostic

Cataloged from PDF version of article.The design and synthesis of a phthalocyanine - Gd-DOTA conjugate is presented to open the way to novel molecular theranostics, combining the properties of MRI contrast imaging with photodynamic therapy. The rational design of the conjugate integrates isomeric purity of the phthalocyanine core substitution, suitable biocompatibility with the use of polyoxo water-solubilizing substituents, and a convergent synthetic strategy ended by the use of click chemistry to graft the Gd-DOTA moiety to the phthalocyanine. Photophysical and photochemical properties, contrast imaging experiments and preliminary in vitro investigations proved that such a combination is relevant and lead to a new type of potential theranostic agent

Bupropion for the treatment of fluoxetine non-responsive trichotillomania: a case report

<p>Abstract</p> <p>Introduction</p> <p>Trichotillomania, classified as an impulse control disorder in the <it>Diagnostic and Statistical Manual of Mental Disorders</it>, is characterized by the recurrent pulling out of one's hair, resulting in noticeable hair loss. The condition has a varied etiology. Specific serotonin reuptake inhibitors are considered the treatment of choice; however some patients fail to respond to this class of drugs. A few older reports suggest possible benefit from treatment with bupropion.</p> <p>Case presentation</p> <p>A 23-year-old Asian woman with fluoxetine non- responsive trichotillomania was treated with sustained release bupropion (up to 450 mg/day) and cognitive behavior therapy. She demonstrated clinically significant improvement on the Clinical Global Impression - Improvement scale by week 13. The improvement persisted throughout the 12-month follow-up period.</p> <p>Conclusions</p> <p>The present case report may be of interest to psychiatrists and dermatologists. Apart from the serotonergic pathway, others, such as the mesolimbic pathway, also appear to be involved in the causation of trichotillomania. Bupropion may be considered as an alternative pharmacological treatment for patients who do not respond to specific serotonin reuptake inhibitors. However, this initial finding needs to be confirmed by well designed double-blind placebo controlled trials.</p

Treatment of acne with intermittent and conventional isotretinoin: a randomized, controlled multicenter study

Oral isotretinoin is the most effective choice in the treatment of severe acne. Application of isotretionin to acne has been expanded to treat those patients with less severe but scarring acne who are responding unsatisfactorily to conventional therapies. However, its use is associated with many side effects, some of which can result in very disastrous consequences. Data related with intermittent isotretinoin therapy is still limited. Our aim was to asses the efficacy and tolerability of two different intermittent isotretinoin courses and compare them with conventional isotretinoin treatment. In this multicenter and controlled study, 66 patients with moderate to severe cases were randomized to receive either isotretionin for the first 10 days of each month for 6 months (group 1), or each day in the first month, afterwards the first 10 days of each month for 5 months (group 2) or daily for 6 months (group 3). The drug dosage was 0.5 mg/kg/day in all groups. Patients were followed-up for 12 months. Efficacy values were evaluable for 22 patients in group 1, 19 patients in group 2, and 19 patients in group 3. Acne scores in each group were significantly lower at the end of treatment and follow-up periods (P < 0.001). When patients were evaluated separately as moderate (n = 31) and severe (n = 29), no statistically significant differences were obtained among the treatment protocols in patients with moderate acne. However, there was a significant difference between groups 1 and 3 to the response of the treatments in severe acne patients at the end of follow-up period (P = 0.013). The frequency and severity of isotretionin-related side effects were found to be lower in groups 1 and 2 compared with group 3. Intermittent isotretinoin may represent an effective alternative treatment, especially in moderate acne with a low incidence and severity of side effects. The intermittent isotretinoin can be recommended in those patients not tolerating the classical dosage

VERITAS Search for VHE Gamma-ray Emission from Dwarf Spheroidal Galaxies

Indirect dark matter searches with ground-based gamma-ray observatories provide an alternative for identifying the particle nature of dark matter that is complementary to that of direct search or accelerator production experiments. We present the results of observations of the dwarf spheroidal galaxies Draco, Ursa Minor, Bootes 1, and Willman 1 conducted by VERITAS. These galaxies are nearby dark matter dominated objects located at a typical distance of several tens of kiloparsecs for which there are good measurements of the dark matter density profile from stellar velocity measurements. Since the conventional astrophysical background of very high energy gamma rays from these objects appears to be negligible, they are good targets to search for the secondary gamma-ray photons produced by interacting or decaying dark matter particles. No significant gamma-ray flux above 200 GeV was detected from these four dwarf galaxies for a typical exposure of ~20 hours. The 95% confidence upper limits on the integral gamma-ray flux are in the range 0.4-2.2x10^-12 photons cm^-2s^-1. We interpret this limiting flux in the context of pair annihilation of weakly interacting massive particles and derive constraints on the thermally averaged product of the total self-annihilation cross section and the relative velocity of the WIMPs. The limits are obtained under conservative assumptions regarding the dark matter distribution in dwarf galaxies and are approximately three orders of magnitude above the generic theoretical prediction for WIMPs in the minimal supersymmetric standard model framework. However significant uncertainty exists in the dark matter distribution as well as the neutralino cross sections which under favorable assumptions could further lower the limits.Comment: 21 pages, 2 figures, updated to reflect version published in ApJ. NOTE: M.D. Wood added as autho

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine: Brussels, Belgium. 15-18 March 2016.

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]

Discovery of very high energy gamma rays from PKS 1424+240 and multiwavelength constraints on its redshift

We report the first detection of very-high-energy (VHE) gamma-ray emission above 140 GeV from PKS 1424+240, a BL Lac object with an unknown redshift. The photon spectrum above 140 GeV measured by VERITAS is well described by a power law with a photon index of 3.8 +- 0.5_stat +- 0.3_syst and a flux normalization at 200 GeV of (5.1 +- 0.9_stat +- 0.5_syst) x 10^{-11} TeV^-1 cm^-2 s^-1, where stat and syst denote the statistical and systematical uncertainty, respectively. The VHE flux is steady over the observation period between MJD 54881 and 55003 (2009 February 19 to June 21). Flux variability is also not observed in contemporaneous high energy observations with the Fermi Large Area Telescope (LAT). Contemporaneous X-ray and optical data were also obtained from the Swift XRT and MDM observatory, respectively. The broadband spectral energy distribution (SED) is well described by a one-zone synchrotron self-Compton (SSC) model favoring a redshift of less than 0.1. Using the photon index measured with Fermi in combination with recent extragalactic background light (EBL) absorption models it can be concluded from the VERITAS data that the redshift of PKS 1424+240 is less than 0.66.Comment: accepted for publication, Ap

Rapid and tunable method to temporally control gene editing based on conditional Cas9 stabilization

The CRISPR/Cas9 system is a powerful tool for studying gene function. Here, we describe a method that allows temporal control of CRISPR/Cas9 activity based on conditional Cas9 destabilization. We demonstrate that fusing an FKBP12-derived destabilizing domain to Cas9 (DD-Cas9) enables conditional Cas9 expression and temporal control of gene editing in the presence of an FKBP12 synthetic ligand. This system can be easily adapted to co-express, from the same promoter, DD-Cas9 with any other gene of interest without co-modulation of the latter. In particular, when co-expressed with inducible Cre-ERT2, our system enables parallel, independent manipulation of alleles targeted by Cas9 and traditional recombinase with single-cell specificity. We anticipate this platform will be used for the systematic characterization and identification of essential genes, as well as the investigation of the interactions between functional genes