Different Factors Are Associated With Sex Hormones and Leydig Cell Function in Israelis and Palestinians in Jerusalem.

Total testosterone (TT) is known to influence health and virility in men. Among men from United States and Europe, numerous sociodemographic and lifestyle factors were reported to be associated with TT. However, associations with TT and Leydig cell function in the Middle East are poorly described. A cross-sectional, population-based sample had a structured interview, physical examinations, and blood tests in two hospitals in Jerusalem, Israel. A subsample (25- to 44-year-old men, n = 286: 124 Israelis, 162 Palestinians) had sex hormone measurements. The primary outcomes were TT and free testosterone/luteinizing hormone (FT/LH) ratio, representing Leydig cell function. Associations with sociodemographic and lifestyle factors, body mass index (BMI), and physical activity (PA) were evaluated using multivariable linear regression. Compared with Palestinians, Israelis had similar TT (4.81 vs. 5.09 ng/mL, p = .405) and higher FT/LH (31.2 vs. 25.8 ng/IU, p = .002). In ln-transformed values, marital status had a stronger association in Palestinians (P for interaction = 0.03). Age, BMI, and PA had a stronger association with TT in Israelis with significant interactions with ethnicity. BMI <25 and a higher PA quartile were associated with a higher TT (p < .001). Among Israelis, age (p = .007), married marital status (p = .007), and BMI <25 were significantly associated with FT/LH. No associations of any factors were identified among Palestinians. Associations with several modifiable factors identified in Western samples were replicated in Israelis and to a lesser degree in Palestinians. Different relationships of several factors with TT and FT/LH could result from ethnically diverse genetic, sociodemographic, and behavioral characteristics that warrant further research.

Congenital Anomalies of the Kidney and Urinary Tract and Adulthood risk of Urinary Tract Cancer.

INTRODUCTION: Congenital anomalies of the kidney and urinary tract (CAKUT) are the most common kidney diseases in childhood. Alterations in genes governing nephrogenesis may cause CAKUT, and in some cases may contribute to development of urinary tract (UT) tumors later in life. We aimed to assess the association between CAKUT and UT cancer in adulthood. METHODS: We conducted a population-based historical cohort study encompassing 1,510,042 recruits to the Israeli army between 1967 and 1997. CAKUT exposure was determined by army medical coding of CAKUT in childhood. Incidence of UT cancer (kidney, ureter, or bladder) was available through record linkage with the Israeli Cancer Registry. Recruits were followed from the prerecruitment assessment until cancer diagnosis, death, or study termination, in 2012. Cox proportional hazards models were constructed to estimate the hazard ratios (HRs) for UT cancer in participants with vs. without CAKUT. RESULTS: During a mean follow-up of 30.4 years, 2959 participants (2573 men and 386 women) developed UT cancer. Men with CAKUT exhibited an increased risk of UT cancer compared with men without CAKUT, yielding an adjusted HR of 1.98 (95% confidence interval [CI] 1.03-3.82). Among women CAKUT was associated with a HR of 5.88 (95% CI 2.19-15.76). Notably, upon stratification according to age of cancer diagnosis, the association between CAKUT and UT cancer was statistically significant only before 45 years of age in women and only after 45 years of age in men. CONCLUSION: CAKUT is associated with a significantly increased risk of UT cancer, although the incidence and absolute risk remained quite low.

Adolescent characteristics and incidence of pre-malignant disease and invasive tumors of the cervix.

