Phase-Sensitive Quantum Measurement without Controlled Operations.

Many quantum algorithms rely on the measurement of complex quantum amplitudes. Standard approaches to obtain the phase information, such as the Hadamard test, give rise to large overheads due to the need for global controlled-unitary operations. We introduce a quantum algorithm based on complex analysis that overcomes this problem for amplitudes that are a continuous function of time. Our method only requires the implementation of real-time evolution and a shallow circuit that approximates a short imaginary-time evolution. We show that the method outperforms the Hadamard test in terms of circuit depth and that it is suitable for current noisy quantum computers when combined with a simple error-mitigation strategy.

Telemedical monitoring in patients with inborn cardiac disease - experience of a tertiary care centre.

BACKGROUND: The number of cardiologically relevant genetic findings will continue to increase. This is due to the use of high-throughput sequencing techniques and the critical role of incidental findings in cardiac disease genes. Telemedicine can be a useful diagnostic tool to monitor the heart rhythm of patients with inborn cardiac diseases. METHODS: Patients were screened once they had been referred to our outpatient department for rare cardiac diseases between January 2020 and May 2022. Those patients who underwent genetic testing and were consequently diagnosed with a genetic disorder were included in this study. Their medical records were evaluated regarding implanted cardiac electronic devices and findings in the telemedical monitoring. RESULTS: 304 patients were seen in our outpatient department for rare cardiac diseases in the mentioned period. In 100 cases, genetic testing was performed. 10 patients (10%) with an identified inborn cardiac disease were monitored via telemedicine until the end of May 2022. 4 patients were monitored by implantable loop recorders (ILR), 4 patients were monitored by Implantable Cardioverter Defibrillators (ICD), and 2 patients received both devices. Clinical relevant arrhythmias making medical intervention necessary were identified in 4 cases. In two cases, data interpretation was hampered by sinus tachycardia caused by physical exercise. DISCUSSION: Telemonitoring of the heart rhythm by medical devices is beneficial for patients with monogenic heart diseases. Especially, when the indication for an ICD is not clear, implantation of a telemonitored ILR can be a suitable choice. However, rhythm analysis can be challenging in young patients who are physically active.

Genetic and phenotypic spectrum in the NONO-associated syndromic disorder.

The non-POU domain-containing octamer-binding (NONO) protein is involved in multiple steps of gene regulation such as RNA metabolism and DNA repair. Hemizygous pathogenic variants in the NONO gene were confirmed to cause a rare X-linked syndromic disorder. Through our in-house diagnostics and subsequent matchmaking, we identified six unrelated male individuals with pathogenic or likely pathogenic NONO variants. For a detailed comparison, we reviewed all published characterizations of the NONO-associated disorder. The combined cohort consists of 16 live-born males showing developmental delay, corpus callosum anomalies, non-compaction cardiomyopathy and relative macrocephaly as leading symptoms. Seven prenatal literature cases were characterized by cardiac malformations. In this study, we extend the phenotypic spectrum through two more cases with epilepsy as well as two more cases with hematologic anomalies. By RNA expression analysis and structural modeling of a new in-frame splice deletion, we reinforce loss-of-function as the pathomechanism for the NONO-associated syndromic disorder.

Excitons in a reconstructed moiré potential in twisted WSe2/WSe2 homobilayers.

Moiré superlattices in twisted van der Waals materials have recently emerged as a promising platform for engineering electronic and optical properties. A major obstacle to fully understanding these systems and harnessing their potential is the limited ability to correlate direct imaging of the moiré structure with optical and electronic properties. Here we develop a secondary electron microscope technique to directly image stacking domains in fully functional van der Waals heterostructure devices. After demonstrating the imaging of AB/BA and ABA/ABC domains in multilayer graphene, we employ this technique to investigate reconstructed moiré patterns in twisted WSe2/WSe2 bilayers and directly correlate the increasing moiré periodicity with the emergence of two distinct exciton species in photoluminescence measurements. These states can be tuned individually through electrostatic gating and feature different valley coherence properties. We attribute our observations to the formation of an array of two intralayer exciton species that reside in alternating locations in the superlattice, and open up new avenues to realize tunable exciton arrays in twisted van der Waals heterostructures, with applications in quantum optoelectronics and explorations of novel many-body systems.

A de novo missense variant in GABRA4 alters receptor function in an epileptic and neurodevelopmental phenotype.

