BACKGROUND: Autism spectrum disorder (ASD) is a developmental disorder with increasing prevalence worldwide, yet has unclear etiology. OBJECTIVE: We explored the association between maternal exposure to particulate matter (PM) air pollution and odds of ASD in her child. METHODS: We conducted a nested case-control study of participants in the Nurses' Health Study II (NHS II), a prospective cohort of 116,430 U.S. female nurses recruited in 1989, followed by biennial mailed questionnaires. Subjects were NHS II participants' children born 1990-2002 with ASD (n = 245), and children without ASD (n = 1,522) randomly selected using frequency matching for birth years. Diagnosis of ASD was based on maternal report, which was validated against the Autism Diagnostic Interview-Revised in a subset. Monthly averages of PM with diameters ≤ 2.5 μm (PM2.5) and 2.5-10 μm (PM10-2.5) were predicted from a spatiotemporal model for the continental United States and linked to residential addresses. RESULTS: PM2.5 exposure during pregnancy was associated with increased odds of ASD, with an adjusted odds ratio (OR) for ASD per interquartile range (IQR) higher PM2.5 (4.42 μg/m3) of 1.57 (95% CI: 1.22, 2.03) among women with the same address before and after pregnancy (160 cases, 986 controls). Associations with PM2.5 exposure 9 months before or after the pregnancy were weaker in independent models and null when all three time periods were included, whereas the association with the 9 months of pregnancy remained (OR = 1.63; 95% CI: 1.08, 2.47). The association between ASD and PM2.5 was stronger for exposure during the third trimester (OR = 1.42 per IQR increase in PM2.5; 95% CI: 1.09, 1.86) than during the first two trimesters (ORs = 1.06 and 1.00) when mutually adjusted. There was little association between PM10-2.5 and ASD. CONCLUSIONS: Higher maternal exposure to PM2.5 during pregnancy, particularly the third trimester, was associated with greater odds of a child having ASD.

We analyzed data from the Israeli National Insurance Institute (NII). Autism Spectrum Disorder (ASD) incidence was calculated for all children born in Israel 1992-2009, and by population groups. Overall, 9,109 ASD cases among 2,431,649 children were identified. ASD cumulative incidence by age 8 years increased 10-fold during 2000-2011, from 0.49% to 0.49%, while other child disabilities in NII increased only 1.65-fold. There was a consistent increase in ASD incidence with advancing birth cohorts born 1992-2004, stabilizing among those born 2005-2009. ASD rates among Israeli Arabs were substantially lower, and increased about 10 years later than the general population. The findings suggest a role for ASD awareness, accessing of the government benefit, or the way the concept of ASD is perceived.

BACKGROUND: Attention deficit-hyperactivity disorder (ADHD) is the most common neuro-developmental disorder in childhood. Its pharmacologic treatment mostly includes methylphenidate, yet many parents seek alternative, "natural," therapeutic options, commonly omega-3 fatty acids. Previous studies of supplementation with fish oil or long-chain omega-3 fatty acids to children with ADHD yielded mixed results. The use of alpha-linolenic acid (ALA), a medium-chained, plant-based omega-3 fatty acid (18:3 n-3), has not been sufficiently examined in this population. METHODS: Forty untreated children with ADHD, aged 6-16 years, were randomized to receive either 2 g/day of oil containing 1 g ALA or placebo, for 8 weeks. Before and after supplementation, the children underwent a physician assessment of ADHD symptoms and a computerized continuous performance functions test. The children's parents and teachers filled out Conners' and DSM questionnaires. RESULTS: Seventeen (42.5%) children completed the study, eight in the supplementation group, nine in the placebo group. Main drop-out reasons were capsule size, poor compliance, and a sense of lack of effect. No significant difference was found in any of the measured variables tested before and after supplementation, in both study groups. No between-group difference was found in the changes of the various measures of ADHD symptoms throughout the study period. CONCLUSION: Supplementation of 2 g/day of oil containing 1 g ALA did not significantly reduce symptoms in children with ADHD. Future studies in this field should consider an alternative method to deliver the oil, a higher dose, and a larger sample size.

