National Rapid Genome Sequencing in Neonatal Intensive Care.

Importance: National implementation of rapid trio genome sequencing (rtGS) in a clinical acute setting is essential to ensure advanced and equitable care for ill neonates. Objective: To evaluate the feasibility, diagnostic efficacy, and clinical utility of rtGS in neonatal intensive care units (NICUs) throughout Israel. Design, Setting, and Participants: This prospective, public health care-based, multicenter cohort study was conducted from October 2021 to December 2022 with the Community Genetics Department of the Israeli Ministry of Health and all Israeli medical genetics institutes (n = 18) and NICUs (n = 25). Critically ill neonates suspected of having a genetic etiology were offered rtGS. All sequencing, analysis, and interpretation of data were performed in a central genomics center at Tel-Aviv Sourasky Medical Center. Rapid results were expected within 10 days. A secondary analysis report, issued within 60 days, focused mainly on cases with negative rapid results and actionable secondary findings. Pathogenic, likely pathogenic, and highly suspected variants of unknown significance (VUS) were reported. Main Outcomes and Measures: Diagnostic rate, including highly suspected disease-causing VUS, and turnaround time for rapid results. Clinical utility was assessed via questionnaires circulated to treating neonatologists. Results: A total of 130 neonates across Israel (70 [54%] male; 60 [46%] female) met inclusion criteria and were recruited. Mean (SD) age at enrollment was 12 (13) days. Mean (SD) turnaround time for rapid report was 7 (3) days. Diagnostic efficacy was 50% (65 of 130) for disease-causing variants, 11% (14 of 130) for VUS suspected to be causative, and 1 novel gene candidate (1%). Disease-causing variants included 12 chromosomal and 52 monogenic disorders as well as 1 neonate with uniparental disomy. Overall, the response rate for clinical utility questionnaires was 82% (107 of 130). Among respondents, genomic testing led to a change in medical management for 24 neonates (22%). Results led to immediate precision medicine for 6 of 65 diagnosed infants (9%), an additional 2 (3%) received palliative care, and 2 (3%) were transferred to nursing homes. Conclusions and Relevance: In this national cohort study, rtGS in critically ill neonates was feasible and diagnostically beneficial in a public health care setting. This study is a prerequisite for implementation of rtGS for ill neonates into routine care and may aid in design of similar studies in other public health care systems.

Uncommon Presentation of Cystic Fibrosis: A Case Report and Literature Review.

Cystic fibrosis (CF) is a multiorgan disease, caused by autosomal recessive (AR) mutations in the cystic fibrosis transmembrane regulator (CFTR) acting primarily as a chloride channel. CF is most commonly diagnosed in Caucasian populations. Common clinical presentations in pediatric patients include chronic cough, respiratory tract infections such as pneumonia, digestive symptoms, and stunted growth, and malnutrition due to gastrointestinal malabsorption and pancreatic insufficiency. Excessive sweat sodium chloride losses due to dysfunctional sweat glands in CFTR result in volume contraction and secondary hyperaldosteronism leading to renal potassium losses and metabolic alkalosis. Hypokalemic hypochloremic metabolic alkalosis is a known but uncommon presenting sign of the disease, documented as pseudo Bartter syndrome. Common mutations in the CFTR gene are now included in prenatal genetic screening programs. We describe the case of an infant of African descent with normal prenatal screening who presented with severe hypokalemic hypochloremic metabolic alkalosis and was diagnosed with CF with further genetic confirmation of the diagnosis.

Effect of Magnetic Resonance Imaging on Acute Surgical Treatment of Pregnant Patients: A Single Institution Study.

