Timing of Radiotherapy (RT) After Radical Prostatectomy (RP): Long-term outcomes in the RADICALS-RT trial [NCT00541047].

BACKGROUND: The optimal timing of radiotherapy (RT) after radical prostatectomy for prostate cancer has been uncertain. RADICALS-RT compared efficacy and safety of adjuvant RT versus an observation policy with salvage RT for PSA failure. METHODS: RADICALS-RT was a randomised controlled trial enrolling patients with ≥1 risk factor (pT3/4, Gleason 7-10, positive margins, pre-op PSA≥10ng/ml) for recurrence after radical prostatectomy. Patients were randomised 1:1 to adjuvant RT ("Adjuvant-RT") or an observation policy with salvage RT for PSA failure ("Salvage-RT") defined as PSA≥0.1ng/ml or 3 consecutive rises. Stratification factors were Gleason score, margin status, planned RT schedule (52.5Gy/20 fractions or 66Gy/33 fractions) and treatment centre. The primary outcome measure was freedom-from-distant metastasis, designed with 80% power to detect an improvement from 90% with Salvage-RT (control) to 95% at 10yr with Adjuvant-RT. Secondary outcome measures were bPFS, freedom-from-non-protocol hormone therapy, safety and patient-reported outcomes. Standard survival analysis methods were used; HR<1 favours Adjuvant-RT. FINDINGS: Between Oct-2007 and Dec-2016, 1396 participants from UK, Denmark, Canada and Ireland were randomised: 699 Salvage-RT, 697 Adjuvant-RT. Allocated groups were balanced with median age 65yr. 93% (649/697) Adjuvant-RT reported RT within 6m after randomisation; 39% (270/699) Salvage-RT reported RT during follow-up. Median follow-up was 7.8 years. With 80 distant metastasis events, 10yr FFDM was 93% for Adjuvant-RT and 90% for Salvage-RT: HR=0.68 (95%CI 0·43-1·07, p=0·095). Of 109 deaths, 17 were due to prostate cancer. Overall survival was not improved (HR=0.980, 95%CI 0.667-1.440, p=0.917). Adjuvant-RT reported worse urinary and faecal incontinence one year after randomisation (p=0.001); faecal incontinence remained significant after ten years (p=0.017). INTERPRETATION: Long-term results from RADICALS-RT confirm adjuvant RT after radical prostatectomy increases the risk of urinary and bowel morbidity, but does not meaningfully improve disease control. An observation policy with salvage RT for PSA failure should be the current standard after radical prostatectomy.

Danish Prostate Registry (DanProst) - an Updated Version of the Danish Prostate Cancer Registry, Methodology, and Early Results.

In 2016, we introduced the Danish Prostate Cancer Registry (DaPCaR) which was built on the National Pathology Register from 1995 to 2011. DaPCaR was laborious to use as most data had to be manually imputed with no regular updates. In here we present a new comprehensive centralized prostate registry called the Danish Prostate Registry (DanProst), which includes all men having undergone any histological evaluation of prostate tissue merged with laboratory-, treatment-, prescription data as well as vital status. Here the data included and the methodology of DanProst are described. DanProst is built upon all men with a histological assessment of the prostate from the Danish National Registry for Pathology. The primary histology and potential prostate cancer histological diagnosis for each unique individual is extracted and translated by newly made algorithms for topography, procedure, diagnostic conclusion, and pathological staging. Further information is added from DaPCaR, the CPR Registry, the Danish Cause of Death Registry, the Danish Cancer Registry, the National Patient Registry, the Danish Register of Laboratory Results for Research, and the Danish National Prescription Registry. The translation algorithms were validated based on the comparison with DaPCaR in the period 2010-2016. DanProst includes 190,422 men. A total of 95,152 (50%) men are diagnosed with prostate cancer until 2021. Median diagnostic PSA was 11 ng/ml, most men are diagnosed by ultrasound-guided biopsy (N = 63,751; 67%), and most frequently defined primary treatment was radical prostatectomy (N = 14,778; 19%). DanProst to DaPCaR coherency was > 99%, 95%, and 94% for the primary histological procedure, primary histological conclusion, and diagnostic histological conclusion, respectively. DanProst is a continuously updated, centrally kept, validated registry with automatic integration of data from other national registries, allowing for contemporary nationwide analysis in men with histological assessment of the prostate.

