Determining the origin of different variants associated with familial mediterranean fever by machine-learning.

A growing number of familial Mediterranean fever (FMF) patients in Israel do not have a single country of origin for all four grandparents. We aimed to predict the Mediterranean fever gene (MEFV) variant most likely to be found for an individual FMF patient, by a machine learning approach. This study was conducted at the Sheba Medical Center, a referral center for FMF in Israel. All Jewish referrals included in this study carried an FMF associated variant in MEFV as shown by genetic testing performed between 2001 and 2017. We introduced the term 'origin score' to capture the dose and different combinations of the grandparents' origin. A machine learning approach was used to analyze the data. In a total of 1781 referrals included in this study, the p.Met694Val variant was the most common, and the variants p.Glu148Gln and p.Val726Ala second and third most common, respectively. Of 26 countries of origin analyzed, those that increased the likelihood of a referral to carry specific variants were identified in North Africa for p.Met694Val, Europe for p.Val726Ala, and west Asia for p.Glu148Gln. Fourteen of the studied countries did not show a highly probable variant. Based on our results, it is possible to describe an association between modern day origins of the three most common MEFV variant types and a geographical region. A strong geographic association could arise from positive selection of a specific MEFV variant conferring resistance to endemic infectious agents.

Trends in Psychiatric Emergency Department Visits in Northern Israel During the COVID-19 Outbreak.

Background: During the spread of coronavirus disease (COVID-19), mandatory quarantines increased social isolation and anxiety, with inevitable consequences on mental health and health seeking behavior. We wished to estimate those trends. Methods: We examined all psychiatric visits to the emergency department (ED) during March, April 2020, compared to identical months in 2018, 2019. We evaluated both number and nature of referrals. Results: Throughout the years, psychiatric referrals comprised about 5% of the total number of ED visits. In March-April 2020, 30% decreases were observed in overall ED visits and in psychiatric referrals in the ED. Compared to 2018-2019, in 2020, the proportions of these diagnoses were higher: anxiety disorders (14.5 vs. 5.4%, p < 0.001), personality disorders (6.7 vs. 3.2%, p = 0.001), psychosis (9.5 vs. 6.7%, p = 0.049), post-traumatic stress disorder (3.2 vs. 1.5%, p = 0.023). Compared to 2018-2019, in 2020, proportions were lower for adjustment disorder (5.8 vs. 8.9%, p = 0.036) and for consultation regarding observation (11.7 vs. 31.6%, p < 0.001). Differences were not observed between 2018-2019 and 2020 in the proportions of other diagnoses including suicide and self-harm disorders. Referrals concerning suicide and self-harm in a rural hospital and community clinic were 30% lower in the COVID-19 lockdown than in the same months in 2018, 2019. Conclusion: Psychiatric ED visits decreased by the same proportion as overall visits to the ED, apparently driven by fears of COVID-19. Referrals relating suicidality and self-harm shown nominal decrease, but their proportioned share remained constant. Increased anxiety and delayed care may eventually lead to increased mental health needs.

Identification of cell-specific targets of sumoylation during mouse spermatogenesis.

Recent findings suggest diverse and potentially multiple roles of small ubiquitin-like modifier (SUMO) in testicular function and spermatogenesis. However, SUMO targets remain uncharacterized in the testis due to the complex multicellular nature of testicular tissue, the inability to maintain and manipulate spermatogenesis in vitro, and the technical challenges involved in identifying low-abundance endogenous SUMO targets. In this study, we performed cell-specific identification of sumoylated proteins using concentrated cell lysates prepared with de-sumoylation inhibitors from freshly purified spermatocytes and spermatids. One-hundred and twenty proteins were uniquely identified in the spermatocyte and/or spermatid fractions. The identified proteins are involved in the regulation of transcription, stress response, microRNA biogenesis, regulation of major enzymatic pathways, nuclear-cytoplasmic transport, cell-cycle control, acrosome biogenesis, and other processes. Several proteins with important roles during spermatogenesis were chosen for further characterization by co-immunoprecipitation, co-localization, and in vitro sumoylation studies. GPS-SUMO Software was used to identify consensus and non-consensus sumoylation sites within the amino acid sequences of the proteins. The analyses confirmed the cell-specific sumoylation and/or SUMO interaction of several novel, previously uncharacterized SUMO targets such as CDK1, RNAP II, CDC5, MILI, DDX4, TDP-43, and STK31. Furthermore, several proteins that were previously identified as SUMO targets in somatic cells (KAP1 and MDC1) were identified as SUMO targets in germ cells. Many of these proteins have a unique role in spermatogenesis and during meiotic progression. This research opens a novel avenue for further studies of SUMO at the level of individual targets.