INTRODUCTION: Pre-malignant cervical disease and invasive cervical cancer present a significant global health burden with respect to morbidity and mortality, mostly in low- and middle-income countries. Human papillomavirus (HPV) infection typically manifests for the first time in adolescence. We aimed to identify adolescent sociodemographic and anthropometric characteristics associated with subsequent risk for pre-malignant cervical disease and cervical cancer, in a country that offers free screening and HPV vaccines. METHODS: This historical cohort study included 969 123 Israeli women examined and anthropometrically measured at age 17 years between January 1967 and December 2011. Data on pre-malignant disease and invasive cervical tumors were obtained from the national cancer registry by linkage. We excluded non-Jewish minorities (a total of 25 472 women) and orthodox/ultraorthodox Jewish women since these populations are not required by law to serve in the military, as well as women with a pre-examination diagnosis of cancer. Cox proportional hazards regression models were applied per each lesion type, adjusted for origin, measured body mass index, height, education, dwelling type, birth year, and age at examination. RESULTS: In total, 5094 and 859 incident pre-malignant cervical disease and cervical cancer cases, respectively, were diagnosed during a median follow-up of 17.6 years. Risk for both lesions was origin-dependent, with higher incidence in women of North-African origin (HR (pre-malignant cervical disease) 1.22, 95% CI 1.04 to 1.42; HR (cervical cancer) 1.87, 95% CI 1.30 to 2.69) compared with European origin. Height, lower education, and later birth year were associated with higher pre-malignant cervical disease and cervical cancer risk also. Adolescent overweight (HR 0.81, 95% CI 0.74 to 0.90) and obesity (HR 0.56, 95% CI 0.43 to 0.71) status were associated with reduced pre-malignant cervical disease but not cervical cancer incidence, as did urban (vs rural) residence. DISCUSSION: Ethnic background, tall stature, and education were associated with pre-malignant cervical disease and cervical cancer incidence, while adolescent overweight and obesity were inversely associated with only pre-malignant cervical disease. Despite free screening and HPV vaccines, these findings suggest that there is still a need for appropriate safe sex and screening education in adolescence.

Association of Leukocyte Telomere Length With Mortality Among Adult Participants in 3 Longitudinal Studies.

Importance: Leukocyte telomere length (LTL) is a trait associated with risk of cardiovascular disease and cancer, the 2 major disease categories that largely define longevity in the United States. However, it remains unclear whether LTL is associated with the human life span. Objective: To examine whether LTL is associated with the life span of contemporary humans. Design, Setting, and Participants: This cohort study included 3259 adults of European ancestry from the Cardiovascular Health Study (CHS), Framingham Heart Study (FHS), and Women's Health Initiative (WHI). Leukocyte telomere length was measured in 1992 and 1997 in the CHS, from 1995 to 1998 in the FHS, and from 1993 to 1998 in the WHI. Data analysis was conducted from February 2017 to December 2019. Main Outcomes and Measures: Death and LTL, measured by Southern blots of the terminal restriction fragments, were the main outcomes. Cause of death was adjudicated by end point committees. Results: The analyzed sample included 3259 participants (2342 [71.9%] women), with a median (range) age of 69.0 (50.0-98.0) years at blood collection. The median (range) follow-up until death was 10.9 (0.2-23.0) years in CHS, 19.7 (3.4-23.0) years in FHS, and 16.6 (0.5-20.0) years in WHI. During follow-up, there were 1525 deaths (482 [31.6%] of cardiovascular disease; 373 [24.5%] of cancer, and 670 [43.9%] of other or unknown causes). Short LTL, expressed in residual LTL, was associated with increased mortality risk. Overall, the hazard ratio for all-cause mortality for a 1-kilobase decrease in LTL was 1.34 (95% CI, 1.21-1.47). This association was stronger for noncancer causes of death (cardiovascular death: hazard ratio, 1.28; 95% CI, 1.08-1.52; cancer: hazard ratio, 1.13; 95% CI, 0.93-1.36; and other causes: hazard ratio, 1.53; 95% CI, 1.32-1.77). Conclusions and Relevance: The results of this study indicate that LTL is associated with a natural life span limit in contemporary humans.

Adolescent obesity and midlife cancer risk: a population-based cohort study of 2·3 million adolescents in Israel.

