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Elad Moisseiev, Shimon Kurtz, Moshe Lazar, Gabi ShemeshDepartment of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, IsraelBackground: The purpose of this study was to evaluate the safety and efficacy of a fixed combination of timolol maleate 0.5% + brimonidine tartrate 0.2% (Combigan®) for reduction for intraocular pressure (IOP) in patients with glaucoma when the dose frequency is increased from twice to three times daily.Methods: The patients included had either primary open angle glaucoma or ocular hypertension. Those who were previously on treatment completed a drug washout period prior to inclusion. IOP was measured at baseline, after 4 weeks of treatment with Combigan twice daily, and again after a further 4 weeks of Combigan three times daily. Blood pressure, heart rate, and oxygen saturation were also recorded at each assessment.Results: Thirty-one eyes from 31 patients were included. Increasing the Combigan dose frequency resulted in a statistically significant (P < 0.001) additional reduction in IOP of 2.25 ± 1.18 mmHg, corresponding to a further 10.3% reduction in IOP from baseline. No local or systemic adverse effects were documented.Conclusion: Treatment with Combigan three times daily was more effective in reducing IOP than the twice-daily regimen, with no increase in adverse effects.Keywords: Combigan®, timolol, brimonidine, glaucoma, dose frequency

IntroductionIn patients with unilateral loss of vestibular function (UVL) vibration of the skull leads to a response of the vestibulo-ocular reflex (VOR) called vibration-induced nystagmus (VIN), with slow phases usually directed toward the paretic ear. This response is thought to result from the difference between the neural discharge in semicircular canal afferents from the healthy and the affected labyrinth. The brain interprets this difference as a sustained imbalance in angular (rotational) vestibular tone, which in natural circumstances would only occur when the head was rotating at a constant acceleration.MethodsTo study this effect, we used a contemporary model of the neural network that combines sensory information about head rotation, translation, and tilt relative to gravity to estimate head orientation and motion. Based on the model we hypothesize that in patients with UVL, the brain may estimate not only a “virtual” rotation from the induced canal imbalance but also a subsequent “virtual” translation from the incorrect computation of the orientation of the head relative to gravity. If this is the case, the pattern of vibration-induced nystagmus will depend on the orientation of the head relative to gravity during the stimulation. This model predicts that this “virtual” translation will alter the baseline VIN elicited with the head upright; augmenting it when the affected ear is down and diminishing it when the affected ear is up.ResultsConfirming this hypothesis, we recorded VIN in 3 patients with UVL (due to vestibular neuritis) in upright, right ear-down, and left ear-down positions and each showed the expected pattern.DiscussionFrom a practical, clinical view, our results and modeling suggest that positional VIN might reveal a hidden imbalance in angular vestibular tone in patients with UVL, when patients have equivocal signs of a vestibular imbalance, such as a minute amount of spontaneous or vibration-induced nystagmus with the head upright. This research provides insights into the underlying mechanisms of vestibular processing, the analysis of nystagmus in patients with UVL, and guides the design of a new bedside diagnostic test to assess vestibular function in patients with dizziness and imbalance.

Objectives This study examines the impact of pulmonary embolism (PE) on mortality among patients with femoral neck fractures, exploring the predictive value of preoperative PE for postoperative occurrences and associated mortality over a 5-year follow-up period. Methods We analyzed 2256 patients over 60 years old admitted with femoral neck fractures, focusing on those who developed DVT or PE postoperatively. Surgical intervention aimed within 48 hours without pharmacological thromboprophylaxis, utilizing mechanical prophylaxis instead. Postoperative management included Enoxaparin administration. Data analysis employed SPSS 21, with chi-squared tests, T-tests, and multivariate logistic regression to explore mortality and PE incidence. Results PE was diagnosed in 1.4% of patients, with a notable mortality contrast between patients with PE (87%) and those without (59.7%) over 5 years. A history of preoperative PE emerged as a significant risk factor for postoperative PE. Despite surgical variations, no significant correlation was found between surgery type and PE incidence. Early postoperative weight-bearing and institutional rehabilitation did not significantly alter PE incidence rates. Conclusions The study underscores the significant mortality risk associated with preoperative PE in femoral neck fracture patients. It highlights the necessity for vigilant PE risk assessment and management, challenging assumptions about the protective role of early mobility and rehabilitation in PE incidence. Further research is essential to refine patient care strategies and improve outcomes.

