Mutation of Arabidopsis SPLICEOSOMAL TIMEKEEPER LOCUS1 Causes Circadian Clock Defects

The circadian clock plays a crucial role in coordinating plant metabolic and physiological functions with predictable environmental variables, such as dusk and dawn, while also modulating responses to biotic and abiotic challenges. Much of the initial characterization of the circadian system has focused on transcriptional initiation, but it is now apparent that considerable regulation is exerted after this key regulatory step. Transcript processing, protein stability, and cofactor availability have all been reported to influence circadian rhythms in a variety of species. We used a genetic screen to identify a mutation within a putative RNA binding protein (SPLICEOSOMAL TIMEKEEPER LOCUS1 [STIPL1]) that induces a long circadian period phenotype under constant conditions. STIPL1 is a homolog of the spliceosomal proteins TFP11 (Homo sapiens) and Ntr1p (Saccharomyces cerevisiae) involved in spliceosome disassembly. Analysis of general and alternative splicing using a high-resolution RT-PCR system revealed that mutation of this protein causes less efficient splicing of most but not all of the introns analyzed. In particular, the altered accumulation of circadian-associated transcripts may contribute to the observed mutant phenotype. Interestingly, mutation of a close homolog of STIPL1, STIP-LIKE2, does not cause a circadian phenotype, which suggests divergence in function between these family members. Our work highlights the importance of posttranscriptional control within the clock mechanism. © 2012 American Society of Plant Biologists. All rights reserved

Tracing Noble Gas Radionuclides in the Environment

Trace analysis of radionuclides is an essential and versatile tool in modern science and technology. Due to their ideal geophysical and geochemical properties, long-lived noble gas radionuclides, in particular, 39Ar (t1/2 = 269 yr), 81Kr (t1/2 = 2.3x10^5 yr) and 85Kr (t1/2 = 10.8 yr), have long been recognized to have a wide range of important applications in Earth sciences. In recent years, significant progress has been made in the development of practical analytical methods, and has led to applications of these isotopes in the hydrosphere (tracing the flow of groundwater and ocean water). In this article, we introduce the applications of these isotopes and review three leading analytical methods: Low-Level Counting (LLC), Accelerator Mass Spectrometry (AMS) and Atom Trap Trace Analysis (ATTA)

eHealth interventions for people with chronic kidney disease

Background Chronic kidney disease (CKD) is associated with high morbidity and death, which increases as CKD progresses to end‐stage kidney disease (ESKD). There has been increasing interest in developing innovative, effective and cost‐efficient methods to engage with patient populations and improve health behaviours and outcomes. Worldwide there has been a tremendous increase in the use of technologies, with increasing interest in using eHealth interventions to improve patient access to relevant health information, enhance the quality of healthcare and encourage the adoption of healthy behaviours. Objectives This review aims to evaluate the benefits and harms of using eHealth interventions to change health behaviours in people with CKD. Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 14 January 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria Randomised controlled trials (RCTs) and quasi‐RCTs using an eHealth intervention to promote behaviour change in people with CKD were included. There were no restrictions on outcomes, language or publication type. Data collection and analysis Two authors independently assessed trial eligibility, extracted data and assessed the risk of bias. The certainty of the evidence was assessed using GRADE. Main results We included 43 studies with 6617 participants that evaluated the impact of an eHealth intervention in people with CKD. Included studies were heterogeneous in terms of eHealth modalities employed, type of intervention, CKD population studied and outcomes assessed. The majority of studies (39 studies) were conducted in an adult population, with 16 studies (37%) conducted in those on dialysis, 11 studies (26%) in the pre‐dialysis population, 15 studies (35%) in transplant recipients and 1 studies (2%) in transplant candidates We identified six different eHealth modalities including: Telehealth; mobile or tablet application; text or email messages; electronic monitors; internet/websites; and video or DVD. Three studies used a combination of eHealth interventions. Interventions were categorised into six types: educational; reminder systems; self‐monitoring; behavioural counselling; clinical decision‐aid; and mixed intervention types. We identified 98 outcomes, which were categorised into nine domains: blood pressure (9 studies); biochemical parameters (6 studies); clinical end‐points (16 studies); dietary intake (3 studies); quality of life (9 studies); medication adherence (10 studies); behaviour (7 studies); physical activity (1 study); and cost‐effectiveness (7 studies). Only three outcomes could be meta‐analysed as there was substantial heterogeneity with respect to study population and eHealth modalities utilised. There was found to be a reduction in interdialytic weight gain of 0.13kg (4 studies, 335 participants: MD ‐0.13, 95% CI ‐0.28 to 0.01; I2 = 0%) and a reduction in dietary sodium intake of 197 mg/day (2 studies, 181 participants: MD ‐197, 95% CI ‐540.7 to 146.8; I2 = 0%). Both dietary sodium and fluid management outcomes were graded as being of low evidence due to high or unclear risk of bias and indirectness (interdialytic weight gain) and high or unclear risk of bias and imprecision (dietary sodium intake). Three studies reported death (2799 participants, 146 events), with 45 deaths/1000 cases compared to standard care of 61 deaths/1000 cases (RR 0.74, CI 0.53 to 1.03; P = 0.08). We are uncertain whether using eHealth interventions, in addition to usual care, impact on the number of deaths as the certainty of this evidence was graded as low due to high or unclear risk of bias, indirectness and imprecision. Authors' conclusions eHealth interventions may improve the management of dietary sodium intake and fluid management. However, overall these data suggest that current evidence for the use of eHealth interventions in the CKD population is of low quality, with uncertain effects due to methodological limitations and heterogeneity of eHealth modalities and intervention types. Our review has highlighted the need for robust, high quality research that reports a core (minimum) data set to enable meaningful evaluation of the literature

