Data standards in drug discovery: A long way to go.

Each year, millions to trillions of data points are generated to evaluate the response of chemicals and biologicals to human cells in vitro and in vivo using various technologies and endpoints. Despite the vast amount of data available, the development process has not become significantly more efficient in recent years. Given the increasing use of more complex physiological models, which are time-consuming and significantly more expensive, it is crucial to maximize the value of these valuable data through improved standardization.

Rethinking data and metadata in the age of machine intelligence.

A continuous cycle of hypotheses, data generation, and revision of theories drives biomedical research forward. Yet, the widely reported lack of reproducibility requires us to revise the very notion of what constitutes relevant scientific data and how it is being captured. This will also pave the way for the unique collaborative strength of combining the human mind and machine intelligence.

Alexithymia and professional quality of life in radiation oncology: The moderator effect of the professional profile.

BACKGROUND AND PURPOSE: Cancer care can be taxing. Alexithymia, a personality construct characterized by difficulties in identifying and describing feeling and emotions, an externally-oriented thinking style and scarcity of imagination and fantasy, is significantly correlated with higher levels of both secondary traumatic stress (STS) and burnout and lower levels of compassion satisfaction in medical professionals in radiation oncology. In this study, we aimed to assess the difference in professional quality of life (QoL) and the association with alexithymia in this multidisciplinary field depending on the specific profession (radiation/clinical oncologist, RO; medical physicist, MP; radiation therapist, RTT). MATERIAL AND METHODS: The study was conducted via an online questionnaire, receiving 1500 submissions between May and October 2018. Alexithymia was assessed via the Toronto Alexithymia Scale (TAS-20) and professional QoL was evaluated using the Professional Quality of Life Scale (ProQoL) version 5. Comparisons between the RO, RTT, and MP groups were performed by ANOVA or MANOVA, followed by Bonferroni corrected ANOVAs for continuous variables, and Pearson's chi-square test for categorical variables. The effect size was determined by calculating partial eta-squared (η2). RESULTS: Profession had a moderator role on the correlation between alexithymia and STS, with RO being at a higher risk than MP and RTT. Further, the results of this study demonstrate the relevant point prevalence of decreased well-being at work even for professional categories such as MP despite the more technical profile and reduced interaction with patients. CONCLUSIONS: This study demonstrates the importance of alexithymia as a factor contributing to decreased professional QoL amongst radiation oncology professionals. Alexithymic ROs are impacted to a higher extent compared to MPs and RTTs by the indirect exposure to patients suffering. It is worth addressing these observations in professional education, aiming to improve QoL for healthcare personnel.

Evaluation of pool-based testing approaches to enable population-wide screening for COVID-19.

OBJECTIVE: Rapid testing is paramount during a pandemic to prevent continued viral spread and excess morbidity and mortality. This study investigates whether testing strategies based on sample pooling can increase the speed and throughput of screening for SARS-CoV-2, especially in resource-limited settings. METHODS: In a mathematical modelling approach conducted in May 2020, six different testing strategies were simulated based on key input parameters such as infection rate, test characteristics, population size, and testing capacity. The situations in five countries were simulated, reflecting a broad variety of population sizes and testing capacities. The primary study outcome measurements were time and number of tests required, number of cases identified, and number of false positives. FINDINGS: The performance of all tested methods depends on the input parameters, i.e. the specific circumstances of a screening campaign. To screen one tenth of each country's population at an infection rate of 1%, realistic optimised testing strategies enable such a campaign to be completed in ca. 29 days in the US, 71 in the UK, 25 in Singapore, 17 in Italy, and 10 in Germany. This is ca. eight times faster compared to individual testing. When infection rates are lower, or when employing an optimal, yet more complex pooling method, the gains are more pronounced. Pool-based approaches also reduce the number of false positive diagnoses by a factor of up to 100. CONCLUSIONS: The results of this study provide a rationale for adoption of pool-based testing strategies to increase speed and throughput of testing for SARS-CoV-2, hence saving time and resources compared with individual testing.

Latest advances in aging research and drug discovery.

An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6th annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7th annual ARDD exhibition will transpire 2nd-4th of September, 2020, in Basel.

Deep Learning: A Review for the Radiation Oncologist.