Optimized quantification of intra-host viral diversity in SARS-CoV-2 and influenza virus sequence data.

High error rates of viral RNA-dependent RNA polymerases lead to diverse intra-host viral populations during infection. Errors made during replication that are not strongly deleterious to the virus can lead to the generation of minority variants. However, accurate detection of minority variants in viral sequence data is complicated by errors introduced during sample preparation and data analysis. We used synthetic RNA controls and simulated data to test seven variant-calling tools across a range of allele frequencies and simulated coverages. We show that choice of variant caller and use of replicate sequencing have the most significant impact on single-nucleotide variant (SNV) discovery and demonstrate how both allele frequency and coverage thresholds impact both false discovery and false-negative rates. When replicates are not available, using a combination of multiple callers with more stringent cutoffs is recommended. We use these parameters to find minority variants in sequencing data from SARS-CoV-2 clinical specimens and provide guidance for studies of intra-host viral diversity using either single replicate data or data from technical replicates. Our study provides a framework for rigorous assessment of technical factors that impact SNV identification in viral samples and establishes heuristics that will inform and improve future studies of intra-host variation, viral diversity, and viral evolution. IMPORTANCE When viruses replicate inside a host cell, the virus replication machinery makes mistakes. Over time, these mistakes create mutations that result in a diverse population of viruses inside the host. Mutations that are neither lethal to the virus nor strongly beneficial can lead to minority variants that are minor members of the virus population. However, preparing samples for sequencing can also introduce errors that resemble minority variants, resulting in the inclusion of false-positive data if not filtered correctly. In this study, we aimed to determine the best methods for identification and quantification of these minority variants by testing the performance of seven commonly used variant-calling tools. We used simulated and synthetic data to test their performance against a true set of variants and then used these studies to inform variant identification in data from SARS-CoV-2 clinical specimens. Together, analyses of our data provide extensive guidance for future studies of viral diversity and evolution.

Photoelectron Spectroscopy of Oppositely Charged Molecular Switches in the Aqueous Phase: Theory and Experiment.

XUV photoelectron spectroscopy (XPS) is a powerful method for investigating the electronic structures of molecules. However, the correct interpretation of results in the condensed phase requires theoretical models that account for solvation. Here we present experimental aqueous-phase XPS of two organic biomimetic molecular switches, NAIP and p-HDIOP. These switches are structurally similar, but have opposite charges and thus present a stringent benchmark for solvation models which need to reproduce the observed ΔeBE = 1.1 eV difference in electron binding energy compared to the 8 eV difference predicted in the gas phase. We present calculations using implicit and explicit solvent models. The latter employs the average solvent electrostatic configuration and free energy gradient (ASEC-FEG) approach. Both nonequilibrium polarizable continuum models and ASEC-FEG calculations give vertical binding energies in good agreement with the experiment for three different computational protocols. Counterions, explicitly accounted for in ASEC-FEG, contribute to the stabilization of molecular states and reduction of ΔeBE upon solvation.

Optimized Quantification of Intrahost Viral Diversity in SARS-CoV-2 and Influenza Virus Sequence Data.

