In the Ashkenazi Jewish (AJ) population of Israel, 11% of breast cancer and 40% of ovarian cancer are due to three inherited founder mutations in the cancer predisposition genes BRCA1 and BRCA2 . For ...carriers of these mutations, risk-reducing salpingo-oophorectomy significantly reduces morbidity and mortality. Population screening for these mutations among AJ women may be justifiable if accurate estimates of cancer risk for mutation carriers can be obtained. We therefore undertook to determine risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained irrespective of personal or family history of cancer. Families harboring mutations in BRCA1 or BRCA2 were ascertained by identifying mutation carriers among healthy AJ males recruited from health screening centers and outpatient clinics. Female relatives of the carriers were then enrolled and genotyped. Among the female relatives with BRCA1 or BRCA2 mutations, cumulative risk of developing either breast or ovarian cancer by age 60 and 80, respectively, were 0.60 (± 0.07) and 0.83 (± 0.07) for BRCA1 carriers and 0.33 (± 0.09) and 0.76 (± 0.13) for BRCA2 carriers. Risks were higher in recent vs. earlier birth cohorts ( P = 0.006). High cancer risks in BRCA1 or BRCA2 mutation carriers identified through healthy males provide an evidence base for initiating a general screening program in the AJ population. General screening would identify many carriers who are not evaluated by genetic testing based on family history criteria. Such a program could serve as a model to investigate implementation and outcomes of population screening for genetic predisposition to cancer in other populations.
Significance Inherited mutations in the tumor suppressor genes BRCA1 and BRCA2 predispose to very high risks of breast and ovarian cancer. For carriers of these mutations, risk-reducing surgery significantly reduces morbidity and mortality. General population screening for BRCA1 and BRCA2 mutations in young adult women could be feasible if accurate estimates of cancer risk for mutation carriers could be obtained. We determined that risks of breast and ovarian cancer for BRCA1 and BRCA2 mutation carriers ascertained from the general population are as high as for mutation carriers ascertained through personal or family history of cancer. General screening of BRCA1 and BRCA2 would identify many carriers who are currently not evaluated and could serve as a model for population screening for genetic predisposition to cancer.
Abstract
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.
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.
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.
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.
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.
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.
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.
Aim: Severe tricuspid insufficiency (TI) after permanent pacemaker implantation (PPI) has been described in small series of patients, though its incidence is not known.
Methods: We retrospectively ...analyzed the data of 545 patients who underwent PPI and had Doppler echocardiograms performed before and after the procedure. We excluded 135 patients who had ≥moderate TI on the 1st Doppler echocardiogram.
Results: Group 1 included 75 patients (18.3%) who had a >2 grades worsening of TI, and group 2 included 335 patients (82%) with <2 grade increase in TI after PPI. Patients in group 1 were 77 ± 7 years of age, versus 72 ± 10 years in group 2 (P < 0.001). There was no difference in left ventricular size and function. The TI gradient before PPI was higher in group 2 (25 ± 13 mmHg versus 19 ± 12 mmHg P < 0.001), though within the normal range in both groups. The mitral E/A ratio was 0.98 in group 1 versus 1.42 in group 2 (P < 0.001). The systolic TI gradient after implantation was 42 ± 12 mmHg in group 1, versus 33 ± 8 mmHg in group 2 (P < 0.001).
Conclusion: Worsening of TI after PPI was not rare and was observed more often in older patients, with abnormal LV relaxation and who developed pulmonary hypertension after the procedure.
Abstract
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.
Severe jaundice leading to kernicterus or death in the newborn is the most devastating consequence of glucose-6-phosphate dehydrogenase (EC 1.1.1.49; G-6-PD) deficiency. We asked whether the TA ...repeat promoter polymorphism in the gene for uridinediphosphoglucuronate glucuronosyltransferase 1 (EC 2.4.1.17; UDPGT1), associated with benign jaundice in adults (Gilbert syndrome), increases the incidence of neonatal hyperbilirubinemia in G-6-PD deficiency. DNA from term neonates was analyzed for UDPGT1 polymorphism (normal homozygotes, heterozygotes, variant homozygotes), and for G-6-PD Mediterranean deficiency. The variant UDPGT1 promoter allele frequency was similar in G-6-PD-deficient and normal neonates. Thirty (22.9%) G-6-PD deficient neonates developed serum total bilirubin ≥ 257 μ mol/liter, vs. 22 (9.2%) normals (P = 0.0005). Of those with the normal homozygous UDPGT1 genotype, the incidence of hyperbilirubinemia was similar in G-6-PD-deficients and controls (9.7% and 9.9%). In contrast, in the G-6-PD-deficient neonates, those with the heterozygous or homozygous variant UDPGT1 genotype had a higher incidence of hyperbilirubinemia than corresponding controls (heterozygotes: 31.6% vs. 6.7%, P < 0.0001; variant homozygotes: 50% vs. 14.7%, P = 0.02). Among G-6-PD-deficient infants the incidence of hyperbilirubinemia was greater in those with the heterozygous (31.6%, P = 0.006) or variant homozygous (50%, P = 0.003) UDPGT1 genotype than in normal homozygotes. In contrast, among those normal for G-6-PD, the UDPGT1 polymorphism had no significant effect (heterozygotes: 6.7%; variant homozygotes: 14.7%). Thus, neither G-6-PD deficiency nor the variant UDPGT1 promoter, alone, increased the incidence of hyperbilirubinemia, but both in combination did. This gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease.
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.
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