TCF3 haploinsufficiency defined by immune, clinical, gene-dosage, and murine studies.

BACKGROUND: TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance. OBJECTIVE: We sought to define TCF3 haploinsufficiency (HI) biology and its association with immunodeficiency. METHODS: Patient clinical data and blood samples were analyzed. Flow cytometry, Western blot analysis, plasmablast differentiation, immunoglobulin secretion, and transcriptional activity studies were conducted on individuals carrying TCF3 variants. Mice with a heterozygous Tcf3 deletion were analyzed for lymphocyte development and phenotyping. RESULTS: Individuals carrying monoallelic LOF TCF3 variants showed B-cell defects (eg, reduced total, class-switched memory, and/or plasmablasts) and reduced serum immunoglobulin levels; most but not all presented with recurrent but nonsevere infections. These TCF3 LOF variants were either not transcribed or translated, resulting in reduced wild-type TCF3 protein expression, strongly suggesting HI pathophysiology for the disease. Targeted RNA sequencing analysis of T-cell blasts from TCF3-null, dominant negative, or HI individuals clustered away from healthy donors, implying that 2 WT copies of TCF3 are needed to sustain a tightly regulated TCF3 gene-dosage effect. Murine TCF3 HI resulted in a reduction of circulating B cells but overall normal humoral immune responses. CONCLUSION: Monoallelic LOF TCF3 mutations cause a gene-dosage-dependent reduction in wild-type protein expression, B-cell defects, and a dysregulated transcriptome, resulting in immunodeficiency. Tcf3+/- mice partially recapitulate the human phenotype, underscoring the differences between TCF3 in humans and mice.

Association between COVID-19 vaccination and myasthenia gravis: A population-based, nested case-control study.

BACKGROUND: Existing data regarding the link between COVID-19 vaccine and myasthenia gravis (MG) are scarce. We aimed to assess the association between Pfizer-BioNTech vaccine with both new-onset MG and MG exacerbation. METHODS: For the first aim, we conducted a nested case-control study in a cohort of 3,052,467 adults, without a diagnosis of MG, from the largest healthcare provider in Israel. Subjects were followed from January 1, 2021 until June 30, 2022 for the occurrence of MG. Ten randomly selected controls were matched to each case of new-onset MG on age and sex. For the second aim, a nested case-control study was conducted in a cohort of 1446 MG patients. Four randomly selected MG patients (controls) were matched to each case of MG exacerbation. Exposure to COVID-19 vaccine in the prior 4 weeks was assessed in cases and controls. RESULTS: Overall, 332 patients had new-onset MG and were matched with 3320 controls. Multivariable conditional logistic regression models showed that the odds ratio (OR) for new-onset MG, associated with COVID-19 vaccine, was 1.14 (95% CI 0.73-1.78). The results were consistent in sensitivity analysis that used more stringent criteria to define MG. Overall, 62 patients with MG exacerbation were matched to 248 MG controls. The multivariable OR for MG exacerbation, associated with COVID-19 vaccine, was 1.35 (95% CI 0.37-4.89). All results were similar when the prior exposure to COVID-19 vaccine was extended to 8 weeks. CONCLUSION: This study suggests that Pfizer-BioNTech vaccine is not associated with increased risk of new-onset nor exacerbation of MG.

Ocular injury from foam dart (Nerf) blasters: a case series.

