Regulated control of gene therapies by drug-induced splicing.

So far, gene therapies have relied on complex constructs that cannot be finely controlled1,2. Here we report a universal switch element that enables precise control of gene replacement or gene editing after exposure to a small molecule. The small-molecule inducers are currently in human use, are orally bioavailable when given to animals or humans and can reach both peripheral tissues and the brain. Moreover, the switch system, which we denote Xon, does not require the co-expression of any regulatory proteins. Using Xon, the translation of the desired elements for controlled gene replacement or gene editing machinery occurs after a single oral dose of the inducer, and the robustness of expression can be controlled by the drug dose, protein stability and redosing. The ability of Xon to provide temporal control of protein expression can be adapted for cell-biology applications and animal studies. Additionally, owing to the oral bioavailability and safety of the drugs used, the Xon switch system provides an unprecedented opportunity to refine and tailor the application of gene therapies in humans.

Rhinoplasty Health Inventory and Nasal Outcomes (RHINO) Scale: Translation, Cross-Cultural Adaptation and Validation for Hebrew-Speaking Patients.

Patient-reported outcomes questionnaires are accepted measurement tools to evaluate procedures results. The Rhinoplasty Health Inventory and Nasal Outcomes (RHINO) scale is an English-language validated and reliable quality-of-life instrument that evaluates both functional and aesthetic outcomes after rhinoplasty, and is not available in Hebrew. We followed the forward-and-back-translation method, defined by the European Organization for Research and Treatment of Cancer. Translation of the RHINO scale and merging it into one version were performed, following back-translation and validation on native Hebrew-speaking patients who underwent rhinoplasty and control healthy group. Lastly, we review and analyzed the results. The translated questionnaire had high reliability measures, demonstrating homogeneity (α value 0.800 in the rhinoplasty group and 0.896 in the control group), test-retest reproducibility with no significant difference (p = 0.5), and high agreement scores represented by the Bland-Altman plot (95% limits of agreement ranged from 8.78 to 9.80). Validity demonstrated by significant differences between the two study groups' mean questionnaire scores (p < 0.001 for rhinoplasty vs. controls, p < 0.001 for preoperative vs. postoperative, and p = 0.002 for postoperative vs. control group) and also between the aesthetic scores and functional scores of the rhinoplasty group before and after the surgery (p < 0.001). There were no reported understanding problems. The Hebrew version of the RHINO scale is a reliable and valid tool for pre- and post-rhinoplasty surgery outcomes measuring among Hebrew-speaking patients, and can improve coordination of expectations, follow-up, and quantify subjective evaluation of the surgery. Level of evidence: IV.

Long-term outcomes after pre-emptive liver transplantation in primary hyperoxaluria type 1.

BACKGROUND: Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disease caused by the liver defect of oxalate metabolism, which leads to kidney failure and systemic manifestations. Until recently, liver transplantation was the only definitive treatment. The timing of liver transplantation can be early, while kidney function is still normal (pre-emptive liver transplantation-PLT), or when the patient reaches stage 5 chronic kidney disease (CKD) and needs combined liver-kidney transplantation. We aimed to determine the long-term kidney outcomes of PLT in PH1 patients. METHODS: A retrospective single-center study of PH1 patients who were followed in our center between 1997 and 2017. We compared the kidney outcomes of patients who underwent PLT to those who presented with preserved kidney function and did not undergo PLT. RESULTS: Out of 36 PH1 patients, 18 patients were eligible for PLT (eGFR > 40 mL/min/1.73 m2 at the time of diagnosis). Seven patients underwent PLT (PLT group), while 11 continued conservative treatments (PLTn group). In the PLT group, the median eGFR at the time of PLT and at the end of the follow-up period (14-20 years) was 72 (range 50-89) and 104 (range 86-108) mL/min/1.73 m2, respectively, and no patient died or reached stage 5 CKD. In the PLTn group, eight patients (72.7%) reached stage 5 CKD (median time to kidney replacement therapy was 11 years), and two patients died from disease complications (18.2%). CONCLUSIONS: Pre-emptive liver transplantation preserved kidney function in patients with PH1 in our cohort. Early intervention can prevent kidney failure and systemic oxalosis in PH1. A higher resolution version of the Graphical abstract is available as Supplementary information.