Introduction: Deep Learning (DL) is a machine learning technique that uses deep neural networks to create a model. The application areas of deep learning in radiation oncology include image segmentation and detection, image phenotyping, and radiomic signature discovery, clinical outcome prediction, image dose quantification, dose-response modeling, radiation adaptation, and image generation. In this review, we explain the methods used in DL and perform a literature review using the Medline database to identify studies using deep learning in radiation oncology. The search was conducted in April 2018, and identified studies published between 1997 and 2018, strongly skewed toward 2015 and later. Methods: A literature review was performed using PubMed/Medline in order to identify important recent publications to be synthesized into a review of the current status of Deep Learning in radiation oncology, directed at a clinically-oriented reader. The search strategy included the search terms "radiotherapy" and "deep learning." In addition, reference lists of selected articles were hand searched for further potential hits of relevance to this review. The search was conducted in April 2018, and identified studies published between 1997 and 2018, strongly skewed toward 2015 and later. Results: Studies using DL for image segmentation were identified in Brain (n = 2), Head and Neck (n = 3), Lung (n = 6), Abdominal (n = 2), and Pelvic (n = 6) cancers. Use of Deep Learning has also been reported for outcome prediction, such as toxicity modeling (n = 3), treatment response and survival (n = 2), or treatment planning (n = 5). Conclusion: Over the past few years, there has been a significant number of studies assessing the performance of DL techniques in radiation oncology. They demonstrate how DL-based systems can aid clinicians in their daily work, be it by reducing the time required for or the variability in segmentation, or by helping to predict treatment outcomes and toxicities. It still remains to be seen when these techniques will be employed in routine clinical practice.

Analysis of relation between hypoxia PET imaging and tissue-based biomarkers during head and neck radiochemotherapy.

BACKGROUND: Tumor hypoxia is associated with poor prognosis and outcome and can be visualized using 18F-MISO-positron emission tomography (PET) imaging. The goal of this study was to evaluate the correlation between biological markers and biological imaging in a group of patients in whom a correlation between biological imaging and outcome has previously been demonstrated. MATERIAL AND METHODS: In a prospective pilot project, 16 patients with locally advanced cancer of the head and neck underwent 18F-MISO-PET scans before and during primary radiochemotherapy in addition to 18F-FDG-PET and computed tomography (CT). Tumor biopsies were stained for three tissue-based markers (Ku80, CAIX, CD44); in addition, human papillomavirus (HPV) status was assessed. H-scores of marker expression were generated and the results were correlated with the biological imaging and clinical outcome. RESULTS: No statistically significant correlation was established between the H-scores for Ku80, CD44 and CAIX or between any of the H-scores and the imaging variables (tumor volume on 18F-FDG-PET in ml, hypoxic subvolume as assessed by 18F-MISO-PET in ml, and SUVmax tumor/SUVmean muscle during the 18F-MISO-PET). A statistically significant negative correlation was found between CD44 H-score and HPV status (p = .004). Cox regression analysis for overall survival and recurrence-free survival showed one significant result for CAIX being associated with improved overall survival [hazard ratio 0.96 (0.93-1.00), p = .047]. CONCLUSION: Expression of Ku80, CAIX and CD44 as assessed by immunohistochemistry of tumor biopsies were not correlated to one another or the biological imaging data. However, there was a significant influence of CAIX on overall survival and between CD44 and HPV.

The radiosensitizing effects of Nelfinavir on pancreatic cancer with and without pancreatic stellate cells.

AIMS: We have previously shown in a phase I trial that nelfinavir (NFV) is safe with chemoradiation in PDAC with good signs for efficacy. Reverse translationally, we aimed to test the influence of PSCs on nelfinavir mediated radiosensitization to PDAC preclinically, because PDAC is very rich in desmoplasia and PSCs are known to mediate radioresistance. METHODS: In a direct co-culture model of several PDAC cell lines with PSC we performed clonogenic assays +/- nelfinavir. This was repeated exposing cells to hypoxic conditions. In xenograft PDAC tumors we tested radiation +/- nelfinavir +/- PSC. RESULTS: NFV sensitized both, PDAC only and PDAC cocultured with PSC (PDAC: Panc-1, MiaPaCa-2, PSN-1). In Panc-1 and PSN-1 this effect was larger +PSC compared to -PSC. Human pancreatic stellate cells (hPSC) were also sensitized by NFV which reduced p-FAK levels in hPSC, an effect that we previously found to sensitize specifically PDAC/PSC coculture. Contrarily, LY294002 reduced p-Akt in PSC (hPSC and LTC-14) but had no impact on PSC radiation survival. In vitro, nelfinavir sensitized Panc-1 and PSN-1 under normoxic and hypoxic conditions. In PSN-1 xenografts, +PSC led to faster tumor regrowth after radiation vs -PSC. The regrowth delay effect of nelfinavir after radiation was dramatically larger +PSC vs -PSC (time to reach 250mm(3) 183% vs 22%). CONCLUSION: NFV mediated radiosensitization in PDAC with stroma is partly mediated by p-FAK inhibition (Chen et al., 2013). In vitro, NFV sensitizes both normoxic and hypoxic PDAC +/- PSC to a roughly similar extent. The dramatic increased effect of xenograft regrowth inhibition by nelfinavir in tumors with PSC is attributed to vascular normalization (Brunner et al., 2014) rather than direct modification of hypoxia as shown by the tumor regrowth after gemcitabine with NFV.

