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Context: Sepsis is a leading cause of young infant mortality., Objective: To evaluate the efficacy of different antibiotic regimens to treat young infant sepsis or possible serious bacterial infection (PSBI) on clinical outcomes., Data Sources: MEDLINE, Embase, CINAHL, World Health Organization Global Index Medicus, Cochrane Central Registry of Trials., Study Selection: We included randomized controlled trials (RCTs) of young infants 0 to 59 days with sepsis or PBSI (population) comparing the efficacy of antibiotic regimens (intervention) with alternate regimens or management (control) on clinical outcomes., Data Extraction: We extracted data and assessed risk of bias in duplicate. We performed random-effects meta-analysis, and used Grading of Recommendations, Assessment, Development, and Evaluation to assess certainty of evidence., Results: Of 2390 publications, we included 41 RCTs (n = 18 054). Thirty-five trials were hospital-based and 6 were nonhospital-based. Meta-analysis of 4 trials demonstrated similar rates of treatment success with intramuscular/intravenous third generation cephalosporins versus intramuscular/intravenous penicillin or ampicillin + gentamicin (RR 1.03, 95% CI 0.93-1.13]; n = 1083; moderate certainty of evidence). Meta-analysis of 3 trials demonstrated similar rates of treatment failure with oral amoxicillin + intramuscular gentamicin versus intramuscular penicillin + gentamicin for nonhospital treatment of clinical severe illness (RR 0.86, 95% CI 0.72-1.02]; n = 5054; low certainty of evidence). Other studies were heterogeneous., Limitations: RCTs evaluated heterogeneous regimens, limiting our ability to pool data., Conclusions: We found limited evidence to support any single antibiotic regimen as superior to alternate regimens to treat young infant sepsis or PSBI.

In this study, we present an in-depth characterization of a diamond-like carbon (DLC) film, using a range of techniques to understand the structure and chemistry of the film both in the interior and particularly at the DLC/air surface and DLC/liquid interface. The DLC film is found to be a combination of sp 2 and sp 3 carbon, with significant oxygen present at the surface. The oxygen seems to be present as OH groups, making the DLC somewhat hydrophilic. Quartz-Crystal Microbalance (QCM) isotherms and complementary neutron reflectivity data indicate significant adsorption of a model additive, bis(2-ethylhexyl) sulfosuccinate sodium salt (AOT) surfactant, onto the DLC from water solutions and indicate the adsorbed film is a bilayer. This initial study of the structure and composition of a model surfactant is intended to give a clearer insight into how DLC and additives function as antiwear systems.

Background: Albinism patients have poor visual acuity in addition to hypopigmentation. Their foveal anatomy is abnormal, but correlation with function is incompletely understood. This study correlates retinal electrophysiology, visual acuity and optical coherence tomography (OCT) anatomy in albinism patients and compares with age-similar controls., Methods: Institutional Review Board approval was obtained (IRB# 201408782). Patients were recruited from clinical practice. Inclusion criteria were at least three clinical features of albinism including iris transillumination, nystagmus, fundus hypopigmentation, or foveal hypoplasia on OCT and/or molecular genetic confirmation. Diagnosys (Lowell, Mass) full-field ERG (ffERG) and VERIS multifocal ERG (mfERG; Electro-Diagnostic Imaging, Milpitas, California) were obtained using standard International Society for Clinical Electrophysiology of Vision protocols. The mfERG protocol was a 4-min 103-hexagon protocol covering approximately 40° in diameter of central retina. Control subjects without albinism were recruited by in-hospital notices and invitations in clinic. OCT central thickness was recorded, and an OCT foveal score was calculated. Nonparametric permutation testing was utilized to determine the statistical significance., Results: A total of 16 albinism patients and 19 age-similar controls were recruited. Four of 16 albinism patients had no nystagmus. Seventeen non-albinism controls had no ocular disorder other than refractive error. Two controls had infantile nystagmus with normal maculas on OCT. There was no statistically significant difference in mfERG amplitude or latency between albinism patients with or without nystagmus (lowest p = 0.68; 0.54, respectively). mfERG: 12 of 16 (75%) albinism patients had average ring 1 amplitudes within one standard deviation of controls despite having abnormal foveal anatomy on OCT. Patients averaged shorter latencies in rings 1 and 2 than controls (p = 0.005, p = 0.02). Patients averaged higher amplitudes than controls in rings 4, 5 and 6 (p = 0.03, p = 0.006, p = 0.004). There was no significant correlation between visual acuity and mfERG amplitudes in any ring (smallest p = 0.15). ffERG: Patients averaged higher amplitudes on 30 Hz flicker (p = 0.008). In all conditions, albinism patients had higher amplitude a-waves (p ≤ 0.03). B-waves were higher amplitude than controls in light-adapted 3.0 (p = 0.03). There was no statistical correlation between ffERG amplitudes and visual acuity (smallest p = 0.45). OCT: In albinism patients, thicker central macula on OCT correlated with lower mfERG amplitudes in all rings except for ring 1 (p < 0.05) and lower ffERG a-wave amplitudes on dark-adapted 0.01 (p = 0.003). Macular thickness on OCT did not correlate with visual acuity (p = 0.51); OCT foveal score did (p = 0.0004)., Conclusions: Amplitude of mfERG does not correlate with visual acuity in any ring in patients with albinism. The slope of the change in amplitude from central to peripheral rings on the mferg is significantly different in albinism patients versus controls whether or not nystagmus is present. The decreased slope of change in amplitudes from center to periphery of the macula in albinism patients indicates changes in macular topography that are more important to visual deficits than the foveal depression.

