Underlying Genetics of aHUS: Which Connection with Outcome and Treatment Discontinuation?

Atypical hemolytic uremic syndrome (aHUS) is a rare disease caused by a genetic dysregulation of the alternative complement pathway, characterized by thrombocytopenia, hemolytic anemia, and acute kidney injury, and included in the group of thrombotic microangiopathies. With the introduction of humanized monoclonal antibodies that inhibit C5 activation, the natural history of aHUS completely changed, with a better prognosis, a quick recovery of renal function, and a significant reduction of end-stage renal disease incidence. Nowadays, there is an increasing interest in the molecular and genetic bases of this severe disease. The aim of this narrative review is to provide readers with a practical guide about different possible involved genes, elucidating the specific role of each transcribed protein in the pathogenesis of aHUS. Moreover, we analyzed the main current evidence about the relationship among genetic mutations, outcomes, and the risk of recurrence of this manifold disease

Volunteer Bias in Recruitment, Retention, and Blood Sample Donation in a Randomised Controlled Trial Involving Mothers and Their Children at Six Months and Two Years: A Longitudinal Analysis

BACKGROUND: The vulnerability of clinical trials to volunteer bias is under-reported. Volunteer bias is systematic error due to differences between those who choose to participate in studies and those who do not. METHODS AND RESULTS: This paper extends the applications of the concept of volunteer bias by using data from a trial of probiotic supplementation for childhood atopy in healthy dyads to explore 1) differences between a) trial participants and aggregated data from publicly available databases b) participants and non-participants as the trial progressed 2) impact on trial findings of weighting data according to deprivation (Townsend) fifths in the sample and target populations. 1) a) Recruits (n = 454) were less deprived than the target population, matched for area of residence and delivery dates (n = 6,893) (mean [SD] deprivation scores 0.09[4.21] and 0.79[4.08], t = 3.44, df = 511, p<0.001). b) i) As the trial progressed, representation of the most deprived decreased. These participants and smokers were less likely to be retained at 6 months (n = 430[95%]) (OR 0.29,0.13-0.67 and 0.20,0.09-0.46), and 2 years (n = 380[84%]) (aOR 0.68,0.50-0.93 and 0.55,0.28-1.09), and consent to infant blood sample donation (n = 220[48%]) (aOR 0.72,0.57-0.92 and 0.43,0.22-0.83). ii) Mothers interested in probiotics or research or reporting infants' adverse events or rashes were more likely to attend research clinics and consent to skin-prick testing. Mothers participating to help children were more likely to consent to infant blood sample donation. 2) In one trial outcome, atopic eczema, the intervention had a positive effect only in the over-represented, least deprived group. Here, data weighting attenuated risk reduction from 6.9%(0.9-13.1%) to 4.6%(-1.4-+10.5%), and OR from 0.40(0.18-0.91) to 0.56(0.26-1.21). Other findings were unchanged. CONCLUSIONS: Potential for volunteer bias intensified during the trial, due to non-participation of the most deprived and smokers. However, these were not the only predictors of non-participation. Data weighting quantified volunteer bias and modified one important trial outcome. TRIAL REGISTRATION: This randomised, double blind, parallel group, placebo controlled trial is registered with the International Standard Randomised Controlled Trials Register, Number (ISRCTN) 26287422. Registered title: Probiotics in the prevention of atopy in infants and children

Zebrafish hoxd4a Acts Upstream of meis1.1 to Direct Vasculogenesis, Angiogenesis and Hematopoiesis

10.1371/journal.pone.0058857PLoS ONE83

SMaRT lncRNA controls translation of a G-quadruplex-containing mRNA antagonizing the DHX36 helicase

Guanine-quadruplexes (G4) included in RNA molecules exert several functions in controlling gene expression at post-transcriptional level; however, the molecular mechanisms of G4-mediated regulation are still poorly understood. Here, we describe a regulatory circuitry operating in the early phases of murine muscle differentiation in which a long non-coding RNA (SMaRT) base pairs with a G4-containing mRNA (Mlx-γ) and represses its translation by counteracting the activity of the DHX36 RNA helicase. The time-restricted, specific effect of lnc-SMaRT on the translation of Mlx-γ isoform modulates the general subcellular localization of total MLX proteins, impacting on their transcriptional output and promoting proper myogenesis and mature myotube formation. Therefore, the circuitry made of lnc-SMaRT, Mlx-γ, and DHX36 not only plays an important role in the control of myogenesis but also unravels a molecular mechanism where G4 structures and G4 unwinding activities are regulated in living cells

Predicting Crystallization of Amorphous Drugs with Terahertz Spectroscopy.

There is a controversy about the extent to which the primary and secondary dielectric relaxations influence the crystallization of amorphous organic compounds below the glass transition temperature. Recent studies also point to the importance of fast molecular dynamics on picosecond-to-nanosecond time scales with respect to the glass stability. In the present study we provide terahertz spectroscopy evidence on the crystallization of amorphous naproxen well below its glass transition temperature and confirm the direct role of Johari-Goldstein (JG) secondary relaxation as a facilitator of the crystallization. We determine the onset temperature Tβ above which the JG relaxation contributes to the fast molecular dynamics and analytically quantify the level of this contribution. We then show there is a strong correlation between the increase in the fast molecular dynamics and onset of crystallization in several chosen amorphous drugs. We believe that this technique has immediate applications to quantify the stability of amorphous drug materials.JS and JAZ would like to acknowledge the UK Engineering and Physical Sciences Research Council for funding (EP/J007803/1).This is the final version of the article. It first appeared from ACS at http://dx.doi.org/10.1021/acs.molpharmaceut.5b0033