BACKGROUND: Abdominal pathology in pregnant patients is a frequent challenge for emergency department physicians. Ultrasound is the imaging modality of choice but is inconclusive in approximately one-third of cases. Magnetic resonance imaging (MRI) is becoming increasingly available, even in acute settings. Multiple studies have defined the sensitivity and specificity of MRI in this population. OBJECTIVES: To evaluate the use of MRI findings in pregnant patients presenting with acute abdominal complaints to the emergency department. METHODS: This retrospective cohort study was conducted at a single institution. Data were collected on pregnant patients who underwent an MRI for acute abdominal complaints between 2010 and 2019 at a university center. Patient demographics, diagnosis at admission, ultrasound and MRI findings, and discharge diagnosis were recorded and evaluated. RESULTS: In total, 203 pregnant patients underwent an MRI for acute abdominal complaints during the study period. MRI was found without pathology in 138 cases (68%). In 65 cases (32%), the MRI showed findings that could explain the patient's clinical presentation. Patients presenting with long-standing abdominal pain (> 24 hours), fever, leukocytosis, or elevated C-reactive protein values were at a significantly increased risk of having an acute pathology. In 46 patients (22.6%), MRI findings changed the primary diagnosis and management while in 45 patients (22.1%) MRI findings improved characterization of the suspected pathology. CONCLUSIONS: MRI is helpful when clinical and sonographic findings are inconclusive, leading to changes in patient management in more than one-fifth of patients.

Ethnic disparity in cervical cancer stage at diagnosis: A retrospective study in an Israeli referral-center.

OBJECTIVE: To compare stage and survival of cervical cancer between Jewish and Arab women in a tertiary medical center in Israel. METHODS: Retrospective study of consecutive women diagnosed with cervical cancer in a single institution between 2010 and 2021. We compared Jewish and Arab patients using univariate, multivariable, and survival curves analysis. RESULTS: Overall, 207 Jewish women and 45 Arab women were included with a median follow up of 20 months (interquartile range 7-46 months). The groups did not differ in median body mass index, mean age at diagnosis, or menopausal status. Arab women had higher parity. Arab women were at a higher risk to be diagnosed with advanced stage disease (≥2b) (84.4% vs. 57% Arab and Jewish women, respectively, P < 0.001). In a multivariable regression analysis, Arab descent was found to be the only independent factor associated with advanced stage disease (odds ratio 3.95, 95% confidence interval 1.54-10.10). Overall survival and stage-specific survival were not different between the ethnic groups. CONCLUSIONS: Advanced stage at diagnosis was more prevalent in Arab women compared with Jewish women with cervical cancer, whereas stage-specific survival was similar. Further studies addressing possible contributing factors to inequality should be undertaken to find corrective measures.

De novo missense variants in the E3 ubiquitin ligase adaptor KLHL20 cause a developmental disorder with intellectual disability, epilepsy, and autism spectrum disorder.

PURPOSE: KLHL20 is part of a CUL3-RING E3 ubiquitin ligase involved in protein ubiquitination. KLHL20 functions as the substrate adaptor that recognizes substrates and mediates the transfer of ubiquitin to the substrates. Although KLHL20 regulates neurite outgrowth and synaptic development in animal models, a role in human neurodevelopment has not yet been described. We report on a neurodevelopmental disorder caused by de novo missense variants in KLHL20. METHODS: Patients were ascertained by the investigators through Matchmaker Exchange. Phenotyping of patients with de novo missense variants in KLHL20 was performed. RESULTS: We studied 14 patients with de novo missense variants in KLHL20, delineating a genetic syndrome with patients having mild to severe intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, hyperactivity, and subtle dysmorphic facial features. We observed a recurrent de novo missense variant in 11 patients (NM_014458.4:c.1069G>A p.[Gly357Arg]). The recurrent missense and the 3 other missense variants all clustered in the Kelch-type ß-propeller domain of the KLHL20 protein, which shapes the substrate binding surface. CONCLUSION: Our findings implicate KLHL20 in a neurodevelopmental disorder characterized by intellectual disability, febrile seizures or epilepsy, autism spectrum disorder, and hyperactivity.

Weak thermal state quadrature-noise shadow imaging.