Regulation of medicines involves complex scientific and public health policies which are reflected in the regulatory approaches used by the European Medicines Agency and the United States Food and Drug Administration for the approval of products developed for metabolic bone diseases. For osteoporosis therapies, utilized by many patients, the approaches and existing guidance for product development of both agencies are similar; confirmatory studies for the approval of osteoporosis products can rely on well-defined efficacy outcome parameters. Therapeutics for rare bone diseases, a rapidly expanding area, often require an individualized regulatory approach. This review outlines key aspects of these regulatory approaches applied by the two agencies for products for metabolic bone diseases., (© 2018 The British Pharmacological Society.)

Use, preferences, and perceptions of flavored electronic cigarettes (e-cigarettes) were investigated in an ethnically diverse sample of pregnant mothers (N = 100; 50% smokers, M age  = 26; 66% low income; 65% minorities) via detailed interviews. Fruit and mint were the most commonly used flavors. Pregnant women endorsed increased use of fruit flavored e-cigarettes in preconception and pregnancy, greater preferences and intentions to use sweet flavors (fruit and candy), and lowest preferences for tobacco flavors. No differences in perceptions of general, pregnancy, or fetal-related health risks emerged across flavors. Latent factor mapping (biplots) based on correspondence analyses of contingency tables revealed clustering of more-preferred fruit and candy flavors versus least-preferred tobacco flavored e-cigarettes, with other sweet flavors-mint and alcohol-clustering more closely with fruit and candy flavors, and more pungent flavors-spice, coffee, chocolate-clustering near tobacco. Correspondence analysis also revealed uncorrelated clustering of preferences and harm perceptions, with intentions showing associations with both preferences and harm perceptions. Preference for fruit and mint flavored e-cigarettes and decreased harm perceptions significantly differentiated lifetime e-cigarette users from non-users. Results highlight preferences for fruit and mint flavored e-cigarettes during preconception and pregnancy, and links between preferences for fruit and mint flavors and lifetime use of e-cigarettes. These findings also highlight the utility of correspondence analysis for elucidating clustering of flavor perceptions and preferences for novel tobacco products., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Independent verification of the dose delivered by complex radiotherapy can be performed by electronic portal imaging device (EPID) dosimetry. This paper presents 5-yr EPID in vivo dosimetry (IVD) data obtained using the Dosimetry Check (DC) software on a large cohort including breast, lung, prostate, and head and neck (H&N) cancer patients., Material and Methods: The difference between in vivo dose measurements obtained by DC and point doses calculated by the Eclipse treatment planning system was obtained on 3795 radiotherapy patients treated with volumetric modulated arc therapy (VMAT) (n = 842) and three-dimensional conformal radiotherapy (3DCRT) (n = 2953) at 6, 10, and 15 MV. In cases where the dose difference exceeded ±10% further inspection and additional phantom measurements were performed., Results: The mean and standard deviation ( μ ± σ ) of the percentage difference in dose obtained by DC and calculated by Eclipse in VMAT was: 0.19 ± 3.89 % in brain, 1.54 ± 4.87 % in H&N, and 1.23 ± 4.61 % in prostate cancer. In 3DCRT, this was 1.79 ± 3.51 % in brain, - 2.95 ± 5.67 % in breast, - 1.43 ± 4.38 % in bladder, 1.66 ± 4.77 % in H&N, 2.60 ± 5.35% in lung and - 3.62 ± 4.00 % in prostate cancer. A total of 153 plans exceeded the ±10% alert criteria, which included: 88 breast plans accounting for 7.9% of all breast treatments; 28 H&N plans accounting for 4.4% of all H&N treatments; and 12 prostate plans accounting for 3.5% of all prostate treatments. All deviations were found to be as a result of patient-related anatomical deviations and not from procedural errors., Conclusions: This preliminary data shows that EPID-based IVD with DC may not only be useful in detecting errors but has the potential to be used to establish site-specific dose action levels. The approach is straightforward and has been implemented as a radiographer-led service with no disruption to the patient and no impact on treatment time., (© 2018 Lothian Health Board Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Tobacco and marijuana are some of the most common prenatal substance exposures worldwide. The social acceptability and political landscape of marijuana and its potency have changed dramatically in the last two decades leading to increased use by pregnant women. Despite evidence for increasing marijuana use and high rates of co-use of tobacco (TOB) and marijuana (MJ) during pregnancy, the impact of prenatal exposure to each substance is typically studied in isolation. We investigated the influence of co-exposure to TOB and MJ on infant neurobehavioral development over the first postnatal month. Participants were 111 mother-infant pairs from a low-income, diverse sample (Mean age = 25 ± 5; 54% minorities). TOB and MJ use were assessed by Timeline Followback interview with biochemical confirmation. Three groups were identified: (a) prenatal MJ + TOB, (b) prenatal TOB only, (c) controls. Newborn neurobehavior was assessed at seven time points over the first postnatal month using the NICU Network Neurobehavioral Scale. MJ + TOB-exposed infants showed decreased ability to self-soothe (Self-regulation) and attend to stimuli (Attention), and increased need for examiner soothing (Handling) and low motor activity (Lethargy) versus unexposed infants. Despite low levels of MJ use in MJ + TOB co-users, co-exposure was associated with nearly double the impact on infant self-soothing and need for examiner soothing versus TOB-exposure alone. Effects of MJ + TOB co-exposure appeared more pronounced for daughters than for sons. Although results are preliminary, they highlight additional risk from dual exposure to MJ + TOB vs. TOB exposure alone, particularly for daughters. Results also highlight the critical importance of investigating prenatal exposures in concert and the need for intervention efforts to address MJ co-use in pregnant TOB users., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hydrogel materials offer many advantages for chemical and biological sensoring due to their response to a small change in their environment with a related change in volume. Several designs have been outlined in the literature in the specific field of hydrogel-based optical sensors, reporting a large number of steps for their fabrication. In this work we present a three-dimensional, hydrogel-based sensor the structure of which is fabricated in a single step using thermal nanoimprint lithography. The sensor is based on a waveguide with a grating readout section. A specific hydrogel formulation, based on a combination of PEGDMA (Poly(Ethylene Glycol DiMethAcrylate)), NIPAAm (N-IsoPropylAcrylAmide), and AA (Acrylic Acid), was developed. This stimulus-responsive hydrogel is sensitive to pH and to water. Moreover, the hydrogel has been modified to be suitable for fabrication by thermal nanoimprint lithography. Once stimulated, the hydrogel-based sensor changes its topography, which is characterised physically by AFM and SEM, and optically using a specific optical set-up.

