Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma.

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

Lymphoma in Sub-Saharan Africa: a scoping review of the epidemiology, treatment challenges, and patient pathways.

PURPOSE: Improving cancer outcomes in Sub-Saharan Africa (SSA) requires effective implementation of evidence-based strategies. This scoping review maps the evidence on lymphoma epidemiology, treatment challenges, and patient pathways in SSA from 2011 to 2022. METHODS: A comprehensive three-step search was conducted without language restrictions. RESULTS: Eighty-four publications were included, 83% published after 2017. Southern and Eastern Africa led in output. Most studies were chart reviews (47.6%) and cohort studies (25%). NHL accounted for over 80% of cases, with an age-standardized rate (ASR) reaching 10.9/100,000, while HL had an ASR of 0.4-2.3/100,000. Compared to studies in Europe and US, SSA studies reported lower incidence rates, higher HIV comorbidity, and younger median ages. Diagnosis is often delayed, incomplete and lacks sub-classification with HIV and tuberculosis further complicating care. One-year survival rates are around 50% for NHL and over 75% for HL. Treatment is well-tolerated with an acceptable treatment-related mortality rate. However, outcomes are affected by diagnostic delays, late presentations, and treatment abandonment. Non-clinical aspects of care such as financial constraints negatively impact patient pathways. CONCLUSION: Addressing diagnostic delays, misdiagnosis, and treatment abandonment is crucial. Strengthening care access, diagnostics, and integrating innovative strategies including a multidisciplinary approach and re-designing efficient clinical diagnostic pathways are vital.

Association of common maternal infections with birth outcomes: a multinational cohort study.

PURPOSE: It is unclear whether common maternal infections during pregnancy are risk factors for adverse birth outcomes. We assessed the association between self-reported infections during pregnancy with preterm birth and small-for-gestational-age (SGA) in an international cohort consortium. METHODS: Data on 120,507 pregnant women were obtained from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA. Self-reported common infections during pregnancy included influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections, cystitis, urinary tract infection, and the symptoms fever and diarrhoea. Birth outcomes included preterm birth, low birth weight and SGA. Associations between maternal infections and birth outcomes were first assessed using Poisson regression in each cohort and then pooled using random-effect meta-analysis. Risk ratios (RR) and 95% confidence intervals (CI) were calculated, adjusted for potential confounders. RESULTS: Vaginal infections (pooled RR, 1.10; 95% CI, 1.02-1.20) and urinary tract infections (pooled RR, 1.17; 95% CI, 1.09-1.26) during pregnancy were associated with higher risk of preterm birth. Similar associations with low birth weight were also observed for these two infections. Fever during pregnancy was associated with higher risk of SGA (pooled RR, 1.07; 95% CI, 1.02-1.12). No other significant associations were observed between maternal infections/symptoms and birth outcomes. CONCLUSION: Vaginal infections and urinary infections during pregnancy were associated with a small increased risk of preterm birth and low birth weight, whereas fever was associated with SGA. These findings require confirmation in future studies with laboratory-confirmed infection diagnosis.

Nationwide Evaluation of Quality of Care Indicators for Individuals with Severe Mental Illness and Diabetes Mellitus, Following Israel's Mental Health Reform.

Diabetes Mellitus (DM) is more common among individuals with severe mental illness (SMI). We aimed to assess quality-of-care-indicators in individuals with SMI following the 2015 Israel's Mental-Health-reform. We analyzed yearly changes in 2015-2019 of quality-of-care-measures and intermediate-DM-outcomes, with adjustment for gender, age-group, and socioeconomic status (SES) and compared individuals with SMI to the general adult population. Adults with SMI had higher prevalences of DM (odds ratio (OR) = 1.64; 95% confidence intervals (CI): 1.61-1.67) and obesity (OR = 2.11; 95% CI: 2.08-2.13), compared to the general population. DM prevalence, DM control, and obesity rates increased over the years in this population. In 2019, HbA1c testing was marginally lower (OR = 0.88; 95% CI: 0.83-0.94) and uncontrolled DM (HbA1c > 9%) slightly more common among patients with SMI (OR = 1.22; 95% CI: 1.14-1.30), control worsened by decreasing SES. After adjustment, uncontrolled DM (adj. OR = 1.02; 95% CI: 0.96-1.09) was not associated with SMI. Cardio-metabolic morbidity among patients with SMI may be related to high prevalences of obesity and DM rather than poor DM control. Effective screening for metabolic diseases in this population and social reforms are required.

