Efficiently mapping quantum circuits onto hardware is an integral part of the quantum compilation process, wherein a quantum circuit is modified in accordance with the stringent architectural demands of a quantum processor. Many techniques exist for solving the quantum circuit mapping problem, many of which relate quantum circuit mapping to classical computer science. This work considers a novel perspective on quantum circuit mapping, in which the routing process of a simplified circuit is viewed as a composition of quantum operations acting on density matrices representing the quantum circuit and processor. Drawing on insight from recent advances in quantum information theory and information geometry, we show that a minimal SWAP gate count for executing a quantum circuit on a device emerges via the minimization of the distance between quantum states using the quantum Jensen-Shannon divergence. Additionally, we develop a novel initial placement algorithm based on a graph similarity search that selects the partition nearest to a graph isomorphism between interaction and coupling graphs. From these two ingredients, we then construct a polynomial-time algorithm for calculating the SWAP gate lower bound, which is directly compared alongside the IBM Qiskit compiler for over 600 realistic benchmark experiments, as well as against a brute-force method for smaller benchmarks. In our simulations, we unambiguously find that neither the brute-force method nor the Qiskit compiler surpass our bound, implying utility as a precise estimation of minimal overhead when realizing quantum algorithms on constrained quantum hardware. This work constitutes the first use of quantum circuit uncomplexity to practically-relevant quantum computing. We anticipate that this method may have diverse applicability outside of the scope of quantum information science, and we discuss several of these possibilities.

Significance Existing targeted therapies for solid tumors harboring FGFR2 alterations include pan-FGFR inhibitors, which often cannot be dosed to maximum efficacy due to FGFR1- and FGFR4-mediated toxicities. The structural similarity among FGFR family members has thwarted conventional approaches to structure-based design of FGFR2-selective inhibitors, so we used long-timescale molecular dynamics simulations to identify differential motions of FGFR2 and FGFR1 that could be leveraged to design FGFR2-selective inhibitors. Our efforts led to lirafugratinib (RLY-4008), an FGFR2 inhibitor exhibiting substantial selectivity over other FGFRs. Lirafugratinib was reported to have a 73% objective response rate in early clinical studies in FGFR-inhibitor naive, FGFR2 fusion-positive intrahepatic cholangiocarcinoma patients treated orally (once daily doses ≥70 mg) without inducing clinically significant adverse effects by inhibiting off-targets.

Background: Although a range of therapeutic options are available in the management of invasive breast carcinomas, spatial segregation of tumour subclones has hampered biomarker identification in single-region samples. Representative sampling (RS) overcomes spatial bias by sampling from a homogenized and well-mixed cancer specimen. The Homogenization of Leftover Surgical Tissue Feasibility Study (HoLST-F - NCT03832062) is a prospective trial aiming to assess the feasibility of RS in tumor tissue leftover after pathology sampling. An interim analysis of the breast cancer cohort is presented. Methods: In the context of the HoLST-F study and pre-specified end-points, representative samples derived from 75 leftover invasive breast carcinoma specimens underwent flow cytometric analysis of CK8/18, CD3, Ki67 and DAPI. Tumor cell enrichment by CK8/18 positivity and ploidy (in aneuploid carcinomas) was performed for downstream DNA extraction and whole exome sequencing. Somatic variants were determined using a bespoke pipeline to remove artefacts associated with fixation. Variant oncogenicity and therapeutic evidence levels were assigned by OncoKB variant annotation. Quantitative image analysis was applied to tissue sections from diagnostic FFPE blocks stained with Ki67 immunohistochemistry (n=78) and H&E for lymphocytic infiltration scores (n=175) to correlate with flow cytometry. Results: In enriched representative samples, oncogenic mutations were commonly identified at high variant allele frequency (VAF) in known breast carcinoma driver genes including PIK3CA, CDH1, TP53, KMT2C and GATA3. Other clinically relevant oncogenic mutations were identified in ESR1, PTEN, ERBB2, RB1, AKT1, BRCA1, NF1 and FOXA1 which have been associated with resistance to various anti-cancer therapies. These mutations occurred at low and high VAFs indicative of both of clonal and sub-clonal resistance mechanisms. Recurrent variants in ESR1 (e.g. D538G) and PIK3CA (e.g. H1047R/L) were associated with Level 1 evidence for use as predictive biomarkers, while variants in twelve other genes across the cohort were associated with Level 2-4 evidence. Lymphocyte infiltration scores and Ki67 expression varied by tumor region, however RS by flow cytometry showed strong correlation with a weighted average across multiregional quantification of Ki67 expression (R=0.81, p=2.8 × 10-8) and lymphocyte infiltration (R=0.61, p<2.2 × 10-16). Conclusions: RS of invasive breast carcinoma in the HoLST-F trial has recapitulated the expected genomic driver landscape in breast cancer, in addition to identifying both clonal and subclonal genomic mechanisms of therapy resistance. Many of these mutations are either current or emerging therapeutic targets. Flow quantification of cells expressing phenotypic biomarkers (Ki67 and CD3) is feasible through RS and early analysis indicates that RS correlates with a weighted average across multiple regions. Leftover surgical tissue is an underutilized resource for biomarker assessment in breast carcinomas and can be examined by RS. Citation Format: Brian Hanley, Lisa Gallegos, Lavinia Spain, Husayn Pallikonda, Zayd Tippu, Samantha Hill, Aoune Barhoumi, Fiona Byrne, Yulia Dogva, Ashley Gilchrist, Glenn Noel-Storr, Hannah Veloz, Stacey Stanislaw, Harold Sansano, Kim Edmonds, Eleanor Carlyle, Nicholas Turner, James Larkin, Nelson Alexander, Samra Turajlic. Representative sampling of invasive breast carcinomas: Interim report from a prospective study (HOLST-F) [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr A007.