Maternal and Cord Anti-SARS-CoV-2-Spike IgG following COVID-19 Vaccination versus Infection during Pregnancy: A Prospective Study, Israel October 2021-March 2022.

OBJECTIVE: Defining how pregnant women respond to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination is critical to optimize vaccination strategies that protect mother and infant at the epidemic. This study aimed to compare anti-SARS-CoV-2-spike immunoglobulin G (IgG) of vaccinated versus infected women and to determine the optimal timing of maternal vaccination during pregnancy at the time of epidemic. STUDY DESIGN: We collected maternal/cord blood at delivery (October 2021-March 2022) and measured anti-SARS-CoV-2-spike IgG geometric mean concentrations (IgG-GMCs) using a quantitative immunoassay. We compared groups according to timing and number of doses and correlated maternal and fetal IgG levels. We described the proportion of women with IgG levels above the 150 AU/mL positivity threshold according to the timing of infection/vaccination and performed a subanalysis for maternal IgG-GMC levels pre- and during the Omicron wave. RESULTS: We included 238 vaccinated women, 125 who received two doses and 113 three doses, and 48 unvaccinated infected women. All groups infected/vaccinated in the second or third trimester had an IgG-GMC above the positivity threshold. Third-trimester vaccination (second/third dose) resulted in higher maternal and cord-blood IgG-GMC compared to the second trimester (maternal-IgG: 102,32 vs. 4,325 AU/mL, p < 0.001; cord-IgG: 12,113 vs. 8,112 AU/mL, p < 0.001). Compared with infected-only women, a higher proportion of vaccinated women with ≥2 doses and their newborns had IgG levels above the positivity threshold at all time points. In vaccinated women, there were higher maternal IgG-GMC levels during the Omicron wave than pre-Omicron. CONCLUSION: At the time of epidemic, receiving an additional COVID-19 vaccine dose in the third trimester resulted in a higher IgG-GMC compared to the second trimester. Relatively higher levels of maternal and cord IgG-GMC were achieved following vaccination than infection. Women infected during or before the first trimester might benefit from an additional third-trimester dose to prevent peripartum infection and to passively immunize their newborn. The higher levels of maternal IgG-GMC in the Omicron period are suggestive of hybrid immunity. KEY POINTS: · Higher maternal anti-SARS-IgGs in vaccinated → infected.. · Higher cord anti-SARS-IgGs in vaccinated → infected.. · Third-trimester vaccine resulted in high-cord IgG levels..

Femtosecond Inscription of a Fiber Bragg Grating Spectral Array in the Same Spatial Location.

A five fiber Bragg grating (FBG) array is inscribed at the same spot with a single uniform phase-mask (PM). The inscription setup consists of a near-infrared femtosecond laser, a PM, a defocusing spherical lens and a cylindrical focusing lens. The tunability of the center Bragg wavelength is achieved by a defocusing lens, and by translating the PM, which results in a different magnification of the PM. A first FBG is inscribed, followed by four cascading FBGs, which are inscribed exactly at the same spot only after the translation of the PM. The transmission and reflection spectra of this array are measured, showing a second-order Bragg wavelength at ~1.56 µm with a transmission dip of ~-8 dB. The spectral wavelength shift between each consecutive FBG is ~2.9 nm, and the total wavelength shift is ~11.7 nm. The reflection spectrum of the third-order Bragg wavelength is measured at ~1.04 µm, showing a wavelength separation of ~1.97 nm between neighboring FBGs, and the total spectral span between the first FBG and the last one is ~8 nm. Finally, the wavelength sensitivity to strain and temperature is measured.

[SPONTANEOUS CEREBROSPINAL FLUID LEAK OF THE TEMPORAL BONE].