Red blood cell distribution width (RDW) has been shown to predict cardiovascular mortality in various populations, but studies were less conclusive regarding cardiovascular morbidity. We aimed at evaluating the prognostic effect of RDW on cardiovascular morbidity and all-cause mortality in the largest community cohort to date.We utilised the computerised database of a large community based healthcare maintenance organization (HMO) in Israel to identify a cohort of 225,006 eligible patients aged 40 or above who performed a blood count during 2006. We evaluated the relationship between 1% increments of RDW values and major cardiovascular events and all-cause mortality over a period of five years. A total of 21,939 incident cases of a major cardiovascular event and 4,287 deaths were documented during a total of six years of follow up, respectively. In comparison with patients with RDW level <13%, the hazard ratio for total mortality gradually increased to 4.57 (95% confidence interval [CI]: 3.35-6.24, p<0.001) among male patients and to 3.26 (95% CI: 2.49-4.28, p<0.001) among female patients with a RDW of 17% or above. Similar results were evident in anaemic and non-anaemic populations. RDW above 17% was also associated with a modest increased risk of major cardiovascular events in females 1.26 (95% CI: 1.03-1.52, p=0.021), while in men it was not significant, 1.08 (95% CI: 0.82-1.41, p=NS). In conclusion, increasing RDW levels significantly increased risk of cardiovascular morbidity and all-cause mortality. Our observation is evident in both anaemic and non-anaemic patients.

PURPOSE: The aim of this population-based study is to describe trends in the characteristics and treatment patterns of statin initiators over the first decade of the 21st century. METHODS: New statin use was studied retrospectively using the database of Maccabi Healthcare Services (MHS), a large Israeli health maintenance organization. Statin initiators were defined as MHS members aged ≥ 30 years who first purchased statins between 2000 and 2010. The starting dose was calculated in simvastatin equivalents based on the World Health Organization's daily defined dose index. Persistence was calculated as the percentage of days covered (PDC) with statins during the first year of therapy. RESULTS: Statin initiation peaked in 2005 and decreased from 38.6 to 18.6 per 1,000 in the period 2005-2010. The average age at therapy initiation decreased from 58.9 (± 12.0) to 54.5 (± 11.7) years, and the average (SD) baseline low-density lipoprotein cholesterol (LDL-C) decreased from 4.2 (± 1.1) to 4.0 (± 0.9) mmol/l during the study period. Women were on average 3 years older than men at treatment initiation, with a higher baseline LDL-C. Among statin initiators, the prevalence of ischemic heart disease (IHD) decreased from 17.8 to 6.7 %, and diabetes prevalence increased from 8.6 to 15.7 %, peaking in 2008 (18.0 %). The PDC with statins ranged between 52.9 and 57.7 %. Simvastatin use at initiation increased from 27.5 % in 2000 to >90 % since 2002. Starting dose increased from 18.5 (± 8.9) to 24.3 (± 13.7) mg simvastatin equivalent. CONCLUSIONS: Among the study population, statin initiators were increasingly characterized by a lower cardiovascular risk-namely, younger individuals without IHD and with a lower baseline LDL-C. These trends underscore the important shift towards statin initiation for primary prevention, as well as the need to balance between benefits and the potential side effect of statins.

Serum vitamin D concentrations (25[OH]D) are associated with physical performance in the general population, but few studies have been published in athletes. 80 competitive adolescent swimmers from both sexes were tested for serum 25(OH)D concentrations, grip strength, balance and swimming performance at several speeds. Spearman's correlations were used to examine the associations between 25(OH)D concentrations and age-adjusted measures of performance. Performance parameters were also compared between vitamin D sufficient (n = 27), insufficient (25[OH]D ranging 20-29.9 ng/ml, n = 42), and deficient (25[OH]D < 20 ng/ ml, n = 11) participants. No significant associations were found between serum 25(OH)D concentrations and any of the performance measures, with no significant differences found between vitamin D sufficient, insufficient and deficient participants. In competitive adolescent swimmers, serum vitamin D concentrations were not associated with strength, balance or swimming performance. Vitamin D insufficient/deficient swimmers did not have reduced performance.

Serum vitamin D concentrations (25[OH]D) are associated with physical performance in the general population, but few studies have been published in athletes. 80 competitive adolescent swimmers from both sexes were tested for serum 25(OH)D concentrations, grip strength, balance and swimming performance at several speeds. Spearman's correlations were used to examine the associations between 25(OH)D concentrations and age-adjusted measures of performance. Performance parameters were also compared between vitamin D sufficient (n = 27), insufficient (25[OH]D ranging 20-29.9 ng/ml, n = 42), and deficient (25[OH]D < 20 ng/ml, n = 11) participants. No significant associations were found between serum 25(OH)D concentrations and any of the performance measures, with no significant differences found between vitamin D sufficient, insufficient and deficient participants. In competitive adolescent swimmers, serum vitamin D concentrations were not associated with strength, balance or swimming performance. Vitamin D insufficient/deficient swimmers did not have reduced performance.