Physical activity and the risk of non-Hodgkin lymphoma subtypes: A pooled analysis.

Non-Hodgkin lymphoma (NHL) is composed of a heterogeneous collection of subtypes with considerable differences in genetics, biology and aetiology. Studies to date on physical activity and NHL risk have not had sufficient sample size to evaluate whether associations differ by subtype. We pooled data from nine case-control studies to examine the association between moderate-to-vigorous intensity physical activity (MVPA) and risk of NHL overall and by subtype (diffuse large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukaemia/small lymphocytic lymphoma, marginal zone lymphoma and mature T-cell lymphoma). A total of 5653 cases and 9115 controls were included in the pooled analysis. Physical activity was harmonised across nine studies and modelled as study-specific tertiles. Multinomial logistic regression was used to estimate the association between physical activity and NHL, adjusting for confounders. The overall odds of NHL was 13% lower among participants in the most active tertile of MVPA compared to the least active tertile (adjusted odds ratio = 0.87, 95% CI = 0.80, 0.95). Similar decreases were observed across NHL subtypes. In summary, in this pooled analysis of case-control studies, physical activity was associated with a modest risk reduction for each NHL subtype examined and with overall NHL.

Catheter-directed thrombolysis compared with systemic thrombolysis and anticoagulation in patients with intermediate- or high-risk pulmonary embolism: systematic review and network meta-analysis.

BACKGROUND: Therapeutic options for intermediate- or high-risk pulmonary embolism (PE) include anticoagulation, systemic thrombolysis and catheter-directed thrombolysis (CDT); however, the role of CDT remains controversial. We sought to compare the efficacy and safety of CDT with other therapeutic options using network meta-analysis. METHODS: We searched PubMed (MEDLINE), Embase, ClinicalTrials.gov and Cochrane Library from inception to Oct. 18, 2022. We included randomized controlled trials and observational studies that compared therapeutic options for PE, including anticoagulation, systemic thrombolysis and CDT among patients with intermediate- or high-risk PE. The efficacy outcome was in-hospital death. Safety outcomes included major bleeding, intracerebral hemorrhage and minor bleeding. RESULTS: We included data from 44 studies, representing 20 006 patients. Compared with systemic thrombolysis, CDT was associated with a decreased risk of death (odd ratio [OR] 0.43, 95% confidence interval [CI] 0.32-0.57), intracerebral hemorrhage (OR 0.44, 95% CI 0.29-0.64), major bleeding (OR 0.61, 95% CI 0.53-0.70) and blood transfusion (OR 0.46, 95% CI 0.28-0.77). However, no difference in minor bleeding was observed between the 2 therapeutic options (OR 1.11, 95% CI 0.66-1.87). Compared with anticoagulation, CDT was also associated with decreased risk of death (OR 0.36, 95% CI 0.25-0.52), with no increased risk of intracerebral hemorrhage (OR 1.33, 95% CI 0.63-2.79) or major bleeding (OR 1.24, 95% CI 0.88-1.75). INTERPRETATION: With moderate certainty of evidence, the risk of death and major bleeding complications was lower with CDT than with systemic thrombolysis. Compared with anticoagulation, CDT was associated with a probable lower risk of death and a similar risk of intracerebral hemorrhage, with moderate certainty of evidence. Although these findings are largely based on observational data, CDT may be considered as a first-line therapy in patients with intermediate- or high-risk PE. PROTOCOL REGISTRATION: PROSPERO - CRD42020182163.

The rate of occupational noise-induced hearing loss among male workers in Israel and implication on hearing surveillance frequency.

OBJECTIVES: To investigate the annual rate of NIHL in Israel, a modern economy with relatively low industrial hazardous noise exposure. To review international protocols of hearing surveillance. To recommend an effective, efficient, hearing screening frequency protocol. METHODS: A historical cohort study was conducted. Audiometric surveillance data from the Jerusalem occupational medicine registry of male employees in various industries from 2006 to 2017 were used. Mean individual annual threshold shifts simulating 1-8 checkup interval years were calculated. Joinpoint regression analysis was used to assess the interval in which the slope of the calculated ATS variability moderates significantly. RESULTS: A total of 263 noise-exposed workers and 93 workers in the comparison group produced 1913 audiograms for analysis. Among the noise-exposed workers, using the 1-4 kHz average, threshold shifts stabilized from 3 years onwards at around 1 dB per year in all age groups and 0.83 dB in the stratum younger than 50 years. No enhanced decline was detected in the first years of exposure. CONCLUSION: Although most countries conduct annual hearing surveillance, hearing threshold shifts of noise-exposed workers become more accurate and show less variability when calculated at 3-year checkup intervals onwards than shorter intervals. Since margins of errors of the test method are much larger than the annual shift found, screening schedule that enables each subsequent test to identify a real deterioration in hearing is necessary. Triennial audiometric screening would be a better surveillance frequency for noise-exposed workers younger than 50 years of age in the category of 85-95 dBLAeq,8 h without other known risk factors.