INTRODUCTION: Spontaneous cerebrospinal fluid (CSF) leak into the temporal air spaces is a prominent risk factor for meningitis, often leading to debilitating neurological morbidities and even death. CSF leaks may arise due to trauma, congenital malformation, or surgery, but in most cases, they develop spontaneously. In spontaneous CSF leaks, no obvious triggering event is apparent in the patient's clinical history that points to this diagnosis, in contrast to some of the other etiologies. The clinical presentation of spontaneous CSF leaks is not unique and is characterized by patients' complaints, such as hearing loss and aural fullness. These symptoms are commonly associated with prevalent conditions, such as serous otitis media. For these reasons, a typical diagnostic delay of spontaneous CSF leaks, which can last for years in some cases, leaves the patients exposed to meningeal infection without being offered an efficient surgical treatment to keep them safe and protected.

COVID-19 classification of X-ray images using deep neural networks.

OBJECTIVES: In the midst of the coronavirus disease 2019 (COVID-19) outbreak, chest X-ray (CXR) imaging is playing an important role in diagnosis and monitoring of patients with COVID-19. We propose a deep learning model for detection of COVID-19 from CXRs, as well as a tool for retrieving similar patients according to the model's results on their CXRs. For training and evaluating our model, we collected CXRs from inpatients hospitalized in four different hospitals. METHODS: In this retrospective study, 1384 frontal CXRs, of COVID-19 confirmed patients imaged between March and August 2020, and 1024 matching CXRs of non-COVID patients imaged before the pandemic, were collected and used to build a deep learning classifier for detecting patients positive for COVID-19. The classifier consists of an ensemble of pre-trained deep neural networks (DNNS), specifically, ReNet34, ReNet50¸ ReNet152, and vgg16, and is enhanced by data augmentation and lung segmentation. We further implemented a nearest-neighbors algorithm that uses DNN-based image embeddings to retrieve the images most similar to a given image. RESULTS: Our model achieved accuracy of 90.3%, (95% CI: 86.3-93.7%) specificity of 90% (95% CI: 84.3-94%), and sensitivity of 90.5% (95% CI: 85-94%) on a test dataset comprising 15% (350/2326) of the original images. The AUC of the ROC curve is 0.96 (95% CI: 0.93-0.97). CONCLUSION: We provide deep learning models, trained and evaluated on CXRs that can assist medical efforts and reduce medical staff workload in handling COVID-19. KEY POINTS: • A machine learning model was able to detect chest X-ray (CXR) images of patients tested positive for COVID-19 with accuracy and detection rate above 90%. • A tool was created for finding existing CXR images with imaging characteristics most similar to a given CXR, according to the model's image embeddings.

Vaccine hesitancy due to vaccine country of origin, vaccine technology, and certification.

Vaccine hesitancy is a global health threat which may hinder the widespread acceptance of several COVID-19 vaccines. Following the collection of 2470 responses from an anonymous questionnaire distributed between October and November 2020 across Israel, we analyzed the responses of physicians, life science graduates (biology, virology, chemistry, etc.), and the general public to whether they would obtain a COVID-19 vaccine with particular vaccine characteristics such as vaccine country of origin, technology, side effect profile, efficacy, and other attributes. Physicians and life science graduates were least likely to accept a vaccine based on mRNA technology (30%) while the general population seemed to adopt any vaccine technology if the declared efficacy is above 90% and the country of manufacturing is the USA/UK rather than China or Russia. However, current inoculation rates in Israel far outpace our predicted rate. Our results highlight the importance of tailored vaccine educational campaigns based on population demographic details and specific vaccine concerns.

Femtosecond Bragg grating inscription in an Yb-doped large-mode-area multicore fiber for high-power laser applications.

We demonstrate a direct inscription of a fiber Bragg grating (FBG) in the active cores of an Yb-doped large mode area multicore fiber (MCF). An ultrashort pulsed laser is used to inscribe the FBG simultaneously in all six cores. In order to validate the FBG reflection and uniformity, the FBG is incorporated as a rear mirror in a fiber laser oscillator setup. The MCF, which has been fabricated in-house, has six cores located in a hexagonal-ring shape, each with a 19 µm diameter and an NA of ∼0.067. A reflection of ∼96% was measured at a center Bragg wavelength of ∼1062nm for the inscribed FBG. The laser performance of the MCF with the femtosecond inscribed FBG at its end shows a similar performance to lasing with a free-space commercial volume Bragg grating as the rear-reflector. A slope efficiency of ∼72.4% and a maximum (pump limited) output power of 51.8 W have been obtained for the FBG setup. An effective M2 of 3.88, indicating a somewhat multimode operation and a narrow bandwidth of ∼0.19nm, has been measured for this fiber laser.