To report clinical outcomes following ocular injury from foam dart (nerf) blasters - a spring-loaded toy guns that fire foam-coated darts or bullets at a relatively low velocity. These guns gained popularity in recent years among children and adolescents. Eleven patients with ocular injuries from foam dart blasters were included in this retrospective, single-center study. Visual acuity (VA), intraocular pressure (IOP), and anterior segment, glaucoma-related, and vitreoretinal complications were recorded at each visit. The average age at presentation was 13.4 years and 82% were male. Mean initial VA was 6/12 (range 6/6 - 1/18); On initial examination, nine patients (82%) had hyphema, three (27%) had corneal abrasions, three (27%) had vitreous hemorrhage, and two (18%) had traumatic mydriasis. Four patients (36%) experienced glaucoma-related complications, including three (27%) with angle recession and three (27%) with increased IOP. Three patients (27%) were diagnosed with posterior segment injuries, including three (27%) with commotio retinae and one (9%) with severe retinal photoreceptor damage. No patients required surgical intervention. CONCLUSION: Foam dart blasters can cause severe blunt ocular trauma and permanent visual loss, illustrating the need for eye protection when handling these toys. WHAT IS KNOWN: • Foam dart blasters, a blanket term for spring-loaded toy guns that fire foam-coated darts or bullets at a relatively low velocity, have gained popularity in recent years among pediatric populations, with an increase in associated ocular injuries. • To date, scattered case reporting provides insufficient insight into the full clinical spectrum of injury and prognosis of foam dart blasters related ocular injury. WHAT IS NEW: • This case series characterizes the myriad foam dart blasters injuries that may afflict the eye, most of which are self-limiting, but some of which may result in poor visual outcomes and lifelong disability in pediatric patients. • We strongly recommend that all users wear eye protection while using foam dart blasters.

Additive Value of a Face-to-Face Visit to Virtual Remote Decision in Patients with Neovascular Age-Related Macular Degeneration.

INTRODUCTION: The increasing high prevalence of neovascular age-related macular degeneration (nvAMD) in the aging population combined with the need for frequent monitoring and treatment for many years, especially in the COVID-19 era, raises the need to establish an effective, reliable, and safe follow-up and treatment model. This study evaluates the difference in treatment decisions comparing between the gold standard face-to-face clinical examination and virtual evaluation approach based only on visual acuity (VA) and optical coherence tomography (OCT) scans without clinical fundoscopic examination in nvAMD patients. METHODS: A single-center retrospective cohort study was conducted that compared an original "face-to-face" visit treatment decision regarding the need for anti-vascular endothelial growth factor drug, interval, and treatment regimen based on routine VA, spectral domain OCT imaging, and dilated fundus examination to two "virtual" treatment decisions based on evaluation of OCT scans and previous medical records before and after revealing VA data on the same nvAMD patients eyes. RESULTS: About 169 eyes of 114 patients were included in the study. Forty-nine patients (43%) suffered from bilateral nvAMD and had both eyes included in the study. Agreement between the "face-to-face visit treatment decision" and "virtual treatment decision" was noted in 74.6% and 71.6% eyes before and after revealing the patient's VA in the study visit, respectively. CONCLUSIONS: Virtual evaluation results in similar treatment decisions for nvAMD patients compared to standard face-to-face clinical examination.

Epiretinal Membrane in Patients with Diabetic Macular Edema.

PURPOSE: The aim of the study was to compare anatomical and functional outcomes of pars plana vitrectomy (PPV) with epiretinal membrane (ERM) peeling in diabetes retinopathy patients with and without diabetic macular edema (DME). METHODS: A retrospective interventional case series of consecutive patients who underwent PPV with ERM peeling. Patients were divided into two groups: those with and without preoperative DME. Visual acuity (VA) and optical coherence tomography parameters were evaluated before surgery and during 12 months of follow-up. RESULTS: A total of 354 patients underwent PPV with ERM peeling, of which 51 met the inclusion criteria. Twenty-three were diagnosed with DME and were younger (66.3 ± 9.6 vs. 73.1 ± 8.2 years, p = 0.001), had longer diabetes mellitus (DM) duration (18.9 ± 7.1 vs. 14.3 ± 10.9 years, p = 0.04) and higher HbA1C% (7.6 ± 1.4 vs. 7.1 ± 1.3, p = 0.04). VA improved from 20/105 to 20/60 Snellen (p = 0.004) and central macular thickness decreased from 469.3 ± 64.9 µm to 331.1 ± 92.2 µm (p < 0.001) in the DME group and from 20/87 to 20/44 Snellen (p < 0.001) and from 463.1 ± 53.5 µm to 341.3 ± 49.5 µm (p = 0.01) in the non-DME group. Yearly intravitreal injection rate decreased from 5.9 ± 2.5 to 2.9 ± 3.0 (p < 0.001) injections in the DME group. CONCLUSIONS: DME patients with ERM experience significant improvement in VA, macular thickness, and yearly intravitreal injections after PPV with ERM peeling. DME patients are younger, with longer duration of DM and higher HbA1C% levels at presentation in comparison to diabetic ERM patients without DME.

