Unsupervised physics-informed deep learning-based reconstruction for time-resolved imaging by multiplexed ptychography.

We explore numerically an unsupervised, physics-informed, deep learning-based reconstruction technique for time-resolved imaging by multiplexed ptychography. In our method, the untrained deep learning model replaces the iterative algorithm's update step, yielding superior reconstructions of multiple dynamic object frames compared to conventional methodologies. More precisely, we demonstrate improvements in image quality and resolution, while reducing sensitivity to the number of recorded frames, the mutual orthogonality of different probe modes, overlap between neighboring probe beams and the cutoff frequency of the ptychographic microscope - properties that are generally of paramount importance for ptychographic reconstruction algorithms.

Single-shot ptychographic imaging of non-repetitive ultrafast events.

We demonstrate experimentally high-speed ptychographic imaging of non-repetitive complex-valued events. Three time-resolved complex-valued frames are reconstructed from data recorded in a single camera snapshot. The temporal resolution of the microscope is determined by delays between illuminating pulses. The ability to image amplitude and phase of nonrepetitive events with ultrafast temporal resolution will open new opportunities in science and technology.

Sensory disturbances in Creutzfeldt-Jakob disease.

BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease characterized by rapidly progressive dementia, motor impairments, and psychiatric symptoms. Sensory disturbances were occasionally reported as well. The study aims to describe the sensory symptoms of the disease. METHODS: The CJD Israeli National Database was screened for patients who presented sensory symptoms throughout the disease course. Symptoms, characteristics, and distribution were reviewed and the demographic and clinical data (sex, etiologies of the disease, age of onset, disease duration, neurological exam finding, tau protein level, EEG and MRI findings) were compared with the demographics and clinical data of CJD without sensory symptoms. Then, the patients with sensory symptoms were divided into patients with symptom distribution consistent with peripheral nervous system (PNS) involvement and central nervous system (CNS) involvement. The demographics and clinical data of the 2 groups were compared. RESULTS: Eighty-four CJD patients with sensory symptoms and 645 CJD patients without sensory symptoms were included in the study. Sensory symptoms were more common in genetic E200K CJD patients (14.6% vs. 5.6% respectively, p = 0.0005) (chi-squared test). Numbness and neuropathic pain were the most common symptoms and distribution of symptoms of "stocking gloves" with decreased deep tendon reflexes suggesting peripheral neuropathy in 44% of the patients. In these patients, the classical EEG findings of Periodic Sharp Wave Complexes were less often found (58% vs. 22%, p = 0.02) (chi-squared test). CONCLUSIONS: Sensory symptoms are more common in E200K patients and often follow peripheral neuropathy distribution that suggests PNS involvement.

Revealing the Interplay between Strong Field Selection Rules and Crystal Symmetries.

Symmetries are ubiquitous in condensed matter physics, playing an important role in the appearance of different phases of matter. Nonlinear light matter interactions serve as a coherent probe for resolving symmetries and symmetry breaking via their link to selection rules of the interaction. In the extreme nonlinear regime, high harmonic generation (HHG) spectroscopy offers a unique spectroscopic approach to study this link, probing the crystal spatial properties with high sensitivity while opening new paths for selection rules in the XUV regime. In this Letter we establish an advanced HHG polarimetry scheme, driven by a multicolor strong laser field, to observe the structural symmetries of solids and their interplay with the HHG selection rules. By controlling the crystal symmetries, we resolve nontrivial polarization states associated with new spectral features in the HHG spectrum. Our scheme opens new opportunities in resolving the symmetries of quantum materials, as well as ultrafast light driven symmetries in condensed matter systems.

Detecting multiple chiral centers in chiral molecules with high harmonic generation.