It is hypothesized that vitamin D insufficiency in athletes might negatively affect sport performance. The objective of this study was to examine the effect of vitamin D3 supplementation on physical performance of adolescent swimmers with vitamin D insufficiency. Fifty-three adolescent competitive swimmers with vitamin D insufficiency (serum 25-hydroxyvitamin-D concentrations (25(OH)D)<30ng/ml, mean 24.2±4.8ng/ml) were randomized to receive 2,000IU/day of vitamin D3 or placebo for 12 weeks. Swimming performance at several speeds, arm-grip strength, and one-legged balance, were measured before and after supplementation. The age-adjusted changes in performance variables during the study were compared between groups. 25(OH)D concentrations at study end were significantly higher in the vitamin group compared with the placebo group (29.6±6.5ng/ml vs. 20.3±4.2ng/ml, p<0.001), yet only 48% of the vitamin group became vitamin D sufficient with this dosing. No between-group differences were found in the changes of the performance variables tested. No significant differences in performance were found between participants that became vitamin D sufficient, and those who did not. No significant correlation was found between the change in serum 25(OH)D and age-adjusted balance, strength or swimming performance at study end. Vitamin D3 supplementation that raised serum 25(OH)D concentrations by a mean of 9.3ng/ml above placebo in adolescent swimmers with vitamin D insufficiency, did not improve physical performance more than placebo.

Epilepsy and attention-deficit hyperactivity disorder (ADHD) were reported to co-occur at rates higher than expected for coincidental findings. This study investigated the prevalence of both disorders in community-based primary care practice. The central database of the second-largest health maintenance organization in Israel was searched for all children aged 6 to 13 years (n = 284 419; 51.5% males) diagnosed as having ADHD according to the physicians' records and/or the filling of at least 10 prescriptions for antiepileptic medications according to pharmacy records. The prevalence of epilepsy in the total population was 5 out of 1000 children, and the prevalence of ADHD was 12.6%. More than one-fourth (27.7%) of the epileptic children were also diagnosed as having ADHD. On multivariate analysis, children with ADHD had almost twice the risk of epilepsy than children without ADHD. This study supports hospital-based findings of a strong interrelationship between ADHD and epilepsy. The high rate of ADHD in Israeli children warrants further investigation.

BACKGROUND: Health care quality indicators encourage outreach programs for screening the elderly who do not voluntarily visit their primary care physician (PCP). The characteristics of this population, however, have never been rigorously studied. The aim of this study was therefore to characterize the demography and health status of the elderly who do not visit PCPs. METHODS: A retrospective database study was carried out in the central district of Maccabi Healthcare Services (MHS) in Israel. People aged 65-100 years were included, excluding those who were registered for home-care treatment. The elderly who did not initiate a PCP visit during October 2007-October 2009 were compared to those who visited a PCP during this period, in terms of demographic characteristics, health services utilization, and major chronic diseases, using the computerized MHS database. RESULTS: The study population consisted of 32,523 elderly, 1663 (5.1%) of whom had not visited PCP for at least two years (October 2007 - October 2009). The non-consulters were, on average, older, included more women and tended to have lower socio-economic class. They had fewer hospitalizations, used less prescribed medications, consulted secondary physicians less frequently and had less laboratory tests and imaging. In line with these findings, only 29% of the non-consulters were diagnosed with a chronic condition, compared with 91% of consulters. CONCLUSION: Our findings suggest that as a group, the older Israelis who do not initiate PCP visits are healthier than those who do. Given the high workload of PCPs in Israel, these findings do not support investing considerable efforts in reaching out to the elderly who do not voluntarily initiate PCP visits.

AIM: To longitudinally assess the neurodevelopmental outcomes of late preterm infants (LPI) through the first year of life and to investigate for perinatal conditions that may affect developmental outcomes. METHODS: The study population comprised of 124 LPI, born in a single Israeli inborn center over an eight months period. Thirty-three term infants (TI) were recruited for comparison. Alberta Infant Motor Scale (AIMS) for gross motor evaluation was performed at 6 months of age and the Griffiths Mental Development Scales (GMDS) were performed at 12 months (chronological age). Maternal and neonatal covariates, potentially associated with low developmental scores, were analyzed by multivariate logistic regression models. RESULTS: At chronological age of 6 and 12 months, LPI performed significantly lower than TI on all subscales, but when scores were corrected for post conception age, developmental scores were similar in the two groups. In a multivariate model of logistic regression, male gender, emergent cesarean section and higher maternal education (>14 years) were found to be associated with increased risk for lower developmental scores at 12 month of age in LPI. CONCLUSIONS: LPI do not complete their neurodevelopmental maturation by the first year of life. Males and those born after emergent cesarean section (CS) are at increased risk for lower developmental scores. Correction of age to term birth in LPI may still be needed at this age.