Serial [18F]-fluoromisonidazole PET during radiochemotherapy for locally advanced head and neck cancer and its correlation with outcome.

PURPOSE: The aim was to assess changes of tumour hypoxia during primary radiochemotherapy (RCT) for head and neck cancer (HNC) and to evaluate their relationship with treatment outcome. MATERIAL AND METHODS: Hypoxia was assessed by FMISO-PET in weeks 0, 2 and 5 of RCT. The tumour volume (TV) was determined using FDG-PET/MRI/CT co-registered images. The level of hypoxia was quantified on FMISO-PET as TBRmax (SUVmaxTV/SUVmean background). The hypoxic subvolume (HSV) was defined as TV that showed FMISO uptake ⩾1.4 times blood pool activity. RESULTS: Sixteen consecutive patients (T3-4, N+, M0) were included (mean follow-up 31, median 44months). Mean TBRmax decreased significantly (p<0.05) from 1.94 to 1.57 (week 2) and 1.27 (week 5). Mean HSV in week 2 and week 5 (HSV2=5.8ml, HSV3=0.3ml) were significantly (p<0.05) smaller than at baseline (HSV1=15.8ml). Kaplan-Meier plots of local recurrence free survival stratified at the median TBRmax showed superior local control for less hypoxic tumours, the difference being significant at baseline and after 2weeks (p=0.031, p=0.016). CONCLUSIONS: FMISO-PET documented that in most HNC reoxygenation starts early during RCT and is correlated with better outcome.

Comparison of toxicity after IMRT and 3D-conformal radiotherapy for patients with pancreatic cancer - a systematic review.

IMRT has been suggested to reduce treatment-related toxicity in pancreatic cancer. We attempted to identify all IMRT-studies indexed in PubMed/Medline, comparing them with recent 3D-CRT trials. The predominant treatment-related toxicities, namely nausea/vomiting, diarrhoea and late GI toxicity, are significantly reduced with IMRT while there was no apparent difference for outcome measures.

FET-PET-based reirradiation and chloroquine in patients with recurrent glioblastoma: first tolerability and feasibility results.

BACKGROUND: Treatment of recurrent glioblastoma (rGBM) remains an unsolved clinical problem. Reirradiation (re-RT) can be used to treat some patients with rGBM, but as a monotherapy it has only limited efficacy. Chloroquine (CQ) is an anti-malaria and immunomodulatory drug that may inhibit autophagy and increase the radiosensitivity of GBM. PATIENTS AND METHODS: Between January 2012 and August 2013, we treated five patients with histologically confirmed rGBM with re-RT and 250 mg CQ daily. RESULTS: Treatment was very well tolerated; no CQ-related toxicity was observed. At the first follow-up 2 months after finishing re-RT, two patients achieved partial response (PR), one patient stable disease (SD), and one patient progressive disease (PD). One patient with reirradiated surgical cavity did not show any sign of PD. CONCLUSION: In this case series, we observed encouraging responses to CQ and re-RT. We plan to conduct a CQ dose escalation study combined with re-RT.

Are European countries prepared for the next big heat-wave?

BACKGROUND: Heat-waves present severe dangers to populations' health. Due to climate change, an increase in the frequency and intensity of heat-waves is to be expected. Public health measures to prevent negative health effects have been developed in several member states of the World Health Organization (WHO) European Region over the past decade. METHODS: This study presents the first comprehensive assessment of the development of heat preparedness planning in WHO European Region member states, using a unique methodology based on criteria developed and pre-tested by the WHO. This indicator-based approach is based on eight core elements that are crucial components of heat-health action plans. RESULTS: Of 53 member states of the WHO European Region, 51 countries were included in the evaluation. Results show that 18 countries have developed heat-health action plans, whereas 33 others have not. The plans developed so far vary in the degree of comprehensiveness with regard to the core elements. Gaps in terms of plan coverage have predominantly been identified in the areas of (intersectorial) long-term measures, surveillance and plan evaluation. CONCLUSIONS: For better preparedness, it can be advocated for further improving, developing and implementing heat-wave preparedness planning and response in European countries. A focus should be placed on developing all elements and strong intersectorial coordination and cooperation as well as the successful implementation of surveillance and evaluation measures.

