Visual conditions affecting eye growth alter diurnal levels of vitreous DOPAC.

In chicks, the diurnal patterns of retinal dopamine synthesis and release are associated with refractive development. To assess the within-day patterns of dopamine release, we assayed vitreal levels of DOPAC (3,4-dihydroxyphenylacetic acid) using high performance liquid chromatography with electrochemical detection, at 4-h intervals over 24 h in eyes with experimental manipulations that change ocular growth rates. Chicks were reared under a 12 h light/12 h dark cycle; experiments began at 12 days of age. Output was assessed by modelling using the robust variance structure of Generalized Estimating Equations. Continuous spectacle lensdefocus or form deprivation: One group experienced non-restricted visual input to both eyes and served as untreated "normal" controls. Three experimental cohorts underwent monocular visual alterations known to alter eye growth and refraction: wearing a diffuser, a negative lens or a positive lens. After one full day of device-wear, chicks were euthanized at 4-h intervals over 24 h (8 birds per time/condition). Brief hyperopic defocus: Chicks wore negative lenses for only 2 daily hours either in the morning (starting at ZT 0; n = 16) or mid-day (starting at ZT 4; n = 8) for 3 days. Vitreal DOPAC was assayed. In chicks with bilateral non-restricted vision, or with continuous defocus or form-deprivation, there was a diurnal variation in vitreal DOPAC levels for all eyes (p < 0.001 for each). In normal controls, DOPAC was highest during the daytime, lowest at night, and equivalent for both eyes. In experimental groups, regardless of whether experiencing a growth stimulatory input (diffuser; negative lens) or growth inhibitory input (positive lens), DOPAC levels were reduced compared both to fellow eyes and to those of normal controls (p < 0.001 for each). These diurnal variations in vitreous DOPAC levels under different visual conditions indicate a complexity for dopaminergic mechanisms in refractive development that requires further study.

Brivaracetam efficacy and tolerability in clinical practice: A UK-based retrospective multicenter service evaluation.

PURPOSE: This multicenter service evaluation explores the efficacy and tolerability of brivaracetam (BRV) in an unselected, consecutive population in 'real-life' clinical settings. METHOD: We retrospectively collected data from patient records at 11 UK hospitals and epilepsy centers. Consecutive patients prescribed BRV with at least 3 months of follow-up (FU) were included. Apart from reporting effectiveness and tolerability of BRV across the whole cohort, we compared treatment outcomes depending on previous levetiracetam use (LEV+ versus LEV-), comorbid learning disability (LD+ versus LD-), and epilepsy syndrome (focal versus generalized epilepsy). RESULTS: Two hundred and ninety patients (46% male, median age: 38 years, range: 15 to 77) with ≥3 months of FU were included. The median duration of BRV exposure was 12 months (range: 1 day to 72 months). Overall BRV retention was 71.1%. While 56.1% of patients improved in terms of seizure frequency category (daily, weekly, monthly, yearly seizures), 23.1% did not improve on this measure and 20.8% deteriorated. In terms of seizure frequency, 21% of patients experienced a ≥50% reduction, with 7.0% of all patients becoming seizure-free. Treatment-emergent adverse events (AEs) were reported by 107 (36.9%) patients, but there were no serious AEs. The commonest AEs were sedation/fatigue (18.3%), mood changes (9.0%), and irritability/aggression (4.8%). There were no significant differences in drug retention, seizure frequency outcomes, or AEs between the LEV+ and LEV- subgroups, or between patients with generalized or focal epilepsies. Although 15.5% of patients in the LD+ group achieved a ≥50% reduction, this rate was lower than in the LD- group. CONCLUSIONS: This 'real-life' evaluation suggests that reductions in seizure frequency can be achieved with BRV in patients with highly refractory epilepsy. Brivaracetam may be a useful treatment option in patients who have previously failed to respond to or tolerate LEV, those with LD, or (off-label) those with generalized epilepsies.

Epilepsy and music: practical notes.

