Tel Aviv University

Purpose/background: Trazodone is indicated for the treatment of major depressive disorder, but more frequently prescribed off-label at lower doses for insomnia in women of childbearing age. The aim of this study was to assess the risks linked to trazodone exposure during pregnancy for which limited safety data are available. Methods/procedures: This multicenter, observational prospective cohort study compared pregnancy outcomes in women exposed to trazodone in early pregnancy against those in a reference group of women exposed to a selective serotonin reuptake inhibitors (SSRIs) between 1996 and 2021. Findings/results: The sample included 221 trazodone and 869 SSRI-exposed pregnancies. Exposure to trazodone in the first trimester was not associated with a significant difference in the risk of major congenital anomalies (trazodone [1/169, 0.6%]; SSRI [19/730, 2.6%]; adjusted odds ratio, 0.2; 95% confidence interval, 0.03-1.77). The cumulative incidences of live birth were 61% and 73% in the trazodone and reference group, respectively (25% vs 18% for pregnancy loss and 14% vs 10% for pregnancy termination). Trazodone exposure was not associated with a significantly increased risk of pregnancy termination and pregnancy loss. The rate of small for gestational age infants did not differ between the groups. Implications/conclusions: This study did not reveal a significant difference in the risk of major congenital anomalies after first trimester exposure to trazodone, compared with SSRI exposure. Although this study is the largest so far, these results call for confirmation through further studies.

The sea urchin Diadema setosum is an ecological key species across its range, particularly on coral reefs. In 2006 D. setosum was first observed in the Mediterranean Sea, and since, it has proliferated to occupy the entire Levantine Basin. Here we report the mass mortality of the invasive D. setosum in the Mediterranean Sea. This is the first report of D. setosum mass mortality. The mortality spans over 1000 km along the Levantine coast of Greece and Turkey. The current mortality shows similar pathologies to previously reported Diadema mass mortality events, suggesting pathogenic infection as the cause of mortalities. Maritime transport, local currents, and fish predation of infected individuals may distribute pathogens at varying geographical scales. Due to the proximity of the Levantine Basin to the Red Sea, the risk of pathogen transport to the native Red Sea D. setosum population is imminent—with potentially catastrophic consequences.

Objective: We aim to study gender representation among the different national gynecologic oncology (GO) societies' presidents over the past decade. Methods: A cross-sectional study examining the period 2013-2022. The leadership positions in 11 GO societies in the USA (SGO), internationally (IGCS), Europe (ESGO), Australia (ASGO), Israel (ISGO), Japan (JSGO), Asia-Oceania (AOGIN), India (INSGO), Latin America (SLAGO), South Africa (SASGO), and Turkey (TRSGO) was studied. The proportion of leadership positions held by women was calculated and trends were evaluated. Results: Overall, the average rate of women's representation during the study period was 26.4%, and for the different organizations was: SASGO 70.0%, SGO 50.0%, ESGO 40.0%, ASGO 30.0%, INSGO 30.0%, and IGCS, ISGO, and SLAGO 20.0% each, TRSGO 10%, and no representation of women in JSGO and AOGIN. There was a significant decrease from 2013 to 2016 (63.6% to 9.1%) (P = 0.009) in women's representation as presidents of societies. From 2017 to 2022, there was no difference in women's representation (ranging from 9.1% to 36.4%) (P = 0.13). Conclusions: This study demonstrates that women are significantly under-represented in leadership positions in GO professional societies; however, in South Africa and the USA their representation in the last decade was close to equality.

Background: Depression is a major cause of disability worldwide. Recent data suggest that, in industrialised countries, the prevalence of depression peaks in middle age. Identifying factors predictive of future depressive episodes is crucial for developing prevention strategies for this age group. Aims: We aimed to identify future depression in middle-aged adults with no previous psychiatric history. Method: To predict a diagnosis of depression 1 year or more following a comprehensive baseline assessment, we used a data-driven, machine-learning methodology. Our data-set was the UK Biobank of middle-aged participants (N = 245 036) with no psychiatric history. Results: Overall, 2.18% of the study population developed a depressive episode at least 1 year following baseline. Basing predictions on a single mental health questionnaire led to an area under the curve of the receiver operating characteristic of 0.66, and a predictive model leveraging the combined results of 100 UK Biobank questionnaires and measurements improved this to 0.79. Our findings were robust to demographic variations (place of birth, gender) and variations in methods of depression assessment. Thus, machine-learning-based models best predict diagnoses of depression when allowing the inclusion of multiple features. Conclusions: Machine-learning approaches show potential for being beneficial for the identification of clinically relevant predictors of depression. Specifically, we can identify, with moderate success, people with no recorded psychiatric history as at risk for depression by using a relatively small number of features. More work is required to improve these models and evaluate their cost-effectiveness before integrating them into the clinical workflow.

