Tumor DNA sequencing data can be interpreted by computational methods that analyze genomic heterogeneity to infer evolutionary dynamics. A growing number of studies have used these approaches to link cancer evolution with clinical progression and response to therapy. Although the inference of tumor phylogenies is rapidly becoming standard practice in cancer genome analyses, standards for evaluating them are lacking. To address this need, we systematically assess methods for reconstructing tumor subclonality. First, we elucidate the main algorithmic problems in subclonal reconstruction and develop quantitative metrics for evaluating them. Then we simulate realistic tumor genomes that harbor all known clonal and subclonal mutation types and processes. Finally, we benchmark 580 tumor reconstructions, varying tumor read depth, tumor type and somatic variant detection. Our analysis provides a baseline for the establishment of gold-standard methods to analyze tumor heterogeneity. Methods for reconstructing tumor evolution are benchmarked in the DREAM Somatic Mutation Calling Tumour Heterogeneity Challenge.

BACKGROUND Impaired neuromotor development is often one of the earliest observations in children with autism spectrum disorder (ASD). We investigated whether a genetic predisposition to developmental disorders was associated with nonoptimal neuromotor development during infancy and examined the genetic correlation between nonoptimal neuromotor development and autistic traits in the general population. METHODS In a population-based cohort in The Netherlands (2002-2006), we calculated polygenic risk scores (PRSs) for ASD and attention-deficit/hyperactivity disorder (ADHD) using genome-wide association study summary statistics. In 1921 children with genetic data, parents rated autistic traits at 6 years of age. Among them, 1174 children (61.1%) underwent neuromotor examinations (tone, responses, senses, and other observations) during infancy (9-20 weeks of age). We used linear regressions to examine associations of PRSs with neuromotor scores and autistic traits. We performed a bivariate genome-based restricted maximum likelihood analysis to explore whether genetic susceptibility underlies the association between neuromotor development and autistic traits. RESULTS Higher PRSs for ASD were associated with less optimal overall infant neuromotor development, in particular low muscle tone. Higher PRSs for ADHD were associated with less optimal senses. PRSs for ASD and those for ADHD both were associated with autistic traits. The single nucleotide polymorphism-based heritability of overall motor development was 20% (SE = .21) and of autistic traits was 68% (SE = .26). The genetic correlation between overall motor development and autistic traits was .35 (SE = .21, p < .001). CONCLUSIONS We found that genetic liabilities for ASD and ADHD covary with neuromotor development during infancy. Shared genetic liability might partly explain the association between nonoptimal neuromotor development during infancy and autistic traits in childhood.

Atopic dermatitis (AD) is a heterogeneous disease with various biological origins and clinical appearances. It is likely that different therapies or treatment intensities are not equally effective for all AD endotypes. The strongest genetic risk factor for AD is a null muta‐ tion in the filaggrin gene (FLG).1 Patients with eczema who carry a FLG null mutation are also prone to more persistent, severe eczema, and earlier onset of AD compared to patients without a FLG null mutation. Stratification of patients based on the FLG null endotype could enable more targeted treatment. Methods to determine FLG null mutations based on genotyping are time consuming and require specialized laboratory infrastructure, further complicated by the existence of over 50 different polymorphisms with widely varying prevalences between ethnic groups.2 In the stratum corneum (SC) filaggrin is enzymatically degraded into its constituting amino acids and their derivatives, together with specific salts and sugars collec‐ tively named natural moisturizing factor (NMF). Decreased NMF provides an accurate surrogate marker for the presence of FLG null polymorphisms.3 This can be measured rapidly and noninvasively by Raman spectroscopy in a clinically compatible test. We have assessed the potential of NMF as a novel clinical marker in AD by examining the association of clinically measured NMF val‐ ues with severity of AD, early onset of AD, and the co‐morbidities of AD: allergic sensitization, food allergy, bronchial hyperreactivity (BHR), asthma, and allergic rhinitis. Of 207 children with AD (0‐18 years of age), NMF values had been measured routinely during a visit to the pediatric atopy cen‐ ter KinderHaven‐Sophia Children's Hospital‐Erasmus MC University Medical Center Rotterdam in The Netherlands. The retrospective study protocol was approved by the medical ethics committee of Erasmus MC (MEC‐2016‐244). AD was diagnosed by a dermatologist according to the UK Working Party's Diagnostic Criteria for Atopic Dermatitis.4 NMF had been measured noninvasively on the palm of the hand by Raman spectroscopy using an in vivo Raman skin ana‐ lyzer (gen2‐SCA, RiverD International BV, Rotterdam). NMF values were classified as normal NMF (>1.14 arbitrary units) or decreased NMF (<0.995 arbitrary units), using a 0.07 confidence interval around the threshold of 1.07 as established by O’Regan et al.3 Patients with a NMF value between 0.995‐1.14 were excluded. The interval was the estimated 95% confidence interval, calculated as the standard error (SE) of the NMF value, averaged over the entire cohort, and multiplied by 1.96. Disease characteristics and comorbidity status were retrieved from the electronic medical patient files by two in‐ dependent researchers (see Appendix S1). Severity (mild to moderate or severe) of AD was measured by proxy of therapy based on the cri‐ teria as described by Wollenberg et al5 (Appendix S1). Associations between NMF status and the clinical parameters were tested by uni‐ variate and multivariate logistic regression models with adjustment for age and gender. Sixty‐seven out of 207 (32.4%) patients had decreased NMF. Figure 1 shows the distribution of disease severity in relation to the groups normal NMF and decreased NMF. Patients with decreased NMF had increased risk of severe AD, OR 2.12 (95% CI 1.02‐4.43), sensitization for food allergens, OR 2.27 (95%CI 1.21‐4.23), sensiti‐ zation for inhalation allergens, OR 2.22 (95%CI 1.13‐4.34), and food allergies, OR 2.79 (95% CI 1.33‐5.86; Table 1 and Table S1). Having decreased NMF did not show an association with early‐onset AD, allergic rhinitis, BHR, asthma and combined asthma, and/or BHR. In this retrospective study, we examined the associations between NMF values and the clinical parameters of the atopic syndrome. NMF