Music processing occurs via a complex network of activity far beyond the auditory cortices. This network may become sensitised to music or may be recruited as part of a temporal lobe seizure, manifesting as either musicogenic epilepsy or ictal musical phenomena. The idea that sound waves may directly affect brain waves has led researchers to explore music as therapy for epilepsy. There is limited and low quality evidence of an antiepileptic effect with the Mozart Sonata K.448. We do not have a pathophysiological explanation for the apparent dichotomous effect of music on seizures. However, clinicians should consider musicality when treating patients with antiepileptic medication or preparing patients for epilepsy surgery. Carbamazepine and oxcarbazepine each may cause a reversible altered appreciation of pitch. Surgical cohort studies suggest that musical memory and perception may be affected, particularly following right temporal lobe surgery, and discussion of this risk should form part of presurgical counselling.

Vocabulary knowledge and reading comprehension account for SES-differences in how school-aged children infer word meanings from sentences.

Socioeconomic status (SES)-related language gaps are known to widen throughout the course of the school years; however, not all children from lower SES homes perform worse than their higher SES peers on measures of language. The current study uses mediation and moderated mediation to examine how cognitive and language abilities (vocabulary, reading, phonological processing, working memory) account for individual differences in a children's ability to infer a novel word's meaning, a key component in word learning, in school-aged children from varying SES backgrounds. Vocabulary and reading comprehension mediated the relationship between SES and accuracy when inferring word meanings. The relationship between SES, vocabulary, and inferring word meaning was moderated by age, such that the influence of vocabulary on task performance was strongest in young children. The reading pathway did not interact with age effects, indicating reading is an important contributor to SES-related differences in how children infer a word's meaning throughout grade school. These findings highlight different paths by which children's trajectories for inferring word meanings may be impacted.

Considerations for realistic atmospheric environments: An application to corrosion testing.

Measured salt compositions in dust collected over roughly the last decade from surfaces of in-service stainless-steel alloys at four locations around the United States are presented, along with the predicted brine compositions that would result from deliquescence of these salts. The salt compositions vary greatly from ASTM seawater and from laboratory salts (i.e., NaCl or MgCl2) commonly used on corrosion testing. The salts contained relatively high amounts of sulfates and nitrates, evolved to basic pH values, and exhibited deliquescence relative humidity values (RH) higher than seawater. Additionally, inert dust in components were quantified and considerations for laboratory testing are presented. The observed dust compositions are discussed in terms of the potential corrosion behavior and are compared to commonly used accelerated testing protocols. Finally, ambient weather conditions and their influence on diurnal fluctuations in temperature (T) and RH on heated metal surfaces are evaluated and a relevant diurnal cycle for laboratory testing a heated surface has been developed. Suggestions for future accelerated tests are proposed that include exploration of the effects of inert dust particles on atmospheric corrosion, chemistry considerations, and realistic diurnal fluctuations in T and RH. Understanding mechanisms in both realistic and accelerated environments will allow development of a corrosion factor (i.e., scaling factor) for the extrapolation of laboratory-scale test results to real world applications.

Barriers and facilitators to conducting radiotherapy clinical trials: Findings from a UK survey.

INTRODUCTION: As an essential component of service delivery, radiotherapy clinical trials were championed within the NHS England service specifications. A call for a 15% increase in research and clinical trial activity, alongside a demand for equity of access for patients with cancer subsequently ensued. National understanding of current radiotherapy clinical trials operational practices is absent, but essential to help establish the current provision required to support the development of a strategic plan for implementation of NHS England's specifications. METHODS: A cross-sectional survey was developed by a multi-disciplinary team and distributed to therapeutic radiography clinical trial leads across the UK to ascertain the current provision of radiotherapy clinical trials only, including workforce resources and the trials management processes to establish a benchmark and identify potential barriers, enablers, and opportunities to increase access to clinical trials. RESULTS: Thirty-two complete responses were obtained equating to 49% of the total UK NHS departments and 74% of those departments invited. Four key findings were identified: 1) research strategy and systems, 2) participation and activity in radiotherapy clinical trials, 3) access to clinical trials at alternative departments and 4) facilitators & barriers. Overarchingly a lack of radiotherapy clinical trials strategy or supported processes were apparent across the UK, aggravating existing barriers to trial activity. CONCLUSION: It is essential for radiotherapy clinical trials to be embedded in to departmental and Trust strategy, this will help to ensure the processes and resources required for trial delivery are not only in place, but also recognised as imperative and important for patients with cancer as radiotherapy treatment delivery. IMPLICATIONS FOR PRACTICE: Failure to address the barriers or build upon the facilitators may result in UK radiotherapy departments facing challenges in achieving the 15% increase in radiotherapy clinical trial activity.

