A joint physics and radiobiology DREAM team vision - Towards better response prediction models to advance radiotherapy.

Radiotherapy developed empirically through experience balancing tumour control and normal tissue toxicities. Early simple mathematical models formalized this practical knowledge and enabled effective cancer treatment to date. Remarkable advances in technology, computing, and experimental biology now create opportunities to incorporate this knowledge into enhanced computational models. The ESTRO DREAM (Dose Response, Experiment, Analysis, Modelling) workshop brought together experts across disciplines to pursue the vision of personalized radiotherapy for optimal outcomes through advanced modelling. The ultimate vision is leveraging quantitative models dynamically during therapy to ultimately achieve truly adaptive and biologically guided radiotherapy at the population as well as individual patient-based levels. This requires the generation of models that inform response-based adaptations, individually optimized delivery and enable biological monitoring to provide decision support to clinicians. The goal is expanding to models that can drive the realization of personalized therapy for optimal outcomes. This position paper provides their propositions that describe how innovations in biology, physics, mathematics, and data science including AI could inform models and improve predictions. It consolidates the DREAM team's consensus on scientific priorities and organizational requirements. Scientifically, it stresses the need for rigorous, multifaceted model development, comprehensive validation and clinical applicability and significance. Organizationally, it reinforces the prerequisites of interdisciplinary research and collaboration between physicians, medical physicists, radiobiologists, and computational scientists throughout model development. Solely by a shared understanding of clinical needs, biological mechanisms, and computational methods, more informed models can be created. Future research environment and support must facilitate this integrative method of operation across multiple disciplines.

Genomic epidemiology of West Nile virus in Europe.

West Nile virus is one of the most widespread mosquito-borne zoonotic viruses, with unique transmission dynamics in various parts of the world. Genomic surveillance has provided important insights in the global patterns of West Nile virus emergence and spread. In Europe, multiple West Nile virus lineages have been isolated, with lineage 1a and 2 being the main lineages responsible for human infections. In contrast to North America, where a single introduction of lineage 1a resulted in the virus establishing itself in a new continent, at least 13 introductions of lineages 1a and 2 have occurred into Europe, which is likely a vast underestimation of the true number of introductions. Historically, lineage 1a was the main lineage circulating in Europe, but since the emergence of lineage 2 in the early 2000s, the latter has become the predominant lineage. This shift in West Nile virus lineage prevalence has been broadly linked to the expansion of the virus into northerly temperate regions, where autochthonous cases in animals and humans have been reported in Germany and The Netherlands. Here, we discuss how genomic analysis has increased our understanding of the epidemiology of West Nile virus in Europe, and we present a global Nextstrain build consisting of publicly available West Nile virus genomes (https://nextstrain.org/community/grubaughlab/WNV-Global). Our results elucidate recent insights in West Nile virus lineage dynamics in Europe, and discuss how expanded programs can fill current genomic surveillance gaps.

Treatment trends for muscle-invasive bladder cancer in Germany from 2006 to 2019.

PURPOSE: To examine national treatment trends of muscle-invasive bladder cancer (MIBC) in Germany with a special focus on radical cystectomy (RC). PATIENTS AND METHODS: Population-based data were derived from the nationwide hospital billing database of the German Federal Statistical Office and institution-related information from the reimbursement.INFO tool based on hospitals' quality reports from 2006 to 2019. Additionally, we used the German National Center for Cancer Registry data to analyze all cases of bladder cancer with stage ≥ T2 who received RC, chemotherapy, radiation therapy or a combination from 2006 to 2017. RESULTS: The annual number of RC cases in Germany increased by 28% from 5627 cases in 2006 to 7292 cases in 2019 (p = 0.001). The proportion of patients undergoing RC remained constant at about 75% in all age groups between 2006 and 2017 (p = 0.3). Relative to all performed RC, the proportion of patients > 75 years increased from 25% in 2006 to 38% in 2019 (p = 0.03). The proportion of patients receiving a combination of RC and chemotherapy increased from 9% in 2006 to 13% in 2017 (p = 0.005). In 2006, 8 of 299 urology departments (2.7%) performed more than 50 RCs per year, which increased to 17 of 360 (4.7%) in 2019. In 2019, 107 departments (29%) performed 25-49 RCs and 236 (66%) departments performed < 25 RCs. CONCLUSION: In Germany, three out of four patients with MIBC receive RC and the proportion of patients > 75 years is increasing. The combination of surgery and chemotherapy is increasingly used. With overall increasing case numbers, there is a slight tendency towards centralization.