High error rates of viral RNA-dependent RNA polymerases lead to diverse intra-host viral populations during infection. Errors made during replication that are not strongly deleterious to the virus can lead to the generation of minority variants. However, accurate detection of minority variants in viral sequence data is complicated by errors introduced during sample preparation and data analysis. We used synthetic RNA controls and simulated data to test seven variant calling tools across a range of allele frequencies and simulated coverages. We show that choice of variant caller, and use of replicate sequencing have the most significant impact on single nucleotide variant (SNV) discovery and demonstrate how both allele frequency and coverage thresholds impact both false discovery and false negative rates. We use these parameters to find minority variants in sequencing data from SARS-CoV-2 clinical specimens and provide guidance for studies of intrahost viral diversity using either single replicate data or data from technical replicates. Our study provides a framework for rigorous assessment of technical factors that impact SNV identification in viral samples and establishes heuristics that will inform and improve future studies of intrahost variation, viral diversity, and viral evolution. IMPORTANCE: When viruses replicate inside a host, the virus replication machinery makes mistakes. Over time, these mistakes create mutations that result in a diverse population of viruses inside the host. Mutations that are neither lethal to the virus, nor strongly beneficial, can lead to minority variants that are minor members of the virus population. However, preparing samples for sequencing can also introduce errors that resemble minority variants, resulting in inclusion of false positive data if not filtered correctly. In this study, we aimed to determine the best methods for identification and quantification of these minority variants by testing the performance of seven commonly used variant calling tools. We used simulated and synthetic data to test their performance against a true set of variants, and then used these studies to inform variant identification in data from clinical SARS-CoV-2 clinical specimens. Together, analyses of our data provide extensive guidance for future studies of viral diversity and evolution.

Experimental and theoretical threshold photoelectron spectra of methylene.

The threshold photoelectron spectrum of methylene (CH2), produced by consecutive H atom abstractions on methane, has been recorded using synchrotron radiation. The experimental spectrum spans the region of the X + 2Π u ← X 3 B 1 ionizing transition. It is modeled starting from ab initio bending potentials and using the bending approach introduced by Coudert et al. [J. Chem. Phys. 148, 054302 (2018)] accounting for the quasilinearity of CH2 and the strong Renner-Teller interaction in CH 2 + . This first calculation yields a theoretical threshold photoelectron spectrum which is in moderate agreement with the experimental one. A more accurate approach treating the three vibrational modes is developed for computing the threshold photoelectron spectrum of triatomic C 2 v molecules. This new treatment is tested modeling the already measured threshold photoelectron spectrum of the X + 2Π u ← X 1 A 1 ionizing transition of the water molecule. The threshold photoelectron spectrum of CH2 computed with the new approach compares more favorably with the experimental spectrum and yields an adiabatic ionization potential of 10.386(6) eV.

Test methods for estimating the efficacy of the fast-acting disinfectant peracetic acid on surfaces of personal protective equipment.

AIMS: The work aimed at developing and evaluating practically relevant methods for testing of disinfectants on contaminated personal protective equipment (PPE). METHODS AND RESULTS: Carriers were prepared from PPE fabrics and contaminated with Bacillus subtilis spores. Peracetic acid (PAA) was applied as a suitable disinfectant. In method 1, the contaminated carrier was submerged in PAA solution; in method 2, the contaminated area was covered with PAA; and in method 3, PAA, preferentially combined with a surfactant, was dispersed as a thin layer. In each method, 0·5-1% PAA reduced the viability of spores by a factor of ≥6 log10 within 3 min. The technique of the most realistic method 3 proved to be effective at low temperatures and also with a high organic load. Vaccinia virus and Adenovirus were inactivated with 0·05-0·1% PAA by up to ≥6 log10 within 1 min. The cytotoxicity of ricin was considerably reduced by 2% PAA within 15 min of exposure. CONCLUSIONS: PAA/detergent mixture enabled to cover hydrophobic PPE surfaces with a thin and yet effective disinfectant layer. SIGNIFICANCE AND IMPACT OF THE STUDY: The test methods are objective tools for estimating the biocidal efficacy of disinfectants on hydrophobic flexible surfaces.

Femtosecond time-resolved photoelectron spectroscopy of the benzyl radical.