Characterization of sub-nanosecond pulsed laser amplification with Er:Yb co-doped phosphate glass fibers.

We present an experimental characterization of the amplification of sub-nanosecond duration laser pulses at a wavelength of 1538 nm in short custom-made Er:Yb phosphate glass fibers with different core diameters. The fibers vary in their diameter from 100 µm (highly multi-mode) down to 12 µm (single-mode). The peak power, energy per pulse, and spectral shape of the amplified signal are presented. With our input pulses, the measurements show that the large core diameter fibers do not increase the amplification of the 1538 nm signal. We believe this is due to the high re-absorption of the Er3+ ions in the phosphate fiber. The optimal fiber geometry was found to have a core diameter of 20 µm with a length of 14 cm. The maximum peak power is 8.25 kW, corresponding to a net gain of 10.9 dB, with a pulse duration of 0.7 ns and a repetition rate of 40 kHz.

Vaccine hesitancy: the next challenge in the fight against COVID-19.

Vaccine hesitancy remains a barrier to full population inoculation against highly infectious diseases. Coincident with the rapid developments of COVID-19 vaccines globally, concerns about the safety of such a vaccine could contribute to vaccine hesitancy. We analyzed 1941 anonymous questionnaires completed by healthcare workers and members of the general Israeli population, regarding acceptance of a potential COVID-19 vaccine. Our results indicate that healthcare staff involved in the care of COVID-19 positive patients, and individuals considering themselves at risk of disease, were more likely to self-report acquiescence to COVID-19 vaccination if and when available. In contrast, parents, nurses, and medical workers not caring for SARS-CoV-2 positive patients expressed higher levels of vaccine hesitancy. Interventional educational campaigns targeted towards populations at risk of vaccine hesitancy are therefore urgently needed to combat misinformation and avoid low inoculation rates.

Femtosecond inscription of fiber Bragg gratings through the coating with a Low-NA lens.

Fiber Bragg grating (FBG) inscription in standard fibers with femtosecond (fs) laser pulses was first reported nearly two decades ago. FBG fs inscription through the fiber polymer coating was recently demonstrated with a phase mask (PM) and High Numerical Aperture (High-NA) cylindrical lenses. In this work, we report on a new technique for FBG inscription through the acrylate polymer coating of optical fibers using a Low-NA lens and the PM. The FBGs were inscribed through the polymer coating of the fiber after a suitable fs photo-treatment process that was done to the polymer coating. We experimentally demonstrate inscription of high-quality FBGs yet with some damage to the coating. We characterize the wavelength sensitivity to strain and temperature of the inscribed FBGs, and compare them to FBGs that were inscribed in fibers that have undergone stripping, inscription, and recoating. The technique may simplify FBGs inscription through the coating especially in large mode area fibers and double clad fibers for laser applications in the future.

High-efficiency Raman conversion in SF6- and CF4-filled hollow-core photonic bandgap fibers.

We present a comparative experimental investigation of vibrational stimulated Raman scattering in hollow-core photonic bandgap fibers pressurized with sulfur hexafluoride (${{\rm SF}_6}$SF6) and tetrafluoromethane (${{\rm CF}_4}$CF4) gases. Nanosecond-duration pulses at a wavelength of 1030 nm are coupled into the gas-filled fiber, and the first and second Stokes orders are measured at the fiber output. We characterize the conversion process as a function of gas, fiber length, and input power. With a 15 m fiber filled with ${{\rm SF}_6}$SF6, we obtain conversion efficiency to the first Stokes of 55.7% at an input peak power of 0.63 kW. In comparison, with ${{\rm CF}_4}$CF4, we obtained a higher conversion threshold and maximum conversion efficiency of 45.4%. To the best of our knowledge, this is the first reported conversion experiment with hollow-core fibers filled with ${{\rm SF}_6}$SF6 gas.

