A retrospective cohort study on European Reference Network for Rare Vascular Diseases 5 outcome measures for Hereditary Haemorrhagic Telangiectasia in Denmark

Background Hereditary Haemorrhagic Telangiectasia (HHT) is an autosomal dominant disorder characterized by several clinical symptoms including epistaxis, arteriovenous malformations (AVM), and telangiectasia. In 2018, European Reference Network for Rare Vascular Diseases (VASCERN) recommended five outcome measures for HHT-patients to guide health care providers, some with limited experience in treating HHT, and thereby maximizing the number of HHT-patients receiving good care. The outcome measures cover the following aspects: (1) 90% of the patients should receive a pulmonary AVM (PAVM) screening; (2) 90% of the patients should receive written advice on nosebleed; (3) 70% should be assessed for iron deficiency; (4) 100% of the patients should receive written advice on antibiotic (AB) prophylaxis prior to dental and surgical procedures, and (5) 100% of relevant patients should receive written advice on pregnancy. We have introduced the outcome measures as Benchmarks in our HHT-centre and wanted to evaluate the extend of implementation we have achieved. We constantly struggle to secure the best possible treatment of our HHT-patients. Methods The study was a non-interventional retrospective study. Data was collected manually from patient records and from the Danish HHT-database. Results A total of 180 HHT-patients were included, all diagnosed in the period from January 1st, 2016, to December 31st, 2020. All patients were screened for PAVM. We could confirm that 66% of patients who had epistaxis received thoroughly advice. Assessment for iron deficiency was performed in 80% of the adult patients. Thoroughly advice on AB prophylaxis was documented in 75%. Thoroughly advice on pregnancy was documented in 80% of female patients 15–45 years of age. There were no significant differences over time for any of the outcome measures. Conclusions The Danish HHT-centre reached the target threshold for outcome measures 1 and 3. It could not be documented that the target thresholds for outcome measures 2, 4, and 5 were achieved. As information and education are a very important part of HHT care, focus on and documentation that all patients receive the relevant advice must be a priority in order to ensure best care.

A complex unit for a complex disease: the HCM-Family Unit

Hypertrophic cardiomyopathy (HCM) is a group of heterogeneous disorders that are most commonly passed on in a heritable manner. It is a relatively rare disease around the globe, but due to increased rates of consanguinity within the Kingdom of Saudi Arabia, we speculate a high incidence of undiagnosed cases. The aim of this paper is to elucidate a systematic approach in dealing with HCM patients and since HCM has variable presentation, we have summarized differentials for diagnosis and how different subtypes and genes can have an impact on the clinical picture, management and prognosis. Moreover, we propose a referral multi-disciplinary team HCM-Family Unit in Saudi Arabia and an integrated role in a network between King Faisal Hospital and Inherited and Rare Cardiovascular Disease Unit-Monaldi Hospital, Italy (among the 24 excellence centers of the European Reference Network (ERN) GUARD-Heart). Graphical Abstract

Simulation and Analysis of Grid Formation Method for UAV Clusters Based on the 3 × 3 Magic Square and the Chain Rules of Visual Reference

Large-scale unmanned aerial vehicle (UAV) formations are vulnerable to disintegration under electromagnetic interference and fire attacks. To address this issue, this work proposed a distributed formation method of UAVs based on the 3 × 3 magic square and the chain rules of visual reference. Enlightened by the biomimetic idea of the plane formation of starling flocks, this method adopts the technical means of airborne vision and a cooperative target. The topological structure of the formation’s visual reference network showed high static stability under the measurement of the network connectivity index. In addition, the dynamic self-healing ability of this network was analyzed. Finally, a simulation of a battlefield using matlab showed that, when the loss of UAVs reaches 85% for formations with different scales, the UAVs breaking formation account for 5.1–6% of the total in the corresponding scale, and those keeping formation account for 54.4–65.7% of the total undestroyed fleets. The formation method designed in this paper can maintain the maximum number of UAVs in formation on the battlefield.