Variants in γ-aminobutyric acid A (GABAA ) receptor genes cause different forms of epilepsy and neurodevelopmental disorders. To date, GABRA4, encoding the α4-subunit, has not been associated with a monogenic condition. However, preclinical evidence points toward seizure susceptibility. Here, we report a de novo missense variant in GABRA4 (c.899C>T, p.Thr300Ile) in an individual with early-onset drug-resistant epilepsy and neurodevelopmental abnormalities. An electrophysiological characterization of the variant, which is located in the pore-forming domain, shows accelerated desensitization and a lack of seizure-protective neurosteroid function. In conclusion, our findings strongly suggest an association between de novo variation in GABRA4 and a neurodevelopmental disorder with epilepsy.

Do children with congenital heart defects meet the vaccination recommendations? Immunisation in children with congenital heart defects.

INTRODUCTION: Congenital heart defects (CHDs) are the most common congenital malformations. Patients with CHD have a higher morbidity and mortality rate and are at greater risk for infectious diseases. The risk might even be higher if complex CHD occurs and if CHD is associated with additional co-morbidities. Therefore, immunisations in these children are essential. MATERIALS AND METHODS: Individuals were recruited at the outpatient centre of the Department of Congenital Heart Defects and Pediatric Cardiology at the German Heart Center Munich in the time between February 2016 and February 2017. Included were children between 23 months and 17 years and a diagnosis of CHD. The vaccination certificate aimed to assess the immunization status. RESULTS: In total, 657 children with CHD were included and analysed. Regarding primary immunisation, only 34 % (n = 221) of the children reached the complete vaccination status within the allowed catch-up time. Among these primary immunisation rates, vaccinations against Hepatitis B, Meningococci, Varicella and Pneumococci were found to have the lowest coverage with all being below 80%. The vaccination rate was partly influenced by the previously performed number of surgeries but not by the diagnosis of specific genetic diseases. At the age of school entry, the immunisation rate in children with CHD was also lower than in the comparable healthy population. CONCLUSION: The vaccination coverage rate in children with CHD is lower than in comparable healthy children, although this is a vulnerable patient group. Further education of parents and treating physicians of children with CHD regarding vaccination is still needed.

A contrast-adaptive method for simultaneous whole-brain and lesion segmentation in multiple sclerosis.

Here we present a method for the simultaneous segmentation of white matter lesions and normal-appearing neuroanatomical structures from multi-contrast brain MRI scans of multiple sclerosis patients. The method integrates a novel model for white matter lesions into a previously validated generative model for whole-brain segmentation. By using separate models for the shape of anatomical structures and their appearance in MRI, the algorithm can adapt to data acquired with different scanners and imaging protocols without retraining. We validate the method using four disparate datasets, showing robust performance in white matter lesion segmentation while simultaneously segmenting dozens of other brain structures. We further demonstrate that the contrast-adaptive method can also be safely applied to MRI scans of healthy controls, and replicate previously documented atrophy patterns in deep gray matter structures in MS. The algorithm is publicly available as part of the open-source neuroimaging package FreeSurfer.

De novo variants in neurodevelopmental disorders-experiences from a tertiary care center.

Up to 40% of neurodevelopmental disorders (NDDs) such as intellectual disability, developmental delay, autism spectrum disorder, and developmental motor abnormalities have a documented underlying monogenic defect, primarily due to de novo variants. Still, the overall burden of de novo variants as well as novel disease genes in NDDs await discovery. We performed parent-offspring trio exome sequencing in 231 individuals with NDDs. Phenotypes were compiled using human phenotype ontology terms. The overall diagnostic yield was 49.8% (n = 115/231) with de novo variants contributing to more than 80% (n = 93/115) of all solved cases. De novo variants affected 72 different-mostly constrained-genes. In addition, we identified putative pathogenic variants in 16 genes not linked to NDDs to date. Reanalysis performed in 80 initially unsolved cases revealed a definitive diagnosis in two additional cases. Our study consolidates the contribution and genetic heterogeneity of de novo variants in NDDs highlighting trio exome sequencing as effective diagnostic tool for NDDs. Besides, we illustrate the potential of a trio-approach for candidate gene discovery and the power of systematic reanalysis of unsolved cases.

Quantum Sampling Algorithms for Near-Term Devices.

Efficient sampling from a classical Gibbs distribution is an important computational problem with applications ranging from statistical physics over Monte Carlo and optimization algorithms to machine learning. We introduce a family of quantum algorithms that provide unbiased samples by preparing a state encoding the entire Gibbs distribution. We show that this approach leads to a speedup over a classical Markov chain algorithm for several examples, including the Ising model and sampling from weighted independent sets of two different graphs. Our approach connects computational complexity with phase transitions, providing a physical interpretation of quantum speedup. Moreover, it opens the door to exploring potentially useful sampling algorithms on near-term quantum devices, as the algorithm for sampling from independent sets on certain graphs can be naturally implemented using Rydberg atom arrays.

