Real World Cost-Effectiveness Analysis of Population Screening for BRCA Variants among Ashkenazi Jews Compared with Family History-Based Strategies.

Identifying carriers of pathogenic BRCA1/BRCA2 variants reduces cancer morbidity and mortality through surveillance and prevention. We analyzed the cost-effectiveness of BRCA1/BRCA2 population screening (PS) in Ashkenazi Jews (AJ), for whom carrier rate is 2.5%, compared with two existing strategies: cascade testing (CT) in carrier's relatives (≥25% carrier probability) and international family history (IFH)-based guidelines (>10% probability). We used a decision analytic-model to estimate quality-adjusted life-years (QALY) gained, and incremental cost-effectiveness ratio for PS vs. alternative strategies. Analysis was conducted from payer-perspective, based on actual costs. Per 1000 women, the model predicted 21.6 QALYs gained, a lifetime decrease of three breast cancer (BC) and four ovarian cancer (OC) cases for PS vs. CT, and 6.3 QALYs gained, a lifetime decrease of 1 BC and 1 OC cases comparing PS vs. IFH. PS was less costly compared with CT (−3097 USD/QALY), and more costly than IFH (+42,261 USD/QALY), yet still cost-effective, from a public health policy perspective. Our results are robust to sensitivity analysis; PS was the most effective strategy in all analyses. PS is highly cost-effective, and the most effective screening strategy for breast and ovarian cancer prevention. BRCA testing should be available to all AJ women, irrespective of family history.

The landscape of medical care consumption in Israel: a nationwide population cross-sectional study.

BACKGROUND: The Ecology of medical care was first published in 1961. The graphical square model showed that 75% of the population in the US and England experience a feeling of illness during a given month, 25% seek medical help and only one percent are hospitalized. In 2001, Green and colleagues found the same findings despite the many changes that occurred over the past decades. The frequency of illness, the desire for assistance and the frequency of seeking and getting medical assistance may differ in different populations due to cultural, economic, social, demographic background and local Health policy. This work describes the ecology of medical care consumption in Israel for the first time and examines the socio-demographic effects on consumption. METHODS: This is a Nationwide cross-sectional study. A telephone survey was conducted among a representative sample of the adult population (> 15 years) in Israel. Subjective morbidity rate in the preceding month, the rate of those considering medical assistance and those who got assistance were calculated. Correlation between socio-demographic variables and patterns of morbidity and medical care consumption was examined using a t-test and chi square for continuous quantitative and categorical variables. Logistic regression was used for multivariate analysis. RESULTS: A total of 1862 people participated; 49.5% reported having symptoms in the previous month, 45% considered seeking medical advice, 35.2% sought out medical assistance and only 1.5% were hospitalized. The vast majority chose to contact their family physician (58%) and the primary care setting provided their needs in 80% of the cases; Subjective morbidity and medical care consumption differed significantly between Israeli Jews and Arabs. Gaps in the availability of medical services were observed as residents of the periphery forewent medical services significantly more than others (OR = 1.42, p = 0.026). CONCLUSIONS: Subjective morbidity is less common in Israel than in other countries, but paradoxically consumption of medical services is higher. An Israeli who feels ill will usually consider receiving assistance and will indeed receive assistance in most cases. However, a greater tendency to forego medical services in the periphery indicates barriers and inequality in the provision of health services. Different cultural perceptions, lack of knowledge and low accessibility to medical services in the periphery probably contribute to the contrast shown between low consumption of medical services and high prevalence of chronic illness in Arab society. The prevailing preference for family medicine and its ability to deal with most requests for assistance suggest that strengthening family medicine in the periphery may reduce those barriers and inequalities.

The Dangers of Inappropriate Screening: Private Director Screening Programs.