Israeli COVID lockdowns mildly reduced overall use of preventive health services, but exacerbated some disparities.

BACKGROUND: During 2020, Israel experienced two COVID-19-related lockdowns that impacted the provision of primary and secondary preventive care. METHODS: We examined the month-by-month performance of selected preventive care services using data from Israel's national Quality Indicators in Community Healthcare program. Process of care measures included hemoglobin A1c (HbA1c) testing, cholesterol testing, colon cancer screening and mammography. Intermediate outcome measures included low-density lipoprotein control and HbA1c control. Measures were stratified by sex and by area-level socioeconomic position (SEP). Diabetes and mammography are presented in this abstract due to space limitations. RESULTS: Annual HbA1c testing among persons with diabetes decreased from 90.9% in 2019 to 88.0% in 2020. Performance of HbA1c tests during lockdown months was as low as half the usual amount. There were compensatory increases in testing during post-lockdown months that did not quite make up for the missed tests. In 2019, 9.0% of Israelis with diabetes had poor glycemic control (HbA1c ≥ 9.0); in 2020, it was 8.8%. In total, 4.5% fewer mammograms were performed in 2020 compared with 2019. Women in the lowest SEP level performed 10.4% fewer mammograms in 2020 than in 2019, while women in the highest SEP level performed 3.1% more mammograms. CONCLUSIONS: Prolonged COVID lockdowns in 2020 were associated with marked decreases in the performance of preventive health services during those months. Compensatory spikes following the end of lockdowns partly, but did not completely, make up for the missed care. COVID lockdowns may have exacerbated socioeconomic disparities in some preventive health services.

A Comprehensive Assessment of Qualitative and Quantitative Prodromal Parkinsonian Features in Carriers of Gaucher Disease-Identifying Those at the Greatest Risk.

Carriers of GBA1 gene variants have a significant risk of developing Parkinson's disease (PD). A cohort study of GBA carriers between 40−75 years of age was initiated to study the presence of prodromal PD features. Participants underwent non-invasive tests to assess different domains of PD. Ninety-eight unrelated GBA carriers were enrolled (43 males) at a median age (range) of 51 (40−74) years; 71 carried the N370S variant (c.1226A > G) and 25 had a positive family history of PD. The Montreal Cognitive Assessment (MoCA) was the most frequently abnormal (23.7%, 95% CI 15.7−33.4%), followed by the ultrasound hyperechogenicity (22%, 95% CI 14−32%), Unified Parkinson's Disease Rating Scale part III (UPDRS-III) (17.2%, 95% CI 10.2−26.4%), smell assessment (12.4%, 95% CI 6.6−20.6%) and abnormalities in sleep questionnaires (11%, 95% CI 5.7−19.4%). Significant correlations were found between tests from different domains. To define the risk for PD, we assessed the bottom 10th percentile of each prodromal test, defining this level as "abnormal". Then we calculated the percentage of "abnormal" tests for each subject; the median (range) was 4.55 (0−43.5%). Twenty-two subjects had more than 15% "abnormal" tests. The limitations of the study included ascertainment bias of individuals with GBA-related PD in relatives, some incomplete data due to technical issues, and a lack of well-characterized normal value ranges in some tests. We plan to enroll additional participants and conduct longitudinal follow-up assessments to build a model for identifying individuals at risk for PD and investigate interventions aiming to delay the onset or perhaps to prevent full-blown PD.

Holocaust Experience and Mortality Patterns: 4-Decade Follow-up in a Population-Based Cohort.

