A Prospective Real-World Multi-Center Study to Evaluate Progression-Free and Overall Survival of Radiotherapy with Cetuximab and Platinum-Based Chemotherapy with Cetuximab in Locally Recurrent Head and Neck Cancer.

Treatment options of locoregional recurrent head and neck squamous cell cancer (HNSCC) include both local strategies as surgery or re-radiotherapy and systemic therapy. In this prospective, multi-center, non-interventional study, patients were treated either with platinum-based chemotherapy and cetuximab (CT + Cet) or re-radiotherapy and cetuximab (RT + Cet). In the current analysis, progression-free survival (PFS) and overall survival (OS) were compared in patients with locoregional recurrence. Four hundred seventy patients were registered in 97 German centers. After exclusion of patients with distant metastases, a cohort of 192 patients was analyzed (129 CT + Cet, 63 RT + Cet). Radiotherapy was delivered as re-irradiation to 70% of the patients. The mean radiation dose was 51.8 Gy, whereas a radiation dose of ≥60 Gy was delivered in 33% of the patients. Chemotherapy mainly consisted of cisplatin/5-flurouracil (40%) or carboplatin/5-flurouracil (29%). The median PFS was 9.2 months in the RT + Cet group versus 5.1 months in the CT + Cet group (hazard ratio for disease progression or death, 0.40, 95% CI, 0.27-0.57, p < 0.0001). Median OS was 12.8 months in the RT + Cet group versus 7.9 months in the CT + Cet group (hazard ratio for death, 0.50, 95% CI, 0.33-0.75, p = 0.0008). In conclusion, radiotherapy combined with cetuximab improved survival compared to chemotherapy combined with cetuximab in locally recurrent HNSCC.

Treatment response lowers tumor symptom burden in recurrent and/or metastatic head and neck cancer.

BACKGROUND: Head and neck squamous cell cancer (HNSCC) frequently causes severe symptoms that may be reduced, when the tumor is successfully treated. The SOCCER trial studied the association of treatment response with patient reported tumor symptom burden in first line treatment of recurrent and/or metastatic HNSCC. METHODS: In this prospective, multi-center, non-interventional trial patients were treated either with platinum-based chemotherapy and cetuximab or radiotherapy and cetuximab. Tumor symptom burden was assessed every four weeks with a questionnaire containing ten visual analogue scales (VAS, range 0-100), which were summarized to the overall VAS score. RESULTS: Fourhundred seventy patients were registered in 97 German centers. A total of 315 patients with at least the baseline and one subsequent questionnaire were available for analysis. Changes in the VAS score were rated as absolute differences from baseline. Negative values indicate improvement of symptoms. The overall VAS score improved significantly at the first post-baseline assessment in responders (- 2.13 vs. non-responders + 1.15, p = 0.048), and even more for the best post-baseline assessment (- 7.82 vs. non-responders - 1.97, p = 0.0005). The VAS for pain (- 16.37 vs. non-responders - 8.89, p = 0.001) and swallowing of solid food (- 16.67 vs. non-responders - 5.06, p = 0.002) improved significantly more in responders (best post-baseline assessment). In the multivariable Cox regression analysis, worse overall VAS scores were associated with worse overall survival (hazard ratio for death 1.12 per 10 points increment on the overall VAS scale, 95% CI 1.05-1.20, p = 0.0009). CONCLUSION: In unselected patients beyond randomized controlled trials, treatment response lowers tumor symptom burden in recurrent and/or metastatic HNSCC. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00122460 . Registered 22 Juli 2005.

XAS investigation of silica aerogel supported cobalt rhenium catalysts for ammonia decomposition.

The implementation of ammonia as a hydrogen vector relies on the development of active catalysts to release hydrogen on-demand at low temperatures. As an alternative to ruthenium-based catalysts, herein we report the high activity of silica aerogel supported cobalt rhenium catalysts. XANES/EXAFS studies undertaken at reaction conditions in the presence of the ammonia feed reveal that the cobalt and rhenium components of the catalyst which had been pre-reduced are initially re-oxidised prior to their subsequent reduction to metallic and bimetallic species before catalytic activity is observed. A synergistic effect is apparent in which this re-reduction step occurs at considerably lower temperatures than for the corresponding monometallic counterpart materials. The rate of hydrogen production via ammonia decomposition was determined to be 0.007 molH2 gcat-1 h-1 at 450 °C. The current study indicates that reduced Co species are crucial for the development of catalytic activity.

