A Review of the Metrics Used to Assess Auto-Contouring Systems in Radiotherapy.

Auto-contouring could revolutionise future planning of radiotherapy treatment. The lack of consensus on how to assess and validate auto-contouring systems currently limits clinical use. This review formally quantifies the assessment metrics used in studies published during one calendar year and assesses the need for standardised practice. A PubMed literature search was undertaken for papers evaluating radiotherapy auto-contouring published during 2021. Papers were assessed for types of metric and the methodology used to generate ground-truth comparators. Our PubMed search identified 212 studies, of which 117 met the criteria for clinical review. Geometric assessment metrics were used in 116 of 117 studies (99.1%). This includes the Dice Similarity Coefficient used in 113 (96.6%) studies. Clinically relevant metrics, such as qualitative, dosimetric and time-saving metrics, were less frequently used in 22 (18.8%), 27 (23.1%) and 18 (15.4%) of 117 studies, respectively. There was heterogeneity within each category of metric. Over 90 different names for geometric measures were used. Methods for qualitative assessment were different in all but two papers. Variation existed in the methods used to generate radiotherapy plans for dosimetric assessment. Consideration of editing time was only given in 11 (9.4%) papers. A single manual contour as a ground-truth comparator was used in 65 (55.6%) studies. Only 31 (26.5%) studies compared auto-contours to usual inter- and/or intra-observer variation. In conclusion, significant variation exists in how research papers currently assess the accuracy of automatically generated contours. Geometric measures are the most popular, however their clinical utility is unknown. There is heterogeneity in the methods used to perform clinical assessment. Considering the different stages of system implementation may provide a framework to decide the most appropriate metrics. This analysis supports the need for a consensus on the clinical implementation of auto-contouring.

An Inter-observer Study to Determine Radiotherapy Planning Target Volumes for Recurrent Gynaecological Cancer Comparing Magnetic Resonance Imaging Only With Computed Tomography-Magnetic Resonance Imaging.

AIMS: Target delineation uncertainty is arguably the largest source of geometric uncertainty in radiotherapy. Several factors can affect it, including the imaging modality used for delineation. It is accounted for by applying safety margins to the target to produce a planning target volume (PTV), to which treatments are designed. To determine the margin, the delineation uncertainty is measured as the delineation error, and then a margin recipe used. However, there is no published evidence of such analysis for recurrent gynaecological cancers (RGC). The aims of this study were first to quantify the delineation uncertainty for RGC gross tumour volumes (GTVs) and to calculate the associated PTV margins and then to quantify the difference in GTV, delineation uncertainty and PTV margin, between a computed tomography-magnetic resonance imaging (CT-MRI) and MRI workflow. MATERIALS AND METHODS: Seven clinicians delineated the GTV for 20 RGC tumours on co-registered CT and MRI datasets (CT-MRI) and on MRI alone. The delineation error, the standard deviation of distances from each clinician's outline to a reference, was measured and the required PTV margin determined. Differences between using CT-MRI and MRI alone were assessed. RESULTS: The overall delineation error and the resulting margin were 3.1 mm and 8.5 mm, respectively, for CT-MRI, reducing to 2.5 mm and 7.1 mm, respectively, for MRI alone. Delineation errors and therefore the theoretical margins, varied widely between patients. MRI tumour volumes were on average 15% smaller than CT-MRI tumour volumes. DISCUSSION: This study is the first to quantify delineation error for RGC tumours and to calculate the corresponding PTV margin. The determined margins were larger than those reported in the literature for similar patients, bringing into question both current margins and margin calculation methods. The wide variation in delineation error between these patients suggests that applying a single population-based margin may result in PTVs that are suboptimal for many. Finally, the reduced tumour volumes and safety margins suggest that patients with RGC may benefit from an MRI-only treatment workflow.

Gender Disparities in Financial Relationships Between Industry and Orthopaedic Surgeons.