Aside from vast deployment cost reduction, Industrial Wireless Sensor and Actuator Networks (IWSAN) introduce a new level of industrial connectivity. Wireless connection of sensors and actuators in industrial environments not only enables wireless monitoring and actuation, it also enables coordination of production stages, connecting mobile robots and autonomous transport vehicles, as well as localization and tracking of assets. All these opportunities already inspired the development of many wireless technologies in an effort to fully enable Industry 4.0. However, different technologies significantly differ in performance and capabilities, none being capable of supporting all industrial use cases. When designing a network solution, one must be aware of the capabilities and the trade-offs that prospective technologies have. This paper evaluates the technologies potentially suitable for IWSAN solutions covering an entire industrial site with limited infrastructure cost and discusses their trade-offs in an effort to provide information for choosing the most suitable technology for the use case of interest. The comparative discussion presented in this paper aims to enable engineers to choose the most suitable wireless technology for their specific IWSAN deployment.

Extracellular vesicles (EVs) are a heterogeneous group of membrane-enclosed vesicles made of a phospholipid bilayer and are secreted by all cell types. EVs are present in a variety of body fluids containing proteins, DNA, RNA species, and lipids, and play an important role in cell- to-cell communication and are worth being considered as biomarkers for both early diagnosis of cancer patients and real-time monitoring of treatment response. Recently, emerging evidence verified EVs to have crucial roles in cancer progression and metastasis and a great potential in therapeutic applications. In this review, we discuss the potential of EVs in monitoring the efficacy of cancer therapies.

Abstract This paper explores the impact of education-job mismatch on the net income of workers in the context of Bosnia-Herzegovina. We used an OLS linear regression method on data from the Measure BiH Youth Survey. A log-transformation of the dependent variable created the left-side semilog functional form, which is typically used in models of the earnings of individuals. Our findings strongly support the statement that education-job mismatch has a significant effect on net income. Workers can expect net income differences between 13% and 15% if their level of education does not match that required for their job. However, our results show that the impact of education-job mismatch depends on the level of schooling and age of respondents. Results regarding education-job mismatch vary across studies, but our study is the first to examine the effect of education-job mismatch on net income in the context of Bosnia-Herzegovina. Second, the effect of education-job mismatch might depend on the choice of estimation method for incidences of overeducation and undereducation. Third, we emphasise the importance of understanding interactions, and fourth, we introduce new variables to understand how they influence earnings. These include religiousness, and the importance of belonging to a family, or a particular city.

Abstract This article uses data from the National Survey of Citizens’ Perceptions in Bosnia-Herzegovina to investigate the determinants of offering a bribe in the form of money, gifts or services to medical personnel, professors, judicial personnel, police officers and public servants. We presented evidence about the spread of corruption in these five sectors of the economy in Bosnia-Herzegovina, and analysed the effects of determinants at the individual level on the likelihood of engaging in bribery. Our results confirmed that specific personal characteristics predicted corrupt behaviour, but results varied across sectors. Logistic regression was used to generate models from which predictions could be made about the likelihood of an individual engaging in corrupt behaviour. Our research shows that corruption is a widespread phenomenon in Bosnia-Herzegovina, and more educated people, people living in urban areas, and individuals with higher incomes are more likely to engage in bribery in several sectors. Measures and policies aimed at reducing corrupt behaviour should be designed in a way that considers the specific characteristics of these individuals.

