The Economic Impact of Blindness in Europe

Purpose: To estimate the annual loss of productivity from blindness and moderate to severe visual impairment (MSVI) in the population aged >50 years in the European Union (EU). Methods: We estimated the cost of lost productivity using three simple models reported in the literature based on (1) minimum wage (MW), (2) gross national income (GNI), and (3) purchasing power parity-adjusted gross domestic product (GDP-PPP) losses. In the first two models, assumptions included that all individuals worked until 65 years of age, and that half of all visual impairment cases in the >50-year age group would be in those aged between 50 and 65 years. Loss of productivity was estimated to be 100% for blind individuals and 30% for those with MSVI. None of these models included direct medical costs related to visual impairment. Results: The estimated number of blind people in the EU population aged >50 years is ~1.28 million, with a further 9.99 million living with MSVI. Based on the three models, the estimated cost of blindness is €7.81 billion, €6.29 billion and €17.29 billion and that of MSVI €18.02 billion, €24.80 billion and €39.23 billion, with their combined costs €25.83 billion, €31.09 billion and €56.52 billion, respectively. The estimates from the MW and adjusted GDP-PPP models were generally comparable, whereas the GNI model estimates were higher, probably reflecting the lack of adjustment for unemployment. Conclusion: The cost of blindness and MSVI in the EU is substantial. Wider use of available cost-effective treatment and prevention strategies may reduce the burden significantly

Article image contrast, image pre-processing, and T₁ mapping affect MRI radiomic feature repeatability in patients with colorectal cancer liver metastases

Imaging biomarkers require technical, biological, and clinical validation to be translated into robust tools in research or clinical settings. This study contributes to the technical validation of radiomic features from magnetic resonance imaging (MRI) by evaluating the repeatability of features from four MR sequences: pre-contrast T_{1}- and T_{2}-weighted images, pre-contrast quantitative T_{1} maps (qT_{1}), and contrast-enhanced T_{1} weighted images. Fifty-one patients with colorectal cancer liver metastases were scanned twice, up to 7 days apart. Repeatability was quantified using the intraclass correlation coefficient (ICC) and repeatability coefficient (RC), and the impact of non-Gaussian feature distributions and image normalisation was evaluated. Most radiomic features had non-Gaussian distributions, but Box–Cox transformations enabled ICCs and RCs to be calculated appropriately for an average of 97% of features across sequences. ICCs ranged from 0.30 to 0.99, with volume and other shape features tending to be most repeatable; volume ICC > 0.98 for all sequences. 19% of features from non-normalised images exhibited significantly different ICCs in pair-wise sequence comparisons. Normalisation tended to increase ICCs for pre-contrast T_{1}- and T_{2}-weighted images, and decrease ICCs for qT_{1} maps. RCs tended to vary more between sequences than ICCs, showing that evaluations of feature performance depend on the chosen metric. This work suggests that feature-specific repeatability, from specific combinations of MR sequence and pre-processing steps, should be evaluated to select robust radiomic features as biomarkers in specific studies. In addition, as different repeatability metrics can provide different insights into a specific feature, consideration of the appropriate metric should be taken in a study-specific context

Comparison of methods for handling missing data on immunohistochemical markers in survival analysis of breast cancer

