Pfizer, UK National Institute for Health Research Biomedical Research Centre.

We conducted a preregistered multilaboratory project ( k = 36; N = 3,531) to assess the size and robustness of ego-depletion effects using a novel replication method, termed the paradigmatic replication approach. Each laboratory implemented one of two procedures that was intended to manipulate self-control and tested performance on a subsequent measure of self-control. Confirmatory tests found a nonsignificant result ( d = 0.06). Confirmatory Bayesian meta-analyses using an informed-prior hypothesis (δ = 0.30, SD = 0.15) found that the data were 4 times more likely under the null than the alternative hypothesis. Hence, preregistered analyses did not find evidence for a depletion effect. Exploratory analyses on the full sample (i.e., ignoring exclusion criteria) found a statistically significant effect ( d = 0.08); Bayesian analyses showed that the data were about equally likely under the null and informed-prior hypotheses. Exploratory moderator tests suggested that the depletion effect was larger for participants who reported more fatigue but was not moderated by trait self-control, willpower beliefs, or action orientation.

Background: Both coplanar and noncoplanar polychlorinated biphenyls (PCBs) exhibit neurotoxic effects in animal studies, but individual congeners do not always produce the same effects as PCB mixtures. Humans genetically have > 60-fold differences in hepatic cytochrome P450 1A2 (CYP1A2)-uninduced basal levels and > 12-fold variability in aryl hydrocarbon receptor (AHR)affinity; because CYP1A2 is known to sequester coplanar PCBs and because AHR ligands include coplanar PCBs, both genotypes can affect PCB response.Objectives: We aimed to develop a mouse paradigm with extremes in Cyp1a2 and Ahr genotypes to explore genetic susceptibility to PCB-induced developmental neurotoxicity using an environmentally relevant mixture of PCBs.Methods: We developed a mixture of eight PCBs to simulate human exposures based on their reported concentrations in human tissue, breast milk, and food supply. We previously characterized specific differences in PCB congener pharmacokinetics and toxicity, comparing high-affinity–AHR Cyp1a2 wild-type [Ahrb1_Cyp1a2(+/+)], poor-affinity–AHR Cyp1a2 wild-type [Ahrd_Cyp1a2(+/+)], and high-affinity–AHR Cyp1a2 knockout [Ahrb1_Cyp1a2(–/–)] mouse lines [Curran CP, Vorhees CV, Williams MT, Genter MB, Miller ML, Nebert DW. 2011. In utero and lactational exposure to a complex mixture of polychlorinated biphenyls: toxicity in pups dependent on the Cyp1a2 and Ahr genotypes. Toxicol Sci 119:189–208]. Dams received a mixture of three coplanar and five noncoplanar PCBs on gestational day 10.5 and postnatal day (PND) 5. In the present study we conducted behavioral phenotyping of exposed offspring at PND60, examining multiple measures of learning, memory, and other behaviors.Results: We observed the most significant deficits in response to PCB treatment in Ahrb1_Cyp1a2(–/–) mice, including impaired novel object recognition and increased failure rate in the Morris water maze. However, all PCB-treated genotypes showed significant differences on at least one measure of learning or behavior.Conclusions: High levels of maternal hepatic CYP1A2 offer the most important protection against deficits in learning and memory in offspring exposed to a mixture of coplanar and noncoplanar PCBs. High-affinity AHR is the next most important factor in protection of offspring.

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Purpose: The UK Glaucoma Treatment Study (UKGTS) demonstrated the effectiveness of an intraocular pressurelowering drug in patients with glaucoma using visual field progression as a primary outcome. We now test the hypothesis that responses on patient reported outcome measures (PROMs-secondary outcome measure) differ between patients receiving a topical prostaglandin analogue (Latanoprost) or placebo eye drops in UKGTS. Design: Multi-centre, randomised, triple-masked, placebo-controlled trial. Participants: Newly diagnosed glaucoma patients recruited into the UKGTS with baseline and exit PROM data (n= 182 and n=168 patients from the treatment and placebo group, respectively). Methods: The UKGTS was a multi-centre, randomised, triple-masked, placebo-controlled trial, where patients with newly diagnosed open angle glaucoma were allocated to receive Latanoprost (treatment) or placebo (trial registration number: ISRCTN96423140); the observation period was 24 months. Patients completed general health PROMs (EQ-5D and SF-36) and PROMs specific to glaucoma (GQL-15 and GAL-9) at baseline and at exit from the trial. Percentage change between baseline and exit measurement on PROMs were calculated for each patient and compared between treatment arms. In addition, differences between stable patients (n=272) and those with glaucomatous progression (n=78), as determined by visual field change (primary outcome), were assessed. Main Outcome Measure: PROMs on health-related and vision-related quality of life. Results: Average percentage change on PROMs was similar for patients in both arms of the trial with no statistically significant differences between treatment and placebo groups (EQ-5D, p = 0.98; EQ-5D VAS, p = 0.88; SF-36, p = 0.94, GQL-15, p = 0.66; GAL-9, p = 0.87). There were statistically significant differences between stable and progressing patients, as determined by visual fields, on glaucoma-specific PROMs (GQL-15, p = 0.02; GAL-9, p = 0.02) but not on general health PROMs (EQ-5D, p = 0.62; EQ-5D VAS, p = 0.23; SF-36, p = 0.65) Conclusions: Average change in PROMs on health-related and visionrelated quality of life was similar for the treatment and placebo group in the UKGTS. PROMs, specifically those used in the UKGTS, may not be sensitive enough to be used as a primary endpoint in clinical trials when participants have newly diagnosed early stage glaucoma. Taxonomy Patient-Reported Outcome, Glaucoma