Guidelines for the use of survivorship care plans: a systematic quality appraisal using the AGREE II instrument

Abstract Background Survivorship care plans (SCPs) are written treatment summaries and follow-up care plans that are intended to facilitate communication and coordination of care among survivors, cancer care providers, and primary care providers. A growing number of guidelines for the use of SCPs exist, yet SCP use in the United States remains limited. Limited use of SCPs may be due to poor quality of these guidelines. The purpose of the study was to evaluate the quality of guidelines for SCP use, tools that are intended to promote evidence-based medicine. Methods We conducted a comprehensive search of the literature using MEDLINE/PubMed, EMBASE (Excerpta Medica Database), and CINAHL (Cumulative Index to Nursing and Allied Health Literature) published through April 2014, in addition to grey literature sources and bibliographic and expert reviews. Guideline quality was assessed using the AGREE II instrument (Appraisal of Guidelines for Research and Evaluation, 2nd edition), a tool developed by an international group of scientists to advance the quality of clinical practice guidelines. To promote consistency with extant studies using the AGREE II instrument and to clearly and unambiguously identify potentially useful guidelines for SCP use, we also summarized AGREE II scores by strongly recommending, recommending, or not recommending the guidelines that we evaluated. Results Of 128 documents screened, we included 16 guidelines for evaluation. We did not strongly recommend any of the 16 guidelines that we evaluated; we recommended 5 and we did not recommend 11. Overall, guidelines scored highest on clarity of presentation (i.e., guideline language, structure, and format): Guidelines were generally unambiguous in their recommendations that SCPs should be used. Guidelines scored lowest on applicability (i.e., barriers and facilitators to implementation, implementation strategies, and resource implications of applying the guideline): Few guidelines discussed facilitators and barriers to guideline application; advice and tools for implementing guidelines were vague; and none explicitly discussed resource implications of implementing the guidelines. Conclusions Guidelines often advocated survivorship care plan use without justification or suggestions for implementation. Improved guideline quality may promote survivorship care plan use

Measures of organizational characteristics associated with adoption and/or implementation of innovations: A systematic review

Abstract Background This paper identifies and describes measures of constructs relevant to the adoption or implementation of innovations (i.e., new policies, programs or practices) at the organizational-level. This work is intended to advance the field of dissemination and implementation research by aiding scientists in the identification of existing measures and highlighting methodological issues that require additional attention. Methods We searched for published studies (1973–2013) in 11 bibliographic databases for quantitative, empirical studies that presented outcome data related to adoption and/or implementation of an innovation. Included studies had to assess latent constructs related to the “inner setting” of the organization, as defined by the Consolidated Framework for Implementation Research. Results Of the 76 studies included, most (86%) were cross sectional and nearly half (49%) were conducted in health care settings. Nearly half (46%) involved implementation of evidence-based or “best practice” strategies; roughly a quarter (26%) examined use of new technologies. Primary outcomes most often assessed were innovation implementation (57%) and adoption (34%); while 4% of included studies assessed both outcomes. There was wide variability in conceptual and operational definitions of organizational constructs. The two most frequently assessed constructs included “organizational climate” and “readiness for implementation.” More than half (55%) of the studies did not articulate an organizational theory or conceptual framework guiding the inquiry; about a third (34%) referenced Diffusion of Innovations theory. Overall, only 46% of articles reported psychometric properties of measures assessing latent organizational characteristics. Of these, 94% (33/35) described reliability and 71% (25/35) reported on validity. Conclusions The lack of clarity associated with construct definitions, inconsistent use of theory, absence of standardized reporting criteria for implementation research, and the fact that few measures have demonstrated reliability or validity were among the limitations highlighted in our review. Given these findings, we recommend that increased attention be devoted toward the development or refinement of measures using common psychometric standards. In addition, there is a need for measure development and testing across diverse settings, among diverse population samples, and for a variety of types of innovations

Elaborating on theory with middle managers’ experience implementing healthcare innovations in practice

Abstract Background The theory of middle managers’ role in implementing healthcare innovations hypothesized that middle managers influence implementation effectiveness by fulfilling the following four roles: diffusing information, synthesizing information, mediating between strategy and day-to-day activities, and selling innovation implementation. The theory also suggested several activities in which middle managers might engage to fulfill the four roles. The extent to which the theory aligns with middle managers’ experience in practice is unclear. We surveyed middle managers (n = 63) who attended a nursing innovation summit to (1) assess alignment between the theory and middle managers’ experience in practice and (2) elaborate on the theory with examples from middle managers’ experience overseeing innovation implementation in practice. Findings Middle managers rated all of the theory’s hypothesized four roles as “extremely important” but ranked diffusing and synthesizing information as the most important and selling innovation implementation as the least important. They reported engaging in several activities that were consistent with the theory’s hypothesized roles and activities such as diffusing information via meetings and training. They also reported engaging in activities not described in the theory such as appraising employee performance. Conclusions Middle managers’ experience aligned well with the theory and expanded definitions of the roles and activities that it hypothesized. Future studies should assess the relationship between hypothesized roles and the effectiveness with which innovations are implemented in practice. If evidence supports the theory, the theory should be leveraged to promote the fulfillment of hypothesized roles among middle managers, doing so may promote innovation implementation