Research on mortality associated with exposure to the Holocaust is relevant for a better understanding of the effects of genocides on survivors. To our knowledge, previous studies have not investigated the long-term cause-specific mortality of Holocaust survivors. We compared mortality rates among Israelis born in European countries controlled by the Nazis during World War II with those among Israelis of European descent who did not have this exposure. Records of 22,671 people (45% women; 5,042 survivors) from the population-based Jerusalem Perinatal Study (1964-1976) were linked to the Israeli Population Registry, which was updated through 2016. Cox models were used for analysis, with 2-sided tests of statistical significance. Risk of all-cause mortality was higher among exposed women (hazard ratio (HR) = 1.15, 95% confidence interval (CI): 1.05, 1.27) than in unexposed women. No association was found between Holocaust exposure and male all-cause mortality. In both sexes, survivors had higher cancer-specific mortality (HR = 1.17 (95% CI: 1.01, 1.35) in women and HR = 1.14 (95% CI: 1.01, 1.28) in men). Exposed men also had excess mortality due to coronary heart disease (HR = 1.39, 95% CI: 1.09, 1.77) and lower mortality from other known causes combined (HR = 0.86, 95% CI: 0.75, 0.99). In summary, experiencing the Holocaust was associated with excess all-cause and cancer-specific mortality in women and cancer- and coronary heart disease-specific mortality in men.

Socioeconomic Disparity Trends in Cancer Screening Among Women After Introduction of National Quality Indicators.

PURPOSE: Primary care physicians have an important role in encouraging adequate cancer screening. Disparities in cancer screening by socioeconomic status (SES) may affect presentation stage and cancer survival. This study aimed to examine whether breast, colorectal, and cervical cancer screening rates in women differed by SES and age, and whether screening rates and SES disparities changed after introduction of a primary care-based national quality indicator program. METHODS: This repeated cross-sectional study spanning 2002-2017 included all female Israeli residents in age ranges appropriate for each cancer screening assessed. SES was measured both as an individual-level variable based on exemption from copayments and as an area-level variable using census data. RESULTS: In 2017, the most recent year in the study period, screening rates among 1,529,233 women were highest for breast cancer (70.5%), followed by colorectal cancer (64.3%) and cervical cancer (49.6%). Women in the highest area-level SES were more likely to undergo cervical cancer screening compared with those in the lowest (odds ratio = 3.56; 99.9% CI, 3.47-3.65). Temporal trends showed that after introduction of quality indicators for breast and colorectal cancer screening in 2004 and 2005, respectively, rates of screening for these cancers increased, with greater reductions in disparities for the former. The quality indicator for cervical cancer screening was introduced in 2015, and no substantial changes have occurred yet for this screening. CONCLUSIONS: We found increased uptake and reduced socioeconomic disparities after introduction of cancer screening indicators. Recent introduction of a cervical cancer screening indicator may increase participation and reduce disparities, as has occurred for breast and colorectal cancer screening. These findings related to Israel's quality indicators program highlight the importance of primary care clinicians in increasing cancer screening rates to improve outcomes and reduce disparities.

Associations between density and quality of health promotion programmes and built environment features across Jerusalem.

BACKGROUND: Health promotion programmes (HPPs) have the potential to influence individual health, depending on their quality and characteristics. Little is known about how they interact with built environment features and neighbourhood demographics in cities with substantial health disparities. METHODS: Using the European Quality Instrument for Health Promotion (EQUIHP), we assessed the quality of HPPs, operating between 2016 and 2017, among adults aged 18-75 in Jerusalem. Areas were characterized by ethnicity and area socioeconomic level. Health information (body mass index, physical activity level) was obtained from the city profile survey. Geospatial information on the location and length of walking paths and bicycle lanes was obtained. Spearman correlations were used to assess associations among variables. RESULTS: Ninety-three HPPs operating in 349 locations in Jerusalem were identified. Programmes were unevenly distributed across urban planning areas (UPAs), with the highest density observed in the southwest, areas populated mainly by non-orthodox Jewish residents. However, the best performing HPPs based on EQUIHP score were in the north and east UPAs, inhabited primarily by Arab residents. At a neighbourhood level, characteristics of the built environment positively correlated with higher total EQUIHP scores: the ratio between walking lane length to the neighbourhood's population size (r = 0.413, P < 0.001) and length of bicycle lane per population (r = 0.309, P = 0.5). Median EQUIHP score negatively correlated with the number of programmes per neighbourhood size (m2) (r = -0.327, P = 0.006) and neighbourhood average socioeconomic status (SES; r = -0.266, P = 0.027). CONCLUSIONS: Our findings suggest that higher quality HPPs were preferentially located in areas of lower SES and served minority populations in Jerusalem.

Birth Weight and Maternal Body Size as Determinants of Blood Pressure at Age 17: Results from the Jerusalem Perinatal Study Cohort.