OBJECTIVE: To assess the adherence and persistence with allopurinol therapy among gout patients and to identify risk factors for therapy discontinuation. METHODS: The study population included adults in Maccabi Healthcare Services, a 2-million member health maintenance organization in Israel, who were diagnosed with gout between 2002 and 2008. Adherence with allopurinol was retrospectively assessed by calculating the proportion of days covered of dispensed prescriptions. Persistence was assessed by calculating the mean proportion of follow-up days covered with allopurinol for every study participant. RESULTS: A total of 7644 patients were identified. Among men, the incidence of gout was strongly associated with age, ranging from 0.5 per 1000 among adults younger than 45 years to more than 36 per 1000 among elderly men aged 85 or older). A total of 1331 gout patients (17% of the study population) were adherent to allopurinol therapy, 36% and 47% had partial and poor adherence, respectively. Persistence analysis indicated that the average duration until therapy was discontinued was similar among men (358 days) and women (379 days). Women aged 45-64 years, non-married individuals, those of low socioeconomic status and those with lower body weight were more likely to discontinue therapy. Logistic regression (n = 2471, 32% of the study sample) showed a 4.5 risk of non-compliance among 45- to 65-year-old women. Better compliance was achieved among those with comorbidities, particularly among patients with concomitant cardiovascular disease. CONCLUSION: Only one out of six gout patients is adherent with allopurinol. Intervention programmes to increase adherence with treatment should focus on high-risk populations.

Dendritic cells are potent antigen-presenting cells, common in inflammatory processes. We sought to investigate dendritic cell expression in papillary thyroid carcinoma and the relationship of dendritic cell density with the extent of thyroiditis and prognosis. Specimens from 69 consecutive patients with papillary thyroid carcinoma were immunohistochemically stained for the S100 protein, and the number of positive dendritic cells was counted. Cells were sparse in normal thyroid tissue and common in areas of thyroiditis and papillary carcinoma. Dendritic cell density in papillary carcinoma correlated with the thyroiditis grade and dendritic cell density in surrounding areas of thyroiditis. High-grade thyroiditis (42% of patients) was inversely associated with 3-year recurrence. Dendritic cell density was not associated with disease-free survival. The lack of prognostic value of dendritic cell density is not compliant with the only other relevant study in the literature, and further research is required.

We describe a survey of children with ASD aged 4-10 years. The main dependent variables were out-of-pocket expenditures for health services and hours of therapy. Multivariable logistic regression models were used in order to find independent predictors for service utilization. Parents of 178 of the children (87 %) agreed to participate. The average annual out-of-pocket cost was $8,288, with a median of $4,473 and a range of $0-89,754. Higher severity of ASD and a parent with an academic degree were associated with higher expenditure. Having at least one older sibling, siblings without developmental disorders, regular education setting, lower parent education and low income were associated with lower expenditure.

Infection might be associated with increased risk of venous thromboembolism (VTE) and arterial thrombosis. Specific hypotheses have been raised regarding the procoagulant response induced by acute cytomegalovirus (CMV) infection. Accordingly, we investigated the 6-month incidence of VTE and/or arterial thrombosis in patients that had been tested positive for CMV-IgM antibodies in a large health maintenance organization. Logistic regression analysis was used to identify independent risk factors for VTE and arterial thrombosis. Among 90,515 patients eligible for the VTE analysis and 90,805 patients eligible for the arterial thrombosis analysis, 6,205 (6.9%) and 6,222 (6.9%) patients were tested positive for CMV-IgM antibodies, respectively. During 6 months of follow-up from index date, the incidence rates per 1,000 capita of VTE among CMV-IgM seropositive and CMV-IgM seronegative patients were 3.06 (19 patients) and 1.36 (115 patients), respectively (odds ratio (OR) 2.25; 95% confidence intervals (95% CI) 1.38-3.66; p = 0.003). CMV-IgM seropositivity was independently associated with VTE appearance (OR 2.49; 95% CI 1.53-4.06; p < 0.0001) following adjustment for age, sex, and other confounders. The incidence rates per 1,000 capita of arterial thrombosis among CMV-IgM seropositive and CMV-IgM seronegative patients were 1.12 (7 patients) and 1.06 (90 patients), respectively (OR 1.06; 95% CI 0.49-2.28; p = 0.840). CMV-IgM seropositivity was not associated with arterial thrombosis. We conclude that acute CMV infection might be associated with an increased short-term VTE risk. To the best of our knowledge, this is the largest study ever to confirm this association.