This article focuses on experiences and perceptions of the Jewish ultra-Orthodox population in Israel—a religious minority—regarding premarital genetic testing. Semistructured interviews with 38 ultra-Orthodox individuals revealed four major themes. These themes reflect strong awareness of testing importance among Ashkenazi ultra-Orthodox, along with a high frequency of testing, while low awareness of testing importance was evident among Sephardi ultra-Orthodox along with a very low frequency of testing. The study’s findings also indicate the central role that the Ashkenazi rabbis have in the routinization of the premarital genetic testing among their communities. Study limitations are discussed, and future research recommendations are provided.

Colistin heteroresistance (HR) refers to a bacterial population comprised of several subpopulations with different levels of resistance to colistin. In this study, we discuss the classic form of HR, in which a resistant subpopulation exists within a predominantly susceptible population. We investigated the prevalence of colistin HR and its evolution into full resistance among 173 clinical carbapenem-resistant Acinetobacter baumannii isolates and examined the effect of HR on clinical outcomes. To determine HR, we performed population analysis profiling. Our results showed a high prevalence of HR (67.1%). To examine evolution of HR strains into full resistance, the HR strains were grown in colistin-containing broth, transferred onto colistin-containing plates, and colonies on these plates were transferred into colistin-free broth. Many of the HR strains (80.2%) evolved into full resistance, 17.2% reverted to HR, and 2.6% were borderline. We used logistic regression to compare 14-day clinical failure and 14-day mortality between patients infected by HR versus susceptible non-HR carbapenem-resistant A. baumannii. In the subgroup of patients with bacteremia, HR was significantly associated with 14-day mortality. IMPORTANCE To our knowledge, this is the first large-scale study to report on HR in Gram-negative bacteria. We described the prevalence of colistin HR in a large sample of carbapenem-resistant A. baumannii isolates, the evolution of many colistin HR isolates to a resistant phenotype following colistin exposure and withdrawal, and the clinical consequences of colistin HR. We found a high prevalence of HR among clinical carbapenem-resistant A. baumannii isolates; most evolved into a resistant phenotype following colistin exposure and withdrawal. In patients treated with colistin, evolution of HR A. baumannii into full resistance could lead to higher rates of treatment failure and contribute to the reservoir of colistin-resistant pathogens in health care settings.

Background and aims: Achieving good glycemic control is a major challenge for adolescents with type 1 diabetes (TID). The introduction of the MiniMed 780G system, an advanced hybrid closed-loop (AHCL), that enables an automatic correction of insulin, gave hope for improved glycemic outcomes in adolescents. We assessed specific characteristics associated with glycemic measures in youth with T1D switching to Minimed 780G. Methods: This retrospective observational real-life multi-center study from the AWeSoMe Group assessed continuous glucose monitoring (CGM) metrics of 22 patients (59% females, median age 13.9 [IQR 11,18] years), from a high socioeconomic background. CGM metrics were recorded for two-week periods prior to AHCL, after 1, 3, 6 months, and at the end of follow-up (median 10.9 [IQR 5.4, 17.4] months). Delta-variables (∆) were calculated as the difference between the end of follow-up and baseline. Results: TIR70-180mg/dL increased from 65% [52,72] to 75% [63,80], p=0.008, from baseline to end. TAR>180mg/dL, decreased from 28% [20,46] to 22% [14,35], p=0.047. Advanced pubertal stage was correlated with less improvement in ∆TAR>180mg/dL, r=0.47, p=0.05, and less CGM usage r=-0.57, p=0.05. A longer disease duration was associated with less improvement in ∆TAR180-250mg/dL, r=0.48, p=0.05. Lower pump site change frequency was associated with higher GMI, r=0.5, p=0.03, and lower TIR70-180mg/dL r=-0.52, p=0.08. Conclusion: The use of AHCL enabled improvements in TIR70-180mg/dL in youth with T1D. More advanced pubertal stages, longer disease duration, and less compliance were associated with less improvement, stressing the need for continuous support and re-education in this age group. .