BACKGROUND: Recent studies in a number of surgical subspecialties have demonstrated that financial relationships with industry differ between men and women. This study aimed to determine if gender disparities exist in industry relationships with orthopaedic surgeons. METHODS: This retrospective study utilized publicly available data from the Centers for Medicare & Medicaid Services (CMS) at OpenPayments.cms.gov. Data were extracted for payments made to orthopaedic surgeons from industry for royalties, licensing, or consulting fees from 2016 to 2017. A physician's profile was used to determine name, gender, practice location, and subspecialty. Years of experience were recorded from publicly available websites. Total number of payments and amounts were compared among men and women, subspecialties, and locations. Multivariable linear regression models were used to determine predictors of total payments and number of payments. RESULTS: Royalties and consulting fees were paid to 3,418 individual physicians (11% of 29,996 physicians in the American Academy of Orthopaedic Surgeons [AAOS] census) and accounted for 88% of total payments. The majority of the total payment amount (99.6%) was made to men, while only 0.4% went to women. Male gender was a predictor of total number of payments (ß = 5.17, p < 0.001), as were years of experience (ß = 0.15 [95% confidence interval (CI): 0.10 to 0.20], p < 0.001), Mountain region (ß = 2.77 [95% CI: 0.37 to 5.17], p = 0.02), and adult reconstructive subspecialty (ß = 4.07 [95% CI: 1.89 to 6.25], p < 0.001). Years of experience (ß = 0.046 [95% CI: 0.039 to 0.052], p < 0.001), male gender (ß = 1.09 [95% CI: 0.67 to 1.51], p < 0.001), Mountain region (ß = 0.35 [95% CI: 0.020 to 0.68], p = 0.04), and adult reconstructive subspecialty (ß = 0.33 [95% CI: 0.030 to 0.63], p = 0.03) were associated with higher payments. CONCLUSIONS: Male gender, years of experience, Mountain region, and adult reconstructive subspecialty are independent predictors of a higher number of industry payments and payment amount. These disparities in industry payments may contribute to continued inequities in scholarship, academic rank, and leadership opportunities.

Evaluation of the exposure, dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 1: Experimental design, aerosol exposure, lung burdens and BAL.

This 90-day repeated-dose inhalation toxicology study of brake-dust (BD) (brakes manufactured with chrysotile) in rats provides a comprehensive understanding of the biokinetics and potential toxicology in the lung and pleura. Exposure was 6 h/d, 5d/wk., 13wks followed by lifetime observation (~20 % survival). Control groups included a particle control (TiO2), chrysotile, commercial crocidolite and amosite asbestos. Aerosol fiber distributions of the chrysotile, crocidolite and amosite were similar (fibers L > 20 µm/cm3: chrysotile-Low/High 29/72; crocidolite 24; amosite 47 fibers/cm3; WHO-fibers/cm3: chrysotile-Low/High 119/233; crocidolite 181; amosite 281 fibers/cm3). The number of particles/cm3 in the BD was similar to that in the chrysotile, crocidolite & amosite exposures (BD 470-715; chrysotile 495-614; crocidolite 415; amosite 417 particles/cm3). In the BD groups, few fibers L > 20 µm were observed in the lungs at the end of exposure and no fibers L > 20 µm at 90d post exposure. In the chrysotile groups, means of 204,000 and 290,000 fibers(L > 20 µm)/lung were measured at 89d. By 180d, means of 1 and 3.9 fibers were counted on the filter corresponding to 14,000 and 55,000 fibers(L > 20 µm)/lung. In the crocidolite and amosite groups mean lung concentrations were 9,055,000 and 11,645,000 fibers(L > 20 µm)/lung at 89d. At 180d the means remained similar with 8,026,000 and 11,591,000 fibers(L > 20 µm)/lung representing 10-13% of the total lung fibers. BAL determined the total number of macrophages, lymphocytes, neutrophils, eosinophils, epithelial-cells and IL-1 beta, TNF-alpha and TGF-beta. At the moderate aerosol concentrations used in this study, neutrophil counts increased ~5 fold in the amphibole asbestos exposure groups. All other groups and parameters showed no important differences at these exposure concentrations. The exposure and lung burden results provide a sound basis for assessing the potential toxicity of the brake dust in comparison to the TiO2 particle control and the chrysotile, crocidolite and amosite asbestos control groups. The BAL results provide an initial indication of the differential response. Part 2 presents the presentation and discussion of the histopathological and confocal microscopy findings in this study through 90 days post exposure.

Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to TiO2, chrysotile, crocidolite or amosite asbestos in a 90-day quantitative inhalation toxicology study - Interim results Part 2: Histopathological examination, Confocal microscopy and collagen quantification of the lung and pleural cavity.