Attenuation Coefficients of Tubular Conduits for Liquid Phase Absorbance Measurement: Shot Noise Limited Optimum Path Length.

We trace the history of liquid core waveguides (LCWs, also called liquid core optical fibers) and the role Teflon AF (TAF) has played in their development. We show that, in any shot noise limited situation, the optimum signal-to-noise ratio (S/N) occurs at a path length of 1/αa{ln[1 + 2(αa/αb)]}, approximately 2/αb under most conditions, αa and αb being the light attenuation coefficient due to the analyte and the background, respectively. The analysis shows that LCW length should be selected depending on the applicable αb value. An overly long LCW may exhibit a lower signal-to-noise ratio. Water-filled TAF-clad fused-silica (FS) tubes show the lowest attenuation across the wavelength range. Nevertheless, except at λ ≥ 600 nm, the observed αb values far exceed those reported for pure water: it appears that both impurities in the water and waveguide losses are involved. In examining the attenuation in various water-filled tubes, we find that the transmission of air-surrounded FS tubes is second only to TAF-clad FS tubes and is better than that of TAF tubes or externally mirrored FS tubes. Surprisingly, except for a window centered at ∼250 nm, light transmission in a water-filled poly(tetrafluoroethylene) (PTFE) tube is worse than in poly(ether ether ketone) (PEEK) tubing. Light transmission in PTFE tubes improves with increasing wall thickness.

G-index: A new metric to describe dynamic refractive index effects in HPLC absorbance detection.

High performance liquid chromatography (HPLC) with a solvent gradient and absorbance detection is one of the most widely used methods in analytical chemistry. The observed absorbance baseline is affected by the changes in the refractive index (RI) of the mobile phase. Near the limited of detection, this complicates peak quantitation. The general aspects of these RI-induced apparent absorbance effects are discussed. Two different detectors with fundamentally different optics and flow cell concepts, a variable-wavelength detector equipped with a conventional flow cell and a diode-array detector equipped with a liquid core waveguide flow cell, are compared with respect to their RI behavior. A simple method to separate static - partly unavoidable - RI effects from dynamic RI effects is presented. It is shown that the dynamic RI behavior of an absorbance detector can be well described using a single, relatively easy-to-determine metric called the G-index. The G-index is typically in the order of a few seconds and its sign depends on the optical flow cell concept.

Flow-Cell-Induced Dispersion in Flow-through Absorbance Detection Systems: True Column Effluent Peak Variance.

Following a brief overview of the emergence of absorbance detection in liquid chromatography, we focus on the dispersion caused by the absorbance measurement cell and its inlet. A simple experiment is proposed wherein chromatographic flow and conditions are held constant but a variable portion of the column effluent is directed into the detector. The temporal peak variance (σt,obs2), which increases as the flow rate (F) through the detector decreases, is found to be well-described as a quadratic function of 1/F. This allows the extrapolation of the results to zero residence time in the detector and thence the determination of the true variance of the peak prior to the detector (this includes contribution of all preceding components). This general approach should be equally applicable to detection systems other than absorbance. We also experiment where the inlet/outlet system remains the same but the path length is varied. This allows one to assess the individual contributions of the cell itself and the inlet/outlet system.to the total observed peak. The dispersion in the cell itself has often been modeled as a flow-independent parameter, dependent only on the cell volume. Except for very long path/large volume cells, this paradigm is simply incorrect.

Molecular absorption measurements with an optical fibre coupled array of ultra-violet light-emitting diodes.

A photometric detector based on eight different light-emitting diodes covering the ultraviolet range from 255 nm to 350 nm is described. These are coupled with fused silica optical fibres to a conventional cuvette with 1 cm optical path length or to a low volume flow through cell for detection in high-performance liquid chromatography. Photodiodes are employed for the measurement of the transmitted intensity as well as of a reference signal and the photocurrents are processed with a log-ratio amplifier to obtain a voltage proportional to absorbance values. The wavelength desired for the measurement at hand is selected by electronically switching on the requisite light-emitting diode. The detector was found to have a low noise level of 80 µAU. In batch-wise measurements as well as in detection for high-performance liquid chromatography dynamic ranges of 2-3 orders of magnitude were possible. Reproducibilities in peak areas for the latter application were better than 1%.