RadArnomaly: Protecting Radar Systems from Data Manipulation Attacks.

Radar systems are mainly used for tracking aircraft, missiles, satellites, and watercraft. In many cases, information regarding the objects detected by a radar system is sent to, and used by, a peripheral consuming system, such as a missile system or a graphical user interface used by an operator. Those systems process the data stream and make real-time operational decisions based on the data received. Given this, the reliability and availability of information provided by radar systems have grown in importance. Although the field of cyber security has been continuously evolving, no prior research has focused on anomaly detection in radar systems. In this paper, we present an unsupervised deep-learning-based method for detecting anomalies in radar system data streams; we take into consideration the fact that a data stream created by a radar system is heterogeneous, i.e., it contains both numerical and categorical features with non-linear and complex relationships. We propose a novel technique that learns the correlation between numerical features and an embedding representation of categorical features in an unsupervised manner. The proposed technique, which allows for the detection of the malicious manipulation of critical fields in a data stream, is complemented by a timing-interval anomaly-detection mechanism proposed for the detection of message-dropping attempts. Real radar system data were used to evaluate the proposed method. Our experiments demonstrated the method's high detection accuracy on a variety of data-stream manipulation attacks (an average detection rate of 88% with a false -alarm rate of 1.59%) and message-dropping attacks (an average detection rate of 92% with a false-alarm rate of 2.2%).

Implementation of oral anticoagulation treatment guidelines in patients with newly diagnosed atrial fibrillation.

AIMS: Oral anticoagulants (OACs) are considered the mainstay in preventing stroke in atrial fibrillation (AF). OAC treatment remains suboptimal among AF patients, even after the introduction of direct oral anticoagulants (DOACs). We aimed to assess trends overtime and current implementation of OAC treatment guidelines in AF, using a large dataset of real world data from Israel. METHODS: This is a retrospective cohort study that includes all adult members of Clalit Health Services, the largest healthcare provider in Israel, with newly diagnosed nonvalvular AF between January 2014 and December 2019 with CHA2 DS2 -VASc score ≥2. OAC treatment rates were calculated and multivariate regression models were used to identify predictors of OACs initiation. RESULTS: Overall, 46 531 patients were included in the study. The 3-months cumulative OAC treatment rates increased consistently over the years: 46.9% (95% confidence interval, 46.1-47.7%), 54.9% (54.1-55.6%) and 61.7% (60.9-62.4%) during 2014-2015, 2016-2017 and 2018-2019, respectively. DOACs constituted 51.3% of prescribed OACs in 2014-2015 and increased to 95.1% during 2018-2019. On multivariate analyses, the likelihood of OACs initiation among AF patients increased across the years and across higher socioeconomic classes, and was more likely among females, Jews, statins users and patients previously screened for colorectal cancer, but less likely among smokers and patients with impaired renal function. The likelihood of treatment increased with higher CHA2 DS2 -VASc score and decreased with higher HAS-BLED score. CONCLUSION: Despite the increasing OAC treatment rates among high-risk AF patients, mainly attributed to the expanding DOAC use, OAC treatment scope is still far from optimal.

PIGMENT EPITHELIAL DETACHMENT IN AGE-RELATED MACULAR DEGENERATION: Long-Term Visual Acuity May Improve With Higher Injection Index.

PURPOSE: To define injection index (II) and assess its impact on visual acuity (VA) in pigment epithelial detachment from age-related macular degeneration over 5 years. METHODS: Injection index is defined as the mean anti-vascular endothelial growth factor injections per year from presentation. A retrospective study of 256 eyes in 213 patients was performed. Patients were stratified by II (high: ≥9, low: <9). RESULTS: Baseline characteristics showed no differences across II groups. Mean (range) follow-up, in years, was 5.02 (1.04-12.74) for all patients. Mean logMAR VA (Snellen VA) were 0.60 (20/80) and 0.56 (20/73) at baseline, 0.52 (20/66) and 0.59 (20/78) at Year 1, 0.45 (20/56) and 0.67 (20/94) at Year 2, 0.38 (20/48) and 0.66 (20/91) at Year 3, 0.41 (20/51) and 0.89 (20/155) at Year 4, and 0.35 (20/45) and 0.79 (20/123) at Year 5 for the high and low II groups, respectively. Linear regression analysis showed a gain of 0.5 approxETDRS letters with each additional injection per year. CONCLUSION: Increased II was associated with better mean VA, suggesting that long-term continuous vascular endothelial growth factor suppression may improve VA in eyes thought to carry poor prognoses.

