TPS9587 Background: Circulating tumor DNA (ctDNA; the tumour derived fraction of circulating free DNA in the blood) has been shown to be a biomarker of tumor burden/progression in many cancers. We recently accurately monitored treatment response and resistance in stage IV melanoma by ctDNA analysis in serial peripheral blood samples. Pre-clinical data has previously revealed that BRAF inhibition provokes a micro-environment with increased T cell infiltration, improved T cell recognition of melanoma associated antigens and reduced production of immunosuppressive cytokines that could enhance immune responses. We aimed to test the hypothesis that ctDNA could be implemented as a personalised, real-time liquid biopsy to identify when tumours are responding to targeted therapy in order optimise a switch to immunotherapy. Methods: We validated the ctDNA assays for BRAF mutation calling as a primary trial endpoint. We designed a phase II multicenter, parallel arm study across 6 UK sites, to assess primary objectives of i). Whether a ctDNA result can be turned around within 7 days and actioned in a clinically relevant timeframe ii). to assess whether a decrease in ctDNA levels of mutant BRAF by ≥80% from baseline on targeted therapy is an appropriate ‘cut off’ to instruct switching to immunotherapy. Secondary endpoints include Overall Response Rate (ORR) to immunotherapy, radiological/clinical and ctDNA determined progression free survival (PFS) on each treatment. Forty patients are planned based on inclusion criteria of stage IV or stage III unresectable cutaneous BRAF mutant melanoma, baseline ctDNA BRAF variant allele frequency (VAF) ≥1.5%, ECOG 0/1/2, no symptomatic brain metastases, no prior adjuvant nivolumab plus ipilimumab (N+I). Prior adjuvant dabrafinib + trametinib (D+T) is allowed as long as recurrence is >6 months from completion. Patients are randomised 1:1 to either standard Arm A; investigator choice of either D+T (150mg BD +2mg OD respectively) or N+I (1 mg/kg N +3 mg/kg I q3 wkly, then N 480mg q4 wkly) first line, then switch on progression to the other treatment. In the experimental Arm B; all patients start on D+T and have BRAF ctDNA monitored q2 wkly for 4 wks then q4 wkly. When ≥80% decrease vs. baseline in ctDNA BRAF VAF occurs, patients switch to N+I. If patients subsequently progress on N+I, they will resume D+T. The study is open with 9 patients enrolled at time of submission. Clinical trial information: NCT03808441.

To run a business successfully, quality determination and customer relations are very important factors. Therefore, it is necessary to measure quality and identify critical points of business. In this paper, an original integrated model for measuring the service quality of reverse logistics (RL) was developed for the company Komunalac Teslić, which was used as an example. The Delphi and Full Consistency Method (FUCOM) was applied to determine the significance of the quality dimensions, while a modified SERVQUAL (SQ) model was used to measure the service quality of the logistics. An original SQ questionnaire was formed with a total of 21 statements that were arranged in five standard dimensions. Examining the reliability of the questionnaire for quality dimensions using the Cronbach Alpha coefficient, it was found that the measurement scales for dimensions are appropriate in terms of user expectations, while in terms of quality perception there is no measurement scale for the empathy dimension. An extensive statistical analysis was then performed to verify the results. A Signum test was applied to identify the relationship between the responses in terms of expectations and perceptions, i.e., to examine their differences. The findings obtained by this research show that the expectations were higher than the perceived quality of the services and that there was a significant statistical difference for 12 of the SQ statements. For two statements, there was a significant statistical difference in favor of perceived quality compared to expectations. Based on the results obtained, the company must improve its services in order for service quality to be at a satisfactory level.

Few research studies have investigated temporal kinematic swallow events in healthy adults to establish normative reference values. Determining cutoffs for normal and disordered swallowing is vital for differentially diagnosing presbyphagia, variants of normal swallowing, and dysphagia; and for ensuring that different swallowing research laboratories produce consistent results in common measurements from different samples within the same population. High-resolution cervical auscultation (HRCA), a sensor-based dysphagia screening method, has accurately annotated temporal kinematic swallow events in patients with dysphagia, but hasn’t been used to annotate temporal kinematic swallow events in healthy adults to establish dysphagia screening cutoffs. This study aimed to determine: (1) Reference values for temporal kinematic swallow events, (2) Whether HRCA can annotate temporal kinematic swallow events in healthy adults. We hypothesized (1) Our reference values would align with a prior study; (2) HRCA would detect temporal kinematic swallow events as accurately as human judges. Trained judges completed temporal kinematic measurements on 659 swallows ( N  = 70 adults). Swallow reaction time and LVC duration weren’t different ( p  > 0.05) from a previously published historical cohort (114 swallows, N  = 38 adults), while other temporal kinematic measurements were different ( p  < 0.05), suggesting a need for further standardization to feasibly pool data analyses across laboratories. HRCA signal features were used as input to machine learning algorithms and annotated UES opening (69.96% accuracy), UES closure (64.52% accuracy), LVC (52.56% accuracy), and LV re-opening (69.97% accuracy); providing preliminary evidence that HRCA can noninvasively and accurately annotate temporal kinematic measurements in healthy adults to determine dysphagia screening cutoffs.

Parent–child story time is an important ritual of contemporary parenting. Recently, robots with artificial intelligence (AI) have become common. Parental acceptance of children’s storytelling robots, however, has received scant attention. To address this, we conducted a qualitative study with 18 parents using the research technique design fiction. Overall, parents held mixed, though generally positive, attitudes toward children’s storytelling robots. In their estimation, these robots would outperform screen-based technologies for children’s story time. However, the robots’ potential to adapt and to express emotion caused some parents to feel ambivalent about the robots, which might hinder their adoption. We found three predictors of parental acceptance of these robots: context of use, perceived agency, and perceived intelligence. Parents’ speculation revealed an uncanny valley of AI: a nonlinear relation between the human likeness of the artificial agent’s mind and affinity for the agent. Finally, we consider the implications of children’s storytelling robots, including how they could enhance equity in children’s access to education, and propose directions for research on their design to benefit family well-being.