The interim results from this 90-day multi-dose, inhalation toxicology study with life-time post-exposure observation has shown an important fundamental difference in persistence and pathological response in the lung between brake dust derived from brake-pads manufactured with chrysotile, TiO2 or chrysotile alone in comparison to the amphiboles, crocidolite and amosite asbestos. In the brake dust exposure groups no significant pathological response was observed at any time. Slight macrophage accumulation of particles was noted. Wagner-scores, were from 1 to 2 (1 = air-control group) and were similar to the TiO2 group. Chrysotile being biodegradable, shows a weakening of its matrix and breaking into short fibers & particles that can be cleared by alveolar macrophages and continued dissolution. In the chrysotile exposure groups, particle laden macrophage accumulation was noted leading to a slight interstitial inflammatory response (Wagner-score 1-3). There was no peribronchiolar inflammation and occasional very slight interstitial fibrosis. The histopathology and the confocal analyses clearly differentiate the pathological response from amphibole asbestos, crocidolite and amosite, compared to that from the brake dust and chrysotile. Both crocidolite and amosite induced persistent inflammation, microgranulomas, and fibrosis (Wagner-scores 4), which persisted through the post exposure period. The confocal microscopy of the lung and snap-frozen chestwalls quantified the extensive inflammatory response and collagen development in the lung and on the visceral and parietal surfaces. The interim results reported here, provide a clear basis for differentiating the effects from brake dust exposure from those following amphibole asbestos exposure. The subsequent results through life-time post-exposure will follow.

Upper limits on perturbations of nuclear decay rates induced by reactor electron antineutrinos.

We report the results of an experiment conducted near the High Flux Isotope Reactor of Oak Ridge National Laboratory, designed to address the question of whether a flux of reactor-generated electron antineutrinos (ν¯e) can alter the rates of weak nuclear interaction induced decays of 54Mn, 22Na, and 60Co. This experiment has small statistical errors but, when systematic uncertainties are included, has null results. Perturbations greater than one part in 104 are excluded at 95% confidence level in ß± decay and electron capture processes, in the presence of an antineutrino flux of 3 × 1012 cm-2s-1. The present experimental methods are applicable to a wide range of radionuclides. Improved sensitivity in future experiments can be anticipated as we continue to better understand and reduce the dominant systematic uncertainties.

In-vivo EPID dosimetry for IMRT and VMAT based on through-air predicted portal dose algorithm.

We have adapted the methodology of Berry et al. (2012) for Intensity Modulated Radiotherapy (IMRT) and Volumetric Modulated Arc Therapy (VMAT) treatments at a fixed source to imager distance (SID) based on the manufacturer's through-air portal dose image prediction algorithm. In order to fix the SID a correction factor was introduced to account for the change in air gap between patient and imager. Commissioning data, collected with multiple field sizes, solid water thicknesses and air gaps, were acquired at 150 cm SID on the Varian aS1200 EPID. The method was verified using six IMRT and seven VMAT plans on up to three different phantoms. The method's sensitivity and accuracy were investigated by introducing errors. A global 3%/3 mm gamma was used to assess the differences between the predicted and measured portal dose images. The effect of a varying air gap on EPID signal was found to be significant - varying by up to 30% with field size, phantom thickness, and air gap. All IMRT plans passed the 3%/3 mm gamma criteria by more than 95% on the three phantoms. 23 of 24 arcs from the VMAT plans passed the 3%/3 mm gamma criteria by more than 95%. This method was found to be sensitive to a range of potential errors. The presented approach provides fast and accurate in-vivo EPID dosimetry for IMRT and VMAT treatments and can potentially replace many pre-treatment verifications.

Evaluation of the dose-response and fate in the lung and pleura of chrysotile-containing brake dust compared to chrysotile or crocidolite asbestos in a 28-day quantitative inhalation toxicology study.