Association between myelofibrosis and risk of non-hematologic malignancies: a population-based retrospective cohort study.

Controversy regarding the risk of non-hematologic malignancies in myelofibrosis patients still exists. We aimed to examine the association between myelofibrosis and non-hematologic malignancies. A cohort of 1,469,790 adults without a diagnosis of myelofibrosis was identified on 1 January 2007, from the electronic medical records of the largest healthcare provider in Israel. Participants were followed up until 31 December 2015, for the occurrence of myelofibrosis. All cases of myelofibrosis were adjudicated by reviewing patients' electronic medical files. Using risk set sampling, four randomly selected controls (without myelofibrosis) were matched to each case of myelofibrosis on age, sex, ethnicity, and index date. Patients with and without myelofibrosis were followed from the index date until 31 December 2016 for the occurrence of non-hematologic malignancies based on the data from the Israel National Cancer Registry. The study included 550 patients with myelofibrosis and 2200 matched controls. Non-hematologic cancers occurred in 35 patients with myelofibrosis and 138 patients without myelofibrosis, reflecting a crude incidence rate of 27.9 and 15.3 per 1000 person-years, respectively. Myelofibrosis was independently associated with increased risk of non-hematologic malignancies with propensity score adjusted HR of 1.85 (95% CI, 1.09-3.15). No significant association was detected between myelofibrosis and the specific sites of non-hematologic malignancies. Treatment with ruxolitinib was not significantly associated with non-hematologic malignancies HR 1.36 (0.60-3.11). In conclusion, myelofibrosis appears to be associated with increased risk of non-hematologic malignancies. However, this study raises concerns about surveillance bias, suggesting that the association might be attributed to earlier detection rather than real increased risk.

Causative Pathogens of Endophthalmitis after Intravitreal Anti-VEGF Injection: An International Multicenter Study.

PURPOSE: The main objective of this study was to investigate the microbiological spectrum of endophthalmitis after anti-VEGF injections and to compare streptococcal with non-streptococcus-associated cases with regard to baseline characteristics and injection procedure. METHODS: Retrospective, international multicenter study of patients with culture-positive endophthalmitis after intravitreal anti-VEGF injection at 17 different retina referral centers. RESULTS: Eighty-three cases with 87 identified pathogens were included. Coagulase-negative staphylococci (59%) and viridans streptococci (15%) were the most frequent pathogens found. The use of postoperative antibiotics and performance of injections in an operating room setting significantly reduced the rate of streptococcus-induced endophthalmitis cases (p = 0.01 for both). CONCLUSION: We found a statistically significant lower rate of postinjectional local antibiotic therapy and operating room-based procedures among the streptococcus-induced cases compared to cases caused by other organisms.

CHANGES IN CHOROIDAL THICKNESS IN CLINICALLY SIGNIFICANT PSEUDOPHAKIC CYSTOID MACULAR EDEMA.