Characterizing chiral is highly important for applications in the pharmaceutical industry, as well as in the study of dynamical chemical and biological systems. However, this task has remained challenging, especially due to the ongoing increasing complexity and size of the molecular structure of drugs and active compounds. In particular, large molecules with many active chiral centers are today ubiquitous, but remain difficult to structurally analyze due to their high number of stereoisomers. Here we theoretically explore the sensitivity of high harmonic generation (HHG) to the chiral of molecules with a varying number of active chiral centers. We find that HHG driven by bi-chromatic non-collinear lasers is a sensitive probe for the stereo-configuration of a chiral molecule. We first show through calculations (from benchmark chiral molecules with up to three chiral centers) that the HHG spectrum is imprinted with information about the handedness of each chiral center in the driven molecule. Next, we show that using both classical- and deep-learning-based reconstruction algorithms, the composition of an unknown mixture of stereoisomers can be reconstructed with high fidelity by a single-shot HHG measurement. Our work illustrates how the combination of non-linear optics and machine learning might open routes for ultra-sensitive sensing in chiral systems.

Genetic Creutzfeldt-Jakob disease in Turkish Jews-demographic and clinical features.

BACKGROUND: The largest cluster of genetic Creutzfeldt- Jakob Disease (CJD) exists in Libyan Jews carrying the E200K mutation in the PRNP gene. However, there is another cluster of genetic CJD with E200K mutation in families of Turkish-Jewish origin. AIMS: In this retrospective study, we aim to describe the demographic and clinical features of this population of patients. MATERIAL AND METHODS: The Israeli National CJD database was searched for demographic, clinical, imaging, and laboratory data of genetic CJD patients of Libyan and Turkish ancestry with the E200K mutation. The data of Libyan and Turkish patients were compared with notice similar or different demographic or clinical courses. RESULTS: Four hundred and twenty-three patients with CJD of Libyan (L) ancestry and 27 patients with CJD of Turkish (T) ancestry were identified. There were no significant differences in demographic and clinical data between the two populations (age of onset: T = 62 ± 8.8, L = 60 ± 9.7; age of death: T = 63 ± 8.6, L = 61 ± 9.7; and disease duration: T = 7.8 ± 8.4 months, L = 9.6 ± 13.6 months). Rapidly progressive dementia was the most common presentation in both groups, followed by pure cerebellar onset. The levels of tau protein in CSF did not differ between groups (T = 1290 ± 397.6 pg/ml, L = 1276 ± 594.2 pg/ml). MRI and EEG showed classical CJD features in most patients in both groups. DISCUSSION: The E200K mutation is the most common mutation among gCJD patients and was reported in different ethnical populations, suggesting several independent haplotypes of the mutation. The Turkish-Jew cluster, first described in this study, shares similar demographic and clinical features with the bigger cluster of Libyan-Jews CJD patients. CONCLUSION: E200K gCJD patients of Turkish ancestry share similar demographic and clinical features to patients of Libyan descent, suggesting a common origin of both populations.

Epidemiological and clinical characteristics of patients with late-onset Creutzfeldt-Jakob disease.

BACKGROUND: Creutzfeldt-Jacob disease (CJD) is a fatal neuro-degenerative disease, characterized by rapid and intense deterioration, mainly cognitive, leading to death. The typical onset of the disease is around the age of 67. PURPOSE: To characterize the demographic and clinical features of the population of CJD patients with late-onset disease. METHODS: In this retrospective study, the Israeli national database of prion diseases was screened for CJD patients with disease age of onset > 80 years between 1960 and 2016. Patient's demographic and clinical data were collected including sex, type of disease (sporadic/ genetic), clinical presentation, lab results including tau protein level, imaging, and EEG characteristics. Then, the clinical and demographic data of patients with late onset (> 80 years) (L) and patients with usual age of onset (< 80 years) (U) were compared. RESULTS: The study included 728 patients, 23 patients (3.3%) with late-onset disease (82.2.4±4 years, range 80-88) and 705 with usual disease onset (61.31 ± 9.47 years, range 34-80). Sporadic CJD was more common in the late-onset group (18/23 patients (78.2%) (L) vs. 256/705 patients (36.3%) (U)) (p = 0.0001, chi-square test). Classical EEG finding of periodic sharp wave activity were seen more often in the late-onset patients (55% (L) vs. 32.5% (U)) (p = 0.05, chi-square test). The rest of the demographic and clinical features were similar in both groups. CONCLUSION: Late- and usual-onset diseases are similar in most of demographic and clinical features suggesting a common disease type with normal distribution of age of onset.

