Mutational robustness and the role of buffer genes in evolvability.

Organisms rely on mutations to fuel adaptive evolution. However, many mutations impose a negative effect on fitness. Cells may have therefore evolved mechanisms that affect the phenotypic effects of mutations, thus conferring mutational robustness. Specifically, so-called buffer genes are hypothesized to interact directly or indirectly with genetic variation and reduce its effect on fitness. Environmental or genetic perturbations can change the interaction between buffer genes and genetic variation, thereby unmasking the genetic variation's phenotypic effects and thus providing a source of variation for natural selection to act on. This review provides an overview of our understanding of mutational robustness and buffer genes, with the chaperone gene HSP90 as a key example. It discusses whether buffer genes merely affect standing variation or also interact with de novo mutations, how mutational robustness could influence evolution, and whether mutational robustness might be an evolved trait or rather a mere side-effect of complex genetic interactions.

Teaching medical students to apply deliberate reflection.

PURPOSE: Deliberate reflection on initial diagnosis has been found to repair diagnostic errors. We investigated the effectiveness of teaching students to use deliberate reflection on future cases and whether their usage would depend on their perception of case difficulty. METHOD: One-hundred-nineteen medical students solved cases either with deliberate-reflection or without instructions to reflect. One week later, all participants solved six cases, each with two equally likely diagnoses, but some symptoms in the case were associated with only one of the diagnoses (discriminating features). Participants provided one diagnosis and subsequently wrote down everything they remembered from it. After the first three cases, they were told that the next three would be difficult cases. Reflection was measured by the proportion of discriminating features recalled (overall; related to their provided diagnosis; related to alternative diagnosis). RESULTS: The deliberate-reflection condition recalled more features for the alternative diagnosis than the control condition (p = .013) regardless of described difficulty. They also recalled more features related to their provided diagnosis on the first three cases (p = .004), but on the last three cases (described as difficult), there was no difference. CONCLUSION: Learning deliberate reflection helped students engage in more reflective reasoning when solving future cases.

Learning deliberate reflection in medical diagnosis: does learning-by-teaching help?

Deliberate reflection has been found to foster diagnostic accuracy on complex cases or under circumstances that tend to induce cognitive bias. However, it is unclear whether the procedure can also be learned and thereby autonomously applied when diagnosing future cases without instructions to reflect. We investigated whether general practice residents would learn the deliberate reflection procedure through 'learning-by-teaching' and apply it to diagnose new cases. The study was a two-phase experiment. In the learning phase, 56 general-practice residents were randomly assigned to one of two conditions. They either (1) studied examples of deliberate reflection and then explained the procedure to a fictitious peer on video; or (2) solved cases without reflection (control). In the test phase, one to three weeks later, all participants diagnosed new cases while thinking aloud. The analysis of the test phase showed no significant differences between the conditions on any of the outcome measures (diagnostic accuracy, p = .263; time to diagnose, p = .598; mental effort ratings, p = .544; confidence ratings, p = .710; proportion of contradiction units (i.e. measure of deliberate reflection), p = .544). In contrast to findings on learning-by-teaching from other domains, teaching deliberate reflection to a fictitious peer, did not increase reflective reasoning when diagnosing future cases. Potential explanations that future research might address are that either residents in the experimental condition did not apply the learned deliberate reflection procedure in the test phase, or residents in the control condition also engaged in reflection.

Identifying and prioritizing educational content from a malpractice claims database for clinical reasoning education in the vocational training of general practitioners.