Osteoporosis is a disorder of the bones in which they are weakened to the extent that they become more prone to fracture. There are various forms of osteoporosis: some of them are induced by drugs, and others occur as a chronic progressive disorder as an individual gets older. As the median age of the population rises across the world, the chronic form of the bone disease is drawing attention as an important worldwide health issue. Developing new treatments for osteoporosis and comparing them with existing treatments are complicated processes due to current acceptance by regulatory authorities of bone mineral density (BMD) and fracture risk as clinical end points, which require clinical trials to be large, prolonged, and expensive to determine clinically significant impacts in BMD and fracture risk. Moreover, changes in BMD and fracture risk are not always correlated, with some clinical trials showing BMD improvement without a reduction in fractures. More recently, bone turnover markers specific to bone formation and resorption have been recognized that reflect bone physiology at a cellular level. These bone turnover markers change faster than BMD and fracture risk, and mathematically linking the biomarkers via a computational model to BMD and/or fracture risk may help in predicting BMD and fracture risk changes over time during the progression of a disease or when under treatment. Here, we discuss important concepts of bone physiology, osteoporosis, treatment options, mathematical modeling of osteoporosis, and the use of these models by the pharmaceutical industry and the Food and Drug Administration., (© 2018, The American College of Clinical Pharmacology.)

Introduction: Infantile nystagmus has many causes, some life threatening. We determined the most common diagnoses in order to develop a testing algorithm., Methods: Retrospective chart review. Exclusion criteria were no nystagmus, acquired after 6 months, or lack of examination., Data Collected: pediatric eye examination findings, ancillary testing, order of testing, referral, and final diagnoses. Final diagnosis was defined as meeting published clinical criteria and/or confirmed by diagnostic testing. Patients with a diagnosis not meeting the definition were "unknown." Patients with incomplete testing were "incomplete." Patients with multiple plausible etiologies were "multifactorial." Patients with negative complete workup were "motor.", Results: A total of 284 charts were identified; 202 met inclusion criteria. The three most common causes were Albinism (19%), Leber Congenital Amaurosis (LCA; 14%), and Non-LCA retinal dystrophy (13%). Anatomic retinal disorders comprised 10%, motor another 10%. The most common first test was MRI (74/202) with a diagnostic yield of 16%. For 28 MRI-first patients, nystagmus alone was the indication; for 46 MRI-first patients other neurologic signs were present. 0/28 nystagmus-only patients had a diagnostic MRI while 14/46 (30%) with neurologic signs did. The yield of ERG as first test was 56%, OCT 55%, and molecular genetic testing 47%. Overall, 90% of patients had an etiology identified., Conclusion: The most common causes of infantile nystagmus were retinal disorders (56%), however the most common first test was brain MRI. For patients without other neurologic stigmata complete pediatric eye examination, ERG, OCT, and molecular genetic testing had a higher yield than MRI scan. If MRI is not diagnostic, a complete ophthalmologic workup should be pursued.

Nanostructured materials have emerged as a key research field in order to confer materials with unique or enhanced properties. The performance of nanocomposites depends on a number of parameters, but the suitable dispersion of nanoparticles remains the key in order to obtain the full nanocomposites' potential in terms of, e.g., flame retardance, mechanical, barrier, thermal properties, etc. Likewise, the performance of nanocoatings to obtain, for example, tailored surface affinity with selected liquids (e.g., for self-cleaning ability or anti-fog properties), protective effects against flame propagation, ultra violet (UV) radiation or gas permeation, is highly dependent on the nanocoating's thickness and homogeneity. In terms of recent advances in the monitoring of nanocomposites and nanocoatings, this review discusses commonly-used offline characterization approaches, as well as promising inline systems. All in all, having good control over both the dispersion and thickness of these materials would help with reaching optimal and consistent properties to allow nanocomposites to extend their use.