Novel non-invasive assessment of upper airway inflammation in obstructive sleep apnea using positron emission tomography/magnetic resonance imaging.

PURPOSE: To develop a novel non-invasive technique to quantify upper airway inflammation using positron emission tomography/magnetic resonance imaging (PET/MRI) in patients with obstructive sleep apnea (OSA). METHODS: Patients with treatment naïve moderate-to-severe OSA underwent [18F]-fluoro-2-deoxy-D-glucose (FDG) PET/MRI. Three readers independently performed tracings of the pharyngeal soft tissue on MRI. Standardized uptake values (SUV) were generated from region of interest (ROI) tracings on corresponding PET images. Background SUV was measured from the sternocleidomastoid muscle. SUV and target-to-background (TBR) were compared across readers using intraclass correlation coefficient (ICC) analyses. SUV from individual image slices were compared between each reader using Bland-Altman plots and Pearson correlation coefficients. All tracings were repeated by one reader for assessment of intra-reader reliability. RESULTS: Five participants completed our imaging protocol and analysis. Median age, body mass index, and apnea-hypopnea index were 41 years (IQR 40.5-68.5), 32.7 kg/m2 (IQR 28.1-38.1), and 30.7 event per hour (IQR 19.5-48.1), respectively. The highest metabolic activity regions were consistently localized to palatine or lingual tonsil adjacent mucosa. Twenty-five ICC met criteria for excellent agreement. The remaining three were TBR measurements which met criteria for good agreement. Head-to-head comparisons revealed strong correlation between each reader. CONCLUSIONS: Our novel imaging technique demonstrated reliable quantification of upper airway FDG avidity. This technology has implications for future work exploring local airway inflammation in individuals with OSA and exposure to pollutants. It may also serve as an assessment tool for response to OSA therapies.

Anti-tumor necrosis factor-alpha therapy for refractory uveitic optic disk neovascularization in active non-infectious posterior and panuveitis.

PURPOSE: Neovascularization of the optic disk (NVD) is mainly a complication of ischemic retinal disorders and of uveitis with vascular occlusion. Rarely, NVD may develop in patients with uveitis in the absence of retinal ischemia. This report aims to present our long-term experience of treating refractory uveitic NVD (uNVD) with adalimumab in three patients with active non-infectious posterior or panuveitis. METHODS: Observational case series was collected from institutional tertiary referral center. Patients with chronic refractory uNVD who completed 24 months of follow-up were included. RESULTS: uNVD was diagnosed on first presentation in all patients (3 eyes). Mean age at presentation was 29 years (median 20, range 18-49). Mean duration of complaints before presentation was 18.7 weeks (median 24, range 4-28). Uveitis was idiopathic in two patients and secondary to Behçet disease in one. All eyes had concomitant cystoid macular edema. Additional posterior segment signs included optic disk hemorrhage, preretinal hemorrhage and vitreous hemorrhage. All eyes showed retinal vascular leakage and macular leakage with no evidence of capillary non-perfusion. All patients were treated with systemic steroids and steroid-sparing agent. Because of NVD refractoriness, anti-TNF-α therapy was introduced at a mean of 24.7 weeks after first presentation (median 20, range 14-40). Complete regression of NVD was observed at a mean of 34.7 weeks (median 32, range 8-64) following adalimumab institution. Mean follow-up time after starting anti-TNF-α agents was 31.3 months. CONCLUSIONS: Our results suggest that targeting TNF-α achieves long-term control of uveitic NVD refractory to conventional treatments.

Deep neural networks in single-shot ptychography.

We develop and explore a deep learning based single-shot ptychography reconstruction method. We show that a deep neural network, trained using only experimental data and without any model of the system, leads to reconstructions of natural real-valued images with higher spatial resolution and better resistance to systematic noise than common iterative algorithms.

Deep learning reconstruction of ultrashort pulses from 2D spatial intensity patterns recorded by an all-in-line system in a single-shot.

