Using the A/T/N framework to examine driving in preclinical Alzheimer’s disease

The A/T/N classification system is the foundation of the 2018 NIA-AA Research Framework and is intended to guide the Alzheimer disease (AD) research agenda for the next 5–10 years. Driving is a widespread functional activity that may be particularly useful in investigation of functional changes in pathological AD before onset of cognitive symptoms. We examined driving in preclinical AD using the A/T/N framework and found that the onset of driving difficulties is most associated with abnormality of both amyloid and tau pathology, rather than amyloid alone. These results have implications for participant selection into clinical trials and for the application time of interventions aimed at prolonging the time of safe driving among older adults with preclinical AD

Deep anterior lamellar keratoplasty versus penetrating keratoplasty for treating keratoconus

Published version made available following 12 month embargo from date of publication (22 July 2014) in accordance with publisher copyright policy.BACKGROUND: Keratoconus is an ectatic (weakening) disease of the cornea, which is the clear surface at the front of the eye. Approximately 10% to 15% of patients diagnosed with keratoconus require corneal transplantation. This may be full-thickness (penetrating) or partial-thickness (lamellar). OBJECTIVES: To compare visual outcomes after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty for keratoconus, and to compare additional outcomes relating to factors which may contribute to poor visual outcomes (e.g. astigmatism, graft rejection and failure). SEARCH METHODS: We searched a number of electronic databases including CENTRAL, PubMed and EMBASE without using any date or language restrictions. We last searched the electronic databases on 31 October 2013. We also handsearched the proceedings of several international ophthalmic conferences. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) comparing the outcomes of DALK and penetrating keratoplasty in the treatment of keratoconus. DATA COLLECTION AND ANALYSIS: Two authors assessed trial quality and extracted data independently. For dichotomous data (graft failure, rejection, achievement of functional vision) results were expressed as odds ratios (ORs) and 95% confidence intervals (CIs). For continuous data (postoperative best corrected visual acuity (BCVA), uncorrected visual acuity (UCVA), keratometric astigmatism and spherical equivalent) results were expressed as mean differences (MDs) and 95% CIs. MAIN RESULTS: We identified two completed studies, with a total of 111 participants (n = 30 and n = 81), both conducted in Iran, that met our inclusion criteria. Participants had moderate to severe keratoconus pre-operatively and were randomly allocated to receive either DALK or penetrating keratoplasty. Only one eye of each participant was treated as part of the trials. The smaller study had 12 month follow-up data for all participants. For the larger study, four DALK surgeries had to be abandoned due to technical failure and visual and refractive outcomes were not measured in these participants. Follow-up length for the remaining 77 participants ranged from 6.8 to 36.4 months, with all 77 followed for at least three months post-suture removal. Details of the randomisation procedure were unavailable for the smaller study and so sensitivity analyses were conducted to determine if the results from this study had affected the overall results of the review.Neither of the included studies reported a difference between groups on any of the measures of post-graft visual achievement, keratometric astigmatism or spherical equivalent. A single case of graft failure in a penetrating keratoplasty was reported. No postoperative graft failures were reported in the DALK group of either study.Instances of graft rejection were reported in both groups, in both studies. The majority of these cases were successfully treated with steroids. The data, which related to all cases in each study - given that the four cases that did not go ahead as planned had already technically failed without presence of rejection - showed that rejection was less likely to occur in DALK (odds ratio (OR): 0.33, 95% confidence interval (CI) 0.14 to 0.81, GRADE rating: moderate).Results of the sensitivity analysis indicated that inclusion of the Razmju 2011 study did not bias the results with regards to rejection episodes. While sensitivity analysis showed altered results with regards to failure rates, the data available from the Javadi 2010 study alone had a very wide 95% CI, suggesting an imprecise estimate. Therefore, even after removal of the Razmju 2011 data, it is still difficult to draw conclusions regarding superiority of one technique over another with regards to graft failure.DALK was unable to be completed as planned in four cases and in a further three cases, complications during dissection required further intervention. Other adverse events, of varying severity, were reported in both intervention groups with similar frequency. For both types of surgery, these included postoperative astigmatism, steroid induced ocular hypertension and persistent epithelial defects. In recipients of DALK, one participant had interface neovascularisation (a proliferation of blood vessels where the host and donor cornea come together) and one had wrinkling of Descemet's membrane, the basement membrane separating the corneal stroma from the corneal endothelium. In the penetrating keratoplasty groups, one participant required graft resuturing and one had an atonic pupil, a condition in which the pupil dilates and is non-reactive.Overall, the quality of the evidence was rated as very low to moderate, with methodological limitations, incomplete data analysis and imprecision of findings, as well as high risk of bias in several areas for both studies. AUTHORS' CONCLUSIONS: We found no evidence to support a difference in outcomes with regards to BCVA at three months post-graft or at any of the other time points analysed (GRADE rating: very low). We also found no evidence of a difference in outcomes with regards to graft survival, final UCVA or keratometric outcomes. We found some evidence that rejection is more likely to occur following penetrating keratoplasty than DALK (GRADE rating: moderate). The small number of studies included in the review and methodological issues relating to the two, mean that the overall quality of the evidence in this review is low. There is currently insufficient evidence to determine which technique may offer better overall outcomes - final visual acuity and time to attain this, keratometric stabilisation, risk of rejection or failure, or both, and risk of other adverse events - for patients with keratoconus. Large randomised trials comparing the outcomes of penetrating keratoplasty and DALK in the treatment of keratoconus are needed