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are debilitating diseases that share causal mutations in ACVR1, a TGF‐β family type I receptor. ACVR1R206H is a frequent mutation in both diseases. Pathogenic signaling via the SMAD1/5 pathway is mediated by Activin A, but how the mutation triggers aberrant signaling is not known. We show that ACVR1 is essential for Activin A‐mediated SMAD1/5 phosphorylation and is activated by two distinct mechanisms. Wild‐type ACVR1 is activated by the Activin type I receptors, ACVR1B/C. In contrast, ACVR1R206H activation does not require upstream kinases, but is predominantly activated via Activin A‐dependent receptor clustering, which induces its auto‐activation. We use optogenetics and live‐imaging approaches to demonstrate Activin A‐induced receptor clustering and show it requires the type II receptors ACVR2A/B. Our data provide molecular mechanistic insight into the pathogenesis of FOP and DIPG by linking the causal activating genetic mutation to disrupted signaling.

Aims: The basic precondition for apple breeding is the genetic diversity of varieties, which implies a large number of different, positive genes that enable adaptation to different weather conditions, resistance to new diseases and pests. One of the reliable sources of genetic diversity are indigenous varieties of Bosnia and Herzegovina. Their genetic identification is the first step in a process that has as its ultimate goal the collection of genetic material. The main goal of this research is to analyze the genetic variability of five indigenous varieties of apple in Tuzla Canton, Bosnia and Herzegovina in terms of contributing to the management of conservation and expansion of existing genetic resources, spreading this material through registered nurseries. Study Design: The research included fiveautochthonous apple varieties: "Ovčji nos“ “Dobrić“, "Šarenika“, "Rančica“ and "Petrovača“. Place and Duration of Study: Samples of young leaves were collected at the site of Donji Moranjci, City of Srebrenik,Tuzla Canton, Bosnia and Herzegovina in the spring of 2019. Methodology: In order to determine the genetic diversity of five indigenous apple varieties were genotyped ten SSR(Simple Sequence Repeats) markers. Original Research Article Salkić et al.; BJI, 25(2): 37-43, 2021; Article no.BJI.67908 38 Results: No cases of synonyms or homonyms were found within the analyzed set.The results of the study indicate a pronounced differentiation, ie all five examined varieties represent unique genotypes. Conclusion: The examined sets of genotypes possess significant genetic variability, which is important especially when we consider that a relatively small number of samples have been analyzed.

Abstract This article examines the role of ethnicity and ethnic parties as stabilizing factors in Southeast European party systems. It compares two ethnically divided countries in Southeast Europe: Bosnia and Herzegovina, where ethnic identities that form the political cleavage are firm, and Montenegro, where they are malleable. Theoretically, it addresses the debate between scholars who either find stability or instability in East European post-communist party systems. The article traces the role of ethnicity in the formation and development of electoral contests and compares the two cases by utilizing measures of block volatility, based on analysis of official electoral data. We argue that party systems in ethnically diverse countries are stable at the subsystems level, but unstable within them. In BiH, firm ethnic identity stabilizes the party system by limiting competition between blocks, leading to closure. Malleable ethnic identity in Montenegro opens competition to non-ethnic parties seeking to bridge ethnic divisions, leading to more instability. We find that party system dynamics in ethnically divided new democracies depend on identity rigidity and cleavage salience, in addition to levels of heterogeneity.

Rydberg excitons are, with their ultrastrong mutual interactions, giant optical nonlinearities, and very high sensitivity to external fields, promising for applications in quantum sensing and nonlinear optics at the single-photon level. To design quantum applications it is necessary to know how Rydberg excitons and other excited states relax to lower-lying exciton states. Here, we present photoluminescence excitation spectroscopy as a method to probe transition probabilities from various excitonic states in cuprous oxide, and we show giant Rydberg excitons at $T=38$ mK with principal quantum numbers up to $n=30$, corresponding to a calculated diameter of 3 $\mu$m.

The genetic evolutionary features of solid tumour growth are becoming increasingly well described, but the spatial and physical nature of subclonal growth remains unclear. Here, we utilize 102 macroscopic whole-tumour images from clear cell renal cell carcinoma patients, with matched genetic and phenotypic data from 756 biopsies. Utilizing a digital image processing pipeline, a renal pathologist marked the boundaries between tumour and normal tissue and extracted positions of boundary line and biopsy regions to X and Y coordinates. We then integrated coordinates with genomic data to map exact spatial subclone locations, revealing how genetically distinct subclones grow and evolve spatially. We observed a phenotype of advanced and more aggressive subclonal growth in the tumour centre, characterized by an elevated burden of somatic copy number alterations and higher necrosis, proliferation rate and Fuhrman grade. Moreover, we found that metastasizing subclones preferentially originate from the tumour centre. Collectively, these observations suggest a model of accelerated evolution in the tumour interior, with harsh hypoxic environmental conditions leading to a greater opportunity for driver somatic copy number alterations to arise and expand due to selective advantage. Tumour subclone growth is predominantly spatially contiguous in nature. We found only two cases of subclone dispersal, one of which was associated with metastasis. The largest subclones spatially were dominated by driver somatic copy number alterations, suggesting that a large selective advantage can be conferred to subclones upon acquisition of these alterations. In conclusion, spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution. The spatial and physical nature of tumour growth remains unclear. Combining whole-tumour images from clear cell renal cell carcinoma with genomic data, the authors show more aggressive subclonal growth and metastasizing subclones in the tumour centre.