We propose a simple all-in-line single-shot scheme for diagnostics of ultrashort laser pulses, consisting of a multi-mode fiber, a nonlinear crystal and a camera. The system records a 2D spatial intensity pattern, from which the pulse shape (amplitude and phase) are recovered, through a fast Deep Learning algorithm. We explore this scheme in simulations and demonstrate the recovery of ultrashort pulses, robustness to noise in measurements and to inaccuracies in the parameters of the system components. Our technique mitigates the need for commonly used iterative optimization reconstruction methods, which are usually slow and hampered by the presence of noise. These features make our concept system advantageous for real time probing of ultrafast processes and noisy conditions. Moreover, this work exemplifies that using deep learning we can unlock new types of systems for pulse recovery.

Experimental time-resolved imaging by multiplexed ptychography.

A recently proposed technique introduced a time-resolved option of fast transient non-repetitive events to ptychographic microscopy. This technique, termed time-resolved imaging by multiplexed ptychography (TIMP), is based on algorithmic reconstruction of multiple frames from data recorded in a single camera acquisition of a single-shot ptychographic microscope. We demonstrate TIMP experimentally, reconstructing thirty-six frames of a dynamical complex-valued object from ptychographic data recorded in a single camera snapshot.

Background-Free Measurement of Ring Currents by Symmetry-Breaking High-Harmonic Spectroscopy.

We propose and explore an all-optical technique for ultrafast characterization of electronic ring currents in atoms and molecules, based on high-harmonic generation (HHG). In our approach, a medium is irradiated by an intense reflection-symmetric laser pulse that leads to HHG, where the polarization of the emitted harmonics is strictly linear if the medium is reflection invariant (e.g., randomly oriented atomic or molecular media). The presence of a ring current in the medium breaks this symmetry, causing the emission of elliptically polarized harmonics, where the harmonics' polarization directly maps the ring current, and the signal is background-free. Scanning the delay between the current excitation and the HHG driving pulse provides an attosecond time-resolved signal for the multielectron dynamics in the excited current (including electron-electron interactions). We analyze the responsible physical mechanism and derive the analytic dependence of the HHG emission on the ring current. The method is numerically demonstrated using quantum models for neon and benzene, as well as through ab initio calculations.

Disease duration in E200K familial Creutzfeldt-Jakob disease is correlated with clinical, radiological, and laboratory variables.

Previous studies have suggested that disease duration in Creutzfeldt-Jakob disease (CJD) may be related to the radiological findings or cerebrospinal fluid (CSF) tau levels; however, it is not yet established whether clinical, radiological, and laboratory findings at diagnosis can predict survival or have a prognostic value. The aim of this study was to examine whether the disease duration is correlated with clinical, radiological, and laboratory variables. The study population consisted of consecutive familial CJD (fCJD) patients that were assessed within 1 week from the diagnosis including the CJD neurological scale (CJD-NS), Minimental Status Examination, Frontal Assessment Battery, NIH Stroke Scale, and the expanded disability status scale. In addition, a single MRI study was done and measurements of the extent of the cortical and subcortical involvement were performed. CSF was examined as part of the workout, and tau levels were determined. Sixty-nine fCJD patients were included in the study (43 males, mean age 59.3 ± 8.4, range 44-79 years). The mean disease duration was 7.3 ± 6.9 months (median 5.6 months, range 2-20 months). A significant correlation was found between the disease duration and the CJD-NS, the disease burden as reflected by the degree of cortical involvement by DWI, and the CSF tau levels. The findings of the current study reveal that several findings at disease onset including the disease severity, the cortical changes, and the tau levels are each individually correlated with disease duration and can be used by the clinician as a tool to predict the disease course and prognosis.

Assessment of carotid artery ultrasonography in the presence of an acoustic shadow artifact.