Controlling Interactions between Quantum Emitters Using Atom Arrays.

We investigate the potential for two-dimensional atom arrays to modify the radiation and interaction of individual quantum emitters. Specifically, we demonstrate that control over the emission linewidths, resonant frequency shifts, and local driving field enhancement in impurity atoms is possible due to strong dipole-dipole interactions within ordered, subwavelength atom array configurations. We demonstrate that these effects can be used to dramatically enhance coherent dipole-dipole interactions between distant impurity atoms within an atom array. Possible experimental realizations and potential applications are discussed.

Reasons for new MIS. Let's be fair: iTIND, Urolift and Rezum.

PURPOSE: To review and discuss the literature regarding iTIND, Urolift and Rezum and investigate the precise clinical indications of all three different approaches for their application in benign prostatic hyperplasia (BPH) treatment. MATERIALS AND METHODS: The PubMed-Medline and Cochrane Library databases were screened to identify recent English literature relevant to iTIND, Urolift and Rezum therapies. The surgical technique and clinical results for each approach were summarized narratively. RESULTS: iTIND, Urolift and Rezum are safe and effective minimally invasive procedures for the symptomatic relief of lower urinary tract symptoms (LUTS) due to BPH. iTIND requires the results of ongoing prospective studies, a long-term follow-up and a comparison against a reference technique to confirm the generalizability of the first pivotal study. Urolift provides symptomatic relief but the improvements are inferior to TURP at 24 months and long-term retreatments have not been evaluated. Rezum requires randomized controlled trials against a reference technique to confirm the first promising clinical results. However, clinical evidence from prospective clinical trials demonstrates the efficacy and safety of these procedures in patients with small- and medium-sized prostates. CONCLUSIONS: Although iTIND, Urolift, and Rezum cannot be applied to all bladder outlet obstruction (BOO) cases resulting from BPH, they provide a safe alternative for carefully selected patients who desire symptom relief and preservation of erectile and ejaculatory function without the potential morbidity of more invasive procedures.

Laser procedures in the treatment of BPH: a bibliometric study.

PURPOSE: To perform a bibliometric analysis of lased-based BPH treatment publications and to obtain an understanding of the publication trends over time. MATERIALS AND METHODS: The Medline database was searched for articles in English language regarding laser-based BPH therapy up to 2018. Matching articles were assigned to at least one of the following categories: Ho:YAG, Tm:YAG, green light, diode, Nd:YAG laser and review articles. The laser categories were analysed using bibliometric procedures regarding citation rate, authors, country of origin and journal of publication. Moreover, the articles on laser BPH therapy included in the EAU, AUA and JUA guidelines were analysed to evaluate the most influential articles. RESULTS: In total, 982 articles were included: 317 articles were assigned to green light, 283 to Ho:YAG, 101 to Tm:YAG, 74 to Nd:YAG and 39 to diode lasers. The publication rate for Nd:YAG laser has declined, but continues to grow for Ho:YAG and Tm:YAG lasers. We found a positive correlation between number of authors and year of publication (R = 0.3, p < 0.001*). Articles on Ho:YAG lasers are cited the most (mean 23.0 ± 37.1). Asia has contributed the most articles. Mostly, countries with high health and research and development (R&D) expenditures influenced the guidelines regarding laser-based approaches. Yet, after adjustment of all search results to GDP, health and R&D expenditure, India and China were the most prolific countries. CONCLUSION: Laser-based approaches for BPH treatment are increasing but have not been implemented worldwide. Asia's contribution should be acknowledged. An inflationary trend regarding the number of authors per article is confirmed.

Visible-frequency hyperbolic metasurface.