In this work, we theoretically and experimentally demonstrate the possibility to create an image of an opaque object using a few-photon thermal optical field. We utilize the quadrature-noise shadow imaging (QSI) technique that detects the changes in the quadrature-noise statistics of the probe beam after its interaction with an object. We show that such a thermal QSI scheme has an advantage over the classical differential imaging when the effect of dark counts is considered. At the same time, the easy availability of thermal sources for any wavelength makes the method practical for broad range of applications, not accessible with, e.g., quantum squeezed light. As a proof of principle, we implement this scheme by two different light sources: a pseudo-thermal beam generated by rotating ground glass (RGG) method and a thermal beam generated by four-wave mixing (FWM) method. The RGG method shows simplicity and robustness of QSI scheme while the FWM method validates theoretical signal-to-noise ratio predictions. Finally, we demonstrate low-light imaging abilities with QSI by imaging a biological specimen on a CCD camera, detecting as low as 0.03 photons on average per pixel per 1.7 µs exposure.

Wave-front reconstruction via single-pixel homodyne imaging.

We combine single-pixel imaging and homodyne detection to perform full object recovery (phase and amplitude). Our method does not require any prior information about the object or the illuminating fields. As a demonstration, we reconstruct the optical properties of several semi-transparent objects and find that the reconstructed complex transmission has a phase precision of 0.02 radians and a relative amplitude precision of 0.01.

The Solubility Limit of Carbon in Alumina at 1,600°C.

The solubility limit of carbon in α-Al2O3 (alumina) equilibrated at 1,600°C under He in a graphite furnace was measured by wavelength-dispersive spectroscopy. Undoped alumina and alumina containing carbon at a concentration resulting in the precipitation of a second phase were prepared and equilibrated at 1,600°C. The undoped alumina was used to quantify the amount of carbon deposited on the surface of samples because of hydrocarbon contamination in the electron microscope, and this background level was removed from the signal measured from carbon-doped samples. The solubility limit of carbon in alumina was found to be 5,300 ± 390 at. ppm, and it is believed that carbon substitutes oxygen as an anion and is charge-compensated by oxygen vacancies. Doping alumina with carbon at concentrations below the solubility limit does not impede densification and reduces grain growth. Doping above the solubility limit hinders densification during sintering.

TrackUSF, a novel tool for automated ultrasonic vocalization analysis, reveals modified calls in a rat model of autism.

BACKGROUND: Various mammalian species emit ultrasonic vocalizations (USVs), which reflect their emotional state and mediate social interactions. USVs are usually analyzed by manual or semi-automated methodologies that categorize discrete USVs according to their structure in the frequency-time domains. This laborious analysis hinders the effective use of USVs as a readout for high-throughput analysis of behavioral changes in animals. RESULTS: Here we present a novel automated open-source tool that utilizes a different approach towards USV analysis, termed TrackUSF. To validate TrackUSF, we analyzed calls from different animal species, namely mice, rats, and bats, recorded in various settings and compared the results with a manual analysis by a trained observer. We found that TrackUSF detected the majority of USVs, with less than 1% of false-positive detections. We then employed TrackUSF to analyze social vocalizations in Shank3-deficient rats, a rat model of autism, and revealed that these vocalizations exhibit a spectrum of deviations from appetitive calls towards aversive calls. CONCLUSIONS: TrackUSF is a simple and easy-to-use system that may be used for a high-throughput comparison of ultrasonic vocalizations between groups of animals of any kind in any setting, with no prior assumptions.

Realistic model of entanglement-enhanced sensing in optical fibers.

Experimental limitations such as optical loss and noise have prevented entanglement-enhanced measurements from demonstrating a significant quantum advantage in sensitivity. Holland-Burnett entangled states can mitigate these limitations and still present a quantum advantage in sensitivity. Here we model a fiber-based Mach-Zehnder interferometer with internal loss, detector efficiency, and external phase noise and without pure entanglement. This model features a practical fiber source that transforms the two-mode squeezed vacuum (TMSV) into Holland-Burnett entangled states. We predict that a phase sensitivity 28% beyond the shot noise limit is feasible with current technology. Simultaneously, a TMSV source can provide about 25 times more photon flux than other entangled sources. This system will make fiber-based quantum-enhanced sensing accessible and practical for remote sensing and probing photosensitive materials.