BACKGROUND: Traditionally, the task of health promotion and early detection screening has been the purview of health maintenance organizations through the family physician. For some years, it has become popular for private health organizations to offer a concentrated day of comprehensive medical testing, which is promoted as a perk by many organizations to their employees. What do these programs offer? Are the tests that are offered evidence based? OBJECTIVES: To describe a concentrated day of comprehensive medical testing program in view of current evidence base medicine (EBM) recommendations. METHODS: We reviewed official internet sites of the most popular concentrated days of comprehensive medical testing and compared the tests offered to the recommendation of several Israeli and international guidelines. RESULTS: Many tests performed at director screening days do not follow EBM recommendations. Tests like mammography, colonoscopy, bone density, and prostate-specific antigen tests are often offered outside of the recommended age and risk groups and without pretest consultation. CONCLUSIONS: We recommend against routine general health examinations for healthy adults. The most important treatment is not screening and early detection but real prevention. We recommend turning these director screening days into real investments in future health by changing the focus from diagnosis to treatment through prevention. One-on-one conversations, explanations, and most importantly tools to encourage lifestyle changes, will really make a difference.

Similarities and differences between two well-performing healthcare systems: a comparison between the Israeli and the Danish healthcare systems.

BACKGROUND: Denmark and Israel both have highly rated and well-performing healthcare systems with marked differences in funding and organization of primary healthcare. Although better population health outcomes are seen in Israel, Denmark has a substantially higher healthcare expenditure. This has caused Danish policy makers to take an interest in Israeli community care organization. Consequently, we aim to provide a more detailed insight into differences between the two countries' healthcare organization and cost, as well as health outcomes. METHODS: A comparative analysis combining data from OECD, WHO, and official sources. World Health Organization (WHO) and the Organisation for Economic Co-operation and Development (OECD) statistics were used, and national official sources were procured from the two healthcare systems. Literature searches were performed in areas relevant to expenditure and outcome. Data were compared on health care expenditure and selected outcome measures. Expenditure was presented as purchasing power parity and as percentage of gross domestic product, both with and without adjustment for population age, and both including and excluding long-term care expenditure. RESULTS: Denmark's healthcare expenditure is higher than Israel's. However, corrected for age and long-term care the difference diminishes. Life expectancy is lower in Denmark than in Israel, and Israel has a significantly better outcome regarding cancer as well as a lower number of Years of Potential Life Lost. Israelis have a healthier lifestyle, in particular a much lower alcohol consumption. CONCLUSION: Attempting to correct for what we deemed to be the most important influencing factors, age and different inclusions of long-term care costs, the Israeli healthcare system still seems to be 25% less expensive, compared to the Danish one, and with better health outcomes. This is not necessarily a function of the Israeli healthcare system but may to a great extent be explained by cultural factors, mainly a much lower Israeli alcohol consumption.

Diagnostic yield of chromosomal microarray and trio whole exome sequencing in cryptogenic cerebral palsy.

OBJECTIVE: To determine the yield of genetic diagnoses using chromosomal microarray (CMA) and trio whole exome sequencing (WES), separately and combined, among patients with cryptogenic cerebral palsy (CP). METHODS: Trio WES of patients with prior CMA analysis for cryptogenic CP, defined as disabling, non-progressive motor symptoms beginning before the age of 3 years without known cause. RESULTS: Given both CMA analysis and trio WES, clinically significant genetic findings were identified for 58% of patients (26 of 45). Diagnoses were eight large CNVs detected by CMA and 18 point mutations detected by trio WES. None had more than one severe mutation. Approximately half of events (14 of 26) were de novo. Yield was significantly higher in patients with CP with comorbidities (69%, 22 of 32) than in those with pure motor CP (31%, 4 of 13; p=0.02). Among patients with genetic diagnoses, CNVs were more frequent than point mutations among patients with congenital anomalies (OR 7.8, 95% CI 1.2 to 52.4) or major dysmorphic features (OR 10.5, 95% CI 1.4 to 73.7). Clinically significant mutations were identified in 18 different genes: 14 with known involvement in CP-related disorders and 4 responsible for other neurodevelopmental conditions. Three possible new candidate genes for CP were ARGEF10, RTF1 and TAOK3. CONCLUSIONS: Cryptogenic CP is genetically highly heterogeneous. Genomic analysis has a high yield and is warranted in all these patients. Trio WES has higher yield than CMA, except in patients with congenital anomalies or major dysmorphic features, but these methods are complementary. Patients with negative results with one approach should also be tested by the other.