Metamaterials are artificial optical media composed of sub-wavelength metallic and dielectric building blocks that feature optical phenomena not present in naturally occurring materials. Although they can serve as the basis for unique optical devices that mould the flow of light in unconventional ways, three-dimensional metamaterials suffer from extreme propagation losses. Two-dimensional metamaterials (metasurfaces) such as hyperbolic metasurfaces for propagating surface plasmon polaritons have the potential to alleviate this problem. Because the surface plasmon polaritons are guided at a metal-dielectric interface (rather than passing through metallic components), these hyperbolic metasurfaces have been predicted to suffer much lower propagation loss while still exhibiting optical phenomena akin to those in three-dimensional metamaterials. Moreover, because of their planar nature, these devices enable the construction of integrated metamaterial circuits as well as easy coupling with other optoelectronic elements. Here we report the experimental realization of a visible-frequency hyperbolic metasurface using single-crystal silver nanostructures defined by lithographic and etching techniques. The resulting devices display the characteristic properties of metamaterials, such as negative refraction and diffraction-free propagation, with device performance greatly exceeding those of previous demonstrations. Moreover, hyperbolic metasurfaces exhibit strong, dispersion-dependent spin-orbit coupling, enabling polarization- and wavelength-dependent routeing of surface plasmon polaritons and two-dimensional chiral optical components. These results open the door to realizing integrated optical meta-circuits, with wide-ranging applications in areas from imaging and sensing to quantum optics and quantum information science.

Cardiovascular Effects Mediated by HMMR and CD44.

Cardiovascular disease (CVD) is the leading cause of death worldwide. The most dangerous life-threatening symptoms of CVD are myocardial infarction and stroke. The causes of CVD are not entirely clear, and new therapeutic targets are still being sought. One of the factors involved in CVD development among vascular damage and oxidative stress is chronic inflammation. It is known that hyaluronic acid plays an important role in inflammation and is regulated by numerous stimuli, including proinflammatory cytokines. The main receptors for hyaluronic acid are CD44 and RHAMM. These receptors are membrane proteins that differ in structure, but it seems that they can perform similar or synergistic functions in many diseases. Both RHAMM and CD44 are involved in cell migration and wound healing. However, their close association with CVD is not fully understood. In this review, we describe the role of both receptors in CVD.

Track and Teach: Identifying Key Movement Patterns in Endoscopic Transurethral Enucleation of the Prostate.

PURPOSE: We evaluated a system for noninvasive quantitative motion tracking to recognize differences in the movement pattern of experienced surgeons and beginners. Since performing endoscopic procedures requires extensive training, and tissue damage due to disruptive movements with sudden acceleration is possible, the learning curve for beginners is of clinical relevance. Steepening this curve may improve patient outcome. MATERIALS AND METHODS: We used a commercial gyroscope sensor with a wireless data link, which was attached to the resectoscope handle (RH). After recording, orientation was retrieved by application of the calculated rotation matrices to the RH vector relative to the sensor under the boundary condition of rotational movement around and quasi-constant distance to the pivot point at pelvic floor level. Data alignment, normalization, interpolation, and analysis were performed in custom software scripts. RESULTS: Experienced surgeons and beginners were recorded in n = 36 and n = 14 holmium laser enucleation of the prostate (HoLEP), respectively. Prostate size, patient age, and recorded procedure duration were comparable. Mean lever angle of the individual normalized motion patterns was considerably lower (19.28 ± 0.54° [SEM]) in the advanced than in the beginners' group (24.52 ± 1.00°; p = 0.0001). Further parameters such as velocity and motion variation demonstrated additional differences between both groups. CONCLUSIONS: We demonstrate the feasibility of motion tracking in HoLEP. Pronounced differences exist between different stages of surgeon experience with this procedure. The method can easily be adopted to aide young surgeons in resectoscope handling and identification of improvable motion patterns. Damage to the pelvic floor and surrounding tissue may thus be reduced.

Oncogenic NRAS Accelerates Rhabdomyosarcoma Formation When Occurring within a Specific Time Frame during Tumor Development in Mice.

In the Ptch+/- mouse model for embryonal rhabdomyosarcoma (ERMS), we recently showed that oncogenic (onc) H-, K- or NRAS mutations do not influence tumor growth when induced at the advanced, full-blown tumor stage. However, when induced at the invisible ERMS precursor stage at 4 weeks of age, tumor development was enforced upon oncHRAS and oncKRAS but not by oncNRAS, which instead initiated tumor differentiation. These data indicate that oncRAS-associated processes differ from each other in dependency on the isoform and their occurrence during tumor development. Here, we investigated the outcome of oncNRAS induction at an earlier ERMS precursor stage at 2 weeks of age. In this setting, oncNRAS accelerates tumor growth because it significantly shortens the ERMS-free survival and increases the ERMS incidence. However, it does not seem to alter the differentiation of the tumors. It is also not involved in tumor initiation. Together, these data show that oncNRAS mutations can accelerate tumor growth when targeting immature ERMS precursors within a specific time window, in which the precursors are permissive to the mutation and show that oncNRAS-associated processes differ from each other in dependency on their occurrence during tumor development.