BACKGROUND: Obesity has been established as a causal factor for several types of cancer, and adolescent obesity is increasing worldwide. We examined associations between measured body-mass index (BMI) at age 17 years and cancer incidence, and with mortality among those who developed cancer. METHODS: In a nationwide, population-based cohort of adolescents, height and weight were measured at pre-recruitment mandatory medical examination during 1967-2010. BMI was classified according to US Center for Disease Control and Prevention percentiles. We applied Cox proportional hazard models to estimate the hazard ratios (HRs) and 95% CIs for incident cases of cancer using the 5th-49th BMI percentile group as a reference. The primary outcome was any cancer diagnosis between Jan 1, 1967, and Dec 31, 2012, as recorded in the Israeli National Cancer Registry. Participants with a diagnosis of cancer at baseline (before military recruitment assessment) were excluded from this analysis. The secondary outcome of this study was all-cause mortality among cohort members who had cancer, between Jan 1, 1967, and Dec 31, 2017. FINDINGS: Of the 2 458 170 participants examined between Jan 1, 1967, and Dec 31, 2010, 160 040 were excluded. 2 298 130 participants of which 928 110 were women and 1 370 020 were men. During 29 542 735 person-years of follow-up in men, 26 353 incident cases of cancer were recorded and in 18 044 863 person-years of follow-up in women, 29 488 incident cases of cancer were recorded. Cancer incidence increased gradually across BMI percentiles. The adjusted HR was 1·26 (95% CI 1·18-1·35) among men with adolescent obesity. Among women, we found no association between obesity and overall cancer, driven by inverse associations of obesity with cervical and breast cancers. When these cancers were excluded, the adjusted HR for cancer was 1·27 (1·13-1·44) among women with adolescent obesity. In both sexes, high BMI (≥85th percentile) was associated with an increased cancer risk after 10 years. This association was accentuated in the late period of the cohort versus the early period of the cohort. BMI was positively associated with a higher risk of mortality. The projected population attributable risk for high BMI was 5·1% (4·2-6·1) for men and 5·7% (4·2-7·3) for women. INTERPRETATION: The increasing prevalence of adolescent obesity and the possible association between adolescent BMI and cancer incidence might increase the future burden of obesity-related cancers. BMI among adolescents could constitute an important intervention target for cancer prevention. FUNDING: None.

Helicobacter pylori infection, serum pepsinogens as markers of atrophic gastritis, and leukocyte telomere length: a population-based study.

BACKGROUND: Persistent infections that induce prolonged inflammation might negatively affect the leukocyte telomere length (LTL); however, the role in LTL of Helicobacter pylori (H. pylori) infection, which persistently colonizes the stomach, remains unknown. The study objective was to examine associations of sero-prevalence of H. pylori immunoglobulin G (IgG) antibody and serum pepsinogens (PGs), as markers of atrophic gastritis, with LTL. A cross-sectional study was performed among 934 Arab residents of East Jerusalem, aged 27-78 years, randomly selected from Israel's national population registry. Sera were tested for H. pylori IgG and PG levels by ELISA. LTL was measured by southern blots. Multiple linear regression models were fitted to adjust for sociodemographic and lifestyle factors. RESULTS: LTL decreased significantly with age (p < 0.001) and was shorter in men than women (p = 0.032). The mean LTL was longer in H. pylori sero-positive persons than negative ones: mean difference 0.13 kb (95% CI 0.02, 0.24), p = 0.016. Participants with atrophic gastritis (PGI < 30 µg/L or a PGI: PGII < 3.0) had shorter LTL than did those without: mean difference - 0.18 (95% CI - 0.32, - 0.04). The difference was of larger magnitude between persons who had past H. pylori infection (sero-negative to H. pylori IgG antibody) and atrophic gastritis, compared to those who were H. pylori sero-negative and did not have atrophic gastritis: mean difference - 0.32 kb (95% CI - 0.55, - 0.10). This association remained significant after adjustment for age, sex, and religiosity: beta coefficient - 0.21 kb (95% CI - 0.41, - 0.001), p = 0.049. The results were similar after further adjustment for lifestyle factors. In bivariate analysis, mean LTL was longer in physically active persons than non-active ones, and shorter in persons with than without obesity; however, these differences were diminished and were not significant in the multivariable model. CONCLUSIONS: H. pylori IgG sero-positivity per se was not related to reduced LTL. However, persons with past H. pylori infection (i.e., lacking H. pylori IgG serum antibody) and with serological evidence of atrophic gastritis, had a significantly shorter LTL than did those without atrophic gastritis.

Smoking does not accelerate leucocyte telomere attrition: a meta-analysis of 18 longitudinal cohorts.