Current Clinical Practice for Thromboprophylaxis Management in Patients With Cushing’s Syndrome Across Reference Centers of the European Reference Network on Rare Endocrine Conditions (Endo-ERN)

Background: Cushing’s syndrome (CS) is associated with an hypercoagulable state and an increased risk of venous thromboembolism (VTE). Evidence-based guidelines on thromboprophylaxis strategies in patients with CS are currently lacking. We aimed to map the current clinical practice for thromboprophylaxis management in patients with CS across reference centers (RCs) of the European Reference Network on Rare Endocrine Conditions (Endo-ERN), which are endorsed specifically for the diagnosis and treatment of CS. Using the EU survey tool, a primary screening survey, and subsequently a secondary, more in-depth survey were developed. Results: The majority of the RCs provided thromboprophylaxis to patients with CS (n=23/25), although only one center had a standardized thromboprophylaxis protocol (n=1/23). RCs most frequently started thromboprophylaxis from CS diagnosis onwards (n=11/23), and the majority stopped thromboprophylaxis based on individual patient characteristics, rather than standardized treatment duration (n=15/23). Factors influencing the initiation of thromboprophylaxis were ‘medical history of VTE’ (n=15/23) and ‘severity of hypercortisolism’ (n=15/23). Low-Molecular-Weight-Heparin was selected as the first-choice anticoagulant drug for thromboprophylaxis by all RCs (n=23/23). Postoperatively, the majority of RCs reported ‘severe immobilization’ as an indication to start thromboprophylaxis in patients with CS (n=15/25). Most RCs (n=19/25) did not provide standardized testing for variables of hemostasis in the postoperative care of CS. Furthermore, the majority of the RCs provided preoperative medical treatment to patients with CS (n=23/25). About half of these RCs (n=12/23) took a previous VTE into account when starting preoperative medical treatment, and about two-thirds (n=15/23) included ‘reduction of VTE risk’ as a goal of treatment. Conclusions: There is a large practice variation regarding thromboprophylaxis management and perioperative medical treatment in patients with CS, even in Endo-ERN RCs. Randomized controlled trials are needed to establish the optimal prophylactic anticoagulant regimen, carefully balancing the increased risk of (perioperative) bleeding, and the presence of additional risk factors for thrombosis.

Hereditary haemorrhagic telangiectasia: development of a regional life-course collaborative clinical care pathway

Hereditary haemorrhagic telangiectasia is a rare, genetic disorder that can present at any age. It is characterised by epistaxis, mucocutaneous telangiectasia and visceral arteriovenous malformations, which can affect multiple organs. Early diagnosis and management reduces the morbidity and mortality associated with the disease. There is a well-established hereditary haemorrhagic telangiectasia clinic in London, and excellent links across Europe via the European Reference Network. However, local coordinated care for patients with hereditary haemorrhagic telangiectasia across the UK can be variable and often absent for children and young people. Some patients travel long distances to receive care in London, while others are referred to local clinicians or lost to follow up entirely. This article presents the experience to date from two regional UK centres (Liverpool and Dundee) where care for patients with hereditary haemorrhagic telangiectasia is being coordinated and streamlined. While there is still a lot to learn, this article highlights some of the successes and challenges identified so far, with suggestions for how these could be addressed. Collaborative regional networks such as these can facilitate the sharing of best practice and ensure that all patients with hereditary haemorrhagic telangiectasia are able to access safe, high-quality care.

Assessment of Multi-Frequency PPP Ambiguity Resolution Using Galileo and BeiDou-3 Signals

From network RTK to PPP-RTK, it is highly expected that high-precision positioning within a few minutes can be achieved with a sparse reference network. In this study, we investigate a rapid multi-frequency PPP convergence strategy based on Galileo E1/E5a/E6 and BeiDou-3 B1C/B2a/B3I signals, whose unambiguous wide-lane observables can efficiently assist in speeding up narrow-lane ambiguity resolution. Furthermore, frequency-specific biases existing on the third-frequency observables have been observed to slow down multi-frequency PPP-AR convergence. In this study, we partially mitigated their effects by estimating a second satellite clock for the third frequency of signals. We validated this approach with one month of data collected from 22 stations. On average, it took about 18 min for PPP wide-lane ambiguity resolution (PPP-WAR) to converge, while 32 min were required for ambiguity-float PPP. Compared with dual-frequency PPP-AR, which needed nearly 12 min to converge, multi-frequency PPP-AR required 6 min only. Once there were more than 10 satellites involved in PPP, the convergence could be achieved within 3 min on average. Meanwhile, 81% and 62% of multi-frequency PPP-AR solutions converged successfully within 5 and 1 min, respectively. Finally, we carried out a vehicle-borne experiment to validate this approach in a kinematic environment. Owing to frequent cycle slips during the movement of vehicle, it took 14 min for B1C/B2a/B3I and E1/E5a/E6 PPP-AR to obtain reliable positions, and 19 min for those using the other signal combinations B1C/B2a/B2b and E1/E5a/E5b, owning to higher noise. Overall, these results are promising for achieving high-precision PPP positioning globally within a few minutes if multi-frequency biases can be handled well in the data processing.