Hypertensive Effect of Downregulation of the Opioid System in Mouse Model of Different Activity of the Endogenous Opioid System.

The opioid system is well-known for its role in modulating nociception and addiction development. However, there are premises that the endogenous opioid system may also affect blood pressure. The main goal of the present study was to determine the impact of different endogenous opioid system activity and its pharmacological blockade on blood pressure. Moreover, we examined the vascular function in hyper- and hypoactive states of the opioid system and its pharmacological modification. In our study, we used two mouse lines which are divergently bred for high (HA) and low (LA) swim stress-induced analgesia. The obtained results indicated that individuals with low endogenous opioid system activity have higher basal blood pressure compared to those with a hyperactive opioid system. Additionally, naloxone administration only resulted in the elevation of blood pressure in HA mice. We also showed that the hypoactive opioid system contributes to impaired vascular relaxation independent of endothelium, which corresponded with decreased guanylyl cyclase levels in the aorta. Together, these data suggest that higher basal blood pressure in LA mice is a result of disturbed mechanisms in vascular relaxation in smooth muscle cells. We believe that a novel mechanism which involves endogenous opioid system activity in the regulation of blood pressure will be a promising target for further studies in hypertension development.

Defining clinical subgroups and genotype-phenotype correlations in NBAS-associated disease across 110 patients.

PURPOSE: Pathogenic variants in neuroblastoma-amplified sequence (NBAS) cause an autosomal recessive disorder with a wide range of symptoms affecting liver, skeletal system, and brain, among others. There is a continuously growing number of patients but a lack of systematic and quantitative analysis. METHODS: Individuals with biallelic variants in NBAS were recruited within an international, multicenter study, including novel and previously published patients. Clinical variables were analyzed with log-linear models and visualized by mosaic plots; facial profiles were investigated via DeepGestalt. The structure of the NBAS protein was predicted using computational methods. RESULTS: One hundred ten individuals from 97 families with biallelic pathogenic NBAS variants were identified, including 26 novel patients with 19 previously unreported variants, giving a total number of 86 variants. Protein modeling redefined the ß-propeller domain of NBAS. Based on the localization of missense variants and in-frame deletions, three clinical subgroups arise that differ significantly regarding main clinical features and are directly related to the affected region of the NBAS protein: ß-propeller (combined phenotype), Sec39 (infantile liver failure syndrome type 2/ILFS2), and C-terminal (short stature, optic atrophy, and Pelger-Huët anomaly/SOPH). CONCLUSION: We define clinical subgroups of NBAS-associated disease that can guide patient management and point to domain-specific functions of NBAS.

Controlling Excitons in an Atomically Thin Membrane with a Mirror.

We demonstrate a new approach for dynamically manipulating the optical response of an atomically thin semiconductor, a monolayer of MoSe_{2}, by suspending it over a metallic mirror. First, we show that suspended van der Waals heterostructures incorporating a MoSe_{2} monolayer host spatially homogeneous, lifetime-broadened excitons. Then, we interface this nearly ideal excitonic system with a metallic mirror and demonstrate control over the exciton-photon coupling. Specifically, by electromechanically changing the distance between the heterostructure and the mirror, thereby changing the local photonic density of states in a controllable and reversible fashion, we show that both the absorption and emission properties of the excitons can be dynamically modulated. This electromechanical control over exciton dynamics in a mechanically flexible, atomically thin semiconductor opens up new avenues in cavity quantum optomechanics, nonlinear quantum optics, and topological photonics.

Electrically Tunable Valley Dynamics in Twisted WSe_{2}/WSe_{2} Bilayers.

The twist degree of freedom provides a powerful new tool for engineering the electrical and optical properties of van der Waals heterostructures. Here, we show that the twist angle can be used to control the spin-valley properties of transition metal dichalcogenide bilayers by changing the momentum alignment of the valleys in the two layers. Specifically, we observe that the interlayer excitons in twisted WSe_{2}/WSe_{2} bilayers exhibit a high (>60%) degree of circular polarization (DOCP) and long valley lifetimes (>40 ns) at zero electric and magnetic fields. The valley lifetime can be tuned by more than 3 orders of magnitude via electrostatic doping, enabling switching of the DOCP from ∼80% in the n-doped regime to <5% in the p-doped regime. These results open up new avenues for tunable chiral light-matter interactions, enabling novel device schemes that exploit the valley degree of freedom.