High variability in the dosing of commonly used antibiotics revealed by a Europe-wide point prevalence study: implications for research and dissemination

BACKGROUND: Antibiotic dosing in neonates varies between countries and centres, suggesting suboptimal exposures for some neonates. We aimed to describe variations and factors influencing the variability in the dosing of frequently used antibiotics in European NICUs to help define strategies for improvement.

METHODS: A sub-analysis of the European Study of Neonatal Exposure to Excipients point prevalence study was undertaken. Demographic data of neonates receiving any antibiotic on the study day within one of three two-week periods from January to June 2012, the dose, dosing interval and route of administration of each prescription were recorded. The British National Formulary for Children (BNFC) and Neofax were used as reference sources. Risk factors for deviations exceeding ±25% of the relevant BNFC dosage recommendation were identified by multivariate logistic regression analysis.

RESULTS: In 89 NICUs from 21 countries, 586 antibiotic prescriptions for 342 infants were reported. The twelve most frequently used antibiotics - gentamicin, penicillin G, ampicillin, vancomycin, amikacin, cefotaxime, ceftazidime, meropenem, amoxicillin, metronidazole, teicoplanin and flucloxacillin - covered 92% of systemic prescriptions. Glycopeptide class, GA <32 weeks, 5(th) minute Apgar score <5 and geographical region were associated with deviation from the BNFC dosage recommendation. While the doses of penicillins exceeded recommendations, antibiotics with safety concerns followed (gentamicin) or were dosed below (vancomycin) recommendations.

CONCLUSIONS: The current lack of compliance with existing dosing recommendations for neonates needs to be overcome through the conduct of well-designed clinical trials with a limited number of antibiotics to define pharmacokinetics/pharmacodynamics, efficacy and safety in this population and by efficient dissemination of the results.

Failure of a numerical quality assessment scale to identify potential risk of bias in a systematic review: a comparison study

BACKGROUND: Assessing methodological quality of primary studies is an essential component of systematic reviews. Following a systematic review which used a domain based system [United States Preventative Services Task Force (USPSTF)] to assess methodological quality, a commonly used numerical rating scale (Downs and Black) was also used to evaluate the included studies and comparisons were made between quality ratings assigned using the two different methods. Both tools were used to assess the 20 randomized and quasi-randomized controlled trials examining an exercise intervention for chronic musculoskeletal pain which were included in the review. Inter-rater reliability and levels of agreement were determined using intraclass correlation coefficients (ICC). Influence of quality on pooled effect size was examined by calculating the between group standardized mean difference (SMD).

RESULTS: Inter-rater reliability indicated at least substantial levels of agreement for the USPSTF system (ICC 0.85; 95% CI 0.66, 0.94) and Downs and Black scale (ICC 0.94; 95% CI 0.84, 0.97). Overall level of agreement between tools (ICC 0.80; 95% CI 0.57, 0.92) was also good. However, the USPSTF system identified a number of studies (n = 3/20) as "poor" due to potential risks of bias. Analysis revealed substantially greater pooled effect sizes in these studies (SMD -2.51; 95% CI -4.21, -0.82) compared to those rated as "fair" (SMD -0.45; 95% CI -0.65, -0.25) or "good" (SMD -0.38; 95% CI -0.69, -0.08).

CONCLUSIONS: In this example, use of a numerical rating scale failed to identify studies at increased risk of bias, and could have potentially led to imprecise estimates of treatment effect. Although based on a small number of included studies within an existing systematic review, we found the domain based system provided a more structured framework by which qualitative decisions concerning overall quality could be made, and was useful for detecting potential sources of bias in the available evidence.

Data-Augmentation for Reducing Dataset Bias in Person Re-identification

In this paper we explore ways to address the issue of dataset bias in person re-identification by using data augmentation to increase the variability of the available datasets, and we introduce a novel data augmentation method for re-identification based on changing the image background. We show that use of data augmentation can improve the cross-dataset generalisation of convolutional network based re-identification systems, and that changing the image background yields further improvements.