Diagnostic reasoning is an important topic in General Practitioners' (GPs) vocational training. Interestingly, research has paid little attention to the content of the cases used in clinical reasoning education. Malpractice claims of diagnostic errors represent cases that impact patients and that reflect potential knowledge gaps and contextual factors. With this study, we aimed to identify and prioritize educational content from a malpractice claims database in order to improve clinical reasoning education in GP training. With input from various experts in clinical reasoning and diagnostic error, we defined five priority criteria that reflect educational relevance. Fifty unique medical conditions from a malpractice claims database were scored on those priority criteria by stakeholders in clinical reasoning education in 2021. Subsequently, we calculated the mean total priority score for each condition. Mean total priority score (min 5-max 25) for all fifty diagnoses was 17,11 with a range from 13,89 to 19,61. We identified and described the fifteen highest scoring diseases (with priority scores ranging from 18,17 to 19,61). The prioritized conditions involved complex common (e.g., cardiovascular diseases, renal insufficiency and cancer), complex rare (e.g., endocarditis, ectopic pregnancy, testicular torsion) and more straightforward common conditions (e.g., tendon rupture/injury, eye infection). The claim cases often demonstrated atypical presentations or complex contextual factors. Including those malpractice cases in GP vocational training could enrich the illness scripts of diseases that are at high risk of errors, which may reduce diagnostic error and related patient harm.

Improving medical residents' self-assessment of their diagnostic accuracy: does feedback help?

When physicians do not estimate their diagnostic accuracy correctly, i.e. show inaccurate diagnostic calibration, diagnostic errors or overtesting can occur. A previous study showed that physicians' diagnostic calibration for easy cases improved, after they received feedback on their previous diagnoses. We investigated whether diagnostic calibration would also improve from this feedback when cases were more difficult. Sixty-nine general-practice residents were randomly assigned to one of two conditions. In the feedback condition, they diagnosed a case, rated their confidence in their diagnosis, their invested mental effort, and case complexity, and then were shown the correct diagnosis (feedback). This was repeated for 12 cases. Participants in the control condition did the same without receiving feedback. We analysed calibration in terms of (1) absolute accuracy (absolute difference between diagnostic accuracy and confidence), and (2) bias (confidence minus diagnostic calibration). There was no difference between the conditions in the measurements of calibration (absolute accuracy, p = .204; bias, p = .176). Post-hoc analyses showed that on correctly diagnosed cases (on which participants are either accurate or underconfident), calibration in the feedback condition was less accurate than in the control condition, p = .013. This study shows that feedback on diagnostic performance did not improve physicians' calibration for more difficult cases. One explanation could be that participants were confronted with their mistakes and thereafter lowered their confidence ratings even if cases were diagnosed correctly. This shows how difficult it is to improve diagnostic calibration, which is important to prevent diagnostic errors or maltreatment.

A participant perspective on collaborative reflection: video-stimulated interviews show what residents value and why.

The potential of reflection for learning and development is broadly accepted across the medical curriculum. Our understanding of how exactly reflection yields its educational promise, however, is limited to broad hints at the relation between reflection and learning. Yet, such understanding is essential to the (re)design of reflection education for learning and development. In this qualitative study, we used participants' video-stimulated comments on actual practice to identify features that do or do not make collaborative reflection valuable to participants. In doing so, we focus on aspects of the interactional process that constitute the educational activity of reflection. To identify valuable and less valuable features of collaborative reflection, we conducted one-on-one video-stimulated interviews with Dutch general practice residents about collaborative reflection sessions in their training program. Residents were invited to comment on any aspect of the session that they did or did not value. We synthesized all positively and negatively valued features and associated explanations put forward in residents' narratives into shared normative orientations about collaborative reflection: what are the shared norms that residents display in telling about positive and negative experiences with collaborative reflection? These normative orientations display residents' views on the aim of collaborative reflection (educational value for all) and the norms that allegedly contribute to realizing this aim (inclusivity and diversity, safety, and efficiency). These norms are also reflected in specific educational activities that ostensibly contribute to educational value. As such, the current synthesis of normative orientations displayed in residents' narratives about valuable and less valuable elements of collaborative reflection deepen our understanding of reflection and its supposed connection with educational outcomes. Moreover, the current empirical endeavor illustrates the value of video-stimulated interviews as a tool to value features of educational processes for future educational enhancements.

Patient complaints in radiology: 9-year experience at a European tertiary care center.