Target of Rapamycin Inhibitors (TOR-I; Sirolimus and Everolimus) for Primary Immunosuppression in Kidney Transplant Recipients

Background: Target of rapamycin inhibitors (TOR-I) (sirolimus, everolimus) are immunosuppressive agents with a novel mode of action but an uncertain clinical role. Objectives: To investigate the benefits and harms of immunosuppressive regimens containing TOR-I when compared to other regimens as initial therapy for kidney transplant recipients. Search strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (in The Cochrane Library, issue 2, 2005), MEDLINE (1966-June 2005), EMBASE (1980-June 2005), the specialised register of the Cochrane Renal Group (June 2005)., and contacted authors and pharmaceutical companies to identify relevant studies. Selection criteria: All randomised controlled trials (RCTs) and quasi-RCTs where drug regimens containing TOR-I were compared to alternative drug regimens in the immediate post-transplant period were included, without age restriction, dosage or language of report. Data collection and analysis: Two reviewers independently assessed trials for eligibility and quality, and extracted data. Results are expressed as relative risk (RR) or weight mean difference (MD) with 95% confidence intervals (CI). Main results: Thirty three trials (142 reports) were included (sirolimus (27), everolimus (5), head-to-head (1)). When TOR-I replaced CNI there was no difference in acute rejection, but serum creatinine was lower (MD -18.31 micromol/L, -30.96 to -5.67), and bone marrow more suppressed (leucopenia: RR 2.02 1.12 to 3.66; thrombocytopenia: RR 6.97 2.97 to 16.36; anaemia: RR 1.67, 1.27 to 2.20). When TOR-I replaced antimetabolites, acute rejection (RR 0.84, 0.71 to 0.99) and cytomegalovirus infection (CMV) (RR 0.49; 0.37 to 0.65) were reduced, but hypercholesterolaemia was increased (RR 1.65, 1.32 to 2.06). For low versus high-dose TOR-I, with equal CNI dose, rejection was increased (RR 1.23, 1.06 to 1.43) but calculated GFR higher (MD 4.27 mL/min, 1.12 to 7.41), and for low-dose TOR-I/standard-dose CNI versus higher-dose TOR-I/reduced CNI, acute rejection (RR 0.67, 0.52 to 0.88) and calculated GFR (MD -9.46 mL/min, -12.16 to -6.76) were reduced. There was no significant difference in mortality, graft loss or malignancy risk for TOR-I in any comparison. Authors' conclusions: TOR-I have been evaluated in four different primary immunosuppressive algorithms; as replacement for CNI and for antimetabolites, in combination with CNI at low and high dose and with variable dose of CNI. Generally, surrogate endpoints for graft survival favour TOR-I (lower risk of acute rejection and higher GFR) and surrogate endpoints for patient outcomes are worsened by TOR-I (bone marrow suppression, lipid disturbance). Long-term hard-endpoint data from methodologically robust RCTs are still needed