Width Based Quantitation of Chromatographic Peaks: Principles and Principal Characteristics.

Height- and area-based quantitation reduce two-dimensional data to a single value. For a calibration set, there is a single height- or area-based quantitation equation. High-speed high-resolution data acquisition now permits rapid measurement of the width of a peak (Wh), at any height h (a fixed height, not a fixed fraction of the peak maximum) leading to any number of calibration curves. We propose a width-based quantitation (WBQ) paradigm complementing height or area based approaches. When the analyte response across the measurement range is not strictly linear, WBQ can offer superior overall performance (lower root-mean-square relative error over the entire range) compared to area- or height-based linear regression methods, rivaling weighted linear regression, provided that response is uniform near the height used for width measurement. To express concentration as an explicit function of width, chromatographic peaks are modeled as two different independent generalized Gaussian distribution functions, representing, respectively, the leading/trailing halves of the peak. The simple generalized equation can be expressed as Wh = p(ln h̅)q, where h̅ is hmax/h, hmax being the peak amplitude, and p and q being constants. This fits actual chromatographic peaks well, allowing explicit expressions for Wh. We consider the optimum height for quantitation. The width-concentration relationship is given as ln C = aWhn + b, where a, b, and n are constants. WBQ ultimately performs quantitation by projecting hmax from the width, provided that width is measured at a fixed height in the linear response domain. A companion paper discusses several other utilitarian attributes of width measurement.

Width Based Characterization of Chromatographic Peaks: Beyond Height and Area.

The preceding paper ( Anal. Chem. 2017 , 10.1021/acs.analchem.6b04857 ) introduced width-based quantitation (WBQ). The present paper focuses on (1) situations where WBQ is effective while height/area-based linear calibrations fail, e.g., when (a) the detector is in a nonlinear response region, (b) the detector/data system is saturated, causing clipping/truncation of the signal, or (c) the detector signal is not a single-valued function of concentration, as when a fluorescence signal goes into the self-quenched domain. (2) Utilization of WBQ in postcolumn reagent addition methods where the reagent produces a significant detector background. WBQ can minimize added reagent without sacrificing the upper determination limit; a limited reagent amount truncates peaks from high analyte concentrations but does not hamper WBQ at a low height. (3) A description of peak asymmetry via leading/trailing half-widths vs relative height (fraction of maximum height) plots. (4) A holistic description of chromatographic peaks through six parameters describing the two independent generalized Gaussian distributions that underlie the WBQ chromatographic peak model. (5) Characterization of shape by widths at multiple heights and shape-based impurity detection.

Pretreatment Cardiometabolic Status in Youth With Early-Onset Psychosis: Baseline Results From the TEA Trial.

OBJECTIVE: To describe pretreatment cardiometabolic constitution in children and adolescents with first-episode psychosis (FEP). METHODS: Baseline cardiometabolic assessment was performed in youths aged 12-17 years with FEP entering the Tolerability and Efficacy of Antipsychotics (TEA) trial and matched healthy controls. Patients were included between June 10, 2010, and January 29, 2014. ICD-10 was used as the diagnostic classification system. Cardiometabolic risk markers were compared between patients versus controls and antipsychotic-naive versus antipsychotic-exposed patients. RESULTS: Comparing 113 youths with FEP (age ± SD = 15.74 ± 1.36 years, males = 30.1%, schizophrenia-spectrum disorders = 92.9%, antipsychotic-naive: n = 57) to 60 controls, patients had higher waist circumference (WC) z scores (1.13 ± 1.65 vs 0.42 ± 1.27, P = .018), cholesterol (4.10 ± 0.71 vs 3.79 ± 0.49 mmol/L, P = .014), low-density lipoproteins (2.37 ± 0.56 vs 2.13 ± 0.51, P = .012), and non-high-density lipoproteins (2.58 ± 1.60 vs 2.52 ± 0.52, P = .018). More patients than controls (42.9% vs 20.3%, P = .019) and antipsychotic-naive than antipsychotic-exposed (51.9% vs 34.0%, P = .023) had a WC > 90th percentile. Hypercholesterolemia (34.0% vs 12.5%, P = .015) was more frequent in patients, while decreased high-density lipoprotein cholesterol was more frequent in controls (32.5% vs 19.0%, P = .032). Family history of type 2 diabetes mellitus was associated with increased body mass index (BMI) z score (P < .001), WC z score (P = .001), insulin (P = .038), and homeostatic model assessment of insulin resistance (HOMA-IR; P = .025). Dyslipidemia was associated with significantly increased insulin (P = .041), HOMA-IR (P = .032), and low-density lipoprotein cholesterol (P = .041). Previous antipsychotic exposure was not associated with increased cardiometabolic risk. Early age at onset predicted increased BMI and WC z scores, while diagnosis of schizophrenia and higher Clinical Global Impression-Severity score were associated with increased blood lipids. CONCLUSIONS: Youths with FEP had significantly greater WC and lipid abnormalities than matched controls, regardless of antipsychotic exposure. In youths with FEP, elevated metabolic risk predates antipsychotic exposure. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01119014; European Clinical Trials Database (EudraCT): 2009-016715-38​​​.