Background:Tissue micro-arrays (TMAs) are increasingly used to generate data of the molecular phenotype of tumours in clinical epidemiology studies, such as studies of disease prognosis. However, TMA data are particularly prone to missingness. A variety of methods to deal with missing data are available. However, the validity of the various approaches is dependent on the structure of the missing data and there are few empirical studies dealing with missing data from molecular pathology. The purpose of this study was to investigate the results of four commonly used approaches to handling missing data from a large, multi-centre study of the molecular pathological determinants of prognosis in breast cancer.Patients and Methods:We pooled data from over 11 000 cases of invasive breast cancer from five studies that collected information on seven prognostic indicators together with survival time data. We compared the results of a multi-variate Cox regression using four approaches to handling missing data-complete case analysis (CCA), mean substitution (MS) and multiple imputation without inclusion of the outcome (MI) and multiple imputation with inclusion of the outcome (MI). We also performed an analysis in which missing data were simulated under different assumptions and the results of the four methods were compared.Results:Over half the cases had missing data on at least one of the seven variables and 11 percent had missing data on 4 or more. The multi-variate hazard ratio estimates based on multiple imputation models were very similar to those derived after using MS, with similar standard errors. Hazard ratio estimates based on the CCA were only slightly different, but the estimates were less precise as the standard errors were large. However, in data simulated to be missing completely at random (MCAR) or missing at random (MAR), estimates for MI were least biased and most accurate, whereas estimates for CCA were most biased and least accurate.Conclusion:In this study, empirical results from analyses using CCA, MS, MI and MI were similar, although results from CCA were less precise. The results from simulations suggest that in general MI is likely to be the best. Given the ease of implementing MI in standard statistical software, the results of MI and CCA should be compared in any multi-variate analysis where missing data are a problem. © 2011 Cancer Research UK. All rights reserved

Oxygen-Enhanced MRI Accurately Identifies, Quantifies, and Maps Tumor Hypoxia in Preclinical Cancer Models.

There is a clinical need for noninvasive biomarkers of tumor hypoxia for prognostic and predictive studies, radiotherapy planning, and therapy monitoring. Oxygen-enhanced MRI (OE-MRI) is an emerging imaging technique for quantifying the spatial distribution and extent of tumor oxygen delivery in vivo. In OE-MRI, the longitudinal relaxation rate of protons (ΔR1) changes in proportion to the concentration of molecular oxygen dissolved in plasma or interstitial tissue fluid. Therefore, well-oxygenated tissues show positive ΔR1. We hypothesized that the fraction of tumor tissue refractory to oxygen challenge (lack of positive ΔR1, termed "Oxy-R fraction") would be a robust biomarker of hypoxia in models with varying vascular and hypoxic features. Here, we demonstrate that OE-MRI signals are accurate, precise, and sensitive to changes in tumor pO2 in highly vascular 786-0 renal cancer xenografts. Furthermore, we show that Oxy-R fraction can quantify the hypoxic fraction in multiple models with differing hypoxic and vascular phenotypes, when used in combination with measurements of tumor perfusion. Finally, Oxy-R fraction can detect dynamic changes in hypoxia induced by the vasomodulator agent hydralazine. In contrast, more conventional biomarkers of hypoxia (derived from blood oxygenation-level dependent MRI and dynamic contrast-enhanced MRI) did not relate to tumor hypoxia consistently. Our results show that the Oxy-R fraction accurately quantifies tumor hypoxia noninvasively and is immediately translatable to the clinic

Serotonin Transporter Promoter Polymorphism Genotype Is Associated With Behavioral Disinhibition and Negative Affect in Children of Alcoholics

Serotonergic (5-HT) dysfunction has been implicated in the etiology of both behavioral disinhibition (BD) and negative affect (NA). This work extends our previous finding of relationships between whole blood 5-HT and both BD and NA in pubescent, but not prepubescent, children of alcoholics and continues examination of a hypothesized role of 5-HT dysfunction in alcoholism risk. The long and short (L and S) variants of the 5-HT transporter gene-linked polymorphic region (5-HTTLPR) are responsible for differing transcriptional efficiencies in 5-HT uptake. Although associations have been found between the SS 5-HTTLPR genotype and severe alcoholism and neuroticism, recent reports describe relationships between the LL genotype and both low level of response to alcohol and alcoholism diagnosis and a predominance of the LL genotype in early-onset alcoholics. Methods : This report is from an ongoing prospective study of the development of risk for alcoholism and other problematic outcomes in a sample of families classified by father's alcoholism subtype. This study examines relationships between 5-HTTLPR genotype and both child BD (Child Behavior Checklist Aggressive Behavior) and NA (Child Behavior Checklist Anxious/Depressed) in offspring from 47 families. Results : Results showed significantly higher levels of BD and NA in the 16 children with the LL genotype than the 46 SS or SL children. Conclusions : Behaviors of undercontrol, which occur at increased rates in children of alcoholics, may be genetically influenced through the regulation of the 5-HT transporter. Due to the small sample size and the preliminary nature of our findings, replication is necessary.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/65855/1/j.1530-0277.2001.tb02302.x.pd