CDK14 expression is down-regulated by cigarette smoke in vivo and in vitro.

In this study, DNA arrays have been employed to monitor gene expression patterns in testis of mice exposed to tobacco smoke for 24 weeks and compared to control animals. The results of the analysis revealed significant changes in expression of several genes that may have a role in spermatogenesis. Cdk14 was chosen for further characterization because of a suggested role in the testis and in regulation of Wnt signaling. RT-PCR analysis confirmed down regulation of Cdk14 in mice exposed to cigarette smoke (CS). Cdk14 is expressed in all testicular cells; spermatogonia- and Sertoli-derived cell lines treated with cigarette smoke extract (CSE) in vitro showed down-regulation of CDK14 mRNA and protein levels as well as down-regulation of ß-catenin levels. CS-induced down-regulation of CDK14 mRNA and protein levels was also observed in several lung epithelium-derived cell lines including primary normal human bronchial epithelial cells (NHBE), suggesting that the effect is not restricted to the testis. Similar to testicular cells, CS-induced down-regulation of CDK14 in lung cells correlated with decreased levels of ß-catenin, a finding suggesting impaired Wnt signaling. In the lungs, CDK14 was localized to the alveolar and bronchial epithelium.

Rationale and staff evaluation of using a "therapeutic milieu" for substance users within a tuberculosis ward.

Approximately 30% of tuberculosis (TB) patients in Israel were treated, in part, in two dedicated hospital wards during the years 2003-2005. A portion of them manifested severe psychosocial conditions. An intervention based on the "Therapeutic Milieu" (TM) model was implemented in the larger ward and included a staff evaluation of this intervention. The concept of TM, based on psychosocial paradigms and behavioral medicine, is aimed at providing a supportive environment for patients. Weekly group patients' meetings and monthly group staff supervisions were performed during 15 months (2003-2005). Forty of the 196 (20%) TB patients, mainly "complex," and 13 of 20 staff members (65%) attended regularly and discussed how to deal with substance abuse, personality disorders, and immigration-related crises. Out of 40 TB cases, 30 (75%) were also substance users. Ten staff members self-analyzed the impact of this intervention in terms of (1) having given adequate tools for the staff, (2) reducing physical violence, (3) increasing adherence to TB treatment, and (4) more efficient treatment for their substance use. No direct evaluation was done among the TB patients. According to staff members, this intervention had a positive overall impact. However, using Therapeutic Milieu in TB ward hospitalization, as a "window of opportunity," remains the first step in a longer journey for rehabilitation. The study's limitations are noted.

["Injecting clean or being clean?" The international and Israeli experiences of Syringe Exchange Programs among injecting drug users].

Injecting drug users (IDU) are a hard-to-reach population. The treatment objectives are to reduce their risk factors, to guide them to total abstinence or to antagonist treatment. When IDU are not ready for detoxification, they are referred to Syringe Exchange Programs (SEP). The objective of SEP is harm reduction of blood-borne viruses (of HIV, HBV, HCV). The authors aimed to define the issues related to harm reduction, to discuss the results of SEP in the world, and to describe our experience. We analyzed the world literature and our experience. In this article, we describe the rehabilitation school of thought (which supports complete drug abstinence), the harm reduction school of thought (which refers to drug addiction as a chronic disease), and the possible continuum between these two schools of thought. The AIDS pandemic and the epidemiology of world drug addiction by injection are described, together with the principles of SEP and their evaluation in the world. In addition, we describe drug use in Israel and HIV infection among IDU. Finally, we analyze our preliminary results of the SEP pilot in Israel, during the years 2004-2005, and included 462 IDUs. In conclusion, considering the difficulties that exist with IDUs, most articles emphasize the importance of SEP in this population while sometimes also expressing its effectiveness in preventing transmissions of blood-borne viruses. In Israel, a pilot project has existed since the end of 2003, and has expanded progressively to three cities. An overall evaluation of this program is under preparation.