BACKGROUND: B-mode and Color Doppler ultrasonography (CDUS) are the methods of choice for screening and determining the degree of Carotid artery stenosis. The evaluation of stenosis with calcification may be hampered by a common CDUS artifact known as acoustic shadow (AS). Our objective was to assess the change in reliability of CDUS readings in the presence of an AS artifact. METHODS: Single center retrospective observational study. Included were patients with either an AS artifact or high-grade stenosis (defined by peak systolic velocity (PSV) > 240 cm/s) demonstrated in CDUS, and had a CT angiography (CTA) done within 6 months of the sonographic exam. All subjects were identified through the Tel-Aviv Sorasky medical center (TASMC) CDUS unit registry from which clinical information was extracted. CDUS images were manually reviewed grading AS magnitude. All CTAs were reviewed and reconstructed for accurate assessment of percent stenosis and were used as gold standard. RESULTS: The study cohort included 227 consecutive patients (corresponding with 454 internal carotid arteries) meeting inclusion criteria. 43.2% of the arteries (n = 195) had an AS artifact present on CDUS, regardless of percent stenosis, with a large artifact present in 6.7% arteries (n = 30). Older age was significantly related to the presence of AS artifact (p < 0.001). In the study cohort as a whole there was a strong correlation between percent stenosis on CTA and PSV values (Pearson's r 0.672, p < 0.001) regardless of AS existence. The CDUS sensitivity and specificity for predicting severe stenosis were 82 and 73% respectively. The presence of a small AS slightly diminished the correlation between CDUS and CTA results without compromising CDUS reliability. A large AS severely affected the correlation between CDUS and CTA exams (Pearson's r = 0.24, p = 0.27) and reduced CDUS reliability with a sensitivity and specificity of 62%. CONCLUSION: The presence of a large AS severely degrades the accuracy of the routine CDUS measurements. In these cases, the patient should be referred to a CDUS exam including doppler-measurement of periorbital arteries and intracranial arteries in addition to other imaging modalities such as CTA or MRA in order to assess future stroke risk.

The association of quantitative EEG and MRI in Creutzfeldt-Jakob Disease.

INTRODUCTION: Previous studies showed concordance between the typical Periodic Sharp Wave Complex (PSWC) activity in EEG of Creutzfeldt-Jakob Disease (CJD) patients and the MRI findings, while the concordance with slow activity in EEG is less established. The aim of this study was to better characterize the association between MRI findings and EEG changes using quantitative EEG (qEEG) analysis. METHODS: The demographics, clinical features, and the MRI findings of 12 familial E200K patients with CJD were gathered. EEG test was done and reviewed for the typical PSWC and for the non-specific slow activity. A possible association between the MRI findings and the EEG activity was examined. Then, EEG was analyzed using qEEG tool, and the association between the qEEG finding and the MRI was examined. RESULTS: Twelve patients were included in the study (67% women). Cortical MRI lesions finding were seen in 6/12 (50%) of the patients, and deep gray mater lesions were seen in 8/12 patients (67%). EEG showed the classic PSWC in 6/12 (50%) of the patients where slow activity was seen in 10/12 (83%). Slow activity and cortical MRI findings were associated in only 2/6 (33%) where deep gray matter findings and the slow activity had concordance of 4/8 (50%). qEEG analysis improved this concordance between slow activity and cortical findings to 3/6 (50%) and with the deep gray matter findings to 5/8 (63%). CONCLUSIONS: Quantitative EEG analysis modesty but not significantly, improves the association of EEG slow activity in familial E200K CJD patients with MRI findings.

VT-1598 inhibits the in vitro growth of mucosal Candida strains and protects against fluconazole-susceptible and -resistant oral candidiasis in IL-17 signalling-deficient mice.