Patterns of alliance development in cognitive behavioral therapy versus attention bias modification for social anxiety disorder: Sawtooth patterns and sudden gains.

OBJECTIVES: We examined patterns in alliance development in cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) compared to attention bias modification (ABM). We focused on the occurrence of sawtooth patterns (increases within- and decreases between-sessions) and sudden gains and their association with outcome. METHODS: Clients received CBT (n = 33) or ABM (n = 17). Client-rated alliance was measured before and after each session. Self-reported and clinician-rated anxiety were measured weekly and monthly, respectively. RESULTS: The alliance increased in CBT in a sawtooth pattern and did not change in ABM. When examining individual clients, sawtooths were more common in CBT (61% clients) than in ABM (6%) and predicted worse outcome in CBT. Sudden gains were equally frequent (CBT, 18%; ABM, 18%) and did not predict outcome. CONCLUSION: The alliance in CBT is dynamic and important for outcome. Sawtooths are common in CBT and may mark worse outcome.

Efficient Simulation of Loop Quantum Gravity: A Scalable Linear-Optical Approach.

The problem of simulating complex quantum processes on classical computers gave rise to the field of quantum simulations. Quantum simulators solve problems, such as boson sampling, where classical counterparts fail. In another field of physics, the unification of general relativity and quantum theory is one of the greatest challenges of our time. One leading approach is loop quantum gravity (LQG). Here, we connect these two fields and design a linear-optical simulator such that the evolution of the optical quantum gates simulates the spin-foam amplitudes of LQG. It has been shown that computing transition amplitudes in simple quantum field theories falls into the bounded-error quantum polynomial time class, which strongly suggests that computing transition amplitudes of LQG are classically intractable. Therefore, these amplitudes are efficiently computable with universal quantum computers, which are, alas, possibly decades away. We propose here an alternative special-purpose linear-optical quantum computer that can be implemented using current technologies. This machine is capable of efficiently computing these quantities. This work opens a new way to relate quantum gravity to quantum information and will expand our understanding of the theory.

HybridMouse: A Hybrid Convolutional-Recurrent Neural Network-Based Model for Identification of Mouse Ultrasonic Vocalizations.

Mice use ultrasonic vocalizations (USVs) to convey a variety of socially relevant information. These vocalizations are affected by the sex, age, strain, and emotional state of the emitter and can thus be used to characterize it. Current tools used to detect and analyze murine USVs rely on user input and image processing algorithms to identify USVs, therefore requiring ideal recording environments. More recent tools which utilize convolutional neural networks models to identify vocalization segments perform well above the latter but do not exploit the sequential structure of audio vocalizations. On the other hand, human voice recognition models were made explicitly for audio processing; they incorporate the advantages of CNN models in recurrent models that allow them to capture the sequential nature of the audio. Here we describe the HybridMouse software: an audio analysis tool that combines convolutional (CNN) and recurrent (RNN) neural networks for automatically identifying, labeling, and extracting recorded USVs. Following training on manually labeled audio files recorded in various experimental conditions, HybridMouse outperformed the most commonly used benchmark model utilizing deep-learning tools in accuracy and precision. Moreover, it does not require user input and produces reliable detection and analysis of USVs recorded under harsh experimental conditions. We suggest that HybrideMouse will enhance the analysis of murine USVs and facilitate their use in scientific research.

The alliance mediates outcome in cognitive-behavioral therapy for social anxiety disorder, but not in attention bias modification.