Infant Serum and Maternal Milk Vitamin B-12 Are Positively Correlated in Kenyan Infant-Mother Dyads at 1-6 Months Postpartum, Irrespective of Infant Feeding Practice.

BackgroundVitamin B-12 is an essential nutrient required for many functions including DNA synthesis, erythropoiesis, and brain development. If maternal milk vitamin B-12 concentrations are low, infants may face elevated risks of deficiency when exclusively breastfed.ObjectiveWe evaluated cross-sectional associations between infant serum vitamin B-12 concentrations and maternal milk vitamin B-12 concentrations at 1-6 mo postpartum among an unsupplemented population in rural western Kenya, and assessed biological demographic, and dietary characteristics associated with adequate infant serum vitamin B-12.MethodsWe modeled 1) infant serum vitamin B-12 using maternal milk vitamin B-12 concentration with linear regression; and 2) adequate (>220 pmol/L) infant serum vitamin B-12 using hypothesized biological, demographic, and dietary predictors with logistic regression. In both models, we used generalized estimating equations to account for correlated observations at the cluster-level.ResultsThe median (quartile 1, quartile 3) infant serum vitamin B-12 concentration was 276 pmol/L (193, 399 pmol/L) and approximately one-third of infants had serum vitamin B-12 ≤220 pmol/L, indicating that they were vitamin B-12 depleted or deficient. There was a positive correlation between maternal milk and infant serum vitamin B-12 (r = 0.36, P < 0.001) and in multivariable analyses, maternal milk vitamin B-12 concentration was significantly associated with infant serum vitamin B-12 adequacy (P-trend = 0.03).ConclusionsDespite a high prevalence (90%) of maternal milk vitamin B-12 concentrations below the level used to establish the Adequate Intake (<310 pmol/L), there was a low prevalence of infant vitamin B-12 deficiency. We found few factors that were associated with infant vitamin B-12 adequacy in this population, including infant feeding practices, although maternal vitamin B-12 status was not measured. The contribution of maternal milk to infant vitamin B-12 status remains important to quantify across populations, given that maternal milk vitamin B-12 concentration is modifiable with supplementation. This trial was registered at clinicaltrials.gov as NCT01704105

Congenital myasthenic syndrome in Golden Retrievers is associated with a novel COLQ mutation.