Quantitative and qualitative differences in subcutaneous adipose tissue stores across lipodystrophy types shown by magnetic resonance imaging

BACKGROUND: Lipodystrophies are characterized by redistributed subcutaneous fat stores. We previously quantified subcutaneous fat by magnetic resonance imaging (MRI) in the legs of two patients with familial partial lipodystrophy subtypes 2 and 3 (FPLD2 and FPLD3, respectively). We now extend the MRI analysis across the whole body of patients with different forms of lipodystrophy. METHODS: We studied five subcutaneous fat stores (supraclavicular, abdominal, gluteal, thigh and calf) and the abdominal visceral fat stores in 10, 2, 1, 1 and 2 female subjects with, respectively, FPLD2, FPLD3, HIV-related partial lipodystrophy (HIVPL), acquired partial lipodystrophy (APL), congenital generalized lipodystrophy (CGL) and in six normal control subjects. RESULTS: Compared with normal controls, FPLD2 subjects had significantly increased supraclavicular fat, with decreased abdominal, gluteal, thigh and calf subcutaneous fat. FPLD3 subjects had increased supraclavicular and abdominal subcutaneous fat, with less severe reductions in gluteal, thigh and calf fat compared to FPLD2 subjects. The repartitioning of fat in the HIVPL subject closely resembled that of FPLD3 subjects. APL and CGL subjects had reduced upper body, gluteal and thigh subcutaneous fat; the APL subject had increased, while CGL subjects had decreased subcutaneous calf fat. Visceral fat was markedly increased in FPLD2 and APL subjects. CONCLUSION: Semi-automated MRI-based adipose tissue quantification indicates differences between various lipodystrophy types in these studied clinical cases and is a potentially useful tool for extended quantitative phenomic analysis of genetic metabolic disorders. Further studies with a larger sample size are essential for confirming these preliminary findings

A Method of Drusen Measurement Based on the Geometry of Fundus Reflectance

BACKGROUND: The hallmarks of age-related macular degeneration, the leading cause of blindness in the developed world, are the subretinal deposits known as drusen. Drusen identification and measurement play a key role in clinical studies of this disease. Current manual methods of drusen measurement are laborious and subjective. Our purpose was to expedite clinical research with an accurate, reliable digital method. METHODS: An interactive semi-automated procedure was developed to level the macular background reflectance for the purpose of morphometric analysis of drusen. 12 color fundus photographs of patients with age-related macular degeneration and drusen were analyzed. After digitizing the photographs, the underlying background pattern in the green channel was leveled by an algorithm based on the elliptically concentric geometry of the reflectance in the normal macula: the gray scale values of all structures within defined elliptical boundaries were raised sequentially until a uniform background was obtained. Segmentation of drusen and area measurements in the central and middle subfields (1000 μm and 3000 μm diameters) were performed by uniform thresholds. Two observers using this interactive semi-automated software measured each image digitally. The mean digital measurements were compared to independent stereo fundus gradings by two expert graders (stereo Grader 1 estimated the drusen percentage in each of the 24 regions as falling into one of four standard broad ranges; stereo Grader 2 estimated drusen percentages in 1% to 5% intervals). RESULTS: The mean digital area measurements had a median standard deviation of 1.9%. The mean digital area measurements agreed with stereo Grader 1 in 22/24 cases. The 95% limits of agreement between the mean digital area measurements and the more precise stereo gradings of Grader 2 were -6.4 % to +6.8 % in the central subfield and -6.0 % to +4.5 % in the middle subfield. The mean absolute differences between the digital and stereo gradings 2 were 2.8 +/- 3.4% in the central subfield and 2.2 +/- 2.7% in the middle subfield. CONCLUSIONS: Semi-automated, supervised drusen measurements may be done reproducibly and accurately with adaptations of commercial software. This technique for macular image analysis has potential for use in clinical research