The aim of this study was to investigate attitudes and preferred therapy choice for first permanent molars (FPM) with Molar-Incisor Hypomineralization (MIH). An online questionnaire was sent out to general dentists (n = 559) working in the Public Dental Service in Region Västra Götaland, orthodontists (n = 293), and pediatric dentists (n = 156) (members from each interest association), in Sweden. The questionnaire contained three parts: general questions regarding the respondents, patient cases, and general questions regarding extraction of FPMs with MIH. Statistics were carried out using Chi-squared tests, with a significance level of 5%. A response rate of 36% was obtained. Orthodontists and pediatric dentists were more prone to extract FPMs with both moderate and severe MIH, compared to general dentists. When restoring FPMs with moderate MIH, resin composite was preferred. Compared to the general dentists, the pediatric dentists were more prone to choose glass-ionomer cement in the FPMs with severe MIH. The most common treatment choice for FPMs with mild MIH was fluoride varnish. “When root furcation is under development of the second permanent molar on radiographs” was chosen as the optimal time for extracting FPMs with severe MIH, and the general dentists based their treatment decisions on recommendations from a pediatric dentist. Extraction of FPMs with moderate and severe MIH is considered a therapy of choice among general dentists and specialists, and the preferred time of extraction is before the eruption of the second permanent molar.

Clear cell Renal Cell Carcinoma (ccRCC) is profoundly angiogenic, characterised by complex yet heterogenous vascular networks. Blood vessels are an important constituent part of the tumour microenvironment (TME) and, in addition to immune cells, are the target of drug therapies in advanced disease. The TME plays an important role in determining disease progression and response to therapy, acting as a selective pressure on the tumour cells thus influencing evolutionary trajectory. This selective pressure is sculpted by cross-talk between blood vessels, immune cells and the tumour cells themselves. Whilst the details of these carefully orchestrated cellular interactions is not understood their final read-out is reflected in tissue morphology, which can be assessed using an H&E-stained slide, a fundamental component of clinical diagnostic histopathological workflows. A computational pathology approach to assess vascular networks from digital H&E whole slide images (H&E WSIs) would present a powerful tool to understand disease biology. It would permit high-throughput analysis of large cohorts where routine multi-regional sampling captures disease heterogeneity. Such work would lay the foundations for developing a computational pathology biomarker to predict survival outcomes that could be easily implemented into existing clinical workflows. Intricacy of vascular network structures makes reproducible analysis challenging, which can be approached either using morphology, a qualitative evaluation of a shape, or using topography to quantify feature dimensions. Here we reconcile the two methods to develop an interpretable computational pathology solution to study the blood vessels in ccRCC. Further, we have built a deep-learning attention UNET model to segment blood vessels from H&E WSIs. By combining these tools we have developed a computational pathology pipeline able to robustly characterise vascular networks directly from H&E WSIs. We leverage 1064 tumour regions from 82 ccRCC tumours of the TRACERx Renal dataset where ex-vivo multi-regional sampling with closely linked specimens for histological and genomic analysis permits interrogation of the histo:genomic relationship contextualised within the evolutionary dynamics of each tumour. We demonstrate that vascular intratumoral heterogeneity is pervasive and we link different vascular topologies to genetic alterations associated with opposing evolutionary trajectories (PBRM1 and BAP1 mutations) and the acquisition of metastatic competence (loss of 9p). Finally, we show that progressive accumulation of genetic alterations alters vascular network structure, suggesting that vascular topology could be used to assess tumour evolution. Our pipeline is a powerful tool to study ccRCC vasculature in large cohorts with multi-regional sampling to capture intratumoral heterogeneity and ultimately could form the basis of a computational pathology biomarker to predict outcome to therapy. Citation Format: Charlotte E. Spencer, Graham Ross, Thomas Mead, Amy Strange, Anna Song, Katie Bentley, Samra Turajlic. Interpretable computational pathology reveals that vascular networks reflect evolutionary dynamics in kidney cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Cancer Evolution and Data Science: The Next Frontier; 2023 Dec 3-6; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_2):Abstract nr PR015.