BackgroundCongenital myasthenic syndromes (CMSs) are a group of inherited disorders of neuromuscular transmission that may be presynaptic, synaptic, or postsynaptic. Causative mutations have been identified in 4 breeds including the Labrador Retriever, Jack Russell Terrier, Heideterrier, and Danish Pointing Dog.Hypothesis/objectiveClinical and genetic characterization of a neuromuscular disorder in Golden Retriever (GR) puppies.AnimalsFour GR puppies from California were evaluated for generalized muscle weakness beginning at weaning. Biological specimens were collected from the affected puppies, and familial information was obtained. Blood or buccal swabs were obtained from 63 unaffected GRs.MethodsComplete physical, neurological, electrodiagnostic, and histological evaluations and biochemical quantification of muscle acetylcholine receptors were performed. Polymerase chain reaction was used to amplify the 17 exons of COLQ, and sequences were obtained by Sanger sequencing. Variant frequency was assessed in unrelated GRs and a public database.ResultsClinical, neurological, and electrodiagnostic evaluations confirmed a disorder of neuromuscular transmission in a GR family. Sequencing of all exons and splice sites of a primary candidate gene, COLQ, identified a point mutation that predicts an amino acid substitution (G294R). The primary COLQ transcript was absent from affected muscle samples. All affected puppies were homozygous for the mutation, which was not detected outside this GR family or in other breeds.Conclusions and clinical importanceWe confirmed the diagnosis of a CMS in GR puppies and identified a novel COLQ mutation. The COLQ gene encodes the collagenous tail of acetylcholinesterase, the enzyme responsible for termination of skeletal muscle contraction by clearing acetylcholine at the neuromuscular junction. Clinicians and breeders should be aware of this CMS in GR puppies with an early onset of weakness

Hepatic effects of tartrazine (E 102) after systemic exposure are independent of oestrogen receptor interactions in the mouse

Tartrazine is a food colour that activates the transcriptional function of the human oestrogen receptor alpha in an in vitro cell model. Since oestrogens are cholestatic, we hypothesised tartrazine will cause periportal injury to the liver in vivo. To test this hypothesis, tartrazine was initially administered systemically to mice resulting in a periportal recruitment of inflammatory cells, increased serum alkaline phosphatase activity and mild periportal fibrosis. To determine whether an oestrogenic effect may be a key event in this response, tartrazine, sulphonated metabolites and a food additive contaminant were screened for their ability to interact with murine oestrogen receptors. In all cases, there were no interactions as agonists or antagonists and further, no oestrogenicity was observed with tartrazine in an in vivo uterine growth assay. To examine the relevance of the hepatic effects of tartrazine to its use as a food additive, tartrazine was orally administered to transgenic NF-κB-Luc mice. Pre- and concurrent oral treatment with alcohol was incorporated given its potential to promote gut permeability and hepatic inflammation. Tartrazine alone induced NF- κB activities in the colon and liver but there was no periportal recruitment of inflammatory cells or fibrosis. Tartrazine, its sulphonated metabolites and the contaminant inhibited sulphotransferase activities in murine hepatic S9 extracts. Given the role of sulfotransferases in bile acid excretion, the initiating event giving rise to periportal inflammation and subsequent hepatic pathology through systemic tartrazine exposure is therefore potentially associated an inhibition of bile acid sulphation and excretion and not on oestrogen receptor-mediated transcriptional function. However, these effects were restricted to systemic exposures to tartrazine and did not occur to any significant effect after oral exposure

Securing circulation pharmaceutically: antiviral stockpiling and pandemic preparedness in the European Union

Governments in Europe and around the world amassed vast pharmaceutical stockpiles in anticipation of a potentially catastrophic influenza pandemic. Yet the comparatively ‘mild’ course of the 2009 H1N1 pandemic provoked considerable public controversy around those stockpiles, leading to questions about their cost–benefit profile and the commercial interests allegedly shaping their creation, as well as around their scientific evidence base. So, how did governments come to view pharmaceutical stockpiling as such an indispensable element of pandemic preparedness planning? What are the underlying security rationalities that rapidly rendered antivirals such a desirable option for government planners? Drawing upon an in-depth reading of Foucault’s notion of a ‘crisis of circulation’, this article argues that the rise of pharmaceutical stockpiling across Europe is integral to a governmental rationality of political rule that continuously seeks to anticipate myriad circulatory threats to the welfare of populations – including to their overall levels of health. Novel antiviral medications such as Tamiflu are such an attractive policy option because they could enable governments to rapidly modulate dangerous levels of (viral) circulation during a pandemic, albeit without disrupting all the other circulatory systems crucial for maintaining population welfare. Antiviral stockpiles, in other words, promise nothing less than a pharmaceutical securing of circulation itself

Predictors of anemia in preschool children: Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project.