Gabi Shemesh,* Uri Soiberman,* Shimon KurtzDepartment of Ophthalmology, Tel Aviv Medical Center, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel*These two authors contributed equally to this workBackground and methods: Myopic photorefractive surgery induces a reduction in central corneal thickness, which may lead to underestimation of intraocular pressure. This retrospective clinical study compared intraocular pressure measurements obtained by Goldmann applanation tonometry (GAT) and dynamic contour tonometry (DCT-Pascal) in eyes undergoing myopic intralaser-assisted in situ keratomileusis (IntraLASIK) or laser-assisted subepithelial keratomileusis (LASEK).Results: Of a total of 51 eyes, 21 underwent LASEK and 30 underwent IntraLASIK. By GAT, mean preoperative intraocular pressure was 16.2 ± 1.99 mmHg and postoperatively was 10.84 ± 1.45 mmHg. By DCT, mean preoperative intraocular pressure was 15.9 ± 2.08 mmHg and postoperatively was 16.1 ± 2.3 mmHg. Both preoperative and postoperative differences between measurements made by GAT and DCT were found to be statistically significant (P < 0.04 and P < 0.01, respectively). GAT and DCT readings were unaffected by type of surgery (P = 0.74 and P = 0.46, respectively).Conclusion: Postoperative GAT measurements were lower than those obtained by DCT. The difference between preoperative and postoperative DCT measurements was minimal, so DCT may be preferable for the measurement of intraocular pressure in eyes undergoing myopic IntraLASIK or LASEK.Keywords: intraocular pressure, Goldmann applanation tonometry, dynamic contour tonometry, intralaser-assisted in situ keratomileusis, laser-assisted subepithelial keratomileusis

Eldar Rosenfeld, Gabi Shemesh, Shimon KurtzDepartment of Ophthalmology, Tel-Aviv Sourasky Medical Center, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, IsraelIntroduction: This study evaluated and compared the efficacy of selective laser trabeculoplasty (SLT) and argon laser trabeculoplasty (ALT) in terms of intraocular pressure (IOP)-lowering effects in pseudophakic patients at various time points after treatment. The primary aim was to compare the efficacy of SLT and ALT in reducing the IOP of pseudophakic glaucoma patients who recently underwent successful cataract extraction surgery. The secondary endpoint was to determine the percentage of SLT and ALT patients whose IOP was successfully reduced by at least 15% from baseline.Patients and methods: This study was a follow-up of a prospective randomized clinical trial. Fifty-two eyes from 52 glaucoma patients with uncontrolled IOP who had previously undergone successful phacoemulsification-assisted cataract excision surgery with intracapsular lens implantation were randomly assigned to treatment with either ALT (n = 30) or SLT (n = 22). Fifteen patients were excluded due to adverse events encountered during the study, leaving a total of 18 and 19 patients in the ALT and SLT groups, respectively. IOP measurements were carried out at scheduled intervals until 12 months post-laser treatment.Results: There were no significant differences in the IOP-lowering effects between the two methods at any time point during the follow-up period. The greatest differences between the two groups were observed at 1 week posttreatment and at the 3-month time point, but neither reached a level of significance. At the final checkup, the mean IOP reduction from baseline was 3.23 mmHg in the ALT group and 4.30 mmHg in the SLT group (P = 0.269). At that visit, six (35.3%) patients in the ALT group and 15 (75%) patients in the SLT group had a reduction of ≥15% from their baseline IOP.Conclusion: SLT and ALT are equally effective in their IOP-lowering capabilities in new pseudophakic glaucoma patients during the first 12 months after treatment.Keywords: selective laser trabeculoplasty, argon laser trabeculoplasty, intraocular pressure, cataract extraction, pseudophakic glaucoma patients