The terms "Oracle Problem" and "Non-testable system" interchangeably refer to programs in which the application of test oracles is infeasible. Test oracles are an integral part of conventional testing techniques; thus, such techniques are inoperable in these programs. The prevalence of the oracle problem has inspired the research community to develop several automated testing techniques that can detect functional software faults in such programs. These techniques include N-Version testing, Metamorphic Testing, Assertions, Machine Learning Oracles, and Statistical Hypothesis Testing. This paper presents a Mapping Study that covers these techniques. The Mapping Study presents a series of discussions about each technique, from different perspectives, e.g. effectiveness, efficiency, and usability. It also presents a comparative analysis of these techniques in terms of these perspectives. Finally, potential research opportunities within the non-testable systems problem domain are highlighted within the Mapping Study. We believe that the aforementioned discussions and comparative analysis will be invaluable for new researchers that are attempting to familiarise themselves with the field, and be a useful resource for practitioners that are in the process of selecting an appropriate technique for their context, or deciding how to apply their selected technique. We also believe that our own insights, which are embedded throughout these discussions and the comparative analysis, will be useful for researchers that are already accustomed to the field. It is our hope that the potential research opportunities that have been highlighted by the Mapping Study will steer the direction of future research endeavours.

Objectives: To determine the incidence and rates of progression of gingivitis and periodontitis in Labrador retrievers.Materials and MethOds: Fifty-three dogs, aged 1·1 to 5·9 years, had their periodontal health assessed every 6 months for up to 2 years. The extent of gingivitis and periodontitis was measured around the whole gingival margin of every tooth under general anaesthesia.results: All dogs had gingivitis at the initial assessment. The majority (64·2%) of tooth aspects had very mild gingivitis. The palatal/lingual aspect of all tooth types was most likely to show bleeding when probed: 63·0% of these aspects had mild or moderate gingivitis. Over 2 years, 56·6% of dogs developed periodontitis and dogs as young as 1·9 years were affected. There was a significant positive correlation between the proportion of teeth with periodontitis and age. In total, 124 teeth (5·7%) developed periodontitis; 88 (71·0%) of these were incisors. The palatal/lingual aspect of the incisors developed the disease first (2·8% of incisor aspects).clinical significance: Periodontitis developed in regions that are difficult to see in conscious dogs implying that detection and treatment of disease requires periodic sedation or anaesthesia.

Organisms using oxygen for aerobic respiration require antioxidants to balance the production of reactive oxygen species during metabolic processes. Various species -including humans and other primates -suffer mutations in the GULO gene encoding L-gulono-γ -lactone oxidase; GULO is the rate-limiting enzyme in the biosynthesis of ascorbate, an important cellular antioxidant. Animals lacking the ability to synthesize vitamin C develop scurvy without dietary supplementation. The Gulo(−/−) knockout (KO) mouse requires oral supplemental vitamin C; without this supplementation the animal dies with a scorbutic condition within several weeks. Vitamin C is known to be most abundant in the brain, where it is believed to play important roles in neuroprotection, neurotransmission and neuromodulation. We therefore hypothesized that ascorbate deficiency in Gulo(−/−) KO mice might lead to an abnormal behavioral phenotype. We established the amount of ascorbate in the drinking water (220 ppm) necessary for generating a chronic low-ascorbate status in the brain, yet clinically the mice appeared healthy throughout 100 days postpartum at which time all behavioral-phenotyping tests were completed. Compared with Gulo(+/+) wild-type littermates, ascorbate-deficient Gulo(−/−) mice were found to be less active in moving in their environment; when in water, these mice swam more slowly in some tests, consistent with a mild motor deficit. We found no evidence of cognitive, anxiety or sensorimotor-gating problems. Despite being less active, Gulo(−/−) mice exhibited exaggerated hyperactivity to the dopaminergic agonist methamphetamine. The subnormal movement, combined with hypersensitivity to a dopamine agonist, point to developmental ascorbate deficiency causing long-term striatal dysfunction.