[THE CHALLENGE OF HEALTHY AGING WITH DIABETES: THE ISRAELI NATIONAL DIABETES COUNCIL GUIDELINES FOR TREATING OLDER PEOPLE].

INTRODUCTION: The prevalence of diabetes increases with age. Diabetes is a risk factor for many complications such as cardiovascular disease, kidney failure, stroke, neuropathy, and retinopathy. Data from recent years indicate that it is also a risk factor for cognitive impairment, dementia, functional disability and frailty. Diabetes is a disease that requires complex self-care capabilities; the individuals with diabetes are required to take medications on time, examine their feet, exercise, maintain a balance diet, preform daily glucose monitoring, cope with hypoglycemia and understand how differing life situations may effect glucose levels. All of these require intact cognitive and functional abilities. Thus, treatment plans should take into consideration the person's cognitive/functional state. Indeed, in the last several years many professional organizations such as the American Diabetes Association, the International Diabetes Federation, and the American Endocrinology Society have published guidelines for treating older people with diabetes. The Israeli National Diabetes Council, headed by Prof. Itamar Raz, in collaboration with other physician unions and other national councils, have recently authorized the Israeli guidelines for treating older people with diabetes. The Israeli guidelines include categorization of older adults with diabetes in relation to their functional status in order to reach determined treatment targets. According to the Israeli guidelines and in accordance with international guidelines, the treatment targets of the elderly person with diabetes should not be determined by the chronological age of the individuals but rather by their risk for functional deterioration. Older people with diabetes are categorized into three groups according to their risk for functional deterioration. Each category has unique glucose, blood pressure and lipid targets. The guidelines offer valid and reliable tools that, in addition to personal acquaintance with the patient, can help determine the level of risk of functional decline.

Academic activism on behalf of children during the COVID-19 pandemic in Israel; beyond public health advocacy.

Among the challenges presented by the SARS-CoV2 pandemic are those related to balancing societal priorities with averting threats to population health. In this exceptional context a group of Israeli physicians and public health scholars (multidisciplinary academic group on children and coronavirus [MACC]) coalesced, examining the role of children in viral transmission and assessing the necessity and consequences of restricted in-class education. Combining critical appraisal and analytical skills with public health experience, MACC advocated for safe and monitored school re-opening, stressing the importance of education as a determinant of health, continuously weighing this stance against evolving COVID-19-risk data. MACC's activities included offering research-based advice to government agencies including Ministries of Health, Finance, and Education. In a setting where government bodies were faced with providing practical solutions to both decreasing disease transmission and maintaining society's vital activities, and various advisors presented decision-makers with disparate views, MACC contributed epidemiological, clinical and health policy expertise to the debate regarding school closure as a pandemic control measure, and adaptations required for safe re-opening. In this paper, we describe the evolution, activities, policy inputs and media profile of MACC, and discuss the role of academics in advocacy and activism in the midst of an unprecedented public health crisis. A general lesson learned is that academics, based on the rigor of their scientific work and their perceived objectivity, can and should be mobilized to pursue and promote policies based on shared societal values as well as empiric data, even when considerable uncertainty exists about the appropriate course of action. Mechanisms should be in place to open channels to multidisciplinary academic groups and bring their input to bear on decision-making.

Population Screening for Inherited Predisposition to Breast and Ovarian Cancer.

The discovery of genes underlying inherited predisposition to breast and ovarian cancer has revolutionized the ability to identify women at high risk for these diseases before they become affected. Women who are carriers of deleterious variants in these genes can undertake surveillance and prevention measures that have been shown to reduce morbidity and mortality. However, under current strategies, the vast majority of women carriers remain undetected until they become affected. In this review, we show that universal testing, particularly of the BRCA1 and BRCA2 genes, fulfills classical disease screening criteria. This is especially true for BRCA1 and BRCA2 in Ashkenazi Jews but is translatable to all populations and may include additional genes. Utilizing genetic information for large-scale precision prevention requires a paradigmatic shift in health-care delivery. To address this need, we propose a direct-to-patient model, which is increasingly pertinent for fulfilling the promise of utilizing personal genomic information for disease prevention.