Gabi Shemesh*, Elad Moisseiev*, Moshe Lazar1, Shimon Kurtz Department of Ophthalmology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Affiliated to the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel*The first two authors contributed equallyPurpose: To evaluate the safety and efficacy in intraocular pressure (IOP) reduction of increasing Cosopt dosage from twice to three times a day.Methods: The study included patients with primary open-angle glaucoma or ocular hypertension. After a washout period, IOP was measured at baseline, after 4 weeks of treatment with Cosopt twice a day, and after another 4 weeks of treatment with Cosopt three times a day. Blood pressure, heart rate, and oxygen saturation levels were also recorded.Results: Twenty-nine eyes of 29 patients were included. Increasing Cosopt dosage resulted in a statistically significant (P < 0.001) additional reduction in IOP of 2.2 ± 1.58 mmHg (10.69% ± 7.49% of the baseline IOP values). There were no local or systemic adverse effects.Conclusion: Treatment with Cosopt three times a day was more effective in reducing IOP than twice a day, with no effect on safety.Keywords: Cosopt, timolol, dorzolamide, glaucoma, intraocular pressure, dosage

In the last 20 years, increasing numbers of students with educational challenges (SECs) have been included in mainstream schools. Inclusion creates complex classroom situations for mainstream teachers who need to have excellent decision-making skills and the ability to face and resolve ethical dilemmas. College students and pre and in-service teachers were asked about their attitudes towards SEC inclusion, as well as three open-ended dilemmas during vignettes depicting challenging situations in inclusive class forcing decision-making. An online closed and open-ended questionnaire was administered (n = 489). The analysis revealed significant differences in the type of solution to these dilemmas in the three groups. There was a significant interaction between high sensitivity to the feelings of the inclusive students and the participants' overall tendency to support the inclusion of the SECs, positive attitudes towards inclusion, low expression of stigma and a higher sense of self-efficacy. Implications and practical offers are discussed.

Abstract Idiopathic intracranial hypertension (IIH) may result in optic nerve fiber loss and even atrophy. The timing of the optical coherence tomography (OCT) indices reaching the lowest point (nadir) and the factors that predict the patient's anatomical outcome are not known. We aimed to determine the timing and the factors that affect nadir retinal nerve fiber layer (RNFL) thickness. The medical records of 99 IIH patients who were treated from December 2009 to January 2020 were retrospectively reviewed. The mean RNFL thickness at presentation was 263.5 ± 106.4 µm. The mean time to nadir was 7.9 ± 6.3 months. The average RNFL and ganglion cell complex (GCC) thickness at the nadir were 92.6 ± 14.5 µm (47% showed thinning) and 77.9 ± 27.8 µm (70% showed thinning), respectively. The Frisén disc edema stage and average RNFL thickness at baseline correlated with a longer time to nadir, (r = 0.28 P = 0.003 and r = 0.24, P = 0.012, respectively). The nadir average RNFL thickness and the nadir average GCC thickness (r = 0.32, P = 0.001, r = 0.29, P = 0.002, respectively) correlated with the baseline visual field mean deviation. The final anatomical outcome of IIH episodes in this study resulted in RNFL and GCC thinning. The time to RNFL nadir and its values correlated with IIH severity at presentation.

Clinical outcomes after lung transplantation, a life-saving therapy for patients with end-stage lung diseases, are limited by primary graft dysfunction (PGD). PGD is an early form of acute lung injury with no specific pharmacologic therapies. Here, we present a large multicenter study of plasma and bronchoalveolar lavage (BAL) samples collected on the first posttransplant day, a critical time for investigations of immune pathways related to PGD. We demonstrated that ligands for NKG2D receptors were increased in the BAL from participants who developed severe PGD and were associated with increased time to extubation, prolonged intensive care unit length of stay, and poor peak lung function. Neutrophil extracellular traps (NETs) were increased in PGD and correlated with BAL TNF-α and IFN-γ cytokines. Mechanistically, we found that airway epithelial cell NKG2D ligands were increased following hypoxic challenge. NK cell killing of hypoxic airway epithelial cells was abrogated with NKG2D receptor blockade, and TNF-α and IFN-γ provoked neutrophils to release NETs in culture. These data support an aberrant NK cell/neutrophil axis in human PGD pathogenesis. Early measurement of stress ligands and blockade of the NKG2D receptor hold promise for risk stratification and management of PGD.