How is intensive care reimbursed? A review of eight European countries.

Reimbursement schemes in intensive care are more complex than in other areas of healthcare, due to special procedures and high care needs. Knowledge regarding the principles of functioning in other countries can lead to increased understanding and awareness of potential for improvement. This can be achieved through mutual exchange of solutions found in other countries. In this review, experts from eight European countries explain their respective intensive care unit reimbursement schemes. Important conclusions include the apparent differences in the countries' reimbursement schemes-despite all of them originating from a DRG system-, the high degree of complexity found, and the difficulties faced in several countries when collecting the data for this collaborative work. This review has been designed to assist the intensivist clinician and researcher in understanding neighbouring countries' approaches and in putting research into the context of a European perspective. In addition, steering committees and decision makers might find this a valuable source to compare different reimbursement schemes.

Hypoxia in Head and Neck Tumors: Characteristics and Development during Therapy.

Cancers of the head and neck are a malignancy causing a considerable health burden. In head and neck cancer patients, tumor hypoxia has been shown to be an important predictor of response to therapy and outcome. Several imaging modalities can be used to determine the amount and localization of tumor hypoxia. Especially PET has been used in a number of studies analyzing this phenomenon. However, only few studies have reported the characteristics and development during (chemoradio-) therapy. Yet, the characterization of tumor hypoxia in the course of treatment is of great clinical importance. Successful delineation of hypoxic subvolumes could make an inclusion into radiation treatment planning feasible, where dose painting is hypothesized to improve the tumor control probability. So far, hypoxic subvolumes have been shown to undergo changes during therapy; in most cases, a reduction in tumor hypoxia can be seen, but there are also differing observations. In addition, the hypoxic subvolumes have mostly been described as geographically rather stable. However, studies specifically addressing these issues are needed to provide more data regarding these initial findings and the hypotheses connected with them.

Exploratory geographical analysis of hypoxic subvolumes using 18F-MISO-PET imaging in patients with head and neck cancer in the course of primary chemoradiotherapy.

BACKGROUND AND PURPOSE: Hypoxia in head and neck tumours is associated with poor prognosis and outcome, and can be visualized using (18)F-MISO-PET imaging; however, it is not clear whether the size and location of hypoxic subvolumes remain stable during therapy. In a pilot project, we conducted an exploratory analysis of persistent tumour hypoxia during treatment. MATERIALS AND METHODS: Sixteen patients with locally advanced head and neck tumours underwent consecutive (18)F-MISO-PET scans before and during primary chemoradiotherapy. The size, location and overlap of the hypoxic subvolumes were analysed using a semi-automatic algorithm based on a tumour to normal tissue ratio of 1.5. RESULTS: Quantitative evaluation showed tumour hypoxia in week 0 in 16 out of 16 and in week 2 in 5 out of 14 patients. For the five patients with persistent hypoxia, both increased and decreased hypoxic subvolumes could be observed. Mean hypoxic subvolume overlap was 55% of the hypoxic volume of the first scan and 72% of the hypoxic volume of the second scan. A stationary (in four out of five patients) and dynamic component (in three out of five patients) could be differentiated. CONCLUSION: In patients with persistent hypoxia after 2 weeks of treatment, the hypoxic subvolumes showed mostly a geographically relatively stable conformation.

Perceptions of heatwave risks to health: results of an qualitative interview study with older people and their carers in Freiburg, Germany.

AIMS AND OBJECTIVES: Heatwaves can pose a severe threat to health, especially to older people. However, warnings do not necessarily lead to preventive action. This study aims at exploring individual risk perception and adaptive measures of older people and their carers. Their views are explored, taking into account personal backgrounds. METHODS: Questionnaire-based interviews were administered to 20 men and women (64-94 years, living in their own homes or nursing homes) and 13 carers. A qualitative analysis following a framework approach was performed. RESULTS: The majority of respondents stated that older people might be compromised by heatwaves; however, a large proportion of respondents saw themselves as less affected than the average population. Most respondents adopted preventive measures during heatwaves and a majority received warnings or pieces of information. The role of general practitioners in direct warning situations was judged controversial. Survey respondents displayed resistance to the use of technical devices to monitor potentially dangerous situations. In addition, the results support many previous findings. In particular, the relative concepts of ageing, variety of information channels used, and control orientations could be confirmed. CONCLUSIONS: General practitioners hold a position of trust and play a central role in the promotion of preventive action, but there are also limitations to their outreach. Many respondents could be classified as socially active, which has implications for preventive information campaigns. Information campaigns using different channels and targeting a larger audience should be considered. The degree of information of carers can partly be improved.