Bilateral Assessment of Functional Tasks for Robot-assisted Therapy Applications

This article presents a novel evaluation system along with methods to evaluate bilateral coordination of arm function on activities of daily living tasks before and after robot-assisted therapy. An affordable bilateral assessment system (BiAS) consisting of two mini-passive measuring units modeled as three degree of freedom robots is described. The process for evaluating functional tasks using the BiAS is presented and we demonstrate its ability to measure wrist kinematic trajectories. Three metrics, phase difference, movement overlap, and task completion time, are used to evaluate the BiAS system on a bilateral symmetric (bi-drink) and a bilateral asymmetric (bi-pour) functional task. Wrist position and velocity trajectories are evaluated using these metrics to provide insight into temporal and spatial bilateral deficits after stroke. The BiAS system quantified movements of the wrists during functional tasks and detected differences in impaired and unimpaired arm movements. Case studies showed that stroke patients compared to healthy subjects move slower and are less likely to use their arm simultaneously even when the functional task requires simultaneous movement. After robot-assisted therapy, interlimb coordination spatial deficits moved toward normal coordination on functional tasks

Goldstini

Supersymmetric phenomenology has been largely bound to the hypothesis that supersymmetry breaking originates from a single source. In this paper, we relax this underlying assumption and consider a multiplicity of sectors which independently break supersymmetry, thus yielding a corresponding multiplicity of goldstini. While one linear combination of goldstini is eaten via the super-Higgs mechanism, the orthogonal combinations remain in the spectrum as physical degrees of freedom. Interestingly, supergravity effects induce a universal tree-level mass for the goldstini which is exactly twice the gravitino mass. Since visible sector fields can couple dominantly to the goldstini rather than the gravitino, this framework allows for substantial departures from conventional supersymmetric phenomenology. In fact, this even occurs when a conventional mediation scheme is augmented by additional supersymmetry breaking sectors which are fully sequestered. We discuss a number of striking collider signatures, including various novel decay modes for the lightest observable-sector supersymmetric particle, gravitinoless gauge-mediated spectra, and events with multiple displaced vertices. We also describe goldstini cosmology and the possibility of goldstini dark matter.Comment: 14 pages, 7 figures; references adde

Target of rapamycin inhibitors (TOR‐I; sirolimus and everolimus) for primary immunosuppression in kidney transplant recipients