Cardiomyocyte sarcomeres contain localized ribosomes, but the factors responsible for their localization and the significance of localized translation are unknown. Using proximity labeling, we identified ribosomal protein SA (RPSA) as a Z-line protein. In cultured cardiomyocytes, the loss of RPSA led to impaired local protein translation and reduced sarcomere integrity. By employing CAS9-expressing mice, along with adeno-associated viruses expressing CRE recombinase and single-guide RNAs targeting Rpsa, we knocked out Rpsa in vivo and observed mislocalization of ribosomes and diminished local translation. These genetic mosaic mice with Rpsa knockout in a subset of cardiomyocytes developed dilated cardiomyopathy, featuring atrophy of RPSA-deficient cardiomyocytes, compensatory hypertrophy of unaffected cardiomyocytes, left ventricular dilation, and impaired contractile function. We demonstrated that RPSA C-terminal domain is sufficient for localization to the Z-lines and that if the microtubule network is disrupted RPSA loses its sarcomeric localization. These findings highlight RPSA as a ribosomal factor essential for ribosome localization to the Z-line, facilitating local translation and sarcomere maintenance., Introduction Local translation has several benefits over diffuse or unlocalized protein production. Importantly, it allows protein synthesis closer to the site of action, is more economic, may prevent protein aggregation, [...]

The blackchin guitarfish Glaucostegus cemiculus has suffered severe declines and regional extirpation throughout its known distributions. While this species and its relative, the common guitarfish Rhinobatos rhinobatos, have been described in the Mediterranean Sea with co-occurring habitat ranges, no research has recorded the existence or extent of these two separate populations along the Israeli coastal waters. Along a particular coast in Israel, Ma’agan Michael, fishermen have reported annual observations of juvenile guitarfish between June to November for the last forty years. Based on these citizen-based observations the main research objective is to establish whether Ma’agan Michael fulfils all three criteria from the literature by Dr Michelle Heupel, allowing it to be acknowledged as a nursery ground for G. cemiculus. The methodology built for this objective integrates biological characteristics data with the identification of a recurrent seasonal distribution. Visual surveys exhibited a significantly higher abundance in Ma’agan Michael when compared to an adjacent area (Caesarea), with 2,096 recorded observations overall. Additionally, using a species-specific modified Catch and Release protocol, a total of 492 juveniles were captured with a beach seine net. During these capturing events, individuals were morphometrically measured and sampled for future genetic analyses. Out of these, 327 specimens were also fitted for PIT tags to track recaptures in subsequent captures. The highest abundance of neonates was caught from August to September each year (2017–2019), and all individuals captured during this study were identified in the field as G. cemiculus, ranging from 20–35 cm in length (85% of captures). Many specimens had an umbilical cord scar (n = 88), with a large percentage possessing visual remains of the yolk sac. For the first time, this study provides an inter-year description of the species Glaucostegus cemiculus present along the Israeli shoreline.

Summary: Studying neuronal morphology requires imaging and accurate extraction of tree-like shapes from noisy microscopy data. Here, we present a protocol for automatic reconstruction of branched structures from microscopy images using Neuronalyzer software. We describe the steps for loading neuron images, denoising, segmentation, and tracing. We then detail feature extraction (e.g., branch curvature and junction angles), data analysis, and plotting. The software allows batch processing and statistical comparisons across datasets. Neuronalyzer is scale-free and handles noise and variation across images.For complete details on the use and execution of this protocol, please refer to Yuval et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Human adaptive-like natural killer (NK) cells express low levels of FcεRIγ (FcRγ-/low) and are reported to accumulate during COVID-19 infection; however, the mechanism underlying and regulating FcRγ expression in NK cells has yet to be fully defined. We observed lower FcRγ protein expression in NK cell subsets from lung transplant patients during rapamycin treatment, suggesting a link with reduced mTOR activity. Further, FcRγ-/low NK cell subsets from healthy donors displayed reduced mTOR activity. We discovered that FcRγ upregulation is dependent on cell proliferation progression mediated by IL-2, IL-15, or IL-12, is sensitive to mTOR suppression, and is inhibited by TGFβ or IFNα. Accordingly, the accumulation of adaptive-like FcRγ-/low NK cells in COVID-19 patients corresponded to increased TGFβ and IFNα levels and disease severity. Our results show that an adaptive-like NK cell phenotype is induced by diminished cell proliferation and has an early prognostic value for increased TGFβ and IFNα levels in COVID-19 infection associated with disease severity.