Alcohol attention bias in adolescent social drinkers: an eye tracking study

Rationale
Previous research on attention bias in nondependent social drinkers has focused on adult samples with limited focus on the presence of attention bias for alcohol cues in adolescent social drinkers.
Objectives
The aim of this study was to examine the presence of alcohol attention bias in adolescents and the relationship of this cognitive bias to alcohol use and alcohol-related expectancies.
Methods
Attention bias in adolescent social drinkers and abstainers was measured using an eye tracker during exposure to alcohol and neutral cues. Questionnaires measured alcohol use and explicit alcohol expectancies.
Results
Adolescent social drinkers spent significantly more time fixating to alcohol stimuli compared to controls. Total fixation time to alcohol stimuli varied in accordance with level of alcohol consumption and was significantly associated with more positive alcohol expectancies. No evidence for automatic orienting to alcohol stimuli was found in adolescent social drinkers.
Conclusion
Attention bias in adolescent social drinkers appears to be underpinned by controlled attention suggesting that whilst participants in this study displayed alcohol attention bias comparable to that reported in adult studies, the bias has not developed to the point of automaticity. Initial fixations appeared to be driven by alternative attentional processes which are discussed further.

Using interviewer random effects to remove selection bias from HIV prevalence estimates

Background: Selection bias in HIV prevalence estimates occurs if non-participation in testing is correlated with HIV status. Longitudinal data suggests that individuals who know or suspect they are HIV positive are less likely to participate in testing in HIV surveys, in which case methods to correct for missing data which are based on imputation and observed characteristics will produce biased results. Methods: The identity of the HIV survey interviewer is typically associated with HIV testing participation, but is unlikely to be correlated with HIV status. Interviewer identity can thus be used as a selection variable allowing estimation of Heckman-type selection models. These models produce asymptotically unbiased HIV prevalence estimates, even when non-participation is correlated with unobserved characteristics, such as knowledge of HIV status. We introduce a new random effects method to these selection models which overcomes non-convergence caused by collinearity, small sample bias, and incorrect inference in existing approaches. Our method is easy to implement in standard statistical software, and allows the construction of bootstrapped standard errors which adjust for the fact that the relationship between testing and HIV status is uncertain and needs to be estimated. Results: Using nationally representative data from the Demographic and Health Surveys, we illustrate our approach with new point estimates and confidence intervals (CI) for HIV prevalence among men in Ghana (2003) and Zambia (2007). In Ghana, we find little evidence of selection bias as our selection model gives an HIV prevalence estimate of 1.4% (95% CI 1.2% – 1.6%), compared to 1.6% among those with a valid HIV test. In Zambia, our selection model gives an HIV prevalence estimate of 16.3% (95% CI 11.0% - 18.4%), compared to 12.1% among those with a valid HIV test. Therefore, those who decline to test in Zambia are found to be more likely to be HIV positive. Conclusions: Our approach corrects for selection bias in HIV prevalence estimates, is possible to implement even when HIV prevalence or non-participation is very high or very low, and provides a practical solution to account for both sampling and parameter uncertainty in the estimation of confidence intervals. The wide confidence intervals estimated in an example with high HIV prevalence indicate that it is difficult to correct statistically for the bias that may occur when a large proportion of people refuse to test.

Adaptor protein-2 sigma subunit mutations causing familial hypocalciuric hypercalcaemia type 3 (FHH3) demonstrate genotype-phenotype correlations, codon bias and dominant-negative effects

The adaptor protein-2 sigma subunit (AP2sigma;2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2sigma;2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca<inf>o</inf>²⁺) homeostasis. To elucidate the role of AP2sigma;2 in Ca<inf>o</inf>²⁺ regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2sigma;2 mutations, characterized their functional consequences and investigated the genetic mechanisms leading to FHH3. AP2sigma;2 mutations were identified in 17 probands, comprising 5 Arg15Cys, 4 Arg15His and 8 Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2sigma;2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2sigma;2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison with FHH1 probands with CaSR mutations, and a calculated index of sCa × sMg/100 × CCCR, which was ≥ 5.0, had a diagnostic sensitivity and specificity of 83 and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2sigma;2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue.

Cancer dormancy: a model of early dissemination and late cancer recurrence

Cancer dormancy is a stage in tumor progression in which residual disease remains occult and asymptomatic for a prolonged period of time. Dormant tumor cells can be present as one of the earliest stages in tumor development, as well as a stage in micrometastases, and/or minimal residual disease left after an apparently successful treatment of the primary tumor. The general mechanisms that regulate the transition of disseminated tumor cells that have lain dormant into a proliferative state remain largely unknown. However, regulation of the growth from dormant tumor cells may be explained in part through the interaction of the tumor cell with its microenvironment, limitations in the blood supply, or an active immune system. An understanding of the regulatory machinery of these processes is essential for identifying early cancer biomarkers and could provide a rationale for the development of novel agents to target dormant tumor cells. This review focuses on the different signaling models responsible for early cancer dissemination and tumor recurrence that are involved in dormancy pathways.