More than 10 years of negotiation and a series of political agreements led to the formation of a new First Nations health governance structure in British Columbia and the beginning of new relationships in health between First Nations, federal, and provincial governments. The First Nations Health Authority is the service delivery arm of this structure and the first-of-its-kind for Canada. Equitable and innovative health service and governance partnerships can bring decision-making closer to home and into the hands of First Nations communities and allows using the best of western medicine combined with holistic and traditional practices. Decolonizing old relationships and building new partnerships are leading to greater alignment of culturally safe and effective health services through coordination, integration, and shared decision-making in British Columbia., (© 2015 The Canadian College of Health Leaders.)

Aims: To analyse our 5 and 10 year prostate brachytherapy outcome data and to assess the impact of PSA nadir on relapse free survival and whether an alternative definition of PSA relapse could detect men destined to fail by the Phoenix definition at an earlier time point., Materials and Methods: 474 men were treated over a 10 year period between 20012 and 2011 and divided into 2 five year cohorts for the purpose of the analysis., Results: The risk of relapse is strongly predicted by post treat prostate-specific antigen (PSA) nadir. After 3 years post-treatment, PSA nadir plus 0.4 ng/ml identified men at risk of relapse 17 months earlier than the Phoenix definition., Conclusion: The Phoenix definition of nadir plus 2.0 ng/ml does not allow the early identification of men destined to relapse. The initiation of salavage therapy at the earliest opportunity could potentially affect subsequent survival and an outline randomised controlled trial proposal is presented., (Copyright © 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

The "textbook" phonon mean free path of heat carrying phonons in silicon at room temperature is ∼40  nm. However, a large contribution to the thermal conductivity comes from low-frequency phonons with much longer mean free paths. We present a simple experiment demonstrating that room-temperature thermal transport in Si significantly deviates from the diffusion model already at micron distances. Absorption of crossed laser pulses in a freestanding silicon membrane sets up a sinusoidal temperature profile that is monitored via diffraction of a probe laser beam. By changing the period of the thermal grating we vary the heat transport distance within the range ∼1-10  μm. At small distances, we observe a reduction in the effective thermal conductivity indicating a transition from the diffusive to the ballistic transport regime for the low-frequency part of the phonon spectrum.

We report on a method to enhance the light-emission efficiency of printable thin films of a polymer doped with luminescent (CdSe)ZnS nanocrystals via metallic nanoparticles and nanoimprinted photonic crystals. We experimentally show a strong fluorescence enhancement of nanocrystals by coupling exciton-plasmon with the localized surface plasmon of metallic nanoparticles. The emitted light is efficiently diffracted by photonic crystals structures directly imprinted in the nanocomposite polymer. By combining the field susceptibility technique with optical Bloch equations, we examine the interaction of the quantum and plasmonic entities at small distances.

We report the changes in dispersion relations of hypersonic acoustic phonons in free-standing silicon membranes as thin as ∼8 nm. We observe a reduction of the phase and group velocities of the fundamental flexural mode by more than 1 order of magnitude compared to bulk values. The modification of the dispersion relation in nanostructures has important consequences for noise control in nano- and microelectromechanical systems (MEMS/NEMS) as well as opto-mechanical devices.

We show how nanoimprint lithographic techniques are particularly suited for the realization of OLED device structures. We tested them to realize nanopatterned metallic electrodes containing photonic crystals to couple the light out and plasmonic crystals showing extraordinary transmission. At similar current densities, a two-fold electroluminescence is achieved with devices having double-sided structured metallic electrodes as compared to a control OLED with an ITO anode. The use of combined nanoimprint lithography processes has the potential to expand the performance range of various organic optoelectronic devices.

Background: The goals of our study are to determine the most appropriate model for alcohol consumption as an exposure for burden of disease, to analyze the effect of the chosen alcohol consumption distribution on the estimation of the alcohol Population- Attributable Fractions (PAFs), and to characterize the chosen alcohol consumption distribution by exploring if there is a global relationship within the distribution., Methods: To identify the best model, the Log-Normal, Gamma, and Weibull prevalence distributions were examined using data from 41 surveys from Gender, Alcohol and Culture: An International Study (GENACIS) and from the European Comparative Alcohol Study. To assess the effect of these distributions on the estimated alcohol PAFs, we calculated the alcohol PAF for diabetes, breast cancer, and pancreatitis using the three above-named distributions and using the more traditional approach based on categories. The relationship between the mean and the standard deviation from the Gamma distribution was estimated using data from 851 datasets for 66 countries from GENACIS and from the STEPwise approach to Surveillance from the World Health Organization., Results: The Log-Normal distribution provided a poor fit for the survey data, with Gamma and Weibull distributions providing better fits. Additionally, our analyses showed that there were no marked differences for the alcohol PAF estimates based on the Gamma or Weibull distributions compared to PAFs based on categorical alcohol consumption estimates. The standard deviation of the alcohol distribution was highly dependent on the mean, with a unit increase in alcohol consumption associated with a unit increase in the mean of 1.258 (95% CI: 1.223 to 1.293) (R2 = 0.9207) for women and 1.171 (95% CI: 1.144 to 1.197) (R2 = 0. 9474) for men., Conclusions: Although the Gamma distribution and the Weibull distribution provided similar results, the Gamma distribution is recommended to model alcohol consumption from population surveys due to its fit, flexibility, and the ease with which it can be modified. The results showed that a large degree of variance of the standard deviation of the alcohol consumption Gamma distribution was explained by the mean alcohol consumption, allowing for alcohol consumption to be modeled through a Gamma distribution using only average consumption.