Abstract The visual continuity illusion involves a shift in visual perception from static to dynamic vision modes when the stimuli arrive at high temporal frequency, and is critical for recognizing objects moving in the environment. However, how this illusion is encoded across the visual pathway remains poorly understood, with disparate frequency thresholds at retinal, cortical, and behavioural levels suggesting the involvement of other brain areas. Here, we employ a multimodal approach encompassing behaviour, whole-brain functional MRI, and electrophysiological measurements, for investigating the encoding of the continuity illusion in rats. Behavioural experiments report a frequency threshold of 18±2 Hz. Functional MRI reveal that superior colliculus signals transition from positive to negative at the behaviourally-driven threshold, unlike thalamic and cortical areas. Electrophysiological recordings indicate that these transitions are underpinned by neural activation/suppression. Lesions in the primary visual cortex reveal this effect to be intrinsic to the superior colliculus (under a cortical gain effect). Our findings highlight the superior colliculus’ crucial involvement in encoding temporal frequency shifts, especially the change from static to dynamic vision modes.

Oxygen isotopes in biogenic silica (δ18OBSi) from lake sediments allow for quantitative reconstruction of past hydroclimate and proxy-model comparison in terrestrial environments. The signals of individual records have been attributed to different factors, such as air temperature (Tair), atmospheric circulation patterns, hydrological changes, and lake evaporation. While every lake has its own local set of drivers of δ18O variability, here we explore the extent to which regional or even global signals emerge from a series of paleoenvironmental records. This study provides a comprehensive compilation and combined statistical evaluation of the existing lake sediment δ18OBSi records, largely missing in other summary publications (i.e. PAGES network). For this purpose, we have identified and compiled 71 down-core records published to date and complemented these datasets with additional lake basin parameters (e.g. lake water residence time and catchment size) to best characterize the signal properties. Records feature widely different temporal coverage and resolution, ranging from decadal-scale records covering the past 150 years to records with multi-millennial-scale resolution spanning glacial–interglacial cycles. The best coverage in number of records (N = 37) and data points (N = 2112) is available for Northern Hemispheric (NH) extratropical regions throughout the Holocene (roughly corresponding to Marine Isotope Stage 1; MIS 1). To address the different variabilities and temporal offsets, records were brought to a common temporal resolution by binning and subsequently filtered for hydrologically open lakes with lake water residence times < 100 years. For mid- to high-latitude (> 45° N) lakes, we find common δ18OBSi patterns among the lake records during both the Holocene and Common Era (CE). These include maxima and minima corresponding to known climate episodes, such as the Holocene Thermal Maximum (HTM), Neoglacial Cooling, Medieval Climate Anomaly (MCA) and the Little Ice Age (LIA). These patterns are in line with long-term air temperature changes supported by previously published climate reconstructions from other archives, as well as Holocene summer insolation changes. In conclusion, oxygen isotope records from NH extratropical lake sediments feature a common climate signal at centennial (for CE) and millennial (for Holocene) timescales despite stemming from different lakes in different geographic locations and hence constitute a valuable proxy for past climate reconstructions.

Abstract Recently, biotechnology and pharmaceutical industries have made strides to adopt and implement Natural Language Processing (NLP) to address challenges faced when extracting and synthesizing high volumes of information found in unstructured and semistructured text. Here we present, and provide a summary of the findings from, a use case where NLP and text mining methodologies were used to extract clinical trial data from ClinicalTrials.gov for mRNA cancer vaccines.