Neural oscillations reveal differences in the process of word learning among school-aged children from lower socioeconomic status backgrounds.

Building a robust vocabulary in grade school is essential for academic success. Children from lower socioeconomic status (SES) households on average perform below their higher SES peers on word learning tasks, negatively impacting their vocabulary; however, significant variability exists within this group. Many children from low SES homes perform as well as, or better than, their higher SES peers on measures of word learning. The current study addresses what processes underlie this variability, by comparing the neural oscillations of 44 better versus worse word learners (ages 8-15 years) from lower SES households as they infer the meaning of unknown words. Better word learners demonstrated increases in theta and beta power as a word was learned, whereas worse word learners exhibited decreases in alpha power. These group differences in neural oscillatory engagement during word learning indicate there may be different strategies employed based on differences in children's skills. Notably, children with greater vocabulary knowledge are more likely to exhibit larger beta increases; a strategy which is associated with better word learning. This sheds new light on the mechanisms that support word learning in children from low SES households.

The changing incidence of childhood-onset type 1 diabetes in Wales: Effect of gender and season at diagnosis and birth.

AIMS: Determinants of the changing incidence of childhood-onset type 1 diabetes remain uncertain. We determined the recent time-trend of type 1 diabetes incidence in Wales and explored the role of vitamin D by evaluating the influence of season both at diagnosis and at birth. METHODS: Data from all Welsh paediatric units 1990-2019, and from primary care to determine ascertainment. RESULTS: Log-linear modelling indicated a non-linear secular trend in incidence with peak and subsequent decline. The peak occurred around June 2010: 31∙3 cases/year/100,000 children aged < 15y. It occurred earlier in children younger at diagnosis and earlier in boys. There were more cases in males aged <2y and >12y but more in females aged 9-10 y. More were diagnosed in winter. Also, children born in winter had less risk of future diabetes. CONCLUSIONS: The risk of developing type 1 diabetes before age 15y in Wales is no longer increasing. The data on season are consistent with a preventative role for vitamin D both during pregnancy and later childhood. Metereological Office data shows increasing hours of sunlight since 1980 likely to increase vitamin D levels with less diabetes. Additional dietary supplementation with vitamin D might further reduce the incidence of type 1 diabetes.

Meta-regression with partial information on summary trial or patient characteristics.

We present a model for meta-regression in the presence of missing information on some of the study level covariates, obtaining inferences using Bayesian methods. In practice, when confronted with missing covariate data in a meta-regression, it is common to carry out a complete case or available case analysis. We propose to use the full observed data, modelling the joint density as a factorization of a meta-regression model and a conditional factorization of the density for the covariates. With the inclusion of several covariates, inter-relations between these covariates are modelled. Under this joint likelihood-based approach, it is shown that the lesser assumption of the covariates being Missing At Random is imposed, instead of the more usual Missing Completely At Random (MCAR) assumption. The model is easily programmable in WinBUGS, and we examine, through the analysis of two real data sets, sensitivity and robustness of results to the MCAR assumption.

General health complaints and sleep associated with new injury within an endurance sporting population: A prospective study.