OBJECTIVES: To investigate the effect of birth weight (BW) and maternal pre-pregnancy BMI (mBMI) on blood pressure (BP) in adolescence. METHODS: A Population-based cohort of 11,729 births in Jerusalem during 1974-1976, with archival data on maternal and birth characteristics was performed. Measurements at age 17 were assessed and linear regression models were used to evaluate the associations of birth characteristics with BP outcomes. RESULTS: BW was inversely associated with both systolic (SBP) and diastolic (DBP) BP at age 17 (SBP: B = - 0.829, p = 0.002; DBP: B = - 0.397, p = 0.033). The interaction term between BW and weight at age 17 was significant for DBP (p = 0.017) and pulse pressure (p = 0.005). mBMI yielded significant positive associations with BP, independent of BW. CONCLUSIONS FOR PRACTICE: Our findings indicate that there are at least two distinct pathways linking early life characteristics with subsequent BP: Intrauterine growth, as reflected by BW and other genetic or environmental factors, reflected by mBMI and maternal education, contribute to offspring adolescent BP. These results warrant replication in other birth cohorts and underline the need to explore specific mechanisms that account for these associations.

Parental occupational exposure to pesticides, animals and organic dust and risk of childhood leukemia and central nervous system tumors: Findings from the International Childhood Cancer Cohort Consortium (I4C).

Parental occupational exposures to pesticides, animals and organic dust have been associated with an increased risk of childhood cancer based mostly on case-control studies. We prospectively evaluated parental occupational exposures and risk of childhood leukemia and central nervous system (CNS) tumors in the International Childhood Cancer Cohort Consortium. We pooled data on 329,658 participants from birth cohorts in five countries (Australia, Denmark, Israel, Norway and United Kingdom). Parental occupational exposures during pregnancy were estimated by linking International Standard Classification of Occupations-1988 job codes to the ALOHA+ job exposure matrix. Risk of childhood (<15 years) acute lymphoblastic leukemia (ALL; n = 129), acute myeloid leukemia (AML; n = 31) and CNS tumors (n = 158) was estimated using Cox proportional hazards models to generate hazard ratios (HR) and 95% confidence intervals (CI). Paternal exposures to pesticides and animals were associated with increased risk of childhood AML (herbicides HR = 3.22, 95% CI = 0.97-10.68; insecticides HR = 2.86, 95% CI = 0.99-8.23; animals HR = 3.89, 95% CI = 1.18-12.90), but not ALL or CNS tumors. Paternal exposure to organic dust was positively associated with AML (HR = 2.38 95% CI = 1.12-5.07), inversely associated with ALL (HR = 0.55, 95% CI = 0.31-0.99) and not associated with CNS tumors. Low exposure prevalence precluded evaluation of maternal pesticide and animal exposures; we observed no significant associations with organic dust exposure. This first prospective analysis of pooled birth cohorts and parental occupational exposures provides evidence for paternal agricultural exposures as childhood AML risk factors. The different risks for childhood ALL associated with maternal and paternal organic dust exposures should be investigated further.

Maternal Infection in Pregnancy and Childhood Leukemia: A Systematic Review and Meta-analysis.

OBJECTIVE: To summarize the published evidence regarding the association between maternal infection during pregnancy and childhood leukemia. STUDY DESIGN: In this systematic review and meta-analysis (PROSPERO number, CRD42018087289), we searched PubMed and Embase to identify relevant studies. We included human studies that reported associations of at least one measure of maternal infection during pregnancy with acute lymphoblastic leukemia (ALL) or all childhood leukemias in the offspring. One reviewer extracted the data first using a standardized form, and the second reviewer independently checked the data for accuracy. Two reviewers used the Newcastle-Ottawa Scale to assess the quality of included studies. We conducted random effects meta-analyses to pool the ORs of specific type of infection on ALL and childhood leukemia. RESULTS: This review included 20 studies (ALL, n = 15; childhood leukemia, n = 14) reported in 32 articles. Most (>65%) included studies reported a positive association between infection variables and ALL or childhood leukemia. Among specific types of infection, we found that influenza during pregnancy was associated with higher risk of ALL (pooled OR, 3.64; 95% CI, 1.34-9.90) and childhood leukemia (pooled OR, 1.77; 95% CI, 1.01-3.11). Varicella (pooled OR, 10.19; 95% CI, 1.98-52.39) and rubella (pooled OR, 2.79; 95% CI, 1.16-6.71) infections were also associated with higher childhood leukemia risk. CONCLUSIONS: Our findings suggest that maternal infection during pregnancy may be associated with a higher risk of childhood leukemia.