The Treatment Decision-making Preferences of Patients with Prostate Cancer Should Be Recorded in Research and Clinical Routine: a Pooled Analysis of Four Survey Studies with 7169 Patients.

Different patients want to take different roles in the treatment decision-making process; these roles can be classified as passive, collaborative, and active. The aim of this study was to investigate the correlation between decision-making preferences among patients with prostate cancer and personal, disease-related, and structural factors. In four survey studies, we asked 7169 prostate cancer patients about their decision-making preferences using the Control Preferences Scale (CPS) and collected clinical, psychological, and quality-of-life measures. Most patients (62.2%) preferred collaborative decision-making, while 2322 (32.4%) preferred an active role, and only 391 (5.5%) preferred a passive role. Age (p < 0.001), data collection mode (p < 0.001), peer-to-peer support (p = 0.018), treatment status (p < 0.001), performed or planned radical prostatectomy (p < 0.001), metastatic disease (p = 0.001), and quality of life (p < 0.001) showed significant associations with patients' preferred decision-making roles. Oncologic risk group, anxiety, and depression were not significant in the model. In particular, younger prostate cancer patients with higher quality of life completing an online survey want to play a more active role in treatment decision-making. Before treatment has started, patients tend to prefer collaborative decision-making. Few prostate cancer patients in Germany prefer a passive role. These patients are mostly older patients, patients with a metastatic disease, and patients who have opted for prostatectomy. Whether this finding reflects a generational effect or a tendency by age group and disease phase should be investigated. Further research is also needed to describe the causalities of these relationships. The CPS offers valuable information for personal counselling and should be applied in clinical routine. In a large group of patients with prostate cancer, we found that there is a strong desire for joint decision-making with the physician before the actual treatment. Especially younger men, men with active online behaviour, and men with a high quality of life want to be actively involved in therapy decision-making processes.

[On the practice of therapy decision in locally limited prostate cancer: surgery vs. radiation-who benefits? : Allocation and results of a monocentric, cumulative long-term study]. / Zur Praxis der Therapieentscheidung beim lokal begrenzten Prostatakarzinom: Operation vs. Bestrahlung ­ wer profitiert? : Allokation und Ergebnisse einer unizentrischen, kumulativen Langzeitstudie.

AIM: The goal of this two-armed observational study was to map the clinical therapy effectiveness of radical prostatovesiculectomy (RPVE) and external beam radiation therapy (EBRT) in locally limited prostate cancer (PCA) in direct comparison over 20 years under clinical conditions. Retrospectively, the various variables and predictors for the individual therapy decision were identified, and the preference was to compared with studies on survival and recurrence characteristics. The presentation of toxicity was not the focus of this work. METHODOLOGY: In all, 743 patients from a single center were enrolled according to biopsy/staging chronologically in the sequence of the initial consultation after clarification and informed consent: 494 patients were in the RPVE arm and 249 patients in the EBRT arm. We used retrospective data analysis with univariate and multivariate comparisons in the alternative therapy arms. Multivariate logical regression models were developed to objectify the allocation process. Univariate processing of survival analyses, the comparison of tumor- and comorbidity-specific mortality rates was co-founded. RESULTS: Predictive variables for RPVE vs. EBRT therapy decision are significantly age, Gleason score, D'Amico index, Charlson index, prostate-specific antigen (PSA), and prostate volume. There was no significance level for the biopsy score. The age gap was in the median 67 (RPVE) and 73 (EBRT) years. Overall survival (n = 734, 20 years, all risks) in the RPVE arm was 56.8% (95% confidence interval [CI] 45.1-67.0%) and in the EBRT arm 19.2% (95%CI 9.2-31.8%). Comorbid risk was highly significantly (p < 0.0001) different (27.1% [95%CI 18.0-36.1%] in the RPVE arm, and 60.4% [95%CI 47.3-73.5%] in the EBRT arm). The risk of tumor-specific death at 16.2% (95%CI 8.1-24.4%) after RPVE and 20.5% (95%CI 11.7-29.3%) after EBRT was not significantly different (p = 0.2122, overlapping 95%CI). After stratification, a clear advantage can be demonstrated for the high-risk tumors after allocation to the RPVE arm. CONCLUSIONS: The complexity of the predictive variables of the PCA further complicates the individual therapy decision. According to our data, the higher D'Amico score, the rather low Charlson index, a high Gleason score and a higher organ volume speak for a valid therapy for RPVE.