Objective: This analysis aimed to estimate the burden of disease and injury caused and prevented by alcohol in 2004 for Canadians aged 0-69 years and compare the effects of different magnitudes of adjustment of survey data on these estimates., Methods: Alcohol indicators were obtained from the Canadian Alcohol and Drug Use Monitoring Survey 2008 and were corrected to 80% coverage using adult per capita recorded and unrecorded consumption. Risk relations were taken from meta-analyses. Estimates of burden of disease and injury were obtained from the World Health Organization., Results: In 2004, 4,721 (95% CI 1,432-8,150) deaths and 274,663 (95% CI 201,397-352,432) disability-adjusted life years lost (DALYs) of Canadians 0-69 years of age were attributable to alcohol. This represented 7.1% (95% CI 2.1-12.2%) of all deaths and 9.3% (95% CI 6.8-11.9%) of DALYs for this age range. The sensitivity analysis showed that the outcome estimates varied substantially based on the adjusted coverage rate., Conclusion: More attention to burden of disease and injury statistics is required to accurately characterize alcohol-related harms. This burden is preventable and could be reduced by implementation of more effective policies.

Background: Alcohol is a substantial risk factor for mortality according to the recent 2010 World Health Assembly strategy to reduce the harmful use of alcohol which outlined the need to characterize and monitor this burden. Accordingly, using new methodology we estimated 1) the number of deaths caused and prevented by alcohol consumption, and 2) the potential years of life lost (PYLLs) attributable to alcohol consumption in Canada in 2005., Methods: Mortality attributable to alcohol consumption was estimated by calculating Alcohol-Attributable Fractions (AAFs) (defined as the proportion of mortality that would be eliminated if the exposure was eliminated) using data from various sources. Indicators for alcohol consumption were obtained from the Canadian Alcohol and Drug Use Monitoring Survey 2008 and corrected for adult per capita recorded and unrecorded alcohol consumption. Risk relations were taken from the Comparative Risk Assessment within the current Global Burden of Disease (GBD) study. Due to concerns about the reliability of information specifying causes of death for people aged 65 or older, our analysis was limited to individuals aged 0 to 64 years. Calculation of the 95% confidence intervals (CIs) for the AAFs was performed using Monte Carlo random sampling. Information on mortality was obtained from Statistics Canada. A sensitivity analysis was performed comparing the mortality results obtained using our study methods to results obtained using previous methodologies., Results: In 2005, 3,970 (95% CI: 810 to 7,170) deaths (4,390 caused and 420 prevented) and 134,555 (95% CI: 36,690 to 236,376) PYLLs were attributable to alcohol consumption for individuals aged 0 to 64 years. These figures represent 7.7% (95% CI: 1.6% to 13.9%) of all deaths and 8.0% (95% CI: 2.2% to 14.1%) of all PYLLs for individuals aged 0 to 64 years. The sensitivity analysis showed that the number of deaths as measured by this new methodology is greater than that if mortality was estimated using previous methodologies., Conclusions: The mortality burden attributable to alcohol consumption for Canada is large, unnecessary, and could be substantially reduced in a short period of time if effective public health policies were implemented. A monitoring system on alcohol consumption is imperative and would greatly assist in planning and evaluating future Canadian public health policies related to alcohol consumption.

Background: Alcohol is a major risk factor for burden of disease and injuries globally. This paper presents a systematic method to compute the 95% confidence intervals of alcohol-attributable fractions (AAFs) with exposure and risk relations stemming from different sources., Methods: The computation was based on previous work done on modelling drinking prevalence using the gamma distribution and the inherent properties of this distribution. The Monte Carlo approach was applied to derive the variance for each AAF by generating random sets of all the parameters. A large number of random samples were thus created for each AAF to estimate variances. The derivation of the distributions of the different parameters is presented as well as sensitivity analyses which give an estimation of the number of samples required to determine the variance with predetermined precision, and to determine which parameter had the most impact on the variance of the AAFs., Results: The analysis of the five Asian regions showed that 150 000 samples gave a sufficiently accurate estimation of the 95% confidence intervals for each disease. The relative risk functions accounted for most of the variance in the majority of cases., Conclusions: Within reasonable computation time, the method yielded very accurate values for variances of AAFs., (© 2011 Gmel et al; licensee BioMed Central Ltd.)

Objective: To compute the burden of cancer attributable to current and former alcohol consumption in eight European countries based on direct relative risk estimates from a cohort study., Design: Combination of prospective cohort study with representative population based data on alcohol exposure. Setting Eight countries (France, Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Denmark) participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study., Participants: 109,118 men and 254,870 women, mainly aged 37-70., Main Outcome Measures: Hazard rate ratios expressing the relative risk of cancer incidence for former and current alcohol consumption among EPIC participants. Hazard rate ratios combined with representative information on alcohol consumption to calculate alcohol attributable fractions of causally related cancers by country and sex. Partial alcohol attributable fractions for consumption higher than the recommended upper limit (two drinks a day for men with about 24 g alcohol, one for women with about 12 g alcohol) and the estimated total annual number of cases of alcohol attributable cancer., Results: If we assume causality, among men and women, 10% (95% confidence interval 7 to 13%) and 3% (1 to 5%) of the incidence of total cancer was attributable to former and current alcohol consumption in the selected European countries. For selected cancers the figures were 44% (31 to 56%) and 25% (5 to 46%) for upper aerodigestive tract, 33% (11 to 54%) and 18% (-3 to 38%) for liver, 17% (10 to 25%) and 4% (-1 to 10%) for colorectal cancer for men and women, respectively, and 5.0% (2 to 8%) for female breast cancer. A substantial part of the alcohol attributable fraction in 2008 was associated with alcohol consumption higher than the recommended upper limit: 33,037 of 178,578 alcohol related cancer cases in men and 17,470 of 397,043 alcohol related cases in women., Conclusions: In western Europe, an important proportion of cases of cancer can be attributable to alcohol consumption, especially consumption higher than the recommended upper limits. These data support current political efforts to reduce or to abstain from alcohol consumption to reduce the incidence of cancer.