There is a scarcity of data regarding the antimicrobial susceptibility testing profiles of nontuberculous mycobacterial (NTM) in Israel and other Middle Eastern countries. We aimed to describe the antimicrobial susceptibility profiles of NTM in Israel. A total of 410 clinical isolates of NTM, identified to the species level using matrix-assisted laser desorption ionization-time of flight mass spectrometry or hsp65 gene sequencing, were included. Minimum inhibitory concentrations for slowly growing mycobacteria (SGM) and rapidly growing mycobacteria (RGM) for 12 and 11 drugs were determined using the Sensititre SLOMYCOI and RAPMYCOI broth microdilution plates, respectively. Mycobacterium avium complex (MAC) was the most frequently isolated species (n = 148; 36%), followed by Mycobacterium simiae (n = 93; 23%), Mycobacterium abscessus group (n = 62; 15%), Mycobacterium kansasii (n = 27; 7%), and Mycobacterium fortuitum (n = 22; 5%) accounting together for 86% of isolates. The most active agents against SGM were amikacin (98%/85%/100%) and clarithromycin (97%/99%/100%), followed by moxifloxacin (25%/10%/100%) and linezolid (3%/6%/100%) for MAC, M. simiae, and M. kansasii, respectively. For RGM, the most active agents were amikacin (98%/100%/88%) followed by linezolid (48%/80%/100%) and clarithromycin (39%/28%/94%) for M. abscessus group, M. fortuitum, and M. chelonae, respectively. These findings can assist in guiding the treatment of NTM infections.

Background: Contact dermatitis is a common condition in the general population, with a global prevalence of 20%. It is an inflammatory skin disease that is classified as irritant contact dermatitis (80%) and allergic contact dermatitis (ACD) (20%). In addition, it is the most common presentation of occupational dermatoses and is one of the primary reasons for seeking medical attention among military personnel. Only few studies have compared the characteristics of contact dermatitis in soldiers and civilians. Objective: To compare the characteristics of ACD between civilians and soldiers. Methods: This large retrospective study was conducted in Israel and involved 1800 civilians and 750 soldiers with suspected ACD. All patients underwent relevant patch tests based on their clinical presentation and medical history. Results: At least 1 positive allergic reaction was found in 382 civilians (21.22%) and 208 soldiers (27.73%) (nonsignificant). Moreover, 69 civilians (18.06%) and 61 soldiers (29.32%) had at least 1 positive occupational allergic reaction (P < 0.05). Widespread dermatitis was significantly more common among soldiers. The most frequent occupations among civilians with positive allergic reactions were hairdressers/beauticians. "Professional, technical, and managerial occupations" were the most frequent categories among soldiers (24.6%), with computing professionals being the most common occupation (46.67%). Conclusion: Military personnel and civilians have different characteristics associated with ACD. Therefore, considering these characteristics before placement in a workplace can help prevent ACD.

Objective: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is an inherited metabolic disorder with a variable phenotype and rate of progression. We aimed to develop and validate a clinical severity scoring (CSS) system applicable to the clinical setting and composed of five domains reflecting the principal manifestations of this disorder: Cognitive, Communication, Motor, Epilepsy, and Psychiatry. Methods: A prospectively characterized cohort of 27 SSADHD subjects [55% females, median (IQR) age 9.2 (4.6-16.2) years] who enrolled in the SSADHD Natural History Study were included. The CSS was validated by comparison to an objective severity scoring system (OSS) based on comprehensive neuropsychologic and neurophysiologic assessments, which mirror and complement the domains of the CSS. Results: The total CSS was sex and age-independent, and 80% of its domains lacked interdependence. With increasing age, there was a significant improvement in communication abilities (p=0.05) and a worsening of epilepsy and psychiatric manifestations (p=0.004 and p=0.02, respectively). There was a significant correlation between all the CSS and OSS domain scores, as well as between the total CSS and OSS (R=0.855, p<0.001). Additionally, there were no significant demographic or clinical differences in the ratio of individuals in the upper quartile to the lower three quartiles of the CSS and OSS. Conclusions: The SSADHD CSS is validated using objective measures and offers a reliable condition-specific instrument universally applicable in clinical settings. This severity score may be utilized for family and patient counseling, genotype-phenotype correlations, biomarker development, clinical trials, and objective descriptions of the natural history of SSADHD. This article is protected by copyright. All rights reserved.