[Trends in uro-oncological surgery in Germany-comparative analyses from population-based data]. / Entwicklung der operativen Uroonkologie in Deutschland ­ vergleichende Analysen aus populationsbasierten Daten.

Although urologic cancer represents a relevant health economic burden with about 100,000 new cases per year, hardly any knowledge exists about the structure and development of the corresponding uro-oncological interventions at the more than 400 urological surgical hospitals in Germany. Thus, we identified all cases of 5 major tumor surgery procedures in Germany from the DRG (diagnosis-related group) database of the Federal Statistical Office (prostatectomy, cystectomy, renal tumor surgery, retroperitoneal lymphadenectomy, penis surgery) from 2006-2013 (or 2016) by database query and investigated the influences of technical innovations, as well as guideline changes on the developments of case numbers. In addition, we analyzed the correlations between annual case numbers and perioperative outcomes. The results showed a clear correlation between case volume (and thus expertise) of a hospital and an improved perioperative outcome. Nevertheless, there is hardly any tendency towards centralization in these uro-oncological interventions. The development in the number of cases seems to depend more on the effect of advertising by means of technical innovations or the regional relation of the patients to a certain clinic. In the past, centrally controlled attempts to introduce minimum case numbers or voluntary certification of centers had little influence on the distribution of case numbers.

Understanding the Barriers to Pooled SARS-CoV-2 Testing in the United States.

Pooled testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection is instrumental for increasing test capacity while decreasing test cost. Pooled testing programs permit sustainable, long-term surveillance measures, which are essential for the early detection of virus resurgence in communities or the emergence of variants of concern. While numerous pooled approaches have been proposed to increase test capacity, uptake by laboratories has been limited. On 9 December 2020, we invited 362 U.S. laboratories that inquired about the Yale School of Public Health SalivaDirect test to participate in a survey to evaluate testing constraints and pooling strategies for SARS-CoV-2 testing. The survey was distributed using Qualtrics, and three reminders were sent. The survey closed on 21 January 2021. Of 93 responses received (25.7% response rate), 90 were from Clinical Laboratory Improvement Amendments (CLIA)-certified laboratories conducting SARS-CoV-2 testing. The remaining three were excluded from the analyses. Responses indicated that the major barriers to the uptake of pooled testing in the United States may not simply be the number of tests a laboratory can process per day, but rather the lack of clear protocols and adequate resources; laboratories are working with fixed physical and human capital constraints. Importantly, laboratories across the country are heterogeneous in infrastructure and workflow. The need for SARS-CoV-2 testing will remain for years to come. Testing programs can be maintained through pooled PCR testing strategies, and while statisticians, operations researchers, and others with expertise in sampling design have important value to add, laboratories require support on how to transition from traditional diagnostic testing to pooled surveillance. IMPORTANCE While numerous pooled SARS-CoV-2 testing approaches have been described in an effort to increase testing capacity and decrease test prices, uptake by laboratories has been limited. Responses to our survey of United States-based laboratories highlight the importance of consulting end-users-those that solutions are being designed for-so challenges can be addressed in a manner tailored to meet the specific needs out in the field. It may be surprising to those designing pooled testing strategies to learn that laboratories view pooling as more time-consuming than testing samples individually, and therefore that it is thought to create delays in test reporting.

Dual Orbital Degeneracy Lifting in a Strongly Correlated Electron System.