A city-wide health promotion programme evaluation using EQUIHP: Jerusalem Community-Academic Partnership (J-CAP).

BACKGROUND: While health promotion initiatives are common, too little is known about their quality, impact and sustainability. Fragmentation between sectors exists and programme evaluation initiatives lack consistency, making comparison of outcomes challenging. METHODS: We used a 'snowball' methodology to detect health promotion programmes (HPPs) in the Municipality of Jerusalem, excluding those in schools. The European Quality Instrument for Health Promotion (EQUIHP) was adapted and used to examine programme quality. The tool was pre-tested among stakeholders, and translated into Hebrew and Arabic between March and December 2017. Trained research assistants collected information on four domains using in-person interviews: (i) compliance with international principles of HPPs, (ii) development and implementation, (iii) project management and (iv) sustainability of programmes. RESULTS: Overall, 93 programmes, including 33 670 participants, were ascertained and evaluated. The majority of HPPs (54.8%) addressed nutrition and physical activity, with 58.1% targeting the non-orthodox Jewish population and 68.8% aimed at both sexes. Cronbach's alpha scores were 0.968 for the entire EQUIHP tool and 0.802, 0.959, 0.918 and 0.718 for the subdomains of Framework, Project Development, Project Management and Sustainability, respectively. Median domain scores were 0.83, 0.61, 0.76 and 0.75. Median score of the entire tool was 0.67. HPPs operated by the Municipality scored lower than those of non-governmental organizations and health providers/organizations in every domain except for Project Management. CONCLUSION: A systematic city-wide evaluation of HPPs is feasible and uncovers strengths and weaknesses, including sustainability and variability by programme provider. Academic-community partnerships may assist planning and improving HPPs in the city.

The association between birth order and childhood leukemia may be modified by paternal age and birth weight. Pooled results from the International Childhood Cancer Cohort Consortium (I4C).

The "delayed infection hypothesis" states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 106 person-years of follow-up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77-0.99) and 0.85: (0.73-0.99), respectively. Being later-born was associated with similarly reduced hazards of CL and ALL compared to being first-born; HRs = 0.78: 95% CI: 0.58-1.05 and 0.73: 0.52-1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later-born and CL, with the lowest risk observed for children born at <3 kg with fathers aged 35+ (HR = 0.18, 95% CI: 0.06-0.50). Our study strengthens the theory that increasing birth order confers protection against CL and ALL risks, but suggests that this association may be modified among subsets of children with different characteristics, notably advanced paternal age and lower birth weight. It is unclear whether these findings can be explained solely by infectious exposures.

[ANTIBIOTIC USE IN COMMUNITY HEALTHCARE IN ISRAEL AS REFLECTED IN THE NATIONAL PROGRAM FOR QUALITY INDICATORS].

AIMS: We sought to evaluate the extent of overall and second-line systemic antibiotic use in the Israeli community, to compare them to international data and to monitor temporal trends. BACKGROUND: Antibiotic overuse is prevalent and has grave implications, primarily the emergence of resistant pathogens - an urgent public health concern worldwide. METHODS: The Israel National Program for Quality Indicators in Community Healthcare (QICH) obtains data from electronic medical records from the 4 health-plans, covering the entire civilian population. We assessed 2 quality indicators, compatible with those of the OECD: 1. Overall volume of antibiotics for systemic use dispensed. 2. Volume of second-line antibiotics as a proportion of all systemic antibiotics. Analysis was stratified by gender, age and socio-economic position (SEP). RESULTS: The volume of systemic antibiotics dispensed in 2016 was 20.76 DDD/1000 person/day, with second-line antibiotics comprising 22.0% of the total. These values have been stable since 2014, and are higher compared with the OECD averages (20.61 DDD/1000 person/day, and 17.02% in 2015). Both overall volume and the proportion of second-line antibiotics rose with age and were higher among women especially in the 20-40 years age bracket (overall volume of 23.98 DDD/1000 person/day, proportion of second-line antibiotics of 23.98% VS 17.41 and 19.17% in men). Higher overall use was observed among patients of low SEP. CONCLUSIONS: The observed volume of systemic antibiotics and the proportion of second-line antibiotics dispensed in the Israeli community were stable and high. Higher use was observed among older individuals, women and patients of low SEP. Our results call for the implementation of a national-level, community-based antibiotic stewardship program. QICH might serve to monitor such a program.