Aims: As part of a larger study to estimate the global burden of disease and injury attributable to alcohol: to evaluate the evidence for a causal impact of average volume of alcohol consumption and pattern of drinking on diseases and injuries; to quantify relationships identified as causal based on published meta-analyses; to separate the impact on mortality versus morbidity where possible; and to assess the impact of the quality of alcohol on burden of disease., Methods: Systematic literature reviews were used to identify alcohol-related diseases, birth complications and injuries using standard epidemiological criteria to determine causality. The extent of the risk relations was taken from meta-analyses., Results: Evidence of a causal impact of average volume of alcohol consumption was found for the following major diseases: tuberculosis, mouth, nasopharynx, other pharynx and oropharynx cancer, oesophageal cancer, colon and rectum cancer, liver cancer, female breast cancer, diabetes mellitus, alcohol use disorders, unipolar depressive disorders, epilepsy, hypertensive heart disease, ischaemic heart disease (IHD), ischaemic and haemorrhagic stroke, conduction disorders and other dysrhythmias, lower respiratory infections (pneumonia), cirrhosis of the liver, preterm birth complications and fetal alcohol syndrome. Dose-response relationships could be quantified for all disease categories except for depressive disorders, with the relative risk increasing with increased level of alcohol consumption for most diseases. Both average volume and drinking pattern were linked causally to IHD, fetal alcohol syndrome and unintentional and intentional injuries. For IHD, ischaemic stroke and diabetes mellitus beneficial effects were observed for patterns of light to moderate drinking without heavy drinking occasions (as defined by 60+ g pure alcohol per day). For several disease and injury categories, the effects were stronger on mortality compared to morbidity. There was insufficient evidence to establish whether quality of alcohol had a major impact on disease burden., Conclusions: Overall, these findings indicate that alcohol impacts many disease outcomes causally, both chronic and acute, and injuries. In addition, a pattern of heavy episodic drinking increases risk for some disease and all injury outcomes. Future studies need to address a number of methodological issues, especially the differential role of average volume versus drinking pattern, in order to obtain more accurate risk estimates and to understand more clearly the nature of alcohol-disease relationships.

Background: Alcohol consumption is a major risk factor in the global burden of disease, with overall volume of exposure as the principal underlying dimension. Two main sources of data on volume of alcohol exposure are available: surveys and per capita consumption derived from routine statistics such as taxation. As both sources have significant problems, this paper presents an approach that triangulates information from both sources into disaggregated estimates in line with the overall level of per capita consumption., Methods: A modeling approach was applied to the US using data from a large and representative survey, the National Epidemiologic Survey on Alcohol and Related Conditions. Different distributions (log-normal, gamma, Weibull) were used to model consumption among drinkers in subgroups defined by sex, age, and ethnicity. The gamma distribution was used to shift the fitted distributions in line with the overall volume as derived from per capita estimates. Implications for alcohol-attributable fractions were presented, using liver cirrhosis as an example., Results: The triangulation of survey data with aggregated per capita consumption data proved feasible and allowed for modeling of alcohol exposure disaggregated by sex, age, and ethnicity. These models can be used in combination with risk relations for burden of disease calculations. Sensitivity analyses showed that the gamma distribution chosen yielded very similar results in terms of fit and alcohol-attributable mortality as the other tested distributions., Conclusions: Modeling alcohol consumption via the gamma distribution was feasible. To further refine this approach, research should focus on the main assumptions underlying the approach to explore differences between volume estimates derived from surveys and per capita consumption figures.

Two approaches to conducting magneto-optical confocal spectroscopy are described, in each of which the confocal head is rotatable with respect to the magnetic field. A coudé arrangement has been shown to give adequate performance for scanned imaging, but lower optical throughput than a system based on single-mode optical fiber transport. The design criteria for a cryogenic fiber-coupling objective are described, and the tolerances demanded in lens alignment are shown to be relatively benign, allowing manufacture without special techniques. The practical use of the rotating confocal system with commercial stick-slip positioners has been shown to be rigid enough, and asymmetric weight distribution and diamagnetic forces are small enough to permit single quantum emitters to be studied over a range of angles and field strengths.