Background Kidney transplantation is the therapy of choice for many patients with end‐stage kidney disease (ESKD) with an improvement in survival rates and satisfactory short term graft survival. However, there has been little improvement in long‐term survival. The place of target of rapamycin inhibitors (TOR‐I) (sirolimus, everolimus), which have different modes of action from other commonly used immunosuppressive agents, in kidney transplantation remains uncertain. This is an update of a review first published in 2006. Objectives To evaluate the short and long‐term benefits and harms of TOR‐I (sirolimus and everolimus) when used in primary immunosuppressive regimens for kidney transplant recipients. Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 20 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register were identified through searches of CENTRAL, MEDLINE and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria All randomised controlled trials (RCTs) and quasi‐RCTs in which drug regimens, containing TOR‐I commenced within seven days of transplant, were compared to alternative drug regimens, were included without age restriction, dosage or language of report. Data collection and analysis Three authors independently assessed study eligibility, risk of bias, and extracted data. Results were reported as risk ratios (RR) with 95% confidence intervals (CI) for dichotomous outcomes and mean difference (MD) with 95% CI for continuous outcomes. Statistical analyses were performed using the random‐effects model. The certainty of the evidence was assessed using GRADE Main results Seventy studies (17,462 randomised participants) were included; eight studies included two comparisons to provide 78 comparisons. Outcomes were reported at six months to three years post transplant. Risk of bias was judged to be low for sequence generation in 25 studies, for allocation concealment in 23 studies, performance bias in four studies, detection bias in 65 studies, attrition bias in 45 studies, selective reporting bias in 48 studies, and for other potential bias in three studies. Risk of bias was judged to be at high risk of bias for sequence generation in two studies, allocation concealment in two studies, performance bias in 61 studies, detection bias in one study, attrition bias in four studies, for selective reporting bias in 11 studies and for other potential risk of bias in 46 studies. Compared with CNI and antimetabolite, TOR‐I with antimetabolite probably makes little or no difference to death (RR 1.31, 95% CI 0.87 to 1.98; 19 studies) or malignancies (RR 0.86, 95% CI 0.50 to 1.48; 10 studies); probably increases graft loss censored for death (RR 1.32, 95% CI 0.96 to 1.81; 15 studies), biopsy‐proven acute rejection (RR 1.60, 95% CI 1.25 to 2.04; 15 studies), need to change treatment (RR 2.42, 95% CI 1.88 to 3.11; 14 studies) and wound complications (RR 2.56, 95% CI 1.94 to 3.36; 12 studies) (moderate certainty evidence); but reduces CMV infection (RR 0.43, 95% CI 0.29 to 0.63; 13 studies) (high certainty evidence). Compared with antimetabolites and CNI, TOR‐I with CNI probably makes little or no difference to death (RR 1.06, 95% CI 0.84 to 1.33; 31 studies), graft loss censored for death (RR 1.09, 95% CI 0.82 to 1.45; 26 studies), biopsy‐proven acute rejection (RR 0.95, 95% CI 0.81 to 1.12; 24 studies); and malignancies (RR 0.83, 95% CI 0.64 to 1.07; 17 studies); probably increases the need to change treatment (RR 1.56, 95% CI 1.28 to 1.90; 25 studies), and wound complications (RR 1.56, 95% CI 1.28 to 1.91; 17 studies); but probably reduces CMV infection (RR 0.44, 95% CI 0.34 to 0.58; 25 studies) (moderate certainty evidence). Lower dose TOR‐I and standard dose CNI compared with higher dose TOR‐I and reduced dose CNI probably makes little or no difference to death (RR 1.07, 95% CI 0.64 to 1.78; 9 studies), graft loss censored for death (RR 1.09, 95% CI 0.54 to 2.20; 8 studies), biopsy‐proven acute rejection (RR 0.87, 95% CI 0.67 to 1.13; 8 studies), and CMV infection (RR 1.42, 95% CI 0.78 to 2.60; 5 studies) (moderate certainty evidence); and may make little or no difference to wound complications (RR 0.95, 95% CI 0.53 to 1.71; 3 studies), malignancies (RR 1.04, 95% CI 0.36 to 3.04; 7 studies), and the need to change treatments (RR 1.18, 95% CI 0.58 to 2.42; 5 studies) (low certainty evidence). Lower dose of TOR‐I compared with higher doses probably makes little or no difference to death (RR 0.84, 95% CI 0.67 to 1.06; 13 studies), graft loss censored for death (RR 0.92, 95% CI 0.71 to 1.19; 12 studies), biopsy‐proven acute rejection (RR 1.26, 95% CI 1.10 to 1.43; 11 studies), CMV infection (RR 0.87, 95% CI 0.63 to 1.21; 9 studies), wound complications (RR 0.92, 95% CI 0.66 to 1.29; 7 studies), and malignancy (RR 0.84, 95% CI 0.54 to 1.32; 10 studies) (moderate certainty evidence); and may make little or no difference to the need to change treatments (RR 0.91, 95% CI 0.78 to 1.05; 10 studies) (low certainty evidence). It is uncertain whether sirolimus and everolimus differ in their effects on kidney function and lipid levels because the certainty of the evidence is very low based on a single small study with only three months of follow‐up. Authors' conclusions In studies with follow‐up to three years, TOR‐I with an antimetabolite increases the risk of graft loss and acute rejection compared with CNI and an antimetabolite. TOR‐I with CNI potentially offers an alternative to an antimetabolite with CNI as rates of graft loss and acute rejection are similar between interventions and TOR‐I regimens are associated with a reduced risk of CMV infections. Wound complications and the need to change immunosuppressive medications are higher with TOR‐I regimens. While further new studies are not required, longer‐term follow‐up data from participants in existing methodologically robust RCTs are needed to determine how useful immunosuppressive regimens, which include TOR‐I, are in maintaining kidney transplant function and survival beyond three years