Correction: Population screening for BRCA1/BRCA2 founder mutations in Ashkenazi Jews: proactive recruitment compared with self-referral.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

How can we change medical students' perceptions of a career in family medicine? Marketing or substance?

Family Medicine (FM) is the care of unselected patients with undifferentiated problems in the settings where people need care in our communities. It is intellectually challenging, providing breadth and depth unparalleled in other areas of medical practice. In one survey only 19% of Israeli students reported being interested in FM. Students interested in FM had greater interest in bedside and direct long-term patient care. Students not planning FM residency training had preconceived notions that the discipline had lower academic opportunities and prestige. What can be done to increase student interest in careers in FM?This commentary includes perspectives of family practice leaders from several countries:The problem isn't the students it is the scope of practice and expectations both of which can and should change if FM in Israel wants to stay viable. The scope of FM should be broadened to include more procedures and new technologies. This may also increase the earning potential of Family Practitioners (FPs). Payment policy and credentialing barriers should be change to expand scope of practice and allow FPs to practice at the full extent of their training.FM should offer clear professional horizon with potential for many sub-specialties and areas of focus. The Israeli HMOs, the Ministry of Health and the Israeli Association of FM should invest heavily in building academic departments of FM and promoting research. This will enhance the image of FM in the eyes of the students, the profession and the public.The clinical work environment should be improved by reducing bureaucratic assignments, such as issuing certifications, dealing with quality measurements and renewing chronic prescriptions. Much of this work can be done by nurse practitioners (NPs) working as part of an FP-led team. These NPs can also take care of patients with limited complaints to make the work of the FP more challenging and attractive.Training must include opportunities to develop longitudinal relationships with patients and families across problems and over time. It is these relationships that add value to the process of care, improve patient outcomes and provide meaning to sustain clinical careers that meet the needs of patients and communities.

Familial communication and cascade testing among relatives of BRCA population screening participants.

PURPOSE: Population BRCA1/BRCA2 screening identifies carriers irrespective of family history, yet this information is actionable for relatives. We examined familial communication rates and cascade testing in the screening setting and assessed sociodemographic and psychosocial predictors. METHODS: Participants in a BRCA1/BRCA2 screening study of healthy Ashkenazi Jews self-administered a family communication questionnaire. Intent to communicate was determined before genetic status was known, along with result communication (carriers and noncarriers) 6 months and 2 years after enrollment. Carriers underwent in-depth interviews and provided cascade testing information. RESULTS: In total, 88% (524/595) of questionnaire responders and 97% (30/32) of carriers informed at least one relative. In multivariate analysis, family history (P = 0.005) and greater Satisfaction With Health Decision scores (P < 0.001) predicted communication of results. Among carriers' adult first- and second-degree relatives, 71 (48%) had cascade testing, more commonly performed in first- (58%) than in second-degree relatives (26%, P = 0.0002), and in females (56%) vs. males (36%, P = 0.02). At least 11% remained uninformed. CONCLUSION: Familial communication rates and characteristics in a screening setting parallel those reported by Cancer Genetics clinics. Universal screening circumvents dependence on familial disclosure. However, our finding that satisfaction-a potentially modifiable factor-predicts communication, raises the hypothesis that improving the testing experience could facilitate familial communication.

Evidence-based HMO care for prostate specific antigen testing.