OBJECTIVES: To examine the association between subjective health complaints, sleep quantity and new injury within an endurance sport population. DESIGN: Prospective cohort study. METHODS: Ninety-five endurance sporting participants were recruited from running, triathlon, swimming, cycling and rowing disciplines. Over 52-week period participants submitted weekly data regarding subjective health complaints (SHCs) (cardiorespiratory, gastrointestinal and psychological/lifestyle), sleep quantity, training load and new injury episodes. Applying a 7- and 14-day lag period, a shared frailty model was used to explore new injury risk associations with total SHCs and sleep quantity. RESULTS: 92.6% of 95 participants completed all 52 weeks of data submission and the remainder of the participants completed ≥30 weeks. Seven-day lag psychological/lifestyle SHCs were significantly associated with new injury risk (Hazard ratio (HR)=1.32; CI 95%=1.01-1.72, p<0.04). In contrast, cardiorespiratory (HR=1.15; CI 95%=0.99-1.36, p=0.07) and gastrointestinal (HR=0.77; CI 95%=0.56-1.05, p=0.09) SHCs were not significantly associated with new injury risk. New injury risk had a significant increased association with 14-day lag <7h/day sleep quantity (HR=1.51; CI 95%=2.02-1.13, p<0.01) and a significant decreased association with >7h/day sleep quantity (HR=0.63, CI 95%=0.45-0.87, p<0.01. A secondary regression analysis demonstrated no significant association with total SHCs and training load factors (Relative Risk (RR)=0.08, CI 95%=0.04-0.21, p=0.20). CONCLUSIONS: To minimise an increased risk of new injuries within an endurance sporting population, this study demonstrates that psychological/lifestyle subjective health complaints and sleep quantity should be considered. The study also highlights a lag period between low sleep quantity and its subsequent impact on new injury risk. No association was demonstrated between subjective health complaints, sleep quantity and training load factors.

Vision related quality of life in multiple sclerosis: correlation with new measures of low and high contrast letter acuity.

OBJECTIVE: To examine the relation between low contrast letter acuity, a new visual function test for multiple sclerosis (MS) trials, and vision targeted health related quality of life (HRQOL). METHODS: Patients in this cross sectional study were part of an ongoing investigation of visual function in MS. Patients were tested binocularly using low contrast letter acuity and Early Treatment Diabetic Retinopathy Study (ETDRS) visual acuity (VA) charts. The 25 Item National Eye Institute Visual Functioning Questionnaire (NEI-VFQ-25), 10 Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25, Impact of Visual Impairment Scale and Short Form 36 Health Survey (SF-36) were administered. RESULTS: Among 167 patients, mean age was 48 (10) years, with median Expanded Disability Status Scale (EDSS) 2.0 (range 1.0-7.5), and median binocular Snellen acuity equivalent (ETDRS charts) 20/16 (range 20/12.5 to 20/100). Reductions in vision specific HRQOL were associated with lower (worse) scores for low contrast letter acuity and VA (p<0.001, linear regression, accounting for age). Two line differences in visual function were associated, on average, with >4 point (6.7-10.9 point) worsening in the NEI-VFQ-25 composite score, reductions that are considered clinically meaningful. Scores for the 10 Item Neuro-Ophthalmic Supplement to the NEI-VFQ-25 also correlated well with visual function. Associations between reduced low contrast acuity and worse vision targeted HRQOL remained significant in models accounting for high contrast VA, EDSS and history of acute optic neuritis. CONCLUSIONS: Low contrast letter acuity scores correlate well with HRQOL in MS. Two line differences in scores for low contrast acuity and VA reflect clinically meaningful differences in vision targeted HRQOL. Low contrast acuity testing provides information on patient reported aspects of vision, supporting use of these measures in MS clinical trials.

Anaesthesia for an adult with Angelman syndrome.