Obsessive-compulsive symptoms and attentional bias: An eye-tracking methodology

Background and objectives: Cognitive models suggest that attentional biases are integral in the maintenance of obsessive-compulsive symptoms (OCS). Such biases have been established experimentally in anxiety disorders; however, the evidence is unclear in Obsessive Compulsive disorder (OCD). In the present study, an eye-tracking methodology was employed to explore attentional biases in relation to OCS.
Methods: A convenience sample of 85 community volunteers was assessed on OCS using the Yale-Brown Obsessive Compulsive Scale-self report. Participants completed an eye-tracking paradigm where they were exposed to OCD, Aversive and Neutral visual stimuli. Indices of attentional bias were derived from the eye-tracking data.
Results: Simple linear regressions were performed with OCS severity as the predictor and eye-tracking measures of the different attentional biases for each of the three stimuli types were the criterion variables. Findings revealed that OCS severity moderately predicted greater frequency and duration of fixations on OCD stimuli, which reflect the maintenance attentional bias. No significant results were found in support of other biases.
Limitations: Interpretations based on a non-clinical sample limit the generalisability of the conclusions, although use of such samples in OCD research has been found to be comparable to clinical populations. Future research would include both clinical and sub-clinical participants.
Conclusions: Results provide some support for the theory of maintained attention in OCD attentional biases, as opposed to vigilance theory. Individuals with greater OCS do not orient to OCD stimuli any faster than individuals with lower OCS, but once a threat is identified, these individuals allocate more attention to OCS-relevant stimuli.

Comparing lateral bias in dogs and humans using the KongTM ball test

The KongTM ball test has been used extensively to assess lateral bias in the domestic dog. Implicit in this challenge is the assumption that dogs use their dominant paw to stabilise the ball. This study examined whether or not this is the case. A comparative approach was adopted, exploring limb use in dogs and humans. In Experiment 1, the paw preference of 48 dogs was assessed on the KongTM ball test. Analysis revealed an equal distribution of paw use, although significantly more dogs were paw-preferent than ambilateral. Significantly more male dogs were classified as right-pawed, while more females were ambilateral. There was no significant effect of canine sex or castration status on the dogs’ paw preferences. In Experiment 2, 94 adult humans were assessed on their ability to remove a piece of paper from a KongTM ball with their mouth, using their left, right or both hands to stabilise the ball. 76% of the right-handed people used their left hand, and 82% of the left-handed participants used their right hand, to hold the KongTM steady. It is concluded that dogs, like humans, are most likely using their non-dominant limb to stabilise the KongTM ball and their dominant side for postural support. This has potential applied implications from an animal welfare perspective.

Lateral bias and temperament in the domestic cat (Felis silvestris)

Research points to a relationship between lateralization and emotional functioning in humans and many species of animal. The present study explored the association between paw preferences and emotional functioning, specifically temperament, in a species thus far overlooked in this area, the domestic cat. Thirty left-pawed, 30 right-pawed, and 30 ambilateral pet cats were recruited following an assessment of their paw preferences using a food-reaching challenge. The animals’ temperament was subsequently assessed using the Feline Temperament Profile (FTP). Cats’ owners also completed a purpose-designed cat temperament (CAT) scale. Analysis revealed a significant relationship between lateral bias and FTP and CAT scale scores. Ambilateral cats had lower positive (FTP+) scores, and were perceived as less affectionate, obedient, friendly, and more aggressive, than left or right-pawed animals. Left and right pawed cats differed significantly on 1 trait on the CAT scale, namely playfulness. The strength of the cats’ paw preferences was related to the animals’ FTP and CAT scores. Cats with a greater strength of paw preference had higher FTP + scores than those with a weaker strength of paw preference. Animals with stronger paw preferences were perceived as more confident, affectionate, active, and friendly than those with weaker paw preferences. Results suggest that motor laterality in the cat is strongly related to temperament and that the presence or absence of lateralization has greater implications for the expression of emotion in this species than the direction of the lateralized bias.