OBJECTIVE: To determine the frequency, nature (using standardized coding taxonomy), and temporal trends of patient complaints about the radiological service provided in a European tertiary care center. METHODS: This retrospective study included all written patient complaints received by the department of radiology of a European tertiary care center within a 9-year period. RESULTS: A total of 94 written patient complaints were included. Overall complaint frequency was 14.4 per 100,000 radiological procedures. Complaint frequencies per 100,000 procedures were 103.7 for interventional radiology, 13.9 for MRI, 6.9 for ultrasonography, 6.5 for CT, 4.5 for fluoroscopy, and 1.2 for conventional radiography. Interventional radiology received significantly more complaints than all other radiological procedures (p < 0.001), and cross-sectional imaging (CT, MRI, and ultrasonography) received significantly more complaints than conventional radiography (p < 0.001). Fifty-three (56.4%) complaints belonged to the clinical domain, 22 (23.4%) to the relationships domain, and 19 (20.2%) to the management domain. Quality (34.0%), safety (22.3%), timing and access (18.1%), and communication (18.1%) constituted almost all complaint categories. Patient journey (19.1%), delays (18.1%), communication breakdown (16.0%), errors in diagnosis (11.7%), quality of care (9.6%), treatment (6.4%), and staff attitudes (2.1%) constituted almost all complaint subcategories. Annual frequency of complaints decreased over time (Mann-Kendall tau = - 0.429), although not significantly (p = 0.174). CONCLUSION: Written patient complaints directed to a department of radiology at a European tertiary care center are relatively few in number and have not shown a temporal increase. Knowledge of sources of patient dissatisfaction may help to reduce the number of patient complaints and improve patient care. KEY POINTS: • Approximately 14.4 written patient complaints per 100,000 radiological procedures are filed in a European tertiary care center, and they have not increased over a 9-year period. • Written patient complaints most frequently involve interventional radiology, and the main complaint categories are quality (34.0%), safety (22.3%), timing and access (18.1%), and communication (18.1%). • Knowledge of the nature of and circumstances under which patient complaints arise may reduce their number and improve patient care.

Focus on the success of others leads to selfish behavior.

It has often been argued that the spectacular cognitive capacities of humans are the result of selection for the ability to gather, process, and use information about other people. Recent studies show that humans strongly and consistently differ in what type of social information they are interested in. Although some individuals mainly attend to what the majority is doing (frequency-based learning), others focus on the success that their peers achieve with their behavior (success-based learning). Here, we show that such differences in social learning have important consequences for the outcome of social interactions. We report on a decision-making experiment in which individuals were first classified as frequency- and success-based learners and subsequently grouped according to their learning strategy. When confronted with a social dilemma situation, groups of frequency-based learners cooperated considerably more than groups of success-based learners. A detailed analysis of the decision-making process reveals that these differences in cooperation are a direct result of the differences in information use. Our results show that individual differences in social learning strategies are crucial for understanding social behavior.

Genetic-genealogy approach reveals low rate of extrapair paternity in historical Dutch populations.

OBJECTIVE: Evolutionary theory has shown that seeking out extrapair paternity (EPP) can be a viable reproductive strategy for both sexes in pair-bonded species, also in humans. As yet, estimates of the contemporary or historical EPP rate in human population are still rare. In the present study, we estimated the historical EPP rate in the Dutch population over the last 400 years and compared the rate with those obtained for other human populations to determine the evolutionary, cultural, and socio-demographic factors that influence human cuckoldry behavior. METHODS: We estimated the historical EPP rate for the Dutch population via the "genealogical pair method", in which the EPP rate is derived from Y-chromosome mismatches between pairs of individuals that, based on genealogical evidence, share a common paternal ancestor. RESULTS: Based on the analysis of 68 representative genealogical pairs, separated by a total of 1013 fertilization events, we estimated that the historical EPP rate for the Dutch population over the last 400 years was 0.96% per generation (95% confidence interval 0.46%-1.76%). CONCLUSION: The Dutch EPP rate fits perfectly within the range reported for other contemporary and historical populations in Western Europe and was highly congruent with that estimated for neighboring Flanders, despite the socio-economic and religious differences between both populations. The estimated low EPP rate challenges the "dual mating strategy hypothesis" that states that women could obtain fitness benefits by securing investment from one man while cuckolding him to obtain good genes from an affair partner.