Abstract Mast cells (MCs) are immune cells that play roles in both normal and abnormal processes. They have been linked to tumor progression in several types of cancer, including non-small cell lung cancer (NSCLC). However, the exact role of MCs in NSCLC is still unclear. Some studies have shown that the presence of a large number of MCs is associated with poor prognosis, while others have suggested that MCs have protective effects. To better understand the role of MCs in NSCLC, we aimed to identify the initial mechanisms underlying the communication between MCs and lung cancer cells. Here, we recapitulated cell-to-cell contact by exposing MCs to membranes derived from lung cancer cells and confirming their activation, as evidenced by increased phosphorylation of the ERK and AKT kinases. Profiling of the microRNAs that were selectively enriched in the extracellular vesicles (EVs) released by the lung cancer-activated MCs revealed that they contained significantly increased amounts of miR-100-5p and miR-125b, two protumorigenic miRNAs. We explored the pathways regulated by these miRNAs via enrichment analysis using the KEGG database, demonstrating that these two miRNAs regulate p53 signaling, cancer pathways, and pathways associated with apoptosis and the cell cycle.

The purpose of the present study was to investigate the mechanism of action of our newly developed green sanitizer formulation comprising a natural phenolic compound, gallic acid (GA), strengthened by the Generally Recognized as Safe (GRAS) materials hydrogen peroxide (H2O2) and DL-lactic acid (LA). Combining 8 mM GA with 1 mM H2O2 resulted in an abundant generation of reactive oxygen species (ROS) and a bactericidal effect towards Gram-negative (Escherichia coli, Pseudomonas syringae, and Pectobacterium brasiliense) and Gram-positive (Bacillus subtilis) bacteria (4 to 8 log CFU mL−1 reduction). However, the exposure to this dual formulation (DF) caused only a modest 0.7 log CFU mL−1 reduction in the Gram-positive L. innocua population. Amending the DF with 20 mM LA to yield a triple formulation (TF) resulted in the efficient synergistic control of L. innocua proliferation without increasing ROS production. Despite the inability to grow on plates (>7 log CFU mL−1 population reduction), the TF-exposed L. innocua maintained high intracellular ATP pools and stable membrane integrity. The response of L. innocua to TF could be qualified as a “viable but nonculturable” (VBNC) phenomenon, while with the other species tested this formulation caused cell death. This research system may offer a platform for exploring the VBNC phenomenon, a critical food safety topic.

IL-12 is an essential cytokine involved in the generation of memory or memory-like NK cells. Mouse cytomegalovirus infection triggers NK receptor-induced, ligand-specific IL-12-dependent NK cell expansion, yet specific IL-12 stimulation ex vivo leading to NK cell proliferation and expansion is not established. Here, we show that IL-12 alone can sustain human primary NK cell survival without providing IL-2 or IL-15 but was insufficient to promote human NK cell proliferation. IL-12 signaling analysis revealed STAT5 phosphorylation and weak mTOR activation, which was enhanced by activating NK receptor upregulation and crosslinking leading to STAT5-dependent, rapamycin-sensitive, or TGFβ-sensitive NK cell IL-12-dependent expansion, independently of IL-12 receptor upregulation. Prolonged IL-2 culture did not impair IL-12-dependent ligand-specific NK cell expansion. These findings demonstrate that activating NK receptor stimulation promotes differential IL-12 signaling, leading to human NK cell expansion, and suggest adopting strategies to provide IL-12 signaling in vivo for ligand-specific IL-2-primed NK cell-based therapies.

The topic of support for students with learning disabilities (LD) has been studied to a considerable extent in recent years, due to the significant increase in the integration of students with learning disabilities in higher education institutions (HEI). However, there is hardly any research examining the support for students with learning disabilities in Israel's Arab sector. The purpose of the current preliminary study is to examine whether support centers for students with learning disabilities assist Arab students with their learning and general academic functioning in Israeli higher education institutions. The study is qualitative, involving semi-structured interviews with eight Arab students diagnosed with learning disabilities studying at two institutions of higher education. Analysis of the interviews revealed four major themes: The double difficulty that students experience due to the fact that they are Arabs for whom Hebrew is a second language, and due to their learning disabilities; lower awareness of learning disabilities in the Arab sector in Israel; post-diagnosis relief; a sense of wellbeing satisfaction with the educational, social and occupational support provided, enabling them to study and succeed. The article addresses also to the limitations of the study as a primary study, along with recommendations for further research based on this preliminary study.