Spontaneous Coronary Artery Dissection as Presenting Feature of Vascular Ehlers-Danlos Syndrome

A spontaneous coronary artery dissection as the sole presenting feature of vascular Ehlers-Danlos syndrome is an uncommon finding. We present a 33-year-old woman with sudden onset chest pain caused by a spontaneous coronary artery dissection. Genetic testing revealed vascular Ehlers-Danlos syndrome as the underlying cause. Specifically, we show the value of genetic testing, which in some patients may be the only way of establishing a diagnosis

Novel cryoballoon 180° ablation system for treatment of Barrett's esophagus-related neoplasia:a first-in-human study

Background The novel 180 degrees cryoballoon (CbAS (180) ) enables semicircumferential treatment over a length of 3cm per application. This first-in-human study evaluates its feasibility, efficacy, and safety for the treatment of Barrett's esophagus (BE) neoplasia. Methods This multicenter study consisted of dose-finding and extension phases. Dose-finding started with the lowest dose possible (1.0mm/s). For each dose, six patients were treated circumferentially over a 3-cm length. The dose was increased until the median BE regression was >= 60% without serious adverse events (SAEs). In the extension phase, the dose was confirmed in 19 new patients. The outcomes were technical success, BE regression after one treatment, and SAEs. Results 25 patients (median Prague C0M3) were included (6 dose-finding/19 extension). In two patients, the CbAS (180) could not be applied because of unstable balloon positioning. The technical success rate was 96% (22/23). In the six dose-finding patients, the starting dose resulted in median BE regression of 94% (95% confidence interval [CI] 60%-97%) without SAEs and was thus considered effective. Overall median BE regression was 80% (95%CI 60%-90%). Conclusion Single-session CbAS (180) seems feasible, safe, and effective, and is a promising technique for the treatment of patients with BE neoplasia

Endoscopic submucosal dissection for early esophageal squamous cell carcinoma:long-term results from a Western cohort

Background Although endoscopic submucosal dissection (ESD) is established as first-choice treatment for early esophageal squamous cell carcinoma (ESCC) worldwide, most data are derived from Asian studies. We aimed to evaluate the long-term outcomes of ESD for patients with early ESCC in a Western cohort. Methods In this retrospective cohort study, patients with early ESCC amenable to ESD were included from four tertiary referral hospitals in the Netherlands between 2012 and 2017. All ESD procedures were performed by experienced endoscopists, after which the decision for additional treatment was made on a per-patient basis. Outcomes were curative resection rate, ESCC-specific survival, and overall survival. Results Of 68 included patients (mean age 69 years; 34 males), ESD was technically successful in 66 (97%; 95%CI 93%-100%), with curative resection achieved in 34/66 (52%; 95%CI 39%-64%). Among patients with noncurative resection, 15/32 (47%) underwent additional treatment, mainly esophagectomy (n = 10) or definitive chemoradiation therapy (n = 4). Endoscopic surveillance was preferred in 17/32 patients (53%), based on severe comorbidities or patient choice. Overall, 31/66 patients (47%) died during a median follow-up of 66 months; 8/31 (26%) were ESCC-related deaths. The 5-year overall and ESCC-specific survival probabilities were 62% (95%CI 52%-75%) and 86% (95%CI 77%-96%), respectively. Conclusion In this Western cohort with long-term follow-up, the effectiveness and safety of ESD for early ESCC was confirmed, although the rate of noncurative resections was substantial. Irrespective of curative status, the long-term prognosis of these patients was limited mainly due to competing mortality

Primrose syndrome: Characterization of the phenotype in 42 patients

Primrose syndrome (PS; MIM# 259050) is characterized by intellectual disability (ID), macrocephaly, unusual facial features (frontal bossing, deeply set eyes, down-slanting palpebral fissures), calcified external ears, sparse body hair and distal muscle wasting. The syndrome is caused by de novo heterozygous missense variants in ZBTB20. Most of the 29 published patients are adults as characteristics appear more recognizable with age. We present 13 hitherto unpublished individuals and summarize the clinical and molecular findings in all 42 patients. Several signs and symptoms of PS develop during childhood, but the cardinal features, such as calcification of the external ears, cystic bone lesions, muscle wasting, and contractures typically develop between 10 and 16 years of age. Biochemically, anemia and increased alpha-fetoprotein levels are often present. Two adult males with PS developed a testicular tumor. Although PS should be regarded as a progressive entity, there are no indications that cognition becomes more impaired with age. No obvious genotype-phenotype correlation is present. A subgroup of patients with ZBTB20 variants may be associated with mild, nonspecific ID. Metabolic investigations suggest a disturbed mitochondrial fatty acid oxidation. We suggest a regular surveillance in all adult males with PS until it is clear whether or not there is a truly elevated risk of testicular cancer.This article is freely available via Open Access. Click on the Publisher URL to access it via the publisher's site.published version, accepted version (12 month embargo) submitted versio