German MedicalTeachingNetwork (MDN) implementing national standards for teacher training.

BACKGROUND: An increasing demand for proof of professionalism in higher education strives for quality assurance (QA) and improvement in medical education. A wide range of teacher trainings is available to medical staff in Germany. Cross-institutional approval of individual certificates is usually a difficult and time consuming task for institutions. In case of non-acceptance it may hinder medical teachers in their professional mobility. AIM: The faculties of medicine aimed to develop a comprehensive national framework, to promote standards for formal faculty development programmes across institutions and to foster professionalization of medical teaching. METHODS AND RESULTS: Addressing the above challenges in a joint approach, the faculties set up the national MedicalTeacherNetwork (MDN). Great importance is attributed to work out nationally concerted standards for faculty development and an agreed-upon quality control process across Germany. Medical teachers benefit from these advantages due to portability of faculty development credentials from one faculty of medicine to another within the MDN system. CONCLUSION: The report outlines the process of setting up the MDN and the national faculty development programme in Germany. Success factors, strengths and limitations are discussed from an institutional, individual and general perspective. Faculties engaged in similar developments might be encouraged to transfer the MDN concept to their countries.

Highly flexible UV-vis radiation sources and novel detection schemes for spectrophotometric HPLC detection.

The concept and performance of the first multiwavelength deep UV light-emitting-diode-based high-performance liquid chromatography (HPLC) absorbance detector are presented. In single-wavelength mode and with optical reference, the limit of detection (LOD) is comparable to conventional state-of-the-art HPLC absorbance detectors. In multiwavelength mode--at present up to eight wavelengths without optical reference--the LOD is about 10 times higher than in single-wavelength mode. Multiplexing and demultiplexing methods are used to separate chromatographic signals in multiwavelength mode and keeps the detector configuration simple and yet flexible. Depending on the operation mode, stray light is either totally negligible or controlled electronically and digitally.

Using an audience response system to improve learning success in practical skills training courses in dental studies - a randomised, controlled cross-over study.

INTRODUCTION: The aim of this study was to examine whether the use of an audience response system (ARS) in a high-quality study design, in a course in pre-clinical dentistry leads to an improvement in cognitive and psycho-motor performance. MATERIALS AND METHODS: As part of the Phantom Course I, a randomised, controlled study in cross-over design with 63 students was conducted over 4 weeks. The intervention was carried out by means of an ARS (TurningPoint(®) ), while a verbal question-and-answer session was conducted within the control group. Differences in learning success were determined via a formative multiple-choice (MC) test (cognitive) and a summative practical test (psycho-motor). RESULTS: Both groups achieved significantly better results in the MC tests with the use of the intervention, when compared with the control group (group A 11.6 vs. 9.5 and group B 13.7 vs. 12.1, maximum 16 points). A further analysis of the results showed that the overall effect was induced primarily by a marked improvement in below-average students. The practical tests showed no clear effect. Despite the careful selection and set-up of the conditions for the study in the regular course of the semester, a cohort effect emerged. This was due to varying degrees of performance between the two groups, because no adequate performance parameters were available, which could have been taken into account for the stratified randomisation. CONCLUSIONS: The results indicate that the use of the ARS leads to better results in cognitive performance, especially where independent learning is required and should be encouraged. Weaker students in particular seem to benefit.