Objective: The aim of the current study was to examine changes in the therapeutic alliance and its role as a mediator of treatment outcome in cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) compared to attention bias modification (ABM). Method: Patients were randomized to 16-20 sessions of CBT (n = 33) or 8 sessions of ABM (n = 17). Patient-rated alliance and self-reported social anxiety were measured weekly and evaluator-rated social anxiety was measured monthly. Results: Early alliance predicted greater subsequent anxiety reduction in CBT but not in ABM. The alliance increased and weekly improvements in alliance predicted weekly contemporaneous and subsequent decreases in anxiety only in CBT. Decreases in anxiety did not predict subsequent improvements in alliance. Both treatments were effective in reducing anxiety, but treatment effects were mediated by stronger early alliance and stronger cross-lagged effects of alliance on outcome in CBT compared to ABM. Conclusions: The results highlight the importance of the alliance in CBT for SAD. Further studies should examine the role of alliance alongside additional mediators to better understand differential mechanisms in CBT and ABM.

The role of expressive suppression and cognitive reappraisal in cognitive behavioral therapy for social anxiety disorder: A study of self-report, subjective, and electrocortical measures.

BACKGROUND: Contemporary models of cognitive behavioral therapy (CBT) for social anxiety disorder (SAD) emphasize emotion dysregulation as a core impairment whose reduction may play a causal role in psychotherapy. The current study examined changes in use of emotion regulation strategies as possible mechanisms of change in CBT for SAD. Specifically, we examined changes in expressive suppression and cognitive reappraisal during CBT and whether these changes predict treatment outcome. METHODS: Patients (n = 34; 13 females; Mean age = 28.36 (6.97)) were allocated to 16-20 sessions of CBT. An electrocortical measure of emotion regulation and a clinician-rated measure of SAD were administered monthly. Self-report measures of emotion regulation and social anxiety were administered weekly. Multilevel models were used to examine changes in emotion regulation during treatment and cross-lagged associations between emotion regulation and anxiety. RESULTS: CBT led to decreased suppression frequency, increased reappraisal self-efficacy, and decreased unpleasantness for SAD-related pictures (ps < .05). At post-treatment, patients were equivalent to healthy controls in terms of suppression frequency and subjective reactivity to SAD-related stimuli. Gains were maintained at 3-months follow-up. Decreases in suppression frequency and electrocortical reactivity to SAD-related pictures predicted lower subsequent anxiety but not the other way around (ps < .05). Lower anxiety predicted greater subsequent increases in reappraisal self-efficacy. LIMITATIONS: The lack of a control group precludes conclusions regarding mechanisms specificity. CONCLUSIONS: Decreased frequency of suppression is a potential mechanism of change in CBT for SAD.

Hyper-Activation of Endogenous GLP-1 System to Gram-negative Sepsis Is Associated With Early Innate Immune Response and Modulated by Diabetes.

BACKGROUND: Culture-positive gram-negative sepsis induces greater magnitude of early innate immunity /inflammatory response compared with culture-negative sepsis. We previously demonstrated increased activation of anti-inflammatory Glucagon Like Peptide-1 (GLP-1) hormone in initial phase of sepsis more pronounced in diabetes patients. However, whether GLP-1 system is hyperactivated during the early innate immune response to gram-negative sepsis and modulated by diabetes remains unknown. OBJECTIVES: Total and active GLP-1, soluble Dipeptidyl peptidase 4 (sDPP-4) enzyme, and innate immunity markers presepsin (sCD14) and procalcitonin (PCT) in plasma were determined by ELISA on admission and after 2 to 4 days in 37 adult patients with and without type 2 diabetes and gram-negative or culture-negative sepsis of different severity. RESULTS: Severe but not non-severe sepsis was associated with markedly increased GLP-1 system response, which correlated with PCT and the organ dysfunction marker lactate. Culture-positive gram-negative bacteria but not culture-negative sepsis induced hyper-activation of GLP-1 system, which correlated with increased innate immune markers sCD14, PCT, and lactate. GLP-1 inhibitory enzyme sDPP-4 was down regulated by sepsis and correlated negatively with sCD14 in gram-negative sepsis. Diabetic patients demonstrated increased GLP-1 response but significantly weaker innate immune response to severe and gram-negative sepsis. CONCLUSIONS: Early stage of gram-negative sepsis is characterized by endogenous GLP-1 system hyperactivity associated with over activation of innate immune response and organ dysfunction, which are modulated by diabetes. Total GLP-1 may be novel marker for rapid diagnosis of gram-negative sepsis and its severity.