Expanding the clinical spectrum of biglycan-related Meester-Loeys syndrome

\ua9 The Author(s) 2024.Pathogenic loss-of-function variants in BGN, an X-linked gene encoding biglycan, are associated with Meester-Loeys syndrome (MRLS), a thoracic aortic aneurysm/dissection syndrome. Since the initial publication of five probands in 2017, we have considerably expanded our MRLS cohort to a total of 18 probands (16 males and 2 females). Segregation analyses identified 36 additional BGN variant-harboring family members (9 males and 27 females). The identified BGN variants were shown to lead to loss-of-function by cDNA and Western Blot analyses of skin fibroblasts or were strongly predicted to lead to loss-of-function based on the nature of the variant. No (likely) pathogenic missense variants without additional (predicted) splice effects were identified. Interestingly, a male proband with a deletion spanning the coding sequence of BGN and the 5’ untranslated region of the downstream gene (ATP2B3) presented with a more severe skeletal phenotype. This may possibly be explained by expressional activation of the downstream ATPase ATP2B3 (normally repressed in skin fibroblasts) driven by the remnant BGN promotor. This study highlights that aneurysms and dissections in MRLS extend beyond the thoracic aorta, affecting the entire arterial tree, and cardiovascular symptoms may coincide with non-specific connective tissue features. Furthermore, the clinical presentation is more severe and penetrant in males compared to females. Extensive analysis at RNA, cDNA, and/or protein level is recommended to prove a loss-of-function effect before determining the pathogenicity of identified BGN missense and non-canonical splice variants. In conclusion, distinct mechanisms may underlie the wide phenotypic spectrum of MRLS patients carrying loss-of-function variants in BGN

Next generation sequencing in clinical practice:Illustrated by studies in hereditary connective tissue disorders

The research in this thesis was performed at the department of human genetics of the Amsterdam UMC. At location AMC there is a long-standing history of care for patients with Marfan syndrome and related disorders. In addition, genetic testing for these disorders has been performed at the diagnostic laboratory of the VUmc for years. Combined, we were able to study both clinical and genetic data in a large patient cohort. This proved us with an excellent opportunity for clinical research, both in relatively large patient cohorts and in families with these connective tissue disorders. In part 1, the outcomes and applications of next generation sequencing (NGS) in different hereditary connective tissue disorders (e.g. hereditary aortic disease and ectopia lentis) are illustrated by several cohort studies and/or literature studies. Based on the outcomes of genetic testing in cohort studies such as those described in part 1, guidelines on whom to offer these tests can be established. In part 2, the importance of raising awareness for genetic diseases is illustrated by several remarkable families with a hereditary connective tissue disorder. The presented cases highlight the clinical value of genetic testing in diagnosing hereditary aortic disease and the opportunities provided by the rapid advances in the field of human genetics

Large sample neutron activation analysis of a ceramic vase

Large Sample Neutron Activation Analysis (LSNAA) was applied to perform non-destructive elemental analysis of a ceramic vase. Appropriate neutron self-shielding and gamma ray detection efficiency calibration factors were derived using Monte Carlo code MCNP5. The results of LSNAA were compared against Instrumental Neutron Activation Analysis (INAA) results and a satisfactory agreement between the two methods was observed. The ratio of derived concentrations between the two methods was within 0.7 and 1.3. Estimation of the activity level decay with time showed that the vase could be released from regulatory control at about 3 months post-irradiation. This study provided an analytical procedure for bulk sample analysis of precious and archaeological objects that need to be preserved intact and cannot be damaged for sampling purposes.Radiation, Radionuclides and ReactorsApplied Science

13.4 A 1GS/s 6-to-8b 0.5mW/Qubit Cryo-CMOS SAR ADC for Quantum Computing in 40nm CMOS

Quantum computers (QCs) promise significant speedup for relevant computational problems that are intractable by classical computers. QCs process information stored in quantum bits (qubits) that must be typically cooled down to cryogenic temperatures. Since state-of-the-art QCs employ only a few qubits, those qubits can be driven and read out by room-temperature electronics connected to the cryogenic qubits by only a few wires. However, practical QCs will require more than thousands of qubits, making this approach impractical due to system complexity and reliability concerns. Although frequency multiplexing would reduce the interconnects to room temperature by fitting many qubit channels in the same physical interconnect, an excessive number of interconnects would still be required. An alternative, more scalable solution is a cryogenic electronic interface operating very close to the quantum processor to keep the whole control loop at cryogenic temperature, hence avoiding any high-speed interconnect to room temperature. This system must comprise drivers, readout circuits (LNAs, ADCs), and a digital controller to steer the quantum-algorithm execution [1]. While cryogenic CMOS (cryo-CMOS) wideband drivers and LNAs supporting qubit frequency multiplexing have been shown before [1] -[3], no wideband cryo-CMOS ADC has been demonstrated yet