This study provides an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake-dust (brakes manufactured with chrysotile). The design included a 28-day repeated multi-dose inhalation exposure (6 h/d, 5 d/wk, 4 wks) followed by 28-days without exposure. Fiber control groups included a similar grade chrysotile as used in the brakes and a commercial crocidolite asbestos. Aerosol fiber distributions of the chrysotile and crocidolite were similar (fiber-length > 20 µm/cm3: Chrysotile-low/high 42/62; Crocidolite-low/high 36/55; WHO-fibers/cm3: Chrysotile-low/high 192/219; Crocidolite-low/high 211/255). The total number of aerosol particles/cm3 in the brake-dust was similar to that in the chrysotile (Brake-dust 710-1065; Chrysotile 532-1442). Brake-dust at particle exposure levels equal to or greater than chrysotile or crocidolite caused no indication of microgranulomas, epithelial hyperplasia, or fibrosis (Wagner score < 1.7) or changes in bronchoalveolar lavage (BAL) indices from the air control. Chrysotile BAL indices did not differ from the air control. Pathologically, there was low level of inflammation and epithelial hyperplasia, but no fibrosis (Wagner score ≤ 3). Crocidolite induced elevated neutrophils and cell damage (BAL), persistent inflammation, microgranulomas, and fibrosis (Wagner scores 4) which persisted through the post exposure period. Confocal microscopy of snap-frozen chestwalls showed no difference between control, brake-dust and chrysotile-HD groups or in thickness of visceral or parietal pleural. The crocidolite exposure resulted in extensive inflammatory response, collagen development and adhesions between the visceral and parietal surfaces with double the surface thickness. These results provide essential information for the design of a subsequent subchronic study.

The Influence of Race and Common Genetic Variations on Outcomes After Pediatric Heart Transplantation.

Significant racial disparity remains in the incidence of unfavorable outcomes following heart transplantation. We sought to determine which pediatric posttransplantation outcomes differ by race and whether these can be explained by recipient demographic, clinical, and genetic attributes. Data were collected for 80 black and 450 nonblack pediatric recipients transplanted at 1 of 6 centers between 1993 and 2008. Genotyping was performed for 20 candidate genes. Average follow-up was 6.25 years. Unadjusted 5-year rates for death (p = 0.001), graft loss (p = 0.015), acute rejection with severe hemodynamic compromise (p = 0.001), late rejection (p = 0.005), and late rejection with hemodynamic compromise (p = 0.004) were significantly higher among blacks compared with nonblacks. Black recipients were more likely to be older at the time of transplantation (p < 0.001), suffer from cardiomyopathy (p = 0.004), and have public insurance (p < 0.001), and were less likely to undergo induction therapy (p = 0.0039). In multivariate regression models adjusting for age, sex, cardiac diagnosis, insurance status, and genetic variations, black race remained a significant risk factor for all the above outcomes. These clinical and genetic variables explained only 8-19% of the excess risk observed for black recipients. We have confirmed racial differences in survival, graft loss, and several rejection outcomes following heart transplantation in children, which could not be fully explained by differences in recipient attributes.

Evaluation of the fate and pathological response in the lung and pleura of brake dust alone and in combination with added chrysotile compared to crocidolite asbestos following short-term inhalation exposure.

This study was designed to provide an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake-dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6h/day for 5 days to either brake-dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake-dust or crocidolite asbestos. The chrysotile fibers were relatively biosoluble whereas the crocidolite asbestos fibers persisted through the life-time of the animal. This was reflected in the lung and the pleura where no significant pathological response was observed at any time point in the brake dust or chrysotile/brake dust exposure groups through 365 days post exposure. In contrast, crocidolite asbestos produced a rapid inflammatory response in the lung parenchyma and the pleura, inducing a significant increase in fibrotic response in both of these compartments. Crocidolite fibers were observed embedded in the diaphragm with activated mesothelial cells immediately after cessation of exposure. While no chrysotile fibers were found in the mediastinal lymph nodes, crocidolite fibers of up to 35 µm were observed. These results provide support that brake-dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung or the pleural cavity following short term inhalation.

N-acetyltransferase 1 polymorphism increases cotinine levels in Caucasian children exposed to secondhand smoke: the CCAAPS birth cohort.

Cotinine is a proxy for secondhand smoke (SHS) exposure. Genetic variation along nicotine and cotinine metabolic pathways may alter the internal cotinine dose, leading to misinterpretations of exposure-health outcome associations. Caucasian children with available SHS exposure and hair cotinine data were genotyped for metabolism-related genes. SHS-exposed children had 2.4-fold higher hair cotinine (0.14±0.22 ng mg(-1)) than unexposed children (0.06±0.05 ng mg(-1), P<0.001). SHS-exposed children carrying the NAT1 minor allele had twofold higher hair cotinine (0.18 ng mg(-1) for heterozygotes and 0.17 ng mg(-1) for homozygotes) compared with major allele homozygotes (0.09 ng mg(-1), P=0.0009), even after adjustment for SHS dose. These findings support that NAT1 has a role in the metabolic pathway of nicotine/cotinine and/or their metabolites. The increased cotinine levels observed for those carrying the minor allele may lead to SHS exposure misclassification in studies utilizing cotinine as a biomarker. Additional studies are required to identify functional single-nucleotide polymorphism(s) (SNP(s)) in NAT1 and elucidate the biological consequences of the mutation(s).