Characterizing the effect of femtosecond photo-treatment on the center wavelength of fiber Bragg gratings.

Various types of pre- and post-treatments to optical fibers are typically used to improve and/or change the properties of fiber Bragg grating (FBG). Here, we investigate experimentally the effects of NIR femtosecond (fs) laser pulses used for pre- and post-treatment on the refractive index of the fiber, and the resulting center wavelength shift of an fs inscribed FBG. We observe "red"-shift when applying a suitable pre-treatment, and both "blue"- and "red"-shifts when applying post-treatment. We characterize the photo-treatment parameters and compare to an FBG inscribed on a fresh fiber without any treatment. We also show that when the photo-treatment is saturated the result is a phase-shifted grating. Our results give further insight into the process of fs photo-treatments and quantify the effects in the case of fs FBG inscription.

Strain-assisted femtosecond inscription of phase-shifted gratings.

Two slightly shifted gratings are inscribed, one over the other, while exploiting fiber strain in a single-mode fiber. The inscription is done with a near-infrared femtosecond laser, a phase mask, and a cylindrical focusing lens. The first fiber Bragg grating (FBG) is inscribed under normal fiber tension, while the second overlapping FBG is inscribed under higher fiber tension. The transmission spectrum of the complex structure is similar to that of a phase-shifted grating, yet the fabrication process is much faster and simpler compared to other standard methods. A high-quality phase-shifted grating with two -30 dB transmission dips, a 25 dB transmission peak, and <50 pm transmission bandwidth is achieved. We observe polarization-dependent transmission in the phase-shifted gratings.

115 W fiber laser with an all solid-structure and a large-mode-area multicore fiber.

We investigate mode-area scaling by means of supermode operation in an all-solid multicore fiber. To obtain a large-mode area (LMA), we designed and fabricated an active double-clad multicore fiber, where each ytterbium-doped core is 19 µm in diameter and has a numerical aperture of 0.067, comparable to the core of the largest available commercial LMA fibers. The six large cores are stacked tightly in a ring structure to enable phase locking of the core fields and supermode operation. The fiber laser performance was investigated in a linear laser cavity with an external Talbot resonator for mode selection. The highest output power achieved was 115 W with an overall 61% slope efficiency corresponding to the pump power. The measured M2 was 1.43 for the central lobe with nearly 70% of the total power.

Hearing loss: mechanisms revealed by genetics and cell biology.

Hearing loss (HL), or deafness in its most severe form, affects an estimated 28 and 22.5 million Americans and Europeans, respectively. The numbers are higher in regions such as India and the Middle East, where consanguinity contributes to larger numbers of recessively inherited hearing impairment (HI). As a result of work-related difficulties, educational and developmental delays, and social stigmas and exclusion, the economic impact of HL is very high. At the other end of the spectrum, a rich deaf culture, particularly for individuals whose parents and even grandparents were deaf, is a social movement that believes that deafness is a difference in human experience rather than a disability. This review attempts to cover the remarkable progress made in the field of the genetics of HL over the past 20 years. Mutations in a significant number of genes have been discovered over the years that contribute to clinically heterogeneous forms of HL, enabling genetic counseling and prediction of progression of HL. Cell biological assays, protein localization in the inner ear, and detailed analysis of spontaneous and transgenic mouse models have provided an incredibly rich resource for elucidating mechanisms of hereditary hearing loss (HHL). This knowledge is providing answers for the families with HL, who contribute a great deal to the research being performed worldwide.

Ns-duration transient Bragg gratings in silica fibers.

We demonstrate, for the first time to our knowledge, fast all-optical switching in standard silica fibers, based on a transient Bragg grating. The grating is implemented in the fiber using an immunization photo-pretreatment process, followed by side illumination with femtosecond laser pulses through a suitable phase mask. Each pulse is nonlinearly absorbed, creating a thermal grating that is washed out by thermal diffusion. Reflections measured from such gratings are characterized by a very fast rise time, nanoseconds duration, and a high extinction ratio.