A novel probabilistic generator for large-scale gene association networks

Motivation Gene expression data provide an opportunity for reverse-engineering gene-gene associations using network inference methods. However, it is difficult to assess the performance of these methods because the true underlying network is unknown in real data. Current benchmarks address this problem by subsampling a known regulatory network to conduct simulations. But the topology of regulatory networks can vary greatly across organisms or tissues, and reference-based generators—such as GeneNetWeaver—are not designed to capture this heterogeneity. This means, for example, benchmark results from the E. coli regulatory network will not carry over to other organisms or tissues. In contrast, probabilistic generators do not require a reference network, and they have the potential to capture a rich distribution of topologies. This makes probabilistic generators an ideal approach for obtaining a robust benchmarking of network inference methods. Results We propose a novel probabilistic network generator that (1) provides an alternative to address the inherent limitation of reference-based generators and (2) is able to create realistic gene association networks, and (3) captures the heterogeneity found across gold-standard networks better than existing generators used in practice. Eight organism-specific and 12 human tissue-specific gold-standard association networks are considered. Several measures of global topology are used to determine the similarity of generated networks to the gold-standards. Along with demonstrating the variability of network structure across organisms and tissues, we show that the commonly used “scale-free” model is insufficient for replicating these structures. Availability This generator is implemented in the R package “SeqNet” and is available on CRAN (https://cran.r-project.org/web/packages/SeqNet/index.html).

Molecular profiling of advanced soft-tissue sarcomas: the MULTISARC randomized trial

Background Soft-tissue sarcomas (STS) represent a heterogeneous group of rare tumors including more than 70 different histological subtypes. High throughput molecular analysis (next generation sequencing exome [NGS]) is a unique opportunity to identify driver mutations that can change the usual one-size-fits-all treatment paradigm to a patient-driven therapeutic strategy. The primary objective of the MULTISARC trial is to assess whether NGS can be conducted for a large proportion of metastatic STS participants within a reasonable time, and, secondarily to determine whether a NGS-guided therapeutic strategy improves participant’s outcome. Methods This is a randomized, multicentre, phase II/III trial inspired by the design of umbrella and biomarker-driven trials. The setting plans up to 17 investigational centres across France and the recruitment of 960 participants. Participants aged at least 18 years, with unresectable locally advanced and/or metastatic STS confirmed by the French sarcoma pathological reference network, are randomized according to 1:1 allocation ratio between the experimental arm “NGS” and the standard “No NGS”. NGS will be considered feasible if (i) NGS results are available and interpretable, and (ii) a report of exome sequencing including a clinical recommendation from a multidisciplinary tumor board is provided to investigators within 7 weeks from reception of the samples on the biopathological platform. A feasibility rate of more than 70% is expected (null hypothesis: 70% versus alternative hypothesis: 80%). In terms of care, participants randomized in “No NGS” arm and who fail treatment will be able to switch to the NGS arm at the request of the investigator. Discussion The MULTISARC trial is a prospective study designed to provide high-level evidence to support the implementation of NGS in routine clinical practice for advanced STS participants, on a large scale. Trial registration clinicaltrial.gov NCT03784014.

Terrestrial photogrammetry at the quarry and validating the accuracy of slope models for monitoring their stability

The paper is devoted to the application of photogrammetry in surveying and geomechanical studies of the state of stability of slopes in a quarry. For deep quarries a particularly important task is to ensure the stability of the slopes of the benches. The purpose of this study is to improve the survey techniques of the slopes using terrestrial photogrammetry, the establishment of the values of the basic errors in the positioning of cameras in local geodetic network. The results of photogrammetric measuring data processing, which are the coordinates of the slope points and its elements, point cloud, surface model, volume and area data, improve the quality of geomechanical monitoring at mining enterprises and provide increase safety of mining operations. The proposed method of survey consists in positioning images (projection centres) in the system of the geodetic reference network by measuring with an electronic total station. Established during the study was dependence of the accuracy of the coordinates of the three-dimensional model of the slopes on the distance between the camera and the total station, between the camera positions in a pair of images. The article contains the results of the practical implementation of the proposed survey method, the results of experiments performed for the purpose of comparison with an alternative measurement method, which was a survey by a total station, graphs of dependencies describing the effect of measurement parameters on the accuracy of work performed. The article is also supplemented by a theoretical analysis of the use of UAVs in the use of work to determine of stability of slopes in a quarry, which is based on the authors’ experience with the use of UAVs in open pit mines. In this theoretical comparison, the emphasis is mainly on the operability of the use of UAV, which in the case of open pit mines creating a practically stable wind vortex with a speed higher than the allowed speed of operation rotors UAVs.