BACKGROUND: There is pressure in the U.S. system to move away from fee-for-service models to a more pre-paid system, which may result in decreased costs, but the impact on evidence-based care is unclear. We examined a large pre-paid Health Maintenance Organizations (HMO) in Israel to see if evidence-based guidelines are followed for prostate specific antigen (PSA) testing. METHODS: A retrospective cohort of ambulatory visits from 2002 to 2011 of patients age >75 receiving care from Clalit Health Services was conducted. Historically reported U.S. cohorts were used for comparison. The main measure was the percent of patients who had at least one PSA after age 75. RESULTS: In each of the 10 years of follow-up, 22% of the yearly Israeli cohort, with no known malignancy or benign prostatic hyperplasia, had at least one PSA, while for the total 10 years, 30% of the men had at least one PSA. These rates are considerably lower than previously reported U.S. rates. CONCLUSIONS: In a pre-paid system in which physicians have no incentive to order tests, they appear to order PSA tests at a lower rate than has been observed in the U.S. system. Additional quality of measures should continue to be examined as the U.S. shifts away from a fee-for-service model. Copyright © 2016 John Wiley & Sons, Ltd.

Are They Complying? Physicians' Knowledge, Attitudes, and Readiness to Change Regarding Low Back Pain Treatment Guideline Adherence.

STUDY DESIGN: Cross-sectional survey of 145 primary care practitioners (PCPs). OBJECTIVE: To examine low back pain (LBP) guideline knowledge, readiness to implement (RTI) these guidelines, and LBP attitudes and beliefs among Israeli PCPs and determine whether physician age, guideline familiarity, and medical specialty affect these variables. SUMMARY OF BACKGROUND DATA: LBP is a common condition managed primarily by PCPs. Little is known, however, about physician's LBP knowledge, attitudes, and beliefs and how these factors (knowledge, A&B) influence their practice behavior. Knowledge, attitudes, and beliefs of PCPs have been shown to influence the course of their patients' LBP, and guidelines were devised in an attempt to improve the effectiveness and quality of LBP care. Research worldwide and in Israel has shown that LBP guideline implementation is not yet optimal. METHODS: Participants completed a questionnaire. Variables were measured using a translated, validated version of the Health Care Providers' Pain and Impairment Relationship Scale; demographic and professional characteristics were analyzed for correlation with the outcome variables. RESULTS: The likelihood of PCPs having nonguideline-consistent attitudes and beliefs (A&B) was greater among those older than 50 years (P < 0.05). Family medicine specialists (family practitioners [FPs]) were more likely to have a high level of guideline knowledge as compared to nonfamily medicine specialists (general practitioners (83.8 vs. 61.9, respectively; P < 0.001). Differences between FPs and general practitioners were also observed for the mean Health Care Providers' Pain and Impairment Relationship Scale score (34.6 vs. 41.1, respectively, P = 0.00), indicating a higher consistency of attitudes and beliefs with guidelines among FPs. No significant association was found between PCPs' knowledge level and RTI the guidelines. CONCLUSION: The present study showed that PCPs, especially FPs, had high levels of LBP guideline knowledge, although RTI was limited. The need for greater exposure to and understanding of the importance of implementation of LBP guidelines is essential for future guideline adherence. LEVEL OF EVIDENCE: 3.

Population screening for BRCA1/BRCA2 founder mutations in Ashkenazi Jews: proactive recruitment compared with self-referral.

PURPOSE: Population screening of three common BRCA1/BRCA2 mutations in Ashkenazi Jews (AJ) apparently fulfills screening criteria. We compared streamlined BRCA screening via self-referral with proactive recruitment in medical settings. METHODS: Unaffected AJ, age ≥25 years without known familial mutations, were either self-referred or recruiter-enrolled. Before testing, participants received written information and self-reported family history (FH). After testing, both non-carriers with significant FH and carriers received in-person genetic counseling. Psychosocial questionnaires were self-administered 1 week and 6 months after enrollment. RESULTS: Of 1,771 participants, 58% were recruiter-enrolled and 42% were self-referred. Screening uptake was 67%. Recruited enrollees were older (mean age 54 vs. 48, P < 0.001) and had less suggestive FH (23 vs. 33%, P < 0.001). Of 32 (1.8%) carriers identified, 40% had no significant FH. Post-test counseling compliance was 100% for carriers and 89% for non-carrier women with FH. All groups expressed high satisfaction (>90%). At 6 months, carriers had significantly increased distress and anxiety, greater knowledge, and similar satisfaction; 90% of participants would recommend general AJ BRCA screening. CONCLUSION: Streamlined BRCA screening results in high uptake, very high satisfaction, and no excess psychosocial harm. Proactive recruitment captured older women less selected for FH. Further research is necessary to target younger women and assess other populations.Genet Med advance online publication 08 December 2016.