Exploring optimal air ambulance base locations in Norway using advanced mathematical modelling.

BACKGROUND: Helicopter emergency medical services are an important part of many healthcare systems. Norway has a nationwide physician staffed air ambulance service with 12 bases servicing a country with large geographical variations in population density. The aim of the study was to estimate optimal air ambulance base locations. METHODS: We used high resolution population data for Norway from 2015, dividing Norway into >300 000 1 km×1 km cells. Inhabited cells had a median (5-95 percentile) of 13 (1-391) inhabitants. Optimal helicopter base locations were estimated using the maximal covering location problem facility location optimisation model, exploring the number of bases needed to cover various fractions of the population for time thresholds 30 and 45 min, both in green field scenarios and conditioning on the current base structure. We reanalysed on municipality level data to explore the potential information loss using coarser population data. RESULTS: For a 45 min threshold, 90% of the population could be covered using four bases, and 100% using nine bases. Given the existing bases, the calculations imply the need for two more bases to achieve full coverage. Decreasing the threshold to 30 min approximately doubles the number of bases needed. Results using municipality level data were remarkably similar to those using fine grid information. CONCLUSIONS: The whole population could be reached in 45 min or less using nine optimally placed bases. The current base structure could be improved by moving or adding one or two select bases. Municipality level data appears sufficient for proper analysis.

Locating helicopter emergency medical service bases to optimise population coverage versus average response time.

BACKGROUND: New South Wales (NSW), Australia has a network of multirole retrieval physician staffed helicopter emergency medical services (HEMS) with seven bases servicing a jurisdiction with population concentrated along the eastern seaboard. The aim of this study was to estimate optimal HEMS base locations within NSW using advanced mathematical modelling techniques. METHODS: We used high resolution census population data for NSW from 2011 which divides the state into areas containing 200-800 people. Optimal HEMS base locations were estimated using the maximal covering location problem facility location optimization model and the average response time model, exploring the number of bases needed to cover various fractions of the population for a 45 min response time threshold or minimizing the overall average response time to all persons, both in green field scenarios and conditioning on the current base structure. We also developed a hybrid mathematical model where average response time was optimised based on minimum population coverage thresholds. RESULTS: Seven bases could cover 98% of the population within 45mins when optimised for coverage or reach the entire population of the state within an average of 21mins if optimised for response time. Given the existing bases, adding two bases could either increase the 45 min coverage from 91% to 97% or decrease the average response time from 21mins to 19mins. Adding a single specialist prehospital rapid response HEMS to the area of greatest population concentration decreased the average state wide response time by 4mins. The optimum seven base hybrid model that was able to cover 97.75% of the population within 45mins, and all of the population in an average response time of 18 mins included the rapid response HEMS model. CONCLUSIONS: HEMS base locations can be optimised based on either percentage of the population covered, or average response time to the entire population. We have also demonstrated a hybrid technique that optimizes response time for a given number of bases and minimum defined threshold of population coverage. Addition of specialized rapid response HEMS services to a system of multirole retrieval HEMS may reduce overall average response times by improving access in large urban areas.

CAST: A retrospective analysis of cabazitaxel and abiraterone acetate sequential treatment in patients with metastatic castrate-resistant prostate cancer previously treated with docetaxel.