Background: A lack of information on the etiology of anemia has hampered the design and monitoring of anemia-control efforts.Objective: We aimed to evaluate predictors of anemia in preschool children (PSC) (age range: 6-59 mo) by country and infection-burden category.Design: Cross-sectional data from 16 surveys (n = 29,293) from the Biomarkers Reflecting Inflammation and Nutritional Determinants of Anemia (BRINDA) project were analyzed separately and pooled by category of infection burden. We assessed relations between anemia (hemoglobin concentration <110 g/L) and severe anemia (hemoglobin concentration <70 g/L) and individual-level (age, anthropometric measures, micronutrient deficiencies, malaria, and inflammation) and household-level predictors; we also examined the proportion of anemia with concomitant iron deficiency (defined as an inflammation-adjusted ferritin concentration <12 μg/L). Countries were grouped into 4 categories on the basis of risk and burden of infectious disease, and a pooled multivariable logistic regression analysis was conducted for each group.Results: Iron deficiency, malaria, breastfeeding, stunting, underweight, inflammation, low socioeconomic status, and poor sanitation were each associated with anemia in >50% of surveys. Associations between breastfeeding and anemia were attenuated by controlling for child age, which was negatively associated with anemia. The most consistent predictors of severe anemia were malaria, poor sanitation, and underweight. In multivariable pooled models, child age, iron deficiency, and stunting independently predicted anemia and severe anemia. Inflammation was generally associated with anemia in the high- and very high-infection groups but not in the low- and medium-infection groups. In PSC with anemia, 50%, 30%, 55%, and 58% of children had concomitant iron deficiency in low-, medium-, high-, and very high-infection categories, respectively.Conclusions: Although causal inference is limited by cross-sectional survey data, results suggest anemia-control programs should address both iron deficiency and infections. The relative importance of factors that are associated with anemia varies by setting, and thus, country-specific data are needed to guide programs

Associations of Infant Nutrition with Insulin Resistance Measures in Early Adulthood: Evidence from the Barry-Caerphilly Growth (BCG) Study

Background: Previous studies suggest that over-nutrition in early infancy may programme long-term susceptibility to insulin resistance. Objective: To assess the association of breast milk and quantity of infant formula and cows ’ milk intake during infancy with insulin resistance measures in early adulthood. Design: Long-term follow-up of the Barry Caerphilly Growth cohort, into which mothers and their offspring had originally been randomly assigned, between 1972–1974, to receive milk supplementation or not. Participants were the offspring, aged 23–27 years at follow-up (n = 679). Breastfeeding and formula/cows ’ milk intake was recorded prospectively by nurses. The main outcomes were insulin sensitivity (ISI0) and insulin secretion (CIR30). Results: 573 (84%) individuals had valid glucose and insulin results and complete covariate information. There was little evidence of associations of breastfeeding versus any formula/cows ’ milk feeding or of increasing quartiles of formula/cows’ milk consumption during infancy (,3 months) with any outcome measure in young adulthood. In fully adjusted models, the differences in outcomes between breastfeeding versus formula/cows ’ milk feeding at 3 months were: fasting glucose (20.07 mmol/l; 95 % CI: 20.19, 0.05); fasting insulin (8.0%; 28.7, 27.6); ISI0 (26.1%; 211.3, 12.1) and CIR30 (3.8%; 219.0, 32.8). There was also little evidence that increasing intakes of formula/cows ’ milk at 3 months were associated with fastin

Mini-mast CSI testbed user's guide

The Mini-Mast testbed is a 20 m generic truss highly representative of future deployable trusses for space applications. It is fully instrumented for system identification and active vibrations control experiments and is used as a ground testbed at NASA-Langley. The facility has actuators and feedback sensors linked via fiber optic cables to the Advanced Real Time Simulation (ARTS) system, where user defined control laws are incorporated into generic controls software. The object of the facility is to conduct comprehensive active vibration control experiments on a dynamically realistic large space structure. A primary goal is to understand the practical effects of simplifying theoretical assumptions. This User's Guide describes the hardware and its primary components, the dynamic characteristics of the test article, the control law implementation process, and the necessary safeguards employed to protect the test article. Suggestions for a strawman controls experiment are also included