Background: Chronic mucocutaneous candidiasis (CMC) treatment often induces drug resistance, posing long-term challenges. A novel broad-spectrum fungal CYP51 inhibitor, VT-1598, specifically targets fungal CYP51, but not human CYP enzymes. Objectives: To determine the efficacy of VT-1598 in the treatment of oral Candida infection caused by fluconazole-susceptible and -resistant clinical isolates. Methods: The MICs of VT-1598 and fluconazole for 28 Candida isolates recovered from patients with inherited CMC were determined using CLSI M27-A3 and M27-S4 guidelines. Plasma and tongue VT-1598 or fluconazole concentrations were measured in mice following oral administration to determine tissue distribution. Tongue fungal load was determined in IL-17 signalling-deficient Act1-/- mice following sublingual Candida albicans infection and oral treatment with fluconazole or VT-1598. Results: Among the 28 Candida isolates, 10 (36%) had fluconazole MICs of ≥4 mg/L, whereas VT-1598 demonstrated potent in vitro activity against all isolates (MIC90, 0.125 mg/L). After oral administration, VT-1598 levels in mouse plasma and tongue were significantly greater than those of fluconazole. In vivo, VT-1598 exhibited significant efficacy against fluconazole-susceptible and -resistant C. albicans, even at low drug doses. Furthermore, after a 10 day washout period, tongue fungal burdens in fluconazole-treated mice returned to vehicle control levels, whereas, in contrast, they were undetectable in mice treated with VT-1598. Conclusions: VT-1598 effectively controls in vitro growth of mucosally derived Candida clinical isolates, including fluconazole-resistant strains. In vivo, VT-1598 eliminates C. albicans, even after a long washout period or at low doses. Therefore, VT-1598 is a promising drug candidate that may significantly improve treatment options for CMC patients.

Multiplexed single-shot ptychography.

We demonstrate experimentally multiplexed single-shot ptychography. Specifically, we present a polarization-resolved single-shot ptychographic microscope, where the orthogonally polarized amplitudes and phases of a polarization-sensitive object are reconstructed from ptychographic data recorded in a single camera exposure. Moreover, the amplitudes, phases, and polarization states of the probe beams are also recovered. That is, altogether we decipher eight images from single-shot ptychographic data. This work is an important step towards experimental demonstration of time-resolved imaging by multiplexed ptychography.

Optical Chirality in Nonlinear Optics: Application to High Harmonic Generation.

Optical chirality (OC)-one of the fundamental quantities of electromagnetic fields-corresponds to the instantaneous chirality of light. It has been utilized for exploring chiral light-matter interactions in linear optics, but has not yet been applied to nonlinear processes. Motivated to explore the role of OC in the generation of helically polarized high-order harmonics and attosecond pulses, we first separate the OC of transversal and paraxial beams to polarization and orbital terms. We find that the polarization-associated OC of attosecond pulses corresponds approximately to that of the pump in the quasimonochromatic case, but not in the multichromatic pump cases. We associate this discrepancy with the fact that the polarization OC of multichromatic pumps vary rapidly in time along the optical cycle. Thus, we propose new quantities, noninstantaneous polarization-associated OC, and time-scale-weighted polarization-associated OC, and show that these quantities link the chirality of multichromatic pumps and their generated attosecond pulses. The presented extension to OC theory should be useful for exploring various nonlinear chiral light-matter interactions. For example, it stimulates us to propose a tricircular pump for generation of highly elliptical attosecond pulses with a tunable ellipticity.

Bright circularly polarized soft X-ray high harmonics for X-ray magnetic circular dichroism.

We demonstrate, to our knowledge, the first bright circularly polarized high-harmonic beams in the soft X-ray region of the electromagnetic spectrum, and use them to implement X-ray magnetic circular dichroism measurements in a tabletop-scale setup. Using counterrotating circularly polarized laser fields at 1.3 and 0.79 µm, we generate circularly polarized harmonics with photon energies exceeding 160 eV. The harmonic spectra emerge as a sequence of closely spaced pairs of left and right circularly polarized peaks, with energies determined by conservation of energy and spin angular momentum. We explain the single-atom and macroscopic physics by identifying the dominant electron quantum trajectories and optimal phase-matching conditions. The first advanced phase-matched propagation simulations for circularly polarized harmonics reveal the influence of the finite phase-matching temporal window on the spectrum, as well as the unique polarization-shaped attosecond pulse train. Finally, we use, to our knowledge, the first tabletop X-ray magnetic circular dichroism measurements at the N4,5 absorption edges of Gd to validate the high degree of circularity, brightness, and stability of this light source. These results demonstrate the feasibility of manipulating the polarization, spectrum, and temporal shape of high harmonics in the soft X-ray region by manipulating the driving laser waveform.