Cabazitaxel and abiraterone have both received approval for treating metastatic castrate-resistant prostate cancer (mCRPC) patients after first-line docetaxel therapy. In the cabazitaxel and abiraterone sequential treatment (CAST) study, the clinical outcome of docetaxel-treated mCRPC patients treated sequentially with both cabazitaxel and abiraterone was studied. Data were collected retrospectively from mCRPC patients at 12 hospitals across the Netherlands who initiated cabazitaxel and/or abiraterone before December 2012. Primary outcome measure was overall survival (OS); secondary measures were progression-free survival (PFS), biochemical PFS, and best clinical and PSA response. Hospital admission data during treatment were collected, as well as toxicities resulting in treatment discontinuation or patient death. Sixty-three and 69 patients received Cab→Abi (cabazitaxel prior to abiraterone) and Abi→Cab before July 10th, 2013, respectively. Median OS was 19.1 months and 17.0 months in Cab→Abi and Abi→Cab treated patients, respectively (p = 0.369). Median PFS and biochemical PFS were significantly longer in Cab→Abi treated patients: 8.1 versus 6.5 (p = 0.050) and 9.5 versus 7.7 months (p = 0.024), respectively. Although partial responses to cabazitaxel occurred in both groups, Abi→Cab treated patients had a significantly decreased antitumor response from cabazitaxel than Cab→Abi treated patients (median PFS 5.0 versus 2.6 months, p < 0.001). Minor differences in toxicities were observed based on therapy sequence; generally, toxicity from cabazitaxel could be severe, while abiraterone toxicity was milder. This retrospective analysis indicates that primary progression on cabazitaxel or abiraterone did not preclude a response to the other agent in mCRPC patients. However, tumor response of both agents, particularly cabazitaxel, was lower when administered as higher-line therapy in the selected study population.

The importance of mechanisms for the evolution of cooperation.

Studies aimed at explaining the evolution of phenotypic traits have often solely focused on fitness considerations, ignoring underlying mechanisms. In recent years, there has been an increasing call for integrating mechanistic perspectives in evolutionary considerations, but it is not clear whether and how mechanisms affect the course and outcome of evolution. To study this, we compare four mechanistic implementations of two well-studied models for the evolution of cooperation, the Iterated Prisoner's Dilemma (IPD) game and the Iterated Snowdrift (ISD) game. Behavioural strategies are either implemented by a 1 : 1 genotype-phenotype mapping or by a simple neural network. Moreover, we consider two different scenarios for the effect of mutations. The same set of strategies is feasible in all four implementations, but the probability that a given strategy arises owing to mutation is largely dependent on the behavioural and genetic architecture. Our individual-based simulations show that this has major implications for the evolutionary outcome. In the ISD, different evolutionarily stable strategies are predominant in the four implementations, while in the IPD each implementation creates a characteristic dynamical pattern. As a consequence, the evolved average level of cooperation is also strongly dependent on the underlying mechanism. We argue that our findings are of general relevance for the evolution of social behaviour, pleading for the integration of a mechanistic perspective in models of social evolution.

Unpredictable benefits of social information can lead to the evolution of individual differences in social learning.

Human ecological success is often attributed to our capacity for social learning, which facilitates the spread of adaptive behaviours through populations. All humans rely on social learning to acquire culture, but there is substantial variation across societies, between individuals and over developmental time. However, it is unclear why these differences exist. Here, we present an evolutionary model showing that individual variation in social learning can emerge if the benefits of social learning are unpredictable. Unpredictability selects for flexible developmental programmes that allow individuals to update their reliance on social learning based on previous experiences. This developmental flexibility, in turn, causes some individuals in a population to end up consistently relying more heavily on social learning than others. We demonstrate this core evolutionary mechanism across three scenarios of increasing complexity, investigating the impact of different sources of uncertainty about the usefulness of social learning. Our results show how evolution can shape how individuals learn to learn from others, with potentially profound effects on cultural diversity.

Effect of the P-glycoprotein inhibitor tamoxifen on edoxaban plasma levels in women with breast cancer.