Due to the varying conditions in traffic and resource availability in networks nowadays, maintaining continuity of network service and satisfying QoS and QoE requirements became a challenging task. If considered in a highly diversified environment in terms of technology and administration, it gets even more complicated, and appropriate service and resource management solutions are mandatory. Thus, the aim of this paper is to present our specific perspective of the ongoing European H2020 5G-CARMEN project, addressing the importance of proactive reconfiguration of network services and their migration between different domains. Leveraging 5G technology and MEC platform, our management platform for automated low-latency-aware VNF placement and migration will enable orchestration of network services and resources across different administrative and technology domains.

We thank dr Yuanjun Dong for his interest in our publication.1 Dr Dong points out that previous and current stressful life events mod‐ ulate gastrointestinal (GI) symptom severity and quality of life (QoL) in patients with irritable bowel syndrome (IBS),2 which is indeed based on recent findings.3 In addition, we would like to note that abdominal pain is the predominant symptom in IBS, as per Rome IV definition. The primary treatment outcome for IBS in clinical tri‐ als, in accordance with FDA and EMA requirements, is reduction in daily abdominal pain.4 Whether a successful treatment, based on these criteria, improves patients’ life satisfaction and QoL remains an item of debate. In the current study, we performed an extensive prospective evaluation of the natural course of IBS which included demographics, gastrointestinal symptoms, symptoms of anxiety and depression, GI‐specific anxiety, satisfaction with life, and QoL. With regard to QoL, we showed among others that general anxiety and depression levels at follow‐up were independently associated with mental quality of life scores at the same time point. Furthermore, no associations were found between GI symptom severity, including abdominal pain, and the change in QoL scores over time.1 With regard to a possible interaction between GI symptoms and stress, in Table 1 we provide data on specific questions and answers from the database of Maastricht IBS cohort regarding the patients’ perspective on this matter. No statistically significant differences were found between Rome‐positive and Rome‐negative IBS patients at follow‐up. However, the current understanding on the relationship between abdominal pain and stress, whether current or related to life events, may be limited by the methods used to assess these factors. Traditionally, data from retrospective reports have been used to de‐ scribe this relationship, but it is known that these questionnaires are limited by recall and ecological bias.4 We therefore believe that the best available method to study the relationship between GI symp‐ toms, comorbid psychological complaints, and daily life stress is re‐ peated momentary symptom assessment.5 Such methodology has been used recently to assess the temporal relationship between ab‐ dominal pain and (preceding) daily life stress.6 We have developed and are currently validating specific questionnaires based on experience sampling method (ESM) which may provide additional leads in this matter.7 In a recently completed study, we demonstrate that real‐time stress scores are positively associated with concurrent abdominal pain scores in IBS, but not in healthy subjects, whereas abdominal pain could not be predicted by preceding stress levels, and vice versa, suggesting an in‐the‐moment rather than a longitudinal association.8 Taken together, we postulate that reduction in abdominal pain is not necessarily accompanied by long‐term improvement in quality of life in patients with IBS. This may indicate that the primary treat‐ ment focus in IBS should shift from solely abdominal pain reduction and improvement of bowel habits, toward a holistic approach, which includes quality of life, comorbid psychological symptoms, and im‐ provement of coping strategies with regard to GI symptoms as well as daily life stress. However, the evidence to support a change in the approach of IBS management is still inconclusive, and further research is needed.

Abstract Employment has been identified at the top of the list of young people’s concerns across Europe. Given the fact that in Bosnia and Herzegovina youth is one of the most vulnerable group, mainly due to the high unemployment rate, the main goal of this paper to determine the key individual and household characteristics of young people that influence their employment probability in order to support further development of decision-making policies in the labour market of Bosnia and Herzegovina. By using the USAID MEASURE-BiH National Youth Survey data set we analyse the effects of various individual and household characteristics on the probability of youth employment in Bosnia and Herzegovina. The analysis has revealed that education, age, gender and certain household characteristics have an impact on the probability of youth employment. The paper is expected to produce useful pieces of information that might be helpful for government decision-makers in Bosnia and Herzegovina in the process of creating employment policies to support young people.

Abstract Paper discusses financial inclusion of youth focussing on effects of remittances on financial inclusion of youth (usage of debit card, credit card, savings and borrowing instruments) in South East Europe. It is argued that remittances, as stable sources of income (capital), contribute to savings and lead to an improvement in financial inclusion of individuals who receive remittances. We test our hypothesis that remittances contribute to increase in savings and in the level of financial inclusion of youth in South East European countries. We estimate probit regression models with a set of dummy dependent variables for financial inclusion: having a debit card, having a credit card, borrowing and savings, and regress them on receipt of remittances controlling for age, gender, education and income level. Results show negative impact of remittances on youth financial inclusion in selected countries with respect to having debit card, credit card and borrowing. On the other hand, results show positive effect of remittances on savings among youth that receive remittances.