Smoking is associated with shorter leucocyte telomere length (LTL), a biomarker of increased morbidity and reduced longevity. This association is widely interpreted as evidence that smoking causes accelerated LTL attrition in adulthood, but the evidence for this is inconsistent. We analysed the association between smoking and LTL dynamics in 18 longitudinal cohorts. The dataset included data from 12 579 adults (4678 current smokers and 7901 non-smokers) over a mean follow-up interval of 8.6 years. Meta-analysis confirmed a cross-sectional difference in LTL between smokers and non-smokers, with mean LTL 84.61 bp shorter in smokers (95% CI: 22.62 to 146.61). However, LTL attrition was only 0.51 bp yr-1 faster in smokers than in non-smokers (95% CI: -2.09 to 1.08), a difference that equates to only 1.32% of the estimated age-related loss of 38.33 bp yr-1. Assuming a linear effect of smoking, 167 years of smoking would be required to generate the observed cross-sectional difference in LTL. Therefore, the difference in LTL between smokers and non-smokers is extremely unlikely to be explained by a linear, causal effect of smoking. Selective adoption, whereby individuals with short telomeres are more likely to start smoking, needs to be considered as a more plausible explanation for the observed pattern of telomere dynamics.

Cancer and mortality in relation to traffic-related air pollution among coronary patients: Using an ensemble of exposure estimates to identify high-risk individuals.

BACKGROUND: Moderate correlations were previously observed between individual estimates of traffic-related air pollution (TRAP) produced by different exposure modeling approaches. This induces exposure misclassification for a substantial fraction of subjects. AIM: We used an ensemble of well-established modeling approaches to increase certainty of exposure classification and reevaluated the association with cancers previously linked to TRAP (lung, breast and prostate), other cancers, and all-cause mortality in a cohort of coronary patients. METHODS: Patients undergoing percutaneous coronary interventions in a major Israeli medical center from 2004 to 2014 (n = 10,627) were followed for cancer (through 2015) and mortality (through 2017) via national registries. Residential exposure to nitrogen oxides (NOx) -a proxy for TRAP- was estimated by optimized dispersion model (ODM) and land use regression (LUR) (rPearson = 0.50). Mutually exclusive groups of subjects classified as exposed by none of the methods (high-certainty low-exposed), ODM alone, LUR alone, or both methods (high-certainty high-exposed) were created. Associations were examined using Cox regression models. RESULTS: During follow-up, 741 incident cancer cases were diagnosed and 3051 deaths occurred. Using a ≥25 ppb cutoff, compared with high-certainty low exposed, the multivariable-adjusted hazard ratios (95% confidence intervals) for lung, breast and prostate cancer were 1.56 (1.13-2.15) in high-certainty exposed, 1.27 (0.86-1.86) in LUR-exposed alone, and 1.13 (0.77-1.65) in ODM-exposed alone. The association of the former category was strengthened using more extreme NOx cutoffs. A similar pattern, albeit less strong, was observed for mortality, whereas no association was shown for cancers not previously linked to TRAP. CONCLUSIONS: Use of an ensemble of TRAP exposure estimates may improve classification, resulting in a stronger association with outcomes.

Prevalence and determinants of serological evidence of atrophic gastritis among Arab and Jewish residents of Jerusalem: a cross-sectional study.

OBJECTIVE: Understanding the correlates of premalignant gastric lesions is essential for gastric cancer prevention. We examined the prevalence and correlates of serological evidence of atrophic gastritis, a premalignant gastric condition, using serum pepsinogens (PGs) in two populations with differing trends in gastric cancer incidence. METHODS: In a cross-sectional study, using ELISA we measured serum PGI and PGII concentrations (Biohit, Finland), Helicobacter pylori serum IgG and cytotoxin-associated gene A (CagA) antigen IgG antibodies in archived sera of 692 Jews and 952 Arabs aged 25-78 years, randomly selected from Israel's population registry in age-sex and population strata. Multivariable logistic regression analyses were performed. RESULTS: Using cut-offs of PGI <30µg/L or PGI:PGII <3.0, the prevalence of atrophic gastritis was higher among Arab than Jewish participants: 8.8% (95% CIs 7.2% to 10.8%) vs 5.9% (95% CI 4.4% to 7.9%), increasing with age in both groups (p<0.001 for trend). Among Jewish participants, infection with H. pylori CagA phenotype was positively related to atrophic gastritis: adjusted OR (aOR) 2.16 (95% CI 0.94 to 4.97), but not to non-CagA infections aOR 1.17 (95% CI 0.53 to 2.55). The opposite was found among Arabs: aOR 0.09 (95% CI 0.03 to 0.24) for CagA positive and aOR 0.15 (95% CI 0.06 to 0.41) for Cag A negative phenotypes (p<0.001 for interaction). Women had a higher atrophic gastritis prevalence than men. Obesity and smoking were not significantly related to atrophic gastritis; physical activity tended to be inversely associated in Arabs (p=0.08 for interaction). CONCLUSIONS: The prevalence of atrophic gastritis was higher among Arabs than Jews and was differently associated with the CagA phenotype.