BACKGROUND: Concomitant use of P-glycoprotein inhibitors can reduce clearance of edoxaban and increase its plasma concentration. Caution is advised with simultaneous use of edoxaban and the frequently used P-glycoprotein inhibitor tamoxifen. However, pharmacokinetic data are lacking. OBJECTIVES: This study aimed to assess the effect of tamoxifen on edoxaban clearance. METHODS: This was a prospective, self-controlled, pharmacokinetic study in breast cancer participants starting tamoxifen. Edoxaban was given at a dose of 60 mg once daily for 4 consecutive days, first without tamoxifen and later with concomitant tamoxifen in steady-state. On day 4 of both edoxaban sequences, serial blood samples were taken. A population pharmacokinetic model was developed using nonlinear mixed effects modelling in which the effect of tamoxifen on edoxaban clearance was assessed. Additionally, mean area under the curves (AUC) were estimated. Geometric least square means (GLM) ratios were calculated and no interaction was concluded if the 90 % CI was within the 80-125 % no-effect boundaries. RESULTS: Twenty-four women with breast cancer scheduled for tamoxifen were included. The median age was 56 years (IQR 51-63). The average edoxaban clearance was 32.0 L/h (95 % CI, 11.1-35.0 L/h). There was no effect of tamoxifen on edoxaban clearance, with a fraction of 100 % (95 % CI 92-108) compared to clearance without tamoxifen. The mean AUCs were 1923 ng*h/ml (SD 695) without tamoxifen and 1947 ng*h/ml (SD 595) with tamoxifen (GLM-ratio 100.4; 90 % CI 98.6-102.2). CONCLUSIONS: Concomitant use of the P-glycoprotein inhibitor tamoxifen does not lead to reduced clearance of edoxaban in patients with breast cancer.

Fibrotic Marker Galectin-3 Identifies Males at Risk of Developing Cancer and Heart Failure.

Background: Cancer and heart failure (HF) are the leading causes of death in the Western world. Shared mechanisms such as fibrosis may underlie either disease entity, furthermore it is unknown whether this relationship is sex-specific. Objectives: We sought to investigate how fibrosis-related biomarker galectin-3 (gal-3) aids in identifying individuals at risk for new-onset cancer and HF, and how this differs between sexes. Methods: Gal-3 was measured at baseline and at 4-year follow-up in 5,786 patients of the PREVEND (Prevention of Renal and Vascular Endstage Disease) study. The total follow-up period was 11.5 years. An increase of ≥50% in gal-3 levels between measurements was considered relevant. We performed sex-stratified log-rank tests and Cox regression analyses overall and by sex to evaluate the association of gal-3 over time with both new-onset cancer and new-onset HF. Results: Of the 5,786 healthy participants (50% males), 399 (59% males) developed new-onset cancer, and 192 (65% males) developed new-onset HF. In males, an increase in gal-3 was significantly associated with new-onset cancer (both combined and certain cancer-specific subtypes), after adjusting for age, body mass index, hypertension, smoking status, estimated glomerular filtration rate, diabetes mellitus, triglycerides, coronary artery disease, and C-reactive protein (HR: 1.89; 95% CI: 1.32-2.71; P < 0.001). Similar analyses demonstrated an association with new-onset HF in males (HR: 1.77; 95% CI: 1.07-2.95; P = 0.028). In females, changes in gal-3 over time were neither associated with new-onset cancer nor new-onset HF. Conclusions: Gal-3, a marker of fibrosis, is associated with new-onset cancer and new-onset HF in males, but not in females.

Clonal haematopoiesis of indeterminate potential: associations with heart failure incidence, clinical parameters and biomarkers.

AIM: We aimed to analyse the association of clonal haematopoiesis of indeterminate potential (CHIP) with incident heart failure (HF) in a European population cohort. METHODS AND RESULTS: From the prospective Prevention of Renal and Vascular End-stage Disease (PREVEND) cohort, we included all 374 participants with incident HF and selected 1:1 age- and sex-matched control subjects. Peripheral blood samples of 705 individuals were successfully analysed by error-corrected next generation sequencing for acquired mutations at a variant allele frequency ≥2% in 27 CHIP driver genes. The median age of the study population was 65 years (interquartile range 58-70) and 35.6% were female. CHIP mutations positively correlated with age, smoking, hypertension and cardiovascular biomarkers including N-terminal pro-B-type natriuretic peptide and mid-regional pro-A-type natriuretic peptide, but the frequency of CHIP was comparable in individuals with incident HF and in control participants (18.4% vs. 17.3%; p = 0.69). In multivariable Cox regression models, CHIP was not significantly associated with incident HF (hazard ratio [HR] 1.24, 95% confidence interval [CI] 0.93-1.65; p = 0.144). This association, however, was modified by age (p for CHIP-age interaction = 0.002). Among people younger than 65 years, CHIP mutations were more frequently detected in the case cohort compared to the control cohort (14.2% vs. 5.8%; p = 0.009), and were significantly associated with new-onset HF (HR 2.07, 95% CI 1.30-3.29; p = 0.002). CONCLUSION: Clonal haematopoiesis of indeterminate potential correlates with HF risk factors and biomarkers, and is associated with incident HF in subjects <65 years of age.