We present a joint experimental and computational study of the nonradiative deactivation of the benzyl radical, C7H7, after UV excitation. Femtosecond time-resolved photoelectron imaging was applied to investigate the photodynamics of the radical. The experiments were accompanied by excited state dynamics simulations using surface hopping. Benzyl has been excited at 265 nm into the D-band (ππ*) and the dynamics was probed using probe wavelengths of 398 nm or 798 nm. At a probe wavelength of 398 nm a single time constant of around 70-80 fs was observed. When the dynamics was probed at 798 nm, a second time constant τ2 = 1.5 ps was visible, which can be attributed to further non-radiative deactivation to the lower-lying D1/D2 states.

Communication: On the first ionization threshold of the C2H radical.

The slow photoelectron spectrum of the ethynyl radical has been recorded for the first time by using the DESIRS beamline of the SOLEIL synchrotron facility. Ethynyl was generated using a microwave discharge flow tube. The observation of the X+Π3←XΣ+2 transition allowed the first direct measurement of the adiabatic ionization threshold of this radical (EI = 11.641(5) eV). The experimental results are supported by ab initio calculations. Our preliminary investigation of the cationic ground state potential energy surfaces predicts a non-negligible Renner-Teller effect which has not been discussed previously.

Synchrotron-based valence shell photoionization of CH radical.

We report the first experimental observations of X(+) (1)Σ(+)←X (2)Π and a(+) (3)Π←X (2)Π single-photon ionization transitions of the CH radical performed on the DESIRS beamline at the SOLEIL synchrotron facility. The radical was produced by successive hydrogen-atom abstractions on methane by fluorine atoms in a continuous microwave discharge flow tube. Mass-selected ion yields and photoelectron spectra were recorded as a function of photon energy using a double imaging photoelectron/photoion coincidence spectrometer. The ion yield appears to be strongly affected by vibrational and electronic autoionizations, which allow the observation of high Rydberg states of the neutral species. The photoelectron spectra enable the first direct determinations of the adiabatic ionization potential and the energy of the first triplet state of the cation with respect to its singlet ground state. This work also brings valuable information on the complex electronic structure of the CH radical and its cation and adds new observations to complement our understanding of Rydberg states and autoionization processes.

[Evaluation of sulfur status in dairy cows in Germany]. / Untersuchungen zur Schwefelversorgung von Milchkühen in Deutschland.

OBJECTIVE: Sulfur deficiency and toxicity in livestock is associated with decreased performance and diseases. However, little is known about the diagnostics of sulfur status in dairy herds. The objectives of this study were to describe sulfur concentrations in feed rations in German dairy herds, to assess associations between feed sulfur concentrations and health and milk yield, to determine suitable laboratory diagnostic methods of sulfur status, and to propose reference values for the assessment of sulfur status in different sample media. MATERIALS AND METHODS: Between 2006 and 2014, a total of 569 dairy herds were visited. Blood, urine, and hair samples were obtained from 10 animals per group in the groups -3 to 0, 0 to 1, 3 to 5, and 15 to 18 weeks post partum (p. p.) (farms > 200 animals) or -3 to 0, 0 to 5, and 6 to 20 weeks p. p. (farms ≤ 200 animals). Pooled whole blood, serum, plasma, urine, and hair samples (n = 5663) were analyzed by ICP-OES. The sulfur content of the total mixed ration (TMR) of the group -3 to 0 weeks p. p. was determined in a certified feed laboratory (n = 625). Data analyses were performed using ANOVA, Chi-squared test and Spearman-correlation. Reference values were determined using the 2.5% and 97.5% percentiles. RESULTS: Median sulfur concentration in the feed rations was 2.3 g/kg dry matter (DM). Deficiency (< 1.6 g/kg DM; 31% of farms) and oversupply (> 4.0 g/kg DM; 11% of farms) of sulfur in feed rations were regularly diagnosed. Sulfur deficiency was associated with reduced milk yield (p  <   0.001), retained placenta (OR  =   1.74; p  =  0.037), milk fever (OR  =  2.68; p  <  0.001) and silent heat (OR  = 2.56; p   =  0.014). Positive correlations were found between sulfur concentration in feed rations and sulfur content in urine (r  =  0.50), serum (r  =  0.17), plasma (r  =  0.18) and whole blood (r = 0.16). Reference values for sulfur diagnostics in dairy herds were proposed. CONCLUSION AND CLINICAL RELEVANCE: Diagnostics of sulfur status in dairy herds is relevant for veterinary practitioners and can be performed using TMR analysis and clinical laboratory parameters. Urine can be considered a short-term parameter, serum, plasma, and whole blood as intermediate parameters, and hair as a long-term parameter for the evaluation of the sulfur status.