Angelman syndrome is a complex genetic condition involving abnormalities of chromosome 15 in the majority of cases. These defects involve a gene encoding an ubiquitin protein ligase and may be associated with abnormal gamma-aminobutyric acid (GABA)(A) receptor subunits. Angelman syndrome may have profound implications for anaesthesia: potential exists for airway difficulties; refractory bradyarrythmias; and pharmacodynamic unpredictability. A case of an adult with Angelman syndrome undergoing dental work under general anaesthesia is presented. Induction and maintenance of anaesthesia was unremarkable but emergence was complicated by generalised muscular hypertonia and temporary respiratory embarrassment which resolved spontaneously.

The HIV-1 protease substitution K55R: a protease-inhibitor-associated substitution involved in restoring viral replication.

OBJECTIVES: The identification and in vitro characterization of novel protease mutations strongly associated with known protease resistance mutations. METHODS: The association between pairs of protease amino acid substitutions was identified using a database of protease sequences derived from protease inhibitor-experienced patients (n = 803). In vitro characterization included drug susceptibility and viral replication studies performed on recombinant viruses harbouring site-directed mutations. RESULTS: The K55R mutation, which is not a natural polymorphism, was identified to be strongly associated with protease mutations M46I/L and to a lesser extent L24I, I54V and V82A/T/S/F. In vitro characterization of the K55R substitution indicated a primary role for this substitution in increasing replicative capacity in the presence of specific protease mutations. CONCLUSIONS: The K55R mutation is a secondary drug resistance mutation that can improve viral replication capacity in the presence of other primary protease mutations.

Reporting and analysis of open-label extension studies of anti-epileptic drugs.

PURPOSE: Open-label extension studies, or follow-on randomised controlled trials (FORCTs) are widely believed to be prone to patient selection biases which may inflate effect estimates. This study investigates the reporting and analysis of efficacy outcomes in FORCTs and critically evaluates the associated underlying assumptions. We propose an alternative method of analysis, in line with that recommended in the analysis of RCTs, the intention to treat (ITT) approach, in which it is assumed that all patients who discontinue treatment are non-responders. METHODS: A systematic review of FORCTs and randomised controlled trials (RCT) of topiramate, levetiracetam and gabapentin as adjuvant therapy in refractory adult epilepsy was conducted. Sample sizes and numbers of responders, along with reported outcomes were extracted. To evaluate the feasibility of the assumptions underlying the various methods of analysis, the most common causes of discontinuation were evaluated. For each FORCT, we compared the reported outcome to the proposed ITT analysis. RESULTS: The 10 FORCT reports identified all excluded from the analysis patients who dropped out of the RCT. Adverse events or inefficacy were the main reasons for treatment discontinuation. Analysis based on the ITT method, led to smaller effect estimates than those reported. For example, a FORCT of levetiracetam reported a responder rate of 43%, which reduced to 28% under an ITT analysis, comparable to an ITT analysis outcome of 26% for the parent RCT. CONCLUSIONS: FORCTs can provide important information about long-term efficacy and tolerability of newer therapies. However, current reporting methods are likely to be misleading as outcomes are reported for the subset of patients continuing with treatment at the end of the FORCT. Since the majority of patients who discontinue treatment do so for reasons associated with inefficacy, an analysis based on the ITT approach more closely reflects the outcomes of the patients.

Overwhelming heterogeneity in systematic reviews of observational anti-epileptic studies.