BACKGROUND: Anemia on admission and during hospitalization is associated with poor short and long term prognosis among patients with acute coronary syndrome (ACS). Our objective was to examine the prognostic implications of longitudinal hemoglobin (Hb) levels following a first acute myocardial infarction (AMI). METHODS: We utilized data obtained from the computerized database of a large community based health care maintenance organization to identify patients who survived for at least 6 months following a first AMI, during the years 2003-2010. Hazard ratios were calculated using Cox proportional regression models with various Hb measurements as dependent variables, and net reclassification improvement (NRI) was applied to evaluate the prognostic usefulness of these Hb measurements. RESULTS: Last Hb measurement during a 6-24 month follow-up period was found to have the highest prognostic power. In males, Hb levels below 13 g/dL were gradually associated with a higher risk of events, reaching a HR of 4.13 at Hb levels <11 g/dL. In females, only Hb levels lower than 11 g/dL were significantly associated with a higher event rate (HR=2.42, p=0.003). Hb decrease was significantly associated with an increased risk in both genders, even among non-anemic patients at baseline. CONCLUSIONS: Anemia and Hb decrement following a first AMI are associated with worse prognosis and elevated risk of combined all cause mortality and recurrent cardiac events.

BACKGROUND: Human papillomavirus (HPV) infection is mostly associated with cervical cancer (CC). However, it can cause other illnesses as well, all of which impact on people's wellbeing and consume healthcare resources. Measures for prevention or early detection of these conditions differ in their effectiveness and cost. An informative evaluation of the projected benefit of these measures depends on understanding the current unmet need, not only limited to CC. OBJECTIVE: To evaluate the burden of HPV-related conditions in Israel, including CC, cervical precancerous lesions and genital warts. METHODS: A retrospective database analysis was conducted for the second largest health management organization (HMO) in Israel, covering approximately 1.8 million people. Records were drawn following a search for key words indicative of related diagnoses, lab results, medications, or procedures for the time period of 2006-2008. Prevalence, incidence and resource utilization were analysed. Findings were extrapolated to the whole Israeli population using age and gender incidence rates. RESULTS: Incidence of CC was found to be 5 per 100,000 females. Incidences of cervical intraepithelial neoplasia (CIN) grades 1, 2 and 3 were 74, 27 and 36 per 100,000 females, respectively. Incidence of genital warts was 239 and 185 per 100,000 for men and women, respectively. The overall annual economic burden was calculated to be $US48,838,058 (year 2010 values). CONCLUSIONS: HPV poses a significant burden in terms of health (clinical and quality of life) and in monetary terms, even for conditions that are sometimes regarded as benign, such as CIN1 or genital warts. Current findings should be used for proper evaluation of measures to reduce HPV-related morbidity and mortality, such as regular screening and vaccination.

BACKGROUND: Autism spectrum disorders [ASD] are characterized by a wide range of neuropsychiatric comorbid disorders which change during early development. Coordinated collaboration between therapists from various disciplines and integrating measurements, may Lead to a comprehensive diagnosis of ASD. A diagnostic kindergarten set-up for children with a preliminary diagnosis of ASD or communication disorder can facilitate a multidisciplinary diagnosis, as an integral part of the child and parental intervention process. GOALS: To examine the changes in the diagnosis of children after one year of observation and treatment in a special education set-up, including aspects such as common neuropsychiatric comorbidity, differential diagnosis and subsequent placement recommendations. METHODS: Changes in the frequencies of ASD diagnoses were calculated prior to and following participation in the kindergarten for 76 children, who studied in the diagnostic kindergarten for ASD at the Weinberg Child Development Center during the last decade. Frequencies of neuropsychiatric comorbid disorders and differential diagnosis were calculated. RESULTS: It was found that: half (44.7%) of the preliminary diagnoses changed after a year of treatment; 14.2% of the children admitted with other developmental diagnoses, were subsequently diagnosed with ASD and in the cases of 25% of the children with ASD, their diagnosis was removed. Neuropsychiatric comorbid disorders appeared in 66% of cases. The most common differential diagnosis was Language disability, which appeared in 76% of the cases. CONCLUSIONS: This study reinforces the importance of a thorough assessment process conducted by a multidisciplinary team during and after treatment. A quarter of the children diagnosed with ASD in early childhood may have a different diagnosis later, usually milder, probably as a consequence of developmental changes combined with intensive treatment.