Aim To analyse the correlation between different surgical methodologies employed in valve diseases treatment and their subsequent impact on the duration of hospitalization. Methods This retrospective study conducted at the Clinical Centre of the University of Sarajevo analysed medical records of 163 valve disease patients treated between January 2019 and November 2022. The patients were divided into two groups: 77 had openheart valve surgery and 86 underwent minimally invasive cardiac surgery (MICS). Results The mean duration of the surgical procedures was 3.9±1.3 hours, with conventional open-heart surgery requiring an average of 3.6±1.1 hours and minimally invasive cardiac surgery (MICS) procedure 4.2±1.5 hours. No substantial disparities were found in the total length of hospitalization between the two groups, as both conventional (8.2±4.5 days) and MICS (8.7±7.0 days) demonstrated similar duration. Similarly, the total duration of intensive care unit (ICU) stay displayed similarity, with conventional surgery patients staying an average of 3.9±2.8 days and MICS patients of 4.2±4.1 days. The pattern of blood transfusion and fresh-frozen plasma usage revealed higher rates in the conventional valve surgery group comparing to the MICS group. Conclusion Minimally invasive valve surgery, despite slightly longer operative times, resulted in lower blood transfusion requirements and comparable hospitalization and ICU stay.

Aim Lung adenocarcinoma (ADC) is a leading subtype of lung cancer, histologically defined with five different architectural growth patterns: lepidic, acinar, papillary, solid and micropapillary. The aim of this study was to explore the prevalence of epidermal growth factor receptor (EGFR) mutation and a relationship between the specific histological patterns of lung ADC in the population of Bosnia and Herzegovina. Methods The study included tumour tissue from 102 patients with completely resected lung ADC from 2015 to 2020. Molecular testing for the presence of EGFR mutations was performed by real-time PCR method. The relationship between EGFR mutation status and clinicopathological parameters was analysed. Results The EGFR mutation was detected in 12 (11.8%) cases of ADC, more often in non-smokers (p=0.007). A higher percentage of solid growth pattern presented in ADC may be an indicator of EGFR negativity (p=0.039), while a higher percentage of micropapillary growth pattern more common in the presence of EGFR mutation (p=0.047). Conclusion The prevalence of EGFR mutation is in accordance with the expected prevalence considering our studied population, Caucasians from South Europe. Better understanding of the relationship between histological patterns and molecular characteristics of lung ADC will enable earlier diagnosis and optimal treatment for patients.

Introduction: The no-reflow phenomenon (persistent microvascular hypoperfusion despite macrovascular angiographic reperfusion) represents an explanation to poor outcome despite successful thrombectomy. There remains no universally-accepted definition to standardise future studies. We aim to compare the clinical features and outcomes of patients identified as having no-reflow using different perfusion MRI/CT definitions. Methods: We performed a pooled analysis of thrombectomy patients who underwent 24-hour follow-up perfusion MRI or CTs in the EXTEND-IA, EXTEND-IA TNK part 1 and 2 RCT. Presence of no-reflow was defined according to four definitions identified from a meta-analysis of 13 studies (Definition A = eTICI2c-3 and >15% asymmetry in CBV or CBF within the infarct on follow-up perfusion MRI/CT; definition B = mTICI2c-3 and >40% CBF asymmetry, definition C = mTICI2b-3 and presence of a Tmax>6s lesion; Definition D = mTICI2b-3 and >90% reduction of baseline Tmax>6s lesion). Receiver Operating Characteristics (ROC) analysis was performed with the outcome variable being poor functional outcome at 90 days (mRS≥3). Results: Of 325 patients analysed, the prevalence of no-reflow varied between definitions from 1.9 to 29.3% (p<0.001). There was poor agreement between definitions (kappa 0.062-0.745, 5 out 6 comparisons <0.196). Among patients identified as exhibiting no-reflow by any definition, there were significant differences in the intralesional interside differences in CBF (p=0.006), CBV (p<0.001) and MTT (p=0.005). Definition A yielded the highest Area Under the ROC Curve (AUC=0.679) for discrimination of 90-day functional outcome (Definitions C=0.649, D=0.597, B=0.515; p<0.0001). Sensitivity analyses testing across the eTICI≥2b, eTICI≥2c and eTICI3 strata showed consistent results. Conclusions: Existing imaging definitions of no-reflow varied significantly in prevalence and post-treatment perfusion imaging profile, suggesting that patients classified as having no-reflow by various definitions differ in their underlying pathophysiological processes. Definition A (eTICI2c-3 & >15% CBV/CBF asymmetry) discriminated prognostic performance best, supporting its use as the reference no-reflow imaging definition.