PURPOSE: Observational studies may provide important information on the long-term effects of treatments for epilepsy, but systematic reviews of observational studies may be more prone to heterogeneity and biases. These issues were investigated in a systematic review of non-randomised add-on anti-epileptic drug studies. METHODS: Searches of MEDLINE (1966-2006), EMBASE (1974-2006), CINAHL (1982-2006), the Cochrane database of systematic reviews, the Cochrane Controlled Trials register, the DARE database and hand-searching congress proceedings were conducted. Randomised controlled trials, follow-on randomised controlled trials and prospective and retrospective cohort studies of gabapentin, topiramate, or levetiracetam as add-on therapy in adults (>12 years old) were identified. Outcomes were 50% responders and proportion seizure free. RESULTS: Thirty-eight non-randomised gabapentin studies, 82 topiramate and 84 levetiracetam studies were identified. There was marked heterogeneity of effect estimates from observational studies which prohibited the pooling of estimates in random effects models. Median effect estimates were larger and more varied for observational studies than randomised placebo-controlled trials (RCTs). For example, the median value (10th and 90th percentile) for 50% responders for gabapentin was 36% (15 and 71%) compared to 23% (19 and 38%) for gabapentin RCTs. Patient and study covariates in meta-regression models could not explain the vast heterogeneity. Publication bias was evident and a sensitivity analysis, allowing for the effects of publication bias, showed that effect estimates could increase by up to 6% for seizure freedom rates. DISCUSSION: Reports of observational anti-epileptic studies give limited information on patient selection and characteristics. Systematic reviews of observational studies are prone to significant heterogeneity and bias which cannot adequately be explained by reported study characteristics. Reporting standards for observational studies of anti-epileptic drugs could be improved by following guidelines for reporting non-randomised studies of interventions.

A metabolomic comparison of urinary changes in type 2 diabetes in mouse, rat, and human.

Type 2 diabetes mellitus is the result of a combination of impaired insulin secretion with reduced insulin sensitivity of target tissues. There are an estimated 150 million affected individuals worldwide, of whom a large proportion remains undiagnosed because of a lack of specific symptoms early in this disorder and inadequate diagnostics. In this study, NMR-based metabolomic analysis in conjunction with multivariate statistics was applied to examine the urinary metabolic changes in two rodent models of type 2 diabetes mellitus as well as unmedicated human sufferers. The db/db mouse and obese Zucker (fa/fa) rat have autosomal recessive defects in the leptin receptor gene, causing type 2 diabetes. 1H-NMR spectra of urine were used in conjunction with uni- and multivariate statistics to identify disease-related metabolic changes in these two animal models and human sufferers. This study demonstrates metabolic similarities between the three species examined, including metabolic responses associated with general systemic stress, changes in the TCA cycle, and perturbations in nucleotide metabolism and in methylamine metabolism. All three species demonstrated profound changes in nucleotide metabolism, including that of N-methylnicotinamide and N-methyl-2-pyridone-5-carboxamide, which may provide unique biomarkers for following type 2 diabetes mellitus progression.

Vinca alkaloids inhibit conversion of arachidonic acid to thromboxane by human platelet microsomes: comparison with other microtubule-active drugs.

The Vinca alkaloid vinblastine causes dose-dependent inhibition of malondialdehyde formation and aggregation in activated human platelets as a result of inhibition of arachidonic acid metabolism via the thromboxane pathway (Brammer, J.P., Kerecsen, L. and Maguire, M.H. (1982) Eur. J. Pharmacol. 81, 577). The nature of the inhibition by vinblastine has been investigated with human platelet microsomes, measuring conversion of arachidonic acid to malondialdehyde and thromboxane B2 via spectrophotometric assay and RIA, respectively, determining arachidonate oxygenation by monitoring oxygen consumption, and identifying metabolites formed from [1-14C]arachidonic acid. Vinblastine was compared with other Vinca alkaloids and with structurally unrelated microtubule-active drugs. Vinca alkaloids were unique in causing dose-dependent inhibition of both malondialdehyde and thromboxane B2. Order of potency was vinblastine = vincristine = vindesine greater than leurosine greater than vinepidine. Inhibition of malondialdehyde and thromboxane B2 by 50 microM vinblastine was at least 60%. Microsomal cyclooxygenase was not inhibited by 200 microM vinblastine. Inhibition by vinblastine of [1-14C]arachidonic acid conversion to thromboxane B2 was associated with a 4-fold increase in prostaglandin E2 formation. Thromboxane B2, but not malondialdehyde, formation was inhibited by colchicine less than nocodazole much less than vinblastine. Results indicate that microsomal thromboxane synthetase is inhibited by Vinca alkaloids and other tubulin-binding drugs, and suggest that the action of vinblastine in inhibiting thromboxane synthesis, aggregation and release in intact platelets is not dependent upon its antimicrotubular actions.