Safety of sublingual immunotherapy Timothy grass tablet in subjects with allergic rhinitis with or without conjunctivitis and history of asthma.

BACKGROUND: Patients with asthma may be more susceptible to adverse events (AEs) with sublingual immunotherapy tablet (SLIT-tablet) treatment, such as severe systemic reactions and asthma-related events. Using data from eight trials of grass SLIT-tablet in subjects with allergic rhinitis with/without conjunctivitis (AR/C), AE frequencies were determined in adults and children with and without reported asthma. METHODS: Data from randomized, double-blind, placebo-controlled trials of Timothy grass SLIT-tablet MK-7243 (2800 BAU/75 000 SQ-T, Merck/ALK-Abelló) were pooled for post hoc analyses. Subjects with uncontrolled and severe asthma were excluded from the trials. Frequencies for treatment-emergent AEs (TEAEs), local allergic swelling (mouth or throat), systemic allergic reactions, and asthma-related treatment-related AEs (TRAEs) were calculated. RESULTS: Among adults (n = 3314) and children (n = 881), 24% and 31%, respectively, had reported asthma. No serious local allergic swellings or serious systemic allergic reactions occurred in subjects with asthma treated with SLIT-tablet. There was no evidence of increased TEAEs, systemic allergic reactions, or severe local allergic swellings in adults or children with asthma treated with grass SLIT-tablet versus subjects without asthma in or outside of pollen season. There were 6/120 asthma-related TRAEs assessed as severe with grass SLIT-tablet and 2/60 with placebo, without a consistent trend among subjects with and without asthma (5 and 3 events, respectively). CONCLUSIONS: In the AR/C subjects with reported well-controlled mild asthma included in these studies, grass SLIT-tablet did not increase TEAE frequency, severe local allergic swelling, or systemic allergic reactions versus subjects without asthma. There was no indication that treatment led to acute asthma worsening.

Duration of day care attendance during infancy predicts asthma at the age of seven: the Cincinnati Childhood Allergy and Air Pollution Study.

BACKGROUND: Studies vary with respect to the reported effects of day care attendance on childhood asthma. OBJECTIVES: To evaluate the independent and combined effects of day care attendance and respiratory infections on the development of asthma at the age of seven in a prospective birth cohort. METHOD: At the age of seven, the study sample included 589 children with complete data of 762 enrolled at birth. Day care hours and number of respiratory infections were reported in follow-up questionnaires through age four. At 7 years of age, asthma was diagnosed in 95 children (16%), based on predefined symptoms criteria confirmed by either asthma FEV1 reversibility after bronchodilator or a positive methacholine test (PC20 ≤ 4 mg/mL). Logistic regression was used to investigate the relationships between asthma at the age of seven, cumulative hours of day care attendance and reported respiratory infections at ages 1-4. RESULTS: In the univariate analyses, day care attendance at 12 months was associated with an increased risk of asthma [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.1-3.0]. Both upper and lower respiratory infections at 12 months also increased the likelihood of asthma [OR = 2.4 (1.4-4.1); OR = 2.3 (1.5-3.7), respectively]. In the final multivariate logistic model, cumulative hours of day care attendance and number of lower respiratory infections at 12 months were associated with asthma [OR = 1.2 (1.1-1.5); OR = 1.4 (1.2-1.7), respectively]. However, a threshold of greater than 37.5 hours per week of day care attendance was associated with a lower risk of asthma [OR = 0.6 (0.4-0.9)]. CONCLUSION: Depending on duration of attendance, day care during infancy can either increase or reduce risk of asthma at the age of seven.

Bivalirudin use in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Insights from the prospective, multi-centre EUROVISION registry.