TripleAiM1: a nationwide registry of de novo metastatic hormone-sensitive prostate cancer with prospective quality-of-life assessment.

INTRODUCTION: The treatment landscape for de novo metastatic hormone sensitive prostate cancer (mHSPC) is rapidly evolving. With an abundance of available treatment strategies, selecting the optimal strategy for an individual patient is becoming increasingly challenging. TripleAiM1 aims to evaluate the impact of mHSPC treatments on health-related quality of life (HRQoL) and to provide real-world data insights on diagnostics, treatment strategies, patient subgroups and related healthcare expenditure for mHSPC. The aspirational target of TripleAiM1 is that in the near future, a more tailored therapy can be offered based on the individual patient's wishes and needs in accordance with the overarching principle of value-based healthcare. METHODS AND ANALYSIS: We describe the TripleAiM1 study design; a nationwide registry comprising a retrospective and prospective cohort of patients with de novo mHSPC. Starting in May 2020, eligible patients are identified, selected and recruited in 14 participating hospitals in the Netherlands. Our hypothesis is that, in a real-world setting, differences in clinically meaningful HRQoL deterioration will be observed for treatment strategies over time. HRQoL data, assessed with patient-reported outcome measures, costs and clinical data will be collected for 24 months.For the retrospective cohort, all patients diagnosed with de novo mHSPC from January 2017 onwards are eligible for inclusion. Patient and tumour characteristics, imaging modalities and treatment patterns will be analysed descriptively to provide a real-world overview.Time-to-event endpoints will be assessed using the Kaplan-Meier method and regression models will be employed to analyse baseline characteristics associated with an increased likelihood of death, progression and HRQoL deterioration. Longitudinal mixed-effects models will be employed to assess change of patient-reported outcome scores from baseline until the end of follow-up. ETHICS AND DISSEMINATION: Ethical approval was obtained from the Medical Research Ethics Committee, Twente. Study results will be published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NL9719.

The social costs of punishment.

Lab experiments on punishment are of limited relevance for understanding cooperative behavior in the real world. In real interactions, punishment is not cheap, but the costs of punishment are of a different nature than in experiments. They do not correspond to direct payments or payoff deductions, but they arise from the repercussions punishment has on social networks and future interactions.

Misrepresentation of group contributions undermines conditional cooperation in a human decision making experiment.

Cooperative behaviour can evolve through conditional strategies that direct cooperation towards interaction partners who have themselves been cooperative in the past. Such strategies are common in human cooperation, but they can be vulnerable to manipulation: individuals may try to exaggerate their past cooperation to elicit reciprocal contributions or improve their reputation for future gains. Little is known about the prevalence and the ramifications of misrepresentation in human cooperation, neither in general nor about its cultural facets (self-sacrifice for the group is valued differently across cultures). Here, we present a large-scale interactive decision making experiment (N = 870), performed in China and the USA, in which individuals had repeated cooperative interactions in groups. Our results show that (1) most individuals from both cultures overstate their contributions to the group if given the opportunity, (2) misrepresentation of cooperation is detrimental to cooperation in future interactions, and (3) the possibility to build up a personal reputation amplifies the effects of misrepresentation on cooperation in China, but not in the USA. Our results suggest that misrepresentation of cooperation is likely to be an important factor in (the evolution of) human social behaviour, with, depending on culture, diverging impacts on cooperation outcomes.