Background: Sentinel node biopsy (SNB) in breast cancer conventionally utilises a preoperative radioisotope injection and lymphoscintigraphy, which is time consuming and painful. The aim of this study was to evaluate a potentially more efficient and practical technique of immediate preoperative injection of blue dye and radiopharmaceutical by the surgeon (without involvement of a nuclear medicine department)., Method: One hundred and sixty three clinically node negative patients with invasive breast cancer undergoing breast-conserving surgery were included. The radiopharmaceutical was delivered to the operating suite and injected by the surgeon in the subareolar region immediately after induction of anaesthesia. Sentinel node biopsy was performed in conjunction with removal of any palpable axillary lymph nodes (axillary node sampling)., Results: Sentinel nodes (SNs) were detected in 161 of 163 women. On average, 3.0 sentinel nodes were identified. Twenty nine patients had involved nodes of whom 28 had a positive sentinel node. Of the two patients with failed identification, one had involved axillary lymph nodes on sampling and the other had an involved intramammary lymph node., Conclusion: This method produces results identical to those obtained with other techniques. This study shows that sentinel node biopsy can be performed safely without involvement of a nuclear medicine department with the added benefits of no preoperative injection and improved efficiency in the operating suite.

Osteoporosis, a disease of compromised bone strength, is a leading cause of fracture, morbidity, and mortality. The past 10 years have resulted in the development of new pharmacologic therapies for the treatment of this disease. Most of these agents have been approved for the treatment of osteoporosis based on placebo-controlled fracture trials. However, recent ethical concerns regarding placebo-controlled trials threaten to derail the development of new, possibly better, treatment options. Novel noninvasive imaging technologies may offer greater insight into the pathophysiology and biomechanics of osteoporosis and fracture. Because of these advances, many hope to find a new biomarker that will predict fracture risk better than the current bone density measurements and that ultimately will replace fracture as the primary endpoint for osteoporosis drug registration trials. This paper discusses the perspective of a Food and Drug Administration reviewer regarding the role of surrogate markers as they relate to the quest for new, safe and efficacious treatments for osteoporosis.

Reduced bone mineral density (BMD) and abnormalities in fat redistribution, glucose homeostasis, and lipid metabolism are prevalent among HIV-infected patients on highly active antiretroviral therapy (HAART). The relationship between the metabolic and skeletal complications of HIV is unclear. Fifty-one HIV patients on HAART (aged 30-54 yr, 86% male) and 21 HIV-negative control subjects (aged 31-51 yr, 82% male) were examined with oral glucose tolerance testing, a fasting lipid profile, and dual x-ray absorptiometry, and markers of bone formation (serum osteocalcin) and resorption (urinary deoxypyridinoline). HIV-infected subjects had a higher prevalence of either osteopenia or osteoporosis (World Health Organization criteria) at the spine, hip, or forearm, compared with HIV-negative controls (63% vs. 32%, P = 0.02) and evidence of increased bone resorption (urine deoxypyridinoline, 14.7 +/- 6.5 vs. 10.9 +/- 2.5 nmol/mmol creatinine, P = 0.012). Among the HIV-infected patients, those with reduced bone mineral density (n = 32) were similar to the group with normal BMD (n = 19) in the use of protease inhibitors, duration of HAART therapy, or other demographic variables. Plasma glucose 2 h after a glucose load (odds ratio 1.02 per 1 mg/dl increase, 95% confidence interval 1.01-1.05, P = 0.009) and central adiposity (trunk fat/total fat) (odds ratio 1.09 per 1% ratio increase, 95% confidence interval 1.00-1.18, P = 0.012) were associated with reduced BMD. These associations remained significant in a multivariate model including age and body mass index. Bone resorption was associated with female gender (P < 0.001) and non-high-density lipoprotein cholesterol (P = 0.034) in a multivariate linear regression model controlling for age, body mass index, protease inhibitor use, duration of HAART, and extremity fat. Reduced BMD is prevalent in HIV-infected patients on HAART and is related to central adiposity and postload hyperglycemia. Bone resorption is independently associated with female gender and dyslipidemia. HIV-infected patients with metabolic abnormalities may represent a population that would benefit from bone density screening.

Background: Gastrointestinal foregut carcinoids make up a small percentage (3% to 6%) of all reported carcinoids. Because these tumors are so uncommon, comparisons between the subtypes have been difficult. The goal of this study was to compare the hormonal and clinical characteristics of gastric, duodenal, and pancreatic carcinoids., Methods: A prospective database of approximately 750 carcinoid patients seen by one author over 25 years was reviewed, and the 104 patients with gastric (33), duodenal (17), or pancreatic (54) carcinoids were selected as the subgroup for analysis. These patients were compared with regard to hormone levels, clinical course, treatment, and survival., Results: Duodenal carcinoids exhibited significantly lower serotoninergic hormone levels than did the gastric and pancreatic carcinoids (urine 5-hydroxyindoleacetic acid [mg/24 h], 5 +/- 1 vs 16 +/- 5 and 47 +/- 12, respectively, P = .03). Pancreatic carcinoids presented with more advanced stage (distant metastases 87% vs 42% and 20% for gastric and duodenal, respectively) and had worse outcomes than patients with gastric and duodenal tumors with 10-year survivals of 10%, 59%, and 58%, respectively (P = .003)., Conclusions: Pancreatic carcinoids produce higher levels of serotoninergic hormones and have a significantly higher stage and worse outcome than other foregut carcinoids. This study demonstrates that the organ of origin is an important determinant of hormonal activity and clinical course for patients with foregut carcinoids.