Background It is unknown whether convalescent immunoglobulins (cIgG) are better than convalescent plasma (CP) for COVID-19 patients. Methods In this randomized trial we assigned high risk COVID-19 with ≤10 days of symptoms, to receive cIgG or CP. The primary endpoint was improvement on day 14 according to the WHO scale. Secondary endpoints were survival on day 14, and improvement, survival, and percent of ventilated patients on day 28 and treatment response in unvaccinated and vaccinated patients. Results 319 patients were included; 166 received cIgG, and 153 CP. Median age was 64-66 years. 112 patients (67.5%) in the cIgG and 103 patients (67.3%) in the CP group reached the primary endpoint. Difference between groups was 0.1 (95%CI -10.1-10.4, p=0.026), failing to reach non-inferiority. More patients receiving cIgG improved by day 28 [136 patients (81.9%) and 108 patients (70.6%), respectively, 95% CI 1.9-20.7, p<0.001, for superiority p=0.018)]. 17 patients in the cIgG group (10.2%) and 25 patients (16.3%) in the CP group required mechanical ventilation (p=0.136). 16 (9.6%) and 23 (15%) patients respectively died (p=0.172). More unvaccinated patients improved by day 28 in the cIgG group (84.1% vs. 66.1%, p<0.024) and survival was better in the cIgG group (89.9% vs. 77.4% p=0.066). Conclusions cIgG failed to reach the primary non-inferiority endpoint on day 14 but was superior to CP on day 28. Survival and improvement by day 28 in unvaccinated patients treated with cIgG were better. In the face of new variants, cIgG is a viable option for treating COVID-19. Trial registration number My Trials MOH_2021-01-14_009667

The interaction between a quantum charge and a dynamic source of a magnetic field is considered in the Aharonov-Bohm scenario. It is shown that, in weak interactions with a post-selection of the source, the effective vector potential is, generally, complex-valued. This leads to new experimental protocols to detect the Aharonov-Bohm phase before the source is fully encircled. While this does not necessarily change the nonlocal status of the Aharonov-Bohm effect, it brings new insights into it. Moreover, we discuss how these results might have consequences for the correspondence principle, making complex vector potentials relevant to the study of classical systems.

Background: Although more common in females, thyroid cancer is deemed to be more aggressive in males. The reasons for sex disparities in thyroid cancer are not well understood. We hypothesised that differences in molecular mutations between females and males contribute to this phenomenon. Methods: Retrospective multicentre multinational study of thyroid nodules that underwent preoperative molecular profiling between 2015 and 2022. The clinical characteristics and mutational profiles of tumours in female and male patients were compared. Collected data included demographics, cytology results, surgical pathology, and molecular alterations. Results: A total of 738 patients were included of which 571 (77.4%) were females. The extrathyroidal extension was more common in malignancies in males (chi-squared, p = 0.028). The rate of point mutations and gene fusions were similar in both sex groups (p > 0.05 for all mutations). Patients with nodules with BRAFV600E mutations were significantly younger than BRAF wild-type nodule patients (t-test, p = 0.0001). Conversely, patients with TERT promoter mutations were significantly older than patients with wild-type TERT (t-test, p < 0.0001). For patients harbouring both BRAFV600E and TERT mutations, the difference in age at presentation was significantly different in females (t-test, p = 0.009) but not in males (t-test, p = 0.433). Among females, patients with BRAFV600E and TERT mutations were significantly older than their wild-type or single-mutation counterpart (t-test, p = 0.003). Conclusion: The absolute rate of molecular mutations was similar in females and males. We found that extrathyroidal extension was more common in males. Moreover, BRAFV600E and TERT mutations occur at a younger age in males than in females. These two findings are factors that may explain the tendency of more aggressive disease in males.

For decades, prenatal screening and genetic testing strategies were limited, requiring less complex decisions. Recently, however, several new advanced technologies were introduced, including chromosomal microarray analysis (CMA) and non-invasive prenatal screening (NIPS), bringing about the need to choose the most appropriate testing for each pregnancy. A worrisome issue is that opposed to the wide implementation and debates over public funding of NIPS, currently invasive testing is still recommended only in selected pregnancies with increased risk for chromosomal aberrations (according to screening tests or sonographic anomalies). This current decision-making regarding public funding for invasive and screening testing might compromise informed consent and patient's autonomy. In this manuscript, we compare several characteristics of CMA vs. NIPS, namely: the accuracy and the diagnostic scope, the risks for miscarriage and for clinically uncertain findings, the timing for testing, and pretest counselling. We argue that it must be recognized that one size might not fit all, and suggest that both options should be presented to all couples through early genetic counseling, with public funding for the specific selected test.