Population screening for BRCA1/BRCA2 mutations: lessons from qualitative analysis of the screening experience.

PURPOSE: Population screening for BRCA1/BRCA2. mutations is being considered for Ashkenazi Jews (AJ) because 2.5% carry recurrent deleterious mutations and effective cancer prevention exists. This study aimed to provide a qualitative focus on perspectives of individuals, particularly carriers, who were tested through a screening trial. In this trial, the pretest process included only written information. METHODS: Interviews were performed with 26 carriers and 10 noncarriers who participated in a BRCA population screening trial for AJ. RESULTS: Attitudes toward screening were generally positive. The main motivator for testing was knowledge of BRCA status to enable cancer risk reduction. Knowledge of carrier status, although challenging, was thus viewed as health-empowering. The screening paradigm was sensed as increasing awareness and as overcoming access, referral, and familial barriers. Streamlining the pretest process was positively perceived as offering gradual, stepwise knowledge commensurate with test results. Participants were concerned that health systems provide the necessary conceptual and infrastructural framework and that individual autonomy be maintained. CONCLUSIONS: BRCA screening in AJ is viewed favorably, even by carriers. Stepwise acquisition of knowledge based on test results was viewed as most relevant to the screening context. Screening program development should account for safeguarding autonomy and providing requisite post-test services.Genet Med advance online publication 01 December 2016.

Physician-facilitated designation of proxy decision-makers: family physician perceptions.

BACKGROUND: Among the challenges encountered during the care of patients at the end-of-life (EOL), eliciting preferences of patients with whom there is no ability to communicate is common and stressful for all those concerned and charged with patient care. Legal facilities available include patient delegation of proxy decision-makers (PDM) prior to communication incapacity. We sought to estimate family physician awareness and attitude with regard to these aspects of patient care. METHODS: A telephone survey of family physicians in the Jerusalem, Israel, district using a standard questionnaire. RESULTS: 74 family physicians responded to the survey. The response rate was 42 % and the cooperation rate was 66 %. Most of the respondents, (64 %), reported knowing that the PDM delegation facility exists, though only 24 % claimed to have suggested to their patients that they consider this option. Approximately three-quarters, (78 %), treat patients with whom they discussed other aspects of severe disease, disability or EOL. None of the physicians working predominantly with religiously observant groups reported suggesting PDM delegation. CONCLUSIONS: There is an apparent gap between family physician knowledge and their performance to empower the persistence of patient autonomy, should communication ability cease. System-wide interventions to increase EOL communication skills, starting at medical school and henceforth, are necessary in order to promote better EOL care and meaningful resource use.

Overcrowding in Psychiatric Wards is Associated With Increased Risk of Adverse Incidents.

OBJECTIVE: To study the association between bed occupancy in psychiatric wards and rate of adverse incidents (AIs) including aggressive behavior and falls. METHODS: This is a retrospective study analyzing bed occupancy and AIs' data in 4 closed wards in a state psychiatric hospital in Israel over a 20-month period. Ward-level daily records were extracted from the hospital's electronic admission-discharge and AI registries, creating a log of 609 days for each of the 4 wards. Relationships between gross and net bed occupancy and AIs rate were calculated, in general and for each ward and type of incidents. RESULTS: Average gross occupancy was 106±14.8% and net occupancy was 96.4±15.6%. Gross occupancy >100% was recorded in 51% of days. Net occupancy was higher on days with at least 1 incident than on no-incident days (98.6±14.8% vs. 95.7±15.7%, P<0.0001). AIs occurred in 18.6% of days in the lowest occupancy quadrant (up to 85% occupancy), compared with 26.7% of days in the highest occupancy quadrant (106% and above). Moreover, aggressive behavior-type incidents were significantly lower in the lowest occupancy quadrant days compared with the highest occupancy quadrant (8.3% vs. 14.1%, P<0.01). Evidence of a dose-response effect of bed occupancy on AIs rate was found. CONCLUSIONS: Overoccupancy is prevalent in psychiatric wards and is associated with an increased rate of aggressive AIs and falls. Policy makers should be convinced about the necessity to reduce overcrowding in psychiatric wards and to improve safety of inpatient facilities.