Neuroendocrine tumors of the cervix are rare and are often under- or misdiagnosed. Because these tumors are very aggressive, early diagnosis and subsequent treatment are warranted. We describe a 46-yr-old woman with carcinoid syndrome caused by an atypical carcinoid of the uterine cervix. At age 44, she had dysplasia on Pap smear and underwent total abdominal hysterectomy with the diagnosis of adenocarcinoma. Fourteen months postoperatively, she developed the carcinoid syndrome and was found to have numerous liver metastases. Histological and immunohistochemical investigations of biopsy specimens from the patient's liver lesions and original cervical lesion ("adenocarcinoma") suggested that this woman had a primary atypical carcinoid of the uterine cervix with metastases to the liver. Treatment with octreotide and alkylating agents decreased the episodes of flushing and diarrhea within 8 weeks. If an adenocarcinoma of the uterine cervix is diagnosed, atypical carcinoid should be in the differential diagnosis. Symptoms of the carcinoid syndrome should be pursued and, if present, a urinary 5-hydroxyindolacetic acid level should be obtained. Timely diagnosis of a neuroendocrine tumor of the cervix may improve survival.

Background and Purpose: A hierarchy of dosimetry, planning and machine performance checks and evaluations of clinical outcomes have been widely used in radiotherapy for decades. Procedures, codes of practice and guidance are readily available on the 'technical aspects' of radiotherapy treatments, maintenance of which is achieved by quality control checks within a quality assurance approach to radiotherapy. Recently a series of high profile, well-publicised treatment 'accidents' resulting in damage to patients have focused the attention of both professionals and the public. There is now pressure to introduce formal quality management systems. Patients and their relatives/carers are having their expectations raised but their definition of a quality service differs from that generally considered by the oncology professionals. Most departmental managers and staff have wide experience of quality control checks. They understand the philosophy of quality assurance. However the idea of formal quality systems/quality management is alien to them. What is a professional/departmental manager to do?, Materials and Methods: This paper addresses that question by discussing the underlying principles of quality management covering service provision as well as technical radiotherapy treatment delivery and by providing some guidance based on experience in the practical implementation of quality management through three stages of development: a QA programme incorporating checks on essential parts of the technical treatment delivery, a formal documented certified QA system focusing on technical treatment delivery, a comprehensive quality management system covering all parts of a service., Results and Conclusions: One possible action plan is provided indicating progress through the three stages of development based on experience in one large Radiation Oncology Department. With planning, resources and commitment, a comprehensive quality of service management system is achievable in radiotherapy.

Recovery of recombinant proteins from endogenous, host molecules can be an experimentally intensive and time-consuming task. Often the time to analyze material during development of recovery procedures is the rate-limiting step. Nowadays, modern techniques and equipment are being specifically engineered to make this effort much more efficient. We present a case study to illustrate how a new, automation tool, designed for easy, systematic methods development, can be used for very rapid process and analytical optimization. This tool uses robotics to integrate process development with rapid LC-based analysis requiring no user intervention. The methods and procedures described can be generalized to any recombinant protein recovery campaign.

The axillary thoracotomy should be the incision of choice for most uncomplicated general thoracic surgical procedures. It can be performed rapidly, avoids major muscle transection, and by employing a double lumen endotracheal tube will permit segmental resection as well as lobectomy without technical problem. One hundred consecutive, elective axillary thoracotomies were performed with minimal morbidity and only one mortality. Twenty-five of the patients were of high surgical risk. The larger posterolateral thoracotomy is reserved for repeat thoracotomy, Pancoast tumors, difficult procedures such as bronchoplasty and/or radical pneumonectomy, and when pleural symphysis is expected. Sometimes called lateral thoracotomy or mini-thoracotomy, the axillary thoracotomy is our most common incision.

We present a case of azathioprine-associated alveolitis diagnosed by gallium-67 scanning and transbronchial biopsy. The patient denied respiratory symptoms, exhibited spiking fevers, and had normal chest roentgenograms. Allopurinol inhibition of azathioprine metabolism may have been a contributing factor.

Twenty-one healthy, middle-aged volunteers and 8 patients with chronic lung disease were given live, attenuated influenza virus vaccine by nasal spray. Forced vital capacity, 1-sec forced expiratory volume, ratio of 1-sec forced expiratory volume to forced vital capacity, residual volume, ratio of airway conductance to lung volume, maximal expiratory flows after exhalation of 50 and of 75 per cent of the forced vital capacity, closing volume, slope of Phase III, volume of isoflow, single-breath diffusing capacity for CO, and arterial blood gases were measured before and 3, 7, 10, and 21 days after exposure. Vaccination was well tolerated by the healthy volunteers without change in pulmonary function. In contrast, the patients tended to develop increased respiratory symptoms and had a slight decrease in mean forced expiratory volume in 1 sec 3 weeks after vaccination.

Cell populations obtained by bronchial lavage from human subjects were examined for the presence of cells related to the mast cell-basophil series. Such bronchial lumen histamine-containing cells (BLHCC) were identified. The BLHCC stained with toluidine blue may be identified by bright field or dark field microscopy. The BLHCC are alive as evidenced by ability to release histamine (H) after exposure to anti-IgE or calcium ionophore. Although H release from peripheral blood leukocytes by these two agents is potentiated by the presence of D2O, H release from BLHCC of the same subjects by anti-IgE or calcium ionophore was not potentiated by D2O. In studies comparing bronchial cell populations of humans and rhesus monkeys with peripheral blood leukocyte populations of the same subjects, the histamine content of the bronchial cell population was much higher in rhesus monkeys. IgE/Alb ratios of respiratory secretions and serum of the same human subjects were of the same order of magnitude in contrast to previous comparisons done on these fluids in rhesus monkeys.