Severe obesity and cardio-metabolic comorbidities: a nationwide study of 2.8 million adolescents.

BACKGROUND: Severe obesity is rising among adolescents, but data on the prevalence of metabolic abnormalities among this group are limited. We assessed the secular trend of severe obesity and its association with major cardio-metabolic morbidities. METHODS: A total of 2,785,227 Israeli adolescents (aged 17.2 ± 0.5 years) who underwent a pre-recruitment medical examination including routine measurements of weight, height and blood pressure between 1967 and 2015 were included. In all, 230,639 adolescents with abnormally excessive BMI were classified into overweight, classes I, II, and III (severe) obesity. Logistic regression was applied to determine the association between BMI groups and prehypertension, high blood pressure and type 2 diabetes (T2DM). RESULTS: There was 45-fold increase in the prevalence of class III obesity during study period. Severe obesity was recorded in 2060 males and 1149 females, in whom nearly 35 and 43% had prehypertension or high blood pressure, respectively. Compared with adolescents with overweight, the odds ratios (ORs) for high blood pressure in classes II and III obesity groups, respectively, were 2.13 (95% CI, 2.04-2.23) and 2.86 (2.60-3.15) in males, and 2.59 (2.43-2.76) and 3.44 (3.04-3.90) in females, whereas the ORs for T2DM were 19.1 (12.3-29.6) and 38.0 (22.6-64.0) in males, and 15.1 (11.4-20.0) and 24.8 (17.2-35.7) in females. Results persisted in extensive sensitivity analyses including a longitudinal follow-up (median: males, 3.4 years; females, 4.9 years). CONCLUSIONS: Severe obesity showed a marked secular increase and was associated with significantly higher risk for abnormal blood pressure and T2DM than lower degrees of obesity, in both males and females.

Cognitive function in adolescence and the risk for premature diabetes and cardiovascular mortality in adulthood.

BACKGROUND: Epidemiological studies have demonstrated a relationship between cognitive function in youth and the future risk of death. Less is known regarding the relationship with diabetes related death. This study assessed the relationship between cognitive function in late adolescence and the risk for diabetes, cardiovascular- (CVD) and all-cause mortality in adulthood. METHODS: This retrospective study linked data from 2,277,188 16-19 year olds who had general intelligence tests (GIT) conducted during pre-military recruitment assessment with cause of death as coded by the Israel Central Bureau of Statistics. The associations between cognitive function and cause-specific mortality were assessed using Cox models. RESULTS: There were 31,268 deaths that were recorded during 41,916,603 person-years of follow-up, with a median follow-up of 19.2 (IQR 10.7, 29.5) years. 3068, 1443, 514 and 457 deaths were attributed to CVD, CHD, stroke, and diabetes, respectively. Individuals in the lowest GIT vs. highest GIT quintiles in unadjusted models had the highest risk for all-cause mortality (HR 1.84, 95% CI 1.78, 1.91), total CVD (HR 3.32, 95% CI 2.93, 3.75), CHD (HR 3.49 95% CI 2.92, 4.18), stroke (HR 3.96 95% CI 2.85, 5.5) and diabetes-related (HR 6.96 95% CI 4.68, 10.36) mortality. These HRs were attenuated following adjustment for age, sex, birth year, body-mass index, residential socioeconomic status, education and country of origin for all-cause (HR 1.23, 95% CI 1.17, 1.28), CVD (HR 1.76, 95% CI 1.52, 2.04), CHD (HR 1.7 95% CI 1.37, 2.11), stroke (HR 2.03, 95% CI 1.39, 2.98) and diabetes-related (HR 3.14 95% CI 2.00, 4.94) mortality. Results persisted in a sensitivity analyses limited to participants with unimpaired health at baseline and that accounted competing risk. CONCLUSIONS: This analysis of over 2 million demonstrates a strong relationship between cognitive function at youth and the risk for diabetes, all-cause and CVD-related mortality independent of adolescent obesity.