Paracetamol (acetaminophen) or non-steroidal anti-inflammatory drugs, alone or combined, for pain relief in acute otitis media in children

BACKGROUND: Acute otitis media (AOM) is one of the most common childhood infectious diseases and a significant reason for antibiotic prescriptions in children worldwide. Pain from middle ear infection and pressure behind the eardrum is the key symptom of AOM. Ear pain is central to children's and parents' experience of the illness. Because antibiotics provide only marginal benefits, analgesic treatment including paracetamol (acetaminophen) and non-steroidal anti-inflammatory drugs (NSAIDs) is regarded as the cornerstone of AOM management in children. OBJECTIVES: Our primary objective was to assess the effectiveness of paracetamol (acetaminophen) or NSAIDs, alone or combined, compared with placebo or no treatment in relieving pain in children with AOM. Our secondary objective was to assess the effectiveness of NSAIDs compared with paracetamol in children with AOM. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 7, July 2016; MEDLINE (Ovid, from 1946 to August 2016), Embase (from 1947 to August 2016), CINAHL (from 1981 to August 2016), LILACS (from 1982 to August 2016) and Web of Science (from 1955 to August 2016) for published trials. We screened reference lists of included studies and relevant systematic reviews for additional trials. We searched WHO ICTRP, ClinicalTrials.gov, and the Netherlands Trial Registry (NTR) for completed and ongoing trials (search date 19 August 2016). SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing the effectiveness of paracetamol or NSAIDs, alone or combined, for pain relief in children with AOM. We also included trials of paracetamol or NSAIDs, alone or combined, for children with fever or upper respiratory tract infections (URTIs) if we were able to extract subgroup data on pain relief in children with AOM either directly or after obtaining additional data from study authors. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed methodological quality of the included trials and extracted data. We used the GRADE approach to rate the overall quality of evidence for each outcome of interest. MAIN RESULTS: We included three RCTs (327 children) which were assessed at low to moderate risk of bias.One RCT included 219 children with AOM, and used a three-arm, parallel group, double-blind design to compare paracetamol versus ibuprofen versus placebo. All children also received antibiotics and those with fever > 39 °C could have received paracetamol (30 mg to 60 mg) additionally to the studied treatments.Another RCT involved 156 febrile children (26 of whom had AOM). The study design was a three-arm, parallel group, double-blind design and compared paracetamol versus ibuprofen versus ibuprofen plus paracetamol.The third RCT included 889 children with respiratory tract infections (82 of whom had AOM). This study applied a 3 x 2 x 2 factorial, open-label design and compared paracetamol versus ibuprofen versus ibuprofen plus paracetamol. Study participants were randomised to one of the three treatment groups as well as two dosing groups (regular versus as required) and two steam inhalation groups (steam versus no steam).Authors of two RCTs provided crude subgroup data on children with AOM. We used data from the remaining trial to inform comparison of paracetamol versus placebo (148 children) and ibuprofen versus placebo (146 children) assessments. Data from all included RCTs informed comparison of ibuprofen versus paracetamol (183 children); data from the two RCTs informed comparison of ibuprofen plus paracetamol versus paracetamol alone (71 children).We found evidence, albeit of low quality, that both paracetamol and ibuprofen as monotherapies were more effective than placebo in relieving pain at 48 hours (paracetamol versus placebo: proportion of children with pain 10% versus 25%, RR 0.38, 95% CI 0.17 to 0.85; number needed to treat to benefit (NNTB) 7; ibuprofen versus placebo: proportion of children with pain 7% versus 25%, RR 0.28, 95% CI 0.11 to 0.70; NNTB 6). Very low quality evidence suggested that adverse events did not significantly differ between children treated with either paracetamol, ibuprofen or placebo.We found insufficient evidence of a difference between ibuprofen and paracetamol in relieving ear pain at 24 hours (2 RCTs, 39 children; RR 0.83, 95% CI 0.59 to 1.18; very low quality evidence), 48 to 72 hours (3 RCTs, 183 children; RR 0.91, 95% CI 0.54 to 1.54; low quality evidence) and four to seven days (2 RCTs, 38 children; RR 0.74, 95% CI 0.17 to 3.23; very low quality evidence).Data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone came from two RCTs that provided crude subgroup data for 71 children with AOM. The small sample provided imprecise effect estimates and we were consequently unable to draw any firm conclusions (very low quality evidence). AUTHORS' CONCLUSIONS: Despite explicit guideline recommendations on its use, current evidence on the effectiveness of paracetamol or NSAIDs, alone or combined, in relieving pain in children with AOM is limited. Low quality evidence indicates that both paracetamol and ibuprofen as monotherapies are more effective than placebo in relieving short-term ear pain in children with AOM. There is insufficient evidence of a difference between ibuprofen and paracetamol in relieving short-term ear pain in children with AOM, whereas data on the effectiveness of ibuprofen plus paracetamol versus paracetamol alone were insufficient to draw any firm conclusions. Further research is needed to provide insights into the role of ibuprofen as adjunct to paracetamol, and other analgesics such as anaesthetic eardrops, for children with AOM