PURPOSE: To investigate choroidal thickness in eyes with clinically significant pseudophakic cystoid macular edema (PCME) during the acute phase and following resolution of the edema, using enhanced depth imaging spectral domain optical coherence tomography (EDI-OCT). METHODS: This is a retrospective, observational clinical study. Patients' records were reviewed for cases of clinically significant PCME after uneventful phacoemulsification surgery. Choroidal thickness was measured at time of PCME diagnosis in both eyes and after CME resolution in the affected eye using enhanced depth imaging spectral domain optical coherence tomography (Spectralis; Heidelberg Engineering). Measurements were taken subfoveal and 1.5 mm nasal, temporal, inferior, and superior from the center of the fovea. Statistical analysis was performed using paired t-test and Pearson correlation. RESULTS: Mean subfoveal choroidal thickness in 34 eyes with PCME measured 258 ± 83 µm at baseline and decreased to 215 ± 79 µm after CME resolution (P < 0.001). Mean subfoveal choroidal thickness measured at baseline in fellow eyes was significantly lower (194 ± 77 µm) compared to acute PCME (P < 0.001) and after CME resolution (P = 0.011). CONCLUSION: Choroidal thickness is increased in eyes with PCME and decreases following edema resolution. These findings may strengthen the hypothesis of an inflammatory pathogenesis in PCME.

A20 inhibits both the degradation and limited processing of the NF-κB p105 precursor: A novel additional layer to its regulator role.

p105 plays dual roles in NF-κB signaling: it generates the active subunit p50 and in its precursor form inhibits NF-κB activation. p105 processing occurs under basal conditions and increases following signaling. IκB kinase ß (IKKß) mediates phosphorylation at the C-terminal domain of p105, leads to accelerated processing and degradation of the precursor. A20 is a dual function deubiquitinating and ubiquitin ligating enzyme, involving in turning-off the NF-κB signaling pathway. Here we show that A20 suppresses TNFα-induced proteolysis of p105. We demonstrate that A20 inhibits both the signal induced processing and the degradation of p105 upstream to IKK stimulation. In addition, A20 represses the constitutive processing of the precursor protein in IKK independent manner. Silencing of A20 in cells by siRNA, restores p105 processing and the generation of p50. Functional analysis of A20, shows that the ubiquitin ligase activity mediated by its zinc finger domain (ZF), is required for the basal processing inhibitory effect. Its N-terminal ovarian tumor (OTU) domain, however, is not obligatory. We show that A20 inhibits p50 generation in cells by reducing the ubiquitination of its precursor, p105. Co-immunoprecipitation experiments show that A20 is immunoprecipitated by p105 only in the presence of its recently identified ligase, KPC1. Our data propose an additional novel mechanism to explain the known NF-κB inhibitory effects of A20: by affecting p105 ubiquitination and subsequently its degradation and limited processing.

Modification by single ubiquitin moieties rather than polyubiquitination is sufficient for proteasomal processing of the p105 NF-kappaB precursor.

Activation of NF-kappaB is regulated via numerous ubiquitin- and proteasome-mediated steps; an important one is processing of the precursor p105 to the p50 active subunit. The mechanisms involved are largely unknown, because this is an exceptional case where the ubiquitin system does not destroy its substrate completely. Here, we demonstrate that proteasomal processing of p105 requires ubiquitin but not generation of polyubiquitin chains. In vitro, ubiquitin species that cannot polymerize mediate processing. In yeasts that express nonpolymerizable ubiquitins, processing proceeds normally, whereas degradation of substrates that are dependent on polyubiquitination is inhibited. Similar results were obtained in mammalian cells. Interestingly, processing requires multiple monoubiquitinations, because progressive elimination of lysines in p105 is accompanied by gradual inhibition of p50 generation. Finally, the proteasome recognizes the multiply monoubiquitinated p105. These findings suggest that a proteolytic signal can be composed of a cluster of single ubiquitins, not necessarily a chain.

An Intervention to Reduce the Time Interval Between Hospital Entry and Emergency Coronary Angiography in Patients with ST-Elevation Myocardial Infarction.