Photocontrolled chignolin-derived ß-hairpin peptidomimetics.

The synthesis of novel, chignolin-derived peptides comprising the azobenzene photoswitch [3-(3-aminomethyl)phenylazo]phenylacetic acid (AMPP) is reported. Reversible photoswitching behavior led to folding into ß-hairpin-like structures, as unequivocally demonstrated by CD, FT-IR and NMR spectroscopy.

[Therapeutic options for weight management in schizophrenic patients treated with atypical antipsychotics]. / Möglichkeiten des Gewichtsmanagements in der Behandlung schizophrener Psychosen mit atypischen Antipsychotika.

Extensive, selective literature review of 2500 articles from the last years (up to December 2007) predominantly from Medline and Cochrane, using as search terms "antipsychotic or schizophrenia or individual drug names (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, ziprasidone)" and the terms "BMI, weight gain, metabolic syndrome, diabetes, lipid(s), cholesterol, triglycerides" was conducted. Regardless of the advantages ascribed to atypical antipsychotics and the special effectiveness of clozapine in patients resistant to therapy and at risk for suicide, the probability of weight gain is considerably increased for some of these substances. Patients with schizophrenia have a considerably reduced life expectancy associated with an increased prevalence of cardiovascular risk factors. There is a lack of practical guidelines integrated into clinical psychiatric care for the management of cardiovascular risk factors. The monitoring of patients treated with atypics, which has been recommended in the APA/ADA Consensus Paper in light of these facts, is insufficiently established in clinical practice. A regular monitoring can convey self control and motivation to the patient. In the case of corresponding risk constellations further decisions regarding indication and therapy have to be considered. Especially patients with a high cardiovascular risk profile are highly recommended to participate in a weight-management program for prevention purposes. Such a special program should include elements of dietetic treatment and behaviour and exercise therapy. First controlled studies suggest an effective prevention of weight gain and metabolic changes when applying such a structured program. The practice oriented step by step concept presented here is meant to provide points of reference for the implementation of required medical and psychoeducative measures facilitating the management of weight and further cardiovascular risk factors in the context of psychiatric care in patients with schizophrenia.

Gold(III) chloride catalyzed cyclization of alpha-hydroxyallenes to 2,5-dihydrofurans.

[reaction: see text] Functionalized alpha-hydroxyallenes 1 were smoothly converted into the corresponding 2,5-dihydrofurans 2 by using 5-10 mol % of gold(III) chloride as catalyst. This mild and efficient cyclization method can be applied to alkyl- and alkenyl-substituted allenes at room temperature, furnishing tri- and tetrasubstituted dihydrofurans in good to excellent chemical yields and with complete axis to center chirality transfer.

Carotenoids in the spermatophores of bushcrickets (Orthoptera: Ephippigerinae).

During mating male bushcrickets transfer large spermatophores, which have been demonstrated to play an important role in female nutrition and egg production. Until now only relatively unspecific substances such as water and proteins were known to be present within these spermatophores. We found that in the bushcricket Ephippiger zelleri the spermatophores contain substantial amounts of carotenoids (mainly lutein and zeaxanthin) that are also found in the eggs of this species. Carotenoids are well known for their positive effects on survival and reproduction in animals. This is the first example, to our knowledge, where such specific vitamin-like substances were found to be transferred from male to female during mating.

Nickel peroxide induced oxidation of canthaxanthin.