Influence of pollen transport dynamics on sire profiles and multiple paternity in flowering plants.

In many flowering plants individual fruits contain a mixture of half- and full- siblings, reflecting pollination by several fathers. To better understand the mechanisms generating multiple paternity within fruits we present a theoretical framework linking pollen carryover with patterns of pollinator movement. This 'sire profile' model predicts that species with more extensive pollen carryover will have a greater number of mates. It also predicts that flowers on large displays, which are often probed consecutively during a single pollinator visitation sequence, will have a lower effective number of mates. We compared these predictions with observed values for bumble bee-pollinated Mimulus ringens, which has restricted carryover, and hummingbird-pollinated Ipomopsis aggregata, which has extensive carryover. The model correctly predicted that the effective number of mates is much higher in the species with more extensive carryover. This work extends our knowledge of plant mating systems by highlighting mechanisms influencing the genetic composition of sibships.

Relation between chromatographic resolution and signal-to-noise ratio in spectrophotometric HPLC detection.

Absorption spectrophotometry has been and still is the industry standard for detection in HPLC. Limit of detection (LOD) and linear dynamic range (LDR) are the primary performance requirements and have driven continuous improvement of spectrophotometric HPLC detectors. Recent advances in HPLC column technology have led to low flow-rate HPLC such as capillary HPLC and nanoflow HPLC and put higher demands on optical HPLC signal detection. However, fundamental principles in spectrophotometric HPLC detection have not been reviewed for many years. In particular the relationship between the detector's signal-to-noise ratio (SNR) and band broadening needs to be re-evaluated. In this work, a new quantitative model is presented which allows the calculation of the trade-off made between chromatographic resolution and SNR in spectrophotometric HPLC detection. Modern optics flow cells based on total internal reflection are included and compared to conventional flow cells.

The influence of distinct pollinators on female and male reproductive success in the Rocky Mountain columbine.

Although there are many reasons to expect distinct pollinator types to differentially affect a plant's reproductive success, few studies have directly examined this question. Here, we contrast the impact of two kinds of pollinators on reproductive success via male and female functions in the Rocky Mountain columbine, Aquilegia coerulea. We set up pollinator exclusion treatments in each of three patches where Aquilegia plants were visited by either day pollinators (majority bumble bees), by evening pollinators (hawkmoths), or by both (control). Day pollinators collected pollen and groomed, whereas evening pollinators collected nectar but did not groom. Maternal parents, potential fathers and progeny arrays were genotyped at five microsatellite loci. We estimated female outcrossing rate and counted seeds to measure female reproductive success and used paternity analysis to determine male reproductive success. Our results document that bumble bees frequently moved pollen among patches of plants and that, unlike hawkmoths, pollen moved by bumble bees sired more outcrossed seeds when it remained within a patch as opposed to moving between patches. Pollinator type differentially affected the outcrossing rate but not seed set, the number of outcrossed seeds or overall male reproductive success. Multiple visits to a plant and more frequent visits by bumble bees could help to explain the lack of impact of pollinator type on overall reproductive success. The increase in selfing rate with hawkmoths likely resulted from the abundant pollen available in experimental flowers. Our findings highlighted a new type of pollinator interactions that can benefit a plant species.

Pollinator visitation patterns strongly influence among-flower variation in selfing rate.