The local structure of NaTiSi_{2}O_{6} is examined across its Ti-dimerization orbital-assisted Peierls transition at 210 K. An atomic pair distribution function approach evidences local symmetry breaking preexisting far above the transition. The analysis unravels that, on warming, the dimers evolve into a short range orbital degeneracy lifted (ODL) state of dual orbital character, persisting up to at least 490 K. The ODL state is correlated over the length scale spanning ∼6 sites of the Ti zigzag chains. Results imply that the ODL phenomenology extends to strongly correlated electron systems.

Variation in Soybean Aphid (Hemiptera: Aphididae) Biotypes Within Fields.

Soybean aphid (Aphis glycines Matsumura (Hemiptera: Aphididae)) has been a major pest of soybean in North America since its detection in this continent in 2000 and subsequent spread. Although several aphid resistance genes have been identified, at least four soybean aphid biotypes have been discovered, with three of them being virulent on soybean cultivars with certain soybean aphid resistance genes. These biotypes are known to vary across years and locations, but information on their variation within single fields is limited. An investigation was conducted to study the variation of soybean aphid biotypes within single townships and fields in Minnesota. Screening of 28 soybean aphid isolates collected from seven soybean fields (six soybean fields in Cairo and Wellington Townships of Renville County, MN and one field in Wilmar Township of Kandiyohi County, MN) revealed the existence of multiple known biotypes of soybean aphid within single fields of soybean. We found up to three biotypes of soybean aphid in a single field. Two biotypes were found in five fields while only one field had only a single biotype. Three isolates presented reactions on a panel of resistant and susceptible indicator lines that were different from known biotypes. These results highlight the importance of characterizing soybean aphid biotypes in small geographical areas and utilizing generated knowledge to develop soybean cultivars pyramided with multiple resistance genes. The outcome will be decreased use of insecticides, thereby improving economic and environmental sustainability of soybean production.

Microbial Butyrate Synthesis Indicates Therapeutic Efficacy of Azathioprine in IBD Patients.

BACKGROUND AND AIMS: The microbial ecosystem seems to be an important player for therapeutic intervenption in inflammatory bowel disease [IBD]. We assessed longitudinal microbiome changes in IBD patients undergoing therapy with either azathioprine [AZA] or anti-tumour necrosis factor [anti-TNF] antibodies. We predicted the metabolic microbial community exchange and linked it to clinical outcome. METHODS: Faecal and blood samples were collected from 65 IBD patients at baseline and after 12 and 30 weeks on therapy. Clinical remission was defined as Crohn's Disease Activity Index [CDAI] < 150 in Crohn´s disease [CD], partial Mayo score <2 in ulcerative colitis [UC], and faecal calprotectin values <150 µg/g and C-reactive protein <5 mg/dl. 16S rRNA amplicon sequencing was performed. To predict microbial community metabolic processes, we constructed multispecies genome-scale metabolic network models. RESULTS: Paired Bray-Curtis distance between baseline and follow-up time points was significantly different for UC patients treated with anti-TNF antibodies. Longitudinal changes in taxa composition at phylum level showed a significant decrease of Proteobacteria and an increase of Bacteroidetes in CD patients responding to both therapies. At family level, Lactobacilli were associated with persistent disease and Bacteroides abundance with remission in CD. In-silico simulations of microbial metabolite exchange predicted a 1.7-fold higher butyrate production capacity of patients in remission compared with patients without remission [p = 0.041]. In this model, the difference in butyrate production between patients in remission and patients without remission was most pronounced in the CD group treated with AZA [p = 0.008]. CONCLUSIONS: In-silico simulation identifies microbial butyrate synthesis predictive of therapeutic efficacy in IBD.

Generation of an iPSC line (UMGWi001-B) from a patient with Floating-Harbor Syndrome (FLHS) carrying a heterozygous SRCAP mutation (p.Arg2444).