Treatment of canthaxanthin (beta,beta-carotene-4,4'-dione) (1) with nickel peroxide in dichloromethane yielded a series of cleavage products, i.e., 4-oxo-beta-ionone (2), (7E, 9E)-4-oxo-beta-apo-11-carotenal (3a), (7E, 9Z)-4-oxo-beta-apo-11-carotenal (3b), 4-oxo-beta-apo-13-carotenone (4), 4-oxo-beta-apo-14'-carotenal (5), 4-oxo-beta-apo-12'-carotenal (6), and 4-oxo-beta-apo-10'-carotenal (7). In addition, oxidized canthaxanthin derivatives, i.e., isomeric ketols all-trans-9, 10-dihydro-9-hydroxy-10-oxo-canthaxanthin (8a), (9'Z)-9, 10-dihydro-9-hydroxy-10-oxo-canthaxanthin (8b), and (13'Z)-9, 10-dihydro-9-hydroxy-10-oxo-canthaxanthin (8c) were obtained together with the tentatively identified (9'Z)-canthaxanthin-20-al (9). Structure elucidation of the reaction products was achieved by mass spectrometry and two-dimensional NMR spectroscopy.

Characterization of the chemical bonding in inner layers of composite materials.

The efficiency of near edge structure investigations in electron energy loss spectroscopy (EELS) is discussed for characterizing the chemical bonding of elements present in the interfacial zone in fibre/matrix composites at nanometre resolution. Two different examples of corresponding analyses are given for a SiC-fibre reinforced borosilicate glass. In particular, the chemical bonding between silicon and carbon or oxygen (e.g. SiC, SiO(2) and SiO(x)C(y)), respectively, is characterized. The results have been attained in a fingerprint manner by comparing the fine structure measured from a material of unknown stoichiometry to that of a standard specimen. In addition, a possibility is demonstrated to image the chemical bonding by energy-filtered microscopy using energy loss near edge structures (ELNES).

Ulcerative colitis specific cytotoxic IgG-autoantibodies against colonic epithelial cancer cells.

Serum antibodies cytotoxic to the colon cancer cell line RPMI 4788 were studied in 42 patients with ulcerative colitis, 61 patients with Crohn's disease, 27 patients with other inflammatory diseases (disease-controls) and 22 healthy controls. Cytotoxicity of antibodies towards RPMI 4788 was studied by means of a chromium release assay using peripheral blood mononuclear leucocytes of healthy subjects as effector cells. Using a four hour antibody dependent cell mediated cytotoxicity assay sera from 29% of ulcerative colitis patients contained antibodies cytotoxic for the target, while only 3% of the Crohn's patients and 6% of the disease controls and non of the healthy controls were positive. When an 18 hour assay was applied, however, not only 40% of ulcerative colitis patients, but also 14% of Crohn's patients and 21% of disease controls were found positive. The reactive antibody in the four hour assay was mainly of the IgG class, which points at a classical antibody dependent cell mediated cytotoxicity mechanism. In the 18 hour cytotoxic assay IgG and particularly IgM antibodies were found to be reactive. This suggests that in the latter case other cellular cytotoxic mechanism might be involved. There was a significant inverse correlation between the appearance of the ulcerative colitis restricted IgG-anticolon epithelial cell antibodies (four hour assay) and the disease activity (p less than 0.01). Absorption studies showed that the reactive antigen is not specific for ulcerative colitis colonic tissue, but is similarly found in Crohn's bowel tissue, and to a lower extent in normal bowel, liver and kidney. The reactive antigen, however, could not be detected in brain and lymphoblastoid cells.

[Intestinal spontaneous cell-mediated cytotoxicity and its immunoregulation in patients with chronic inflammatory bowel disease and controls]. / Untersuchungen der intestinalen spontanen zellvermittelten Zytotoxizität und ihrer Immunregulation bei Patienten mit chronisch-entzündlichen Darmerkrankungen und Kontrollen.

Isolated intestinal mononuclear cells (IMNL) exhibit spontaneous cell-mediated cytotoxicity (SCMC) in one third of the cases. IMNL suppress the SCMC of peripheral blood lymphocytes. The suppression by IMNL of patients with chronic inflammatory bowel disease is diminished.