BACKGROUND: The effectiveness of bivalirudin in patients undergoing percutaneous coronary intervention for acute myocardial infarction has been tested in clinical trials, but its use in a real-world scenario has never been reported. METHODS: From the total number of patients enrolled in the EUROVISION registry, 678 subjects affected by ST-elevation myocardial infarction were selected and included in the analysis. Posology and usage patterns of bivalirudin, as evaluated by dose and time of drug bolus and infusion administered, were evaluated. The 30-day outcome has been assessed by efficacy and safety endpoints. RESULTS: All patients received an initial intravenous bolus of bivalirudin (0.70±0.25 mg/kg) followed by an infusion (1.58±0.47 mg/kg/h; duration: 60 [30, 107] min) in 99.3% of cases. An additional bolus (0.49±0.06 mg/kg) was administered in 9.3% of patients. Bivalirudin infusion was prolonged after procedure in 62.2%. Death occurred in 2.1% of patients, non-fatal myocardial reinfarction in 0.3%, unplanned revascularization in 0.6% and non-fatal stroke in 0.4%. Acute stent thrombosis was not observed. Major bleeding occurred in 1.5% of patients. CONCLUSIONS: Bivalirudin usage in the setting of primary PCI provided excellent results in terms of 30-day outcome even in a real-world population.

A comparative analysis of symptom and medication scoring methods used in clinical trials of sublingual immunotherapy for seasonal allergic rhinitis.

Symptom and medication use are the key outcomes for assessing the efficacy of subcutaneous (SCIT) and sublingual allergen immunotherapy (SLIT). Our objective was to explore the similarities and differences between existing scoring mechanisms used in clinical trials of SLIT for seasonal allergens and characterize the impact that such differences may have on efficacy reporting. Randomized, double-blind, placebo-controlled clinical trials investigating the efficacy of SLIT for seasonal allergic rhinitis (2009-2013) were selected for review. Simulated and published data were used to demonstrate differences in scoring methods. Symptom and medication scoring methods across trials, although all designed to achieve the same objective, included important differences. The maximum daily symptom score (DSS) can vary widely depending on the number of symptoms assessed, and terminology of symptoms is not consistent. Similarly, daily medication scoring (DMS) methods differ greatly among studies and are dependent on medications allowed and weighting of scores assigned to each medication. When published DSS and DMS scores were used to calculate simulated daily combined scores (DCSs) based on various published methods, changes from placebo ranged from 19% to 29% when assuming all variables other than the DSS and DMS methods were equal. Variations in trial design, analysis, and seasonal characteristics also have effects on symptom and medication scoring outcomes. We identified multiple differences in trial scoring methods and design that make comparison among trials difficult. Symptom, medication, or combined scores cannot be indirectly compared among trials without taking the methods of scoring and other trial differences into account.

Magnitude of efficacy measurements in grass allergy immunotherapy trials is highly dependent on pollen exposure.

BACKGROUND: The objective was to evaluate the association between grass pollen exposure, allergy symptoms and impact on measured treatment effect after grass sublingual immunotherapy (SLIT)-tablet treatment. METHODS: The association between grass pollen counts and total combined rhinoconjunctivitis symptom and medication score (TCS) was based on a post hoc analysis of data collected over six trials and seven grass pollen seasons across North America and Europe, including 2363 subjects treated with grass SLIT-tablet or placebo. Daily pollen counts were obtained from centralized pollen databases. The effect of treatment on the relationship between the TCS and pollen counts was investigated, and the relative difference between grass SLIT-tablet and placebo as a function of average grass pollen counts was modelled by linear regression. RESULTS: The magnitude of treatment effect based on TCS was greater with higher pollen exposure (P < 0.001). The relative treatment effect in terms of TCS for each trial was correlated with the average grass pollen exposure during the first period of the season, with predicted reduction in TCS = 12% + 0.35% × pollen count (slope significantly different from 0, P = 0.003; R(2)  = 0.66). Corresponding correlations to the entire grass pollen season and to the peak season were equally good, whereas there was a poor correlation between difference in measured efficacy and pollen exposure during the last part of the season. CONCLUSIONS: In seasonal allergy trials with grass SLIT-tablet, the observed treatment effect is highly dependent on pollen exposure with the magnitude being greater with higher pollen exposure. This is an important relationship to consider when interpreting individual clinical trial results.

Safety and immunogenicity of a glycoprotein D genital herpes vaccine in healthy girls 10-17 years of age: results from a randomised, controlled, double-blind trial.