BACKGROUND AND AIMS: Adjacent flowers on Mimulus ringens floral displays often vary markedly in selfing rate. We hypothesized that this fine-scale variation in mating system reflects the tendency of bumble-bee pollinators to probe several flowers consecutively on multiflower displays. When a pollinator approaches a display, the first flower probed is likely to receive substantial outcross pollen. However, since pollen carryover in this species is limited, receipt of self pollen should increase rapidly for later flowers. Here the first direct experimental test of this hypothesis is described. METHODS: In order to link floral visitation sequences with selfing rates of individual flowers, replicate linear arrays were established, each composed of plants with unique genetic markers. This facilitated unambiguous assignment of paternity to all sampled progeny. A single wild bumble-bee was permitted to forage on each linear array, recording the order of floral visits on each display. Once fruits had matured, 120 fruits were harvested (four flowers from each of five floral displays in each of six arrays). Twenty-five seedlings from each fruit were genotyped and paternity was unambiguously assigned to all 3000 genotyped progeny. KEY RESULTS: The order of pollinator probes on Mimulus floral displays strongly and significantly influenced selfing rates of individual fruits. Mean selfing rates increased from 21 % for initial probes to 78 % for the fourth flower probed on each display. CONCLUSIONS: Striking among-flower differences in selfing rate result from increased deposition of geitonogamous (among-flower, within-display) self pollen as bumble-bees probe consecutive flowers on each floral display. The resulting heterogeneity in the genetic composition of sibships may influence seedling competition and the expression of inbreeding depression.

Patterns of multiple paternity in fruits of Mimulus ringens (Phrymaceae).

Multiply sired fruits provide unambiguous evidence that pollen from two or more donors was deposited on a stigma and successfully fertilized ovules. Such multiple paternity within fruits can have important consequences for both parental and offspring fitness, but little is known about the frequency of multiple paternity or the mechanisms causing it. In this study we quantify the extent of multiple paternity in replicate experimental arrays of Mimulus ringens (square-stem monkeyflower) and use observations of pollinator behavior to infer mechanisms generating multiply sired fruits. In each array, floral displays were trimmed to two, four, eight, or 16 flowers per plant to span the range of display sizes observed in nature. In our sample of 204 fruits, more than 95% had two or more outcross pollen donors. The number of sires per fruit averaged 4.63 ± 0.10 (mean ± 1 SE), including selfs, and did not vary significantly with floral display treatment. Patterns of bumble bee foraging, combined with limited pollen carryover, suggest that observed levels of multiple paternity cannot be fully explained by single probes that deposited mixed pollen loads. Multiple probes to flowers, each delivering pollen from 1-3 different sires, are more likely to have caused the observed patterns. These sequential visits may reduce the potential for pollen competition and female choice based on pollen tube growth rate.

Control of triglyceride storage by a WD40/TPR-domain protein.

Obesity is a metabolic disorder related to improper control of energy uptake and expenditure, which results in excessive accumulation of body fat. Initial insights into the genetic pathways that regulate energy metabolism have been provided by a discrete number of obesity-related genes that have been identified in mammals. Here, we report the identification of the adipose (adp) gene, the mutation of which causes obesity in Drosophila. Loss of adp activity promotes increased fat storage, which extends the lifespan of mutant flies under starvation conditions. By contrast, adp gain-of-function causes a specific reduction of the fat body in Drosophila. adp encodes an evolutionarily conserved WD40/tetratricopeptide-repeat-domain protein that is likely to represent an intermediate in a novel signalling pathway.

Denitrifying Bacteria in the Earthworm Gastrointestinal Tract and In Vivo Emission of Nitrous Oxide (N(inf2)O) by Earthworms.

Earthworms (Lumbricus rubellus and Octolasium lacteum) and gut homogenates did not produce CH(inf4), and methanogens were not readily culturable from gut material. In contrast, the numbers of culturable denitrifiers averaged 7 x 10(sup7) and 9 x 10(sup6) per g (dry weight) of gut material for L. rubellus and O. lacteum, respectively; these values were 256- and 35-fold larger than the numbers of culturable denitrifiers in the soil from which the earthworms were obtained. Anaerobically incubated earthworm gut homogenates supplemented with nitrate produced N(inf2)O at rates exceeding that of soil homogenates. Furthermore, living earthworms emitted N(inf2)O under aerobic conditions, and N(inf2)O emission was stimulated by acetylene. For earthworms collected from a mildly acidic (pH 6) beech forest soil, the rates of N(inf2)O emission for earthworms and soil averaged 884 and 2 pmol per h per g (fresh weight), respectively. In contrast, for earthworms collected from a more acidic (pH 4.6) oak-beech forest soil, N(inf2)O emission by earthworms and soil averaged 145 and 45 pmol per h per g (fresh weight), respectively. Based on the extrapolation of this data, earthworms accounted for an estimated 16 and 0.25% of the total N(inf2)O produced at the stand level of these beech and oak-beech forest soils, respectively.