Do advanced mathematics skills predict success in biology and chemistry degrees?

The mathematical preparedness of science undergraduates has been a subject of debate for some time. This paper investigates the relationship between school mathematics attainment and degree outcomes in biology and chemistry across England, a much larger scale of analysis than has hitherto been reported in the literature. A unique dataset which links the National Pupil Database for England (NPD) and Higher Education Statistics Agency (HESA) data is used to track the educational trajectories of a national cohort of 16-year-olds through their school and degree programmes. Multilevel regression models indicate that students who completed advanced mathematics qualifications prior to their university study of biology and chemistry were no more likely to attain the best degree outcomes than those without advanced mathematics. The models do, however, suggest that success in advanced chemistry at school predicts outcomes in undergraduate biology and vice versa. There are important social background differences and the impact of the university attended is considerable. We discuss a range of possible explanations of these findings

How do you say ‘hello’? Personality impressions from brief novel voices

On hearing a novel voice, listeners readily form personality impressions of that speaker. Accurate or not, these impressions are known to affect subsequent interactions; yet the underlying psychological and acoustical bases remain poorly understood. Furthermore, hitherto studies have focussed on extended speech as opposed to analysing the instantaneous impressions we obtain from first experience. In this paper, through a mass online rating experiment, 320 participants rated 64 sub-second vocal utterances of the word ‘hello’ on one of 10 personality traits. We show that: (1) personality judgements of brief utterances from unfamiliar speakers are consistent across listeners; (2) a two-dimensional ‘social voice space’ with axes mapping Valence (Trust, Likeability) and Dominance, each driven by differing combinations of vocal acoustics, adequately summarises ratings in both male and female voices; and (3) a positive combination of Valence and Dominance results in increased perceived male vocal Attractiveness, whereas perceived female vocal Attractiveness is largely controlled by increasing Valence. Results are discussed in relation to the rapid evaluation of personality and, in turn, the intent of others, as being driven by survival mechanisms via approach or avoidance behaviours. These findings provide empirical bases for predicting personality impressions from acoustical analyses of short utterances and for generating desired personality impressions in artificial voices