Floating-Harbor syndrome (FLHS) is a rare genetic disease caused by mutations in the SRCAP gene. Here, we generated an induced pluripotent stem cell line from gingival fibroblasts of a male patient with a heterozygous mutation in exon 34 of the SRCAP gene (c.7330C > T, p.Arg2444*). The iPSC colonies have an atypical morphology with diffuse borders and disintegrate quickly upon touch. Still, the cell line expresses pluripotency markers and differentiates into three germ layers. The cell line can be used as patient-specific disease model and help elucidate the molecular mechanisms involving SRCAP in the context of FLHS.

Liquid compound refractive X-ray lens.

We introduce the concept of a liquid compound refractive X-ray zoom lens. The lens is generated by pumping a suitable liquid lens material like water, alcohol or heated lithium through a line of nozzles each forming a jet with the cross section of lens elements. The system is housed, so there is a liquid-circulation. This lens can be used in white beam at high brilliance synchrotron sources, as radiation damages are cured by the continuous reformation of the lens. The focal length can be varied by closing nozzles, thus reducing the number of lens elements in the beam.

New species of Entolomataceae from Cameroon.

Six species of Entoloma (Entolomataceae, Agaricales, Basidiomycota) are described from recent Cameroonian collections: E. bisterigmatum, E. brunneoloaurantiacum, E. djaense, E. intricatum, E. versiforme, and E. parvistellatum.These species occur in tropical rainforests dominated by ectomycorrhizal trees in the genera Gilbertiodendron and Uapaca. Data on macromorphology, micromorphology, DNA sequences, habitat and comparisons with similar taxa are provided for each. This is the first contemporary taxonomic work on the Entolomataceae from Cameroon.

Local orbital degeneracy lifting as a precursor to an orbital-selective Peierls transition.

Fundamental electronic principles underlying all transition metal compounds are the symmetry and filling of the d-electron orbitals and the influence of this filling on structural configurations and responses. Here we use a sensitive local structural technique, x-ray atomic pair distribution function analysis, to reveal the presence of fluctuating local-structural distortions at high temperature in one such compound, CuIr2S4. We show that this hitherto overlooked fluctuating symmetry-lowering is electronic in origin and will modify the energy-level spectrum and electronic and magnetic properties. The explanation is a local, fluctuating, orbital-degeneracy-lifted state. The natural extension of our result would be that this phenomenon is likely to be widespread amongst diverse classes of partially filled nominally degenerate d-electron systems, with potentially broad implications for our understanding of their properties.

New species of Amanita subgen. Lepidella from Guyana.

New species of Amanita subgen. Lepidella are described from Guyana. Amanita cyanochlorinosma sp. nov., Amanita fulvoalba sp. nov., and Amanita guyanensis sp. nov. represent the latest additions to the growing body of newly described ectomycorrhizal fungi native to Dicymbe-dominated tropical rainforests. Macro- and micromorphological characters, habitat, and DNA sequence data for the ITS, nrLSU, rpb2, and ef1-α are provided for each taxon, and ß-tubulin for most. Distinctive morphological features warrant the recognition of the three new species and a molecular phylogenetic analysis of taxa across Amanita subgen. Lepidella corroborates their infrageneric placements.

'Tailception': using neural networks for assessing tail lesions on pictures of pig carcasses.

Tail lesions caused by tail biting are a widespread welfare issue in pig husbandry. Determining their prevalence currently involves labour intensive, subjective scoring methods. Increased societal interest in tail lesions requires fast, reliable and cheap systems for assessing tail status. In the present study, we aimed to test the reliability of neural networks for assessing tail pictures from carcasses against trained human observers. Three trained observers scored tail lesions from automatically recorded pictures of 13 124 pigs. Nearly all pigs had been tail docked. Tail lesions were classified using a 4-point score (0=no lesion, to 3=severe lesion). In addition, total tail loss was recorded. Agreement between observers was tested prior and during the assessment in a total of seven inter-observer tests with 80 pictures each. We calculated agreement between observer pairs as exact agreement (%) and prevalence-adjusted bias-adjusted κ (PABAK; value 1=optimal agreement). Out of the 13 124 scored pictures, we used 80% for training and 20% for validating our neural networks. As the position of the tail in the pictures varied (high, low, left, right), we first trained a part detection network to find the tail in the picture and select a rectangular part of the picture which includes the tail. We then trained a classification network to categorise tail lesion severity using pictures scored by human observers whereby the classification network only analysed the selected picture parts. Median exact agreement between the three observers was 80% for tail lesions and 94% for tail loss. Median PABAK for tail lesions and loss were 0.75 and 0.87, respectively. The agreement between classification by the neural network and human observers was 74% for tail lesions and 95% for tail loss. In other words, the agreement between the networks and human observers were very similar to the agreement between human observers. The main reason for disagreement between observers and thereby higher variation in network training material were picture quality issues. Therefore, we expect even better results for neural network application to tail lesions if training is based on high quality pictures. Very reliable and repeatable tail lesion assessment from pictures would allow automated tail classification of all pigs slaughtered, which is something that some animal welfare labels would like to do.