BACKGROUND: Outcomes of patients with acute ST-elevation myocardial infarction (STEMI) are strongly correlated to the time interval from hospital entry to primary percutaneous coronary intervention (PPCI). Current guidelines recommend a door to balloon time of < 90 minutes. OBJECTIVES: To reduce the time from hospital admission to PPCI and to increase the proportion of patients treated within 90 minutes. METHODS: In March 2013 the authors launched a seven-component intervention program:  Direct patient evacuation by out-of-hospital emergency medical services to the coronary intensive care unit or catheterization laboratory Education program for the emergency department staff Dissemination of information regarding the urgency of the PPCI decision Activation of the catheterization team by a single phone call Reimbursement for transportation costs to on-call staff who use their own cars Improvement in the quality of medical records Investigation of failed cases and feedback. RESULTS: During the 14 months prior to the intervention, initiation of catheterization occurred within 90 minutes of hospital arrival in 88/133 patients(65%); during the 18 months following the start of the intervention, the rate was 181/200 (90%) (P < 0.01). The respective mean/median times to treatment were 126/67 minutes and 52/47 minutes (P < 0.01). Intervention also resulted in shortening of the time interval from hospital entry to PPCI on nights and weekends. CONCLUSIONS: Following implementation of a comprehensive intervention, the time from hospital admission to PPCI of STEMI patients shortened significantly, as did the proportion of patients treated within 90 minutes of hospital arrival.

[THE EFFECT OF BIOLOGIC THERAPY ON THE LIPID PROFILE OF RHEUMATOID ARTHRITIS (RA), PSORIATIC ARTHRITIS (PSA) AND ANKYLOSING SPONDYLITIS (AS) PATIENTS].

INTRODUCTION: Cardiovascular (CV) morbidity and mortality is elevated in rheumatoid arthritis (RA), psoriatic arthritis (PSA) and ankylosing spondylitis (AS) patients. The inflammation not only accelerates atherosclerosis, but also influences CV risk factors such as lipid profile, blood pressure and insulin resistance. RA and PSA patients are initially treated with DMARDS (disease modifying anti-rheumatic drugs). However, if remission is not achieved in RA, a variety of biologics (anti- TNF rituximab, tocilizumab, abatacept) are added to the treatment regimen. In PSA, only anti-TNF drugs are approved. AS is treated solely by NSAIDS and anti-TNF drugs. DMARDS were found to reduce the CV morbidity in RA patients, in addition to their anti-inflammatory affect. However, it has not been proven that anti-inflammatory therapy reduces the cardiovascular risk in PSA and AS patients. Anti-TNF drugs have been shown to reduce CV morbidity and mortality in RA and AS patients, however their effect on these patient's lipid profile in not yet clear. Despite the scarce evidence available, it seems that rituximab may have a positive influence on the patient's lipid profile. Even though tocilizumab adversely affects the lipid profile, this drug's overall CV effect is still being examined in clinical trials. There is not enough evidence to determine the effect of abatacept on the lipid profile. These issues are currently in the focus of many clinical trials and no doubt these issues will be clarified in the future.

Adaptation and Validation of the Israeli Version of the Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL).

BACKGROUND: Chronic urticaria (CU) is a common disabling disorder. The CU-Q2oL (Chronic Urticaria Quality of Life Questionnaire) is a specific questionnaire for evaluating quality of life in CU patients. It consists of 23 items divided into six quality-of-life dimensions. It was initially developed in Italy and later validated in other countries. OBJECTIVES: To validate and adapt the CU-Q2oL to the Hebrew language in order to make it suitable for use in Israel. METHODS: The CU-Q2oL questionnaire was translated to Hebrew. A group of 119 CU patients were asked to complete this version, in addition to the Dermatology Life Quality Index (DLQI) and Urticaria Activity Score (UAS) questionnaires. A factorial analysis was performed to identify CU-Q2oL subscales, internal consistency and convergent validity assessment, as well as factors determining quality-of-life scores. RESULTS: The factor analysis identified six scales of the Israeli CU-Q2oL: (i) sleep and concentration, (ii) function and mental status, (iii) embarrassment and clothing limitations, (iv) itching, (v) eating behavior and medication side effects, and (vi) swelling, which accounted for 77% of the data variance. Five scales showed good internal consistency over 0.81. The mean ± SD score of CU-Q2oL in our patients with CIU was 41 ± 21.7. We found a strong positive correlation between the overall scores of CU-Q2oL and DLQI questionnaires (r = 0.8, P < 0.01). Additionally, we found a positive correlation between UAS and both CU-Q2oL and DLQI (r = 0.62, P < 0.01, and r = 0.53, P < 0.01, respectively). CONCLUSIONS: This study demonstrates that the Israeli CU-Q2oL questionnaire is suitable for both clinical use and research in Israel.