OBJECTIVE: The investigational AS04-adjuvanted herpes simplex virus type 2 (HSV-2) glycoprotein D (gD2) subunit prophylactic vaccine ('HSV vaccine'; GlaxoSmithKline Vaccines) has been shown to be well tolerated in adults, but limited data exist for pre-teen and adolescent girls, a likely target population. The primary objective of this study was to compare the occurrence of serious adverse events (SAEs) over 12 months between HSV vaccine recipients and saline recipients (placebo control group) in pre-teen and adolescent girls. The immunogenicity of the HSV vaccine was also assessed. METHODS: Healthy girls aged 10-17 years, stratified by age (10-15 years; 16-17 years), were randomised 2:1:1 to receive the HSV vaccine, a hepatitis A vaccine (Havrix™; HAV control) or placebo (saline) according to a 0-, 1-, 6-month schedule. Participants and study personnel not involved in the preparation or administration of vaccines were blinded to treatment. Safety and immunogenicity analyses were performed overall and by age (10-15 years; 16-17 years) and HSV serostatus. RESULTS: No statistically significant difference in the percentage of subjects with SAEs was observed between the HSV and saline group, or between the HSV and pooled control (HAV and saline) groups. The HSV vaccine was well tolerated, although a higher incidence of solicited local symptoms was observed in the HSV group than in the control group. Neither age nor HSV serostatus at the time of study entry had an impact on the safety profile of this vaccine. The HSV vaccine was immunogenic regardless of pre-vaccination HSV serostatus. Higher anti-gD geometric mean concentrations were observed in HSV-1 seropositive participants than in HSV-1 seronegative participants. CONCLUSION: The HSV vaccine had an acceptable safety profile, and was well tolerated and immunogenic when administered to girls aged 10-17 years regardless of age or HSV pre-vaccination serostatus.

Nanoscale spin reversal by non-local angular momentum transfer following ultrafast laser excitation in ferrimagnetic GdFeCo.

Ultrafast laser techniques have revealed extraordinary spin dynamics in magnetic materials that equilibrium descriptions of magnetism cannot explain. Particularly important for future applications is understanding non-equilibrium spin dynamics following laser excitation on the nanoscale, yet the limited spatial resolution of optical laser techniques has impeded such nanoscale studies. Here we present ultrafast diffraction experiments with an X-ray laser that probes the nanoscale spin dynamics following optical laser excitation in the ferrimagnetic alloy GdFeCo, which exhibits macroscopic all-optical switching. Our study reveals that GdFeCo displays nanoscale chemical and magnetic inhomogeneities that affect the spin dynamics. In particular, we observe Gd spin reversal in Gd-rich nanoregions within the first picosecond driven by the non-local transfer of angular momentum from larger adjacent Fe-rich nanoregions. These results suggest that a magnetic material's microstructure can be engineered to control transient laser-excited spins, potentially allowing faster (~ 1 ps) spin reversal than in present technologies.

Optimized threshold for serum HCV RNA to predict treatment outcomes in hepatitis C patients receiving peginterferon alfa-2a/ribavirin.

It is unclear whether the current threshold for 'high' hepatitis C virus (HCV) RNA level (800,000 IU/mL) is optimal for predicting sustained virological response (SVR). We retrospectively analysed pretreatment HCV RNA levels and SVR rates in 1529 mono-infected and 176 HIV-HCV co-infected patients treated with peginterferon alfa-2a (40 kD) plus ribavirin. We improved the threshold for differentiating low and high viral load by fitting semiparametric generalized additive logistic regression models to the data and constructing receiver operating characteristics curves. Among HCV genotype 1 mono-infected patients, the difference in SVR rates between those with low and high baseline HCV RNA levels was 27% (70%vs 43%) when 400,000 IU/mL was used and 16% (59%vs 43%) when 800,000 IU/mL was used. In HIV-HCV genotype 1 co-infected patients, the difference was 51% (71%vs 20%) when 400,000 IU/mL was used and 43% (61%vs 18%) when 800,000 IU/mL was used. A lower threshold (200,000 IU/mL) was identified for genotype 1 mono-infected patients with 'normal' alanine aminotransferase (ALT) levels. No threshold could be identified in HCV genotype 2 or 3 patients. A threshold HCV RNA level of 400,000 IU/mL is optimal for differentiating high and low probability of SVR in genotype 1-infected individuals with elevated ALT.