Quantum-Limited Squeezed Light Detection with a Camera.

We present a technique for squeezed light detection based on direct imaging of the displaced-squeezed-vacuum state using a CCD camera. We show that the squeezing parameter can be accurately estimated using only the first two moments of the recorded pixel-to-pixel photon fluctuation statistics, with accuracy that rivals that of the standard squeezing detection methods such as a balanced homodyne detection. Finally, we numerically simulate the camera operation, reproducing the noisy experimental results with low signal samplings and confirming the theory with high signal samplings.

SETD5 Gene Haploinsufficiency in Three Patients With Suspected KBG Syndrome.

Mendelian disorders of the epigenetic machinery (MDEMs), also named chromatin modifying disorders, are a broad group of neurodevelopmental disorders, caused by mutations in functionally related chromatin genes. Mental retardation autosomal dominant 23 (MRD23) syndrome, due to SETD5 gene mutations, falls into this group of disorders. KBG syndrome, caused by ANKRD11 gene haploinsufficiency, is a chromatin related syndrome not formally belonging to this category. We performed high resolution array CGH and trio-based WES on three molecularly unsolved patients with an initial KBGS clinical diagnosis. A de novo deletion of 116 kb partially involving SETD5 and two de novo frameshift variants in SETD5 were identified in the patients. The clinical re-evaluation of the patients was consistent with the molecular findings, though still compatible with KBGS due to overlapping phenotypic features of KBGS and MRD23. Careful detailed expert phenotyping ascertained some facial and physical features that were consistent with MRD23 rather than KBGS. Our results provide further examples that loss-of-function pathogenic variants in genes encoding factors shaping the epigenetic landscape, lead to a wide phenotypic range with significant clinical overlap. We recommend that clinicians consider SETD5 gene haploinsufficiency in the differential diagnosis of KBGS. Due to overlap of clinical features, careful and detailed phenotyping is important and a large gene panel approach is recommended in the diagnostic workup of patients with a clinical suspicion of KBGS.

Bi-allelic ADARB1 Variants Associated with Microcephaly, Intellectual Disability, and Seizures.

The RNA editing enzyme ADAR2 is essential for the recoding of brain transcripts. Impaired ADAR2 editing leads to early-onset epilepsy and premature death in a mouse model. Here, we report bi-allelic variants in ADARB1, the gene encoding ADAR2, in four unrelated individuals with microcephaly, intellectual disability, and epilepsy. In one individual, a homozygous variant in one of the double-stranded RNA-binding domains (dsRBDs) was identified. In the others, variants were situated in or around the deaminase domain. To evaluate the effects of these variants on ADAR2 enzymatic activity, we performed in vitro assays with recombinant proteins in HEK293T cells and ex vivo assays with fibroblasts derived from one of the individuals. We demonstrate that these ADAR2 variants lead to reduced editing activity on a known ADAR2 substrate. We also demonstrate that one variant leads to changes in splicing of ADARB1 transcript isoforms. These findings reinforce the importance of RNA editing in brain development and introduce ADARB1 as a genetic etiology in individuals with intellectual disability, microcephaly, and epilepsy.

Identification of a novel PCNT founder pathogenic variant in the Israeli Druze population.

Majewski Osteodysplastic Primordial Dwarfism type II (MOPDII) is a form of dwarfism associated with severe microcephaly, characteristic skeletal findings, distinct dysmorphic features and increased risk for cerebral infarctions. The condition is caused by bi-allelic loss-of-function variants in the gene PCNT. Here we describe the identification of a novel founder pathogenic variant c.3465-1G > A observed in carriers from multiple Druze villages in Northern Israel. RNA studies show that the variant results in activation of a cryptic splice site causing a coding frameshift. The study was triggered by the diagnosis of a single child with MOPDII and emphasizes the advantages of applying next generation sequencing technologies in community genetics and the importance of establishing population-specific sequencing databases.