TODRA, a lncRNA at the RAD51 Locus, Is Oppositely Regulated to RAD51, and Enhances RAD51-Dependent DSB (Double Strand Break) Repair.

Expression of RAD51, a crucial player in homologous recombination (HR) and DNA double-strand break (DSB) repair, is dysregulated in human tumors, and can contribute to genomic instability and tumor progression. To further understand RAD51 regulation we functionally characterized a long non-coding (lnc) RNA, dubbed TODRA (Transcribed in the Opposite Direction of RAD51), transcribed 69bp upstream to RAD51, in the opposite direction. We demonstrate that TODRA is an expressed transcript and that the RAD51 promoter region is bidirectional, supporting TODRA expression (7-fold higher than RAD51 in this assay, p = 0.003). TODRA overexpression in HeLa cells induced expression of TPIP, a member of the TPTE family which includes PTEN. Similar to PTEN, we found that TPIP co-activates E2F1 induction of RAD51. Analysis of E2F1's effect on the bidirectional promoter showed that E2F1 binding to the same site that promotes RAD51 expression, results in downregulation of TODRA. Moreover, TODRA overexpression induces HR in a RAD51-dependent DSB repair assay, and increases formation of DNA damage-induced RAD51-positive foci. Importantly, gene expression in breast tumors supports our finding that E2F1 oppositely regulates RAD51 and TODRA: increased RAD51 expression, which is associated with an aggressive tumor phenotype (e.g. negative correlation with positive ER (r = -0.22, p = 0.02) and positive PR status (r = -0.27, p<0.001); positive correlation with ki67 status (r = 0.36, p = 0.005) and HER2 amplification (r = 0.41, p = 0.001)), correlates as expected with lower TODRA and higher E2F1 expression. However, although E2F1 induction resulted in TPIP downregulation in cell lines, we find that TPIP expression in tumors is not reduced despite higher E2F1 expression, perhaps contributing to increased RAD51 expression. Our results identify TPIP as a novel E2F1 co-activator, suggest a similar role for other TPTEs, and indicate that the TODRA lncRNA affects RAD51 dysregulation and RAD51-dependent DSB repair in malignancy. Importantly, gene expression in breast tumors supports our finding that E2F1 oppositely regulates RAD51 and TODRA: increased RAD51 expression, which is associated with an aggressive tumor phenotype (e.g. negative correlation with positive ER (r = -0.22, p = 0.02) and positive PR status (r = -0.27, p<0.001); positive correlation with ki67 status (r = 0.36, p = 0.005) and HER2 amplification (r = 0.41, p = 0.001)), correlates as expected with lower TODRA and higher E2F1 expression. However, although E2F1 induction resulted in TPIP downregulation in cell lines, we find that TPIP expression in tumors is not reduced despite higher E2F1 expression, perhaps contributing to increased RAD51 expression. Our results identify TPIP as a novel E2F1 co-activator, suggest a similar role for other TPTEs, and indicate that the TODRA lncRNA affects RAD51 dysregulation and RAD51-dependent DSB repair in malignancy.

[ISRAELI GUIDELINES FOR THE TREATMENT OF HYPERLIPIDEMIA - 2014 UPDATE].

Atherosclerosis is one of the leading causes of morbidity and mortality in the world, including in Israel. This document updates the clinical recommendations of the Israeli medical societies (The Society for Research, Prevention and Treatment of Atherosclerosis, The Israel Heart Society, The Israel Association of Family Physicians, The Israel Society of Internal Medicine) from 2012. The need for an update stems from new studies and from the 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults. These recommendations take into account the guidelines of leading medical organizations in the world, as well as the specific circumstances and needs of the medical system in Israel.