Pretest probability assessment derived from attribute matching

BACKGROUND: Pretest probability (PTP) assessment plays a central role in diagnosis. This report compares a novel attribute-matching method to generate a PTP for acute coronary syndrome (ACS). We compare the new method with a validated logistic regression equation (LRE). METHODS: Eight clinical variables (attributes) were chosen by classification and regression tree analysis of a prospectively collected reference database of 14,796 emergency department (ED) patients evaluated for possible ACS. For attribute matching, a computer program identifies patients within the database who have the exact profile defined by clinician input of the eight attributes. The novel method was compared with the LRE for ability to produce PTP estimation <2% in a validation set of 8,120 patients evaluated for possible ACS and did not have ST segment elevation on ECG. 1,061 patients were excluded prior to validation analysis because of ST-segment elevation (713), missing data (77) or being lost to follow-up (271). RESULTS: In the validation set, attribute matching produced 267 unique PTP estimates [median PTP value 6%, 1(st)–3(rd )quartile 1–10%] compared with the LRE, which produced 96 unique PTP estimates [median 24%, 1(st)–3(rd )quartile 10–30%]. The areas under the receiver operating characteristic curves were 0.74 (95% CI 0.65 to 0.82) for the attribute matching curve and 0.68 (95% CI 0.62 to 0.77) for LRE. The attribute matching system categorized 1,670 (24%, 95% CI = 23–25%) patients as having a PTP < 2.0%; 28 developed ACS (1.7% 95% CI = 1.1–2.4%). The LRE categorized 244 (4%, 95% CI = 3–4%) with PTP < 2.0%; four developed ACS (1.6%, 95% CI = 0.4–4.1%). CONCLUSION: Attribute matching estimated a very low PTP for ACS in a significantly larger proportion of ED patients compared with a validated LRE

Alternative Mechanisms for Tn5 Transposition

Bacterial transposons are known to move to new genomic sites using either a replicative or a conservative mechanism. The behavior of transposon Tn5 is anomalous. In vitro studies indicate that it uses a conservative mechanism while in vivo results point to a replicative mechanism. To explain this anomaly, a model is presented in which the two mechanisms are not independent—as widely believed—but could represent alternate outcomes of a common transpositional pathway

Just-in-Time Information Improved Decision-Making in Primary Care: A Randomized Controlled Trial

BACKGROUND: The "Just-in-time Information" (JIT) librarian consultation service was designed to provide rapid information to answer primary care clinical questions during patient hours. This study evaluated whether information provided by librarians to answer clinical questions positively impacted time, decision-making, cost savings and satisfaction. METHODS AND FINDING: A randomized controlled trial (RCT) was conducted between October 2005 and April 2006. A total of 1,889 questions were sent to the service by 88 participants. The object of the randomization was a clinical question. Each participant had clinical questions randomly allocated to both intervention (librarian information) and control (no librarian information) groups. Participants were trained to send clinical questions via a hand-held device. The impact of the information provided by the service (or not provided by the service), additional resources and time required for both groups was assessed using a survey sent 24 hours after a question was submitted. The average time for JIT librarians to respond to all questions was 13.68 minutes/question (95% CI, 13.38 to 13.98). The average time for participants to respond their control questions was 20.29 minutes/question (95% CI, 18.72 to 21.86). Using an impact assessment scale rating cognitive impact, participants rated 62.9% of information provided to intervention group questions as having a highly positive cognitive impact. They rated 14.8% of their own answers to control question as having a highly positive cognitive impact, 44.9% has having a negative cognitive impact, and 24.8% with no cognitive impact at all. In an exit survey measuring satisfaction, 86% (62/72 responses) of participants scored the service as having a positive impact on care and 72% (52/72) indicated that they would use the service frequently if it were continued. CONCLUSIONS: In this study, providing timely information to clinical questions had a highly positive impact on decision-making and a high approval rating from participants. Using a librarian to respond to clinical questions may allow primary care professionals to have more time in their day, thus potentially increasing patient access to care. Such services may reduce costs through decreasing the need for referrals, further tests, and other courses of action. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN96823810