Influenza virus and factors that are associated with ICU admission, pulmonary co-infections and ICU mortality.

PURPOSE: While most influenza patients have a self-limited respiratory illness, 5-10% of hospitalized patients develop severe disease requiring ICU admission. The aim of this study was to identify influenza-specific factors associated with ICU admission and mortality. Furthermore, influenza-specific pulmonary bacterial, fungal and viral co-infections were investigated. METHODS: 199 influenza patients, admitted to two academic hospitals in the Netherlands between 01-10-2015 and 01-04-2016 were investigated of which 45/199 were admitted to the ICU. RESULTS: A history of Obstructive/Central Sleep Apnea Syndrome, myocardial infarction, dyspnea, influenza type A, BMI > 30, the development of renal failure and bacterial and fungal co-infections, were observed more frequently in patients who were admitted to the ICU, compared with patients at the normal ward. Co-infections were evident in 55.6% of ICU-admitted patients, compared with 20.1% of patients at the normal ward, mainly caused by Staphylococcus aureus, Streptococcus pneumoniae, and Aspergillus fumigatus. Non-survivors suffered from diabetes mellitus and (pre-existent) renal failure more often. CONCLUSIONS: The current study indicates that a history of OSAS/CSAS, myocardial infarction and BMI > 30 might be related to ICU admission in influenza patients. Second, ICU patients develop more pulmonary co-infections. Last, (pre-existent) renal failure and diabetes mellitus are more often observed in non-survivors.

Effect of Periodontal Treatment on HbA1c among Patients with Prediabetes.

Evidence is limited regarding whether periodontal treatment improves hemoglobin A1c (HbA1c) among people with prediabetes and periodontal disease, and it is unknown whether improvement of metabolic status persists >3 mo. In an exploratory post hoc analysis of the multicenter randomized controlled trial "Antibiotika und Parodontitis" (Antibiotics and Periodontitis)-a prospective, stratified, double-blind study-we assessed whether nonsurgical periodontal treatment with or without an adjunctive systemic antibiotic treatment affects HbA1c and high-sensitivity C-reactive protein (hsCRP) levels among periodontitis patients with normal HbA1c (≤5.7%, n = 218), prediabetes (5.7% < HbA1c < 6.5%, n = 101), or unknown diabetes (HbA1c ≥ 6.5%, n = 8) over a period of 27.5 mo. Nonsurgical periodontal treatment reduced mean pocket probing depth by >1 mm in both groups. In the normal HbA1c group, HbA1c values remained unchanged at 5.0% (95% CI, 4.9% to 6.1%) during the observation period. Among periodontitis patients with prediabetes, HbA1c decreased from 5.9% (95% CI, 5.9% to 6.0%) to 5.4% (95% CI, 5.3% to 5.5%) at 15.5 mo and increased to 5.6% (95% CI, 5.4% to 5.7%) after 27.5 mo. At 27.5 mo, 46% of periodontitis patients with prediabetes had normal HbA1c levels, whereas 47.9% remained unchanged and 6.3% progressed to diabetes. Median hsCRP values were reduced in the normal HbA1c and prediabetes groups from 1.2 and 1.4 mg/L to 0.7 and 0.7 mg/L, respectively. Nonsurgical periodontal treatment may improve blood glucose values among periodontitis patients with prediabetes (ClinicalTrials.gov NCT00707369).