Background and Purpose: Cancer increases the risk for acute ischemic stroke (AIS) and deep venous thrombosis. The role of paradoxical embolization as a stroke etiology in patients with cancer is uncertain. Our study investigated the relationship between cancer-related stroke and the presence of a patent foramen ovale (PFO). Methods: We included AIS patients hospitalized at our comprehensive stroke center between January 2015 and December 2020 with available PFO status as detected on transesophageal echocardiography. Active cancer, including cancer known at the time of stroke as well as occult cancer newly diagnosed within one year after stroke, were retrospectively identified. The association between PFO status and active cancer was assessed with multivariable logistic regression and reported using adjusted odds ratios (aOR) and their 95% confidence intervals (CI). Results: Among 2236 AIS patients (median age 68.3 years, female sex 36.4%), 103 (4.6%) had active cancer, of whom 24 (23%) were diagnosed with PFO. This included 32 patients (1.4%) with occult cancer, of whom 19% were diagnosed with PFO. Conversely, among 2133 AIS patients without active cancer, 774 were diagnosed with PFO (36%). In multivariable analysis (Fig 1), the absence of PFO was associated with active cancer (aOR 2.62, 95% CI 1.28-5.38). This association appeared stronger when patients older than 80 years of age were excluded (aOR 3.06, 95% CI 1.42 - 6.58) and persisted among patients with occult cancer at the time of AIS (aOR 5.39, 95% CI 1.18-24.74). Conclusions: In patients with AIS, PFO was diagnosed more commonly among patients without cancer than those with cancer. This might be due to cancer-related stroke being related to arterial coagulopathy rather than paradoxical emboli resulting from venous thrombi. Further studies are needed to confirm these findings and to assess the diagnostic role of PFO in patients with cancer and AIS.

The paper describes the factorial design of the experiment with three input factors that change on two levels. For given values of the input parameters, it is shown how to obtain a variance analysis table and which factors and interactions between factors are significant. The example was done in the software intended for the design of the experiment and in the software R. It is shown how to use the software R to arrive at the final solution of the given example.

Remote driving plays an essential role in coordinating automated vehicles in some challenging situations. Due to the changed driving environment, the experiences and behaviors of remote drivers would undergo some changes compared to conventional drivers. To study this, a continuous real-life and remote driving experiment is conducted under different driving conditions. In addition, the effect of steering force feedback (SFF) on the driving experience is also investigated. In order to achieve this, three types of SFF modes are compared. According to the results, no SFF significantly worsens the driving experience in both remote and real-life driving. Additionally, less force and returnability on steering wheel are needed in remote driving, and the steering force amplitude appears to influence the steering velocity of remote drivers. Furthermore, there is an increase in lane following deviation during remote driving. Remote drivers are also prone to driving at lower speeds and have a higher steering reversal rate. They also give larger steering angle inputs when crossing the cones in a slalom manoeuvre and cause the car to experience larger lateral acceleration. These findings provide indications on how to design SFF and how driving behavior and experience change in remote driving.

We examine how perturbations off the Poisson manifold affect chimeras and traveling waves (TWs) in Kuramoto models with two sub-populations. Our numerical study is based on simulations on invariant manifolds, which contain von Mises probability distributions. Our study demonstrates that chimeras and TWs off the Poisson manifold always "breathe", and the effect of breathing is more pronounced further from the Poisson manifold. On the other side, TWs arising in similar models on the sphere always breathe moderately, no matter if the dynamics take place near the Poisson manifold or far away from it.