Body mass index is negatively associated with telomere length: a collaborative cross-sectional meta-analysis of 87 observational studies.

Background: Even before the onset of age-related diseases, obesity might be a contributing factor to the cumulative burden of oxidative stress and chronic inflammation throughout the life course. Obesity may therefore contribute to accelerated shortening of telomeres. Consequently, obese persons are more likely to have shorter telomeres, but the association between body mass index (BMI) and leukocyte telomere length (TL) might differ across the life span and between ethnicities and sexes. Objective: A collaborative cross-sectional meta-analysis of observational studies was conducted to investigate the associations between BMI and TL across the life span. Design: Eighty-seven distinct study samples were included in the meta-analysis capturing data from 146,114 individuals. Study-specific age- and sex-adjusted regression coefficients were combined by using a random-effects model in which absolute [base pairs (bp)] and relative telomere to single-copy gene ratio (T/S ratio) TLs were regressed against BMI. Stratified analysis was performed by 3 age categories ("young": 18-60 y; "middle": 61-75 y; and "old": >75 y), sex, and ethnicity. Results: Each unit increase in BMI corresponded to a -3.99 bp (95% CI: -5.17, -2.81 bp) difference in TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -7.67 bp (95% CI: -10.03, -5.31 bp) difference. Each unit increase in BMI corresponded to a -1.58 × 10(-3) unit T/S ratio (0.16% decrease; 95% CI: -2.14 × 10(-3), -1.01 × 10(-3)) difference in age- and sex-adjusted relative TL in the total pooled sample; among young adults, each unit increase in BMI corresponded to a -2.58 × 10(-3) unit T/S ratio (0.26% decrease; 95% CI: -3.92 × 10(-3), -1.25 × 10(-3)). The associations were predominantly for the white pooled population. No sex differences were observed. Conclusions: A higher BMI is associated with shorter telomeres, especially in younger individuals. The presently observed difference is not negligible. Meta-analyses of longitudinal studies evaluating change in body weight alongside change in TL are warranted.

Sero-prevalence of Helicobacter pylori CagA immunoglobulin G antibody, serum pepsinogens and haemoglobin levels in adults.

Associations observed of Helicobacter pylori infection with haemoglobin levels are inconsistent. We examined associations of H. pylori sero-prevalence and serum pepsinogens (PGs), as non-invasive markers of atrophic gastritis, with haemoglobin levels. A cross-sectional study was undertaken among 654 Jewish and 937 Arab residents of Jerusalem, aged 25-78 years, randomly selected from Israel's national population registry in age-sex and population strata. Sera were tested for H. pylori IgG, cytotoxin-associated gene A (CagA) antigen IgG antibody and PGs levels. Multivariable models were fitted to account for confounders. Participants with atrophic gastritis (PGI < 30 µg/L or a PGI: PGII < 3.0) had lower haemoglobin levels than those without: beta-coefficient -0.34 (95% CI -0.59, -0.09); in men -0.27 (95% CI -0.67, 0.12), and in women -0.43 (95% CI -0.74, -0.12). Lower haemoglobin levels were noted in persons with CagA antibody than in those H. pylori sero-negative or H. pylori-CagA sero-negative: beta-coefficient -0.14 (95% CI -0.29, 0.01). Anaemia was more common among women and men with than without atrophic gastritis: adjusted OR 2.58 (95% CI 1.48, 4.48) and 1.52 (95% CI 0.59, 3.95), respectively. In conclusion, independent of known correlates, atrophic gastritis and apparently CagA sero-positivity, a marker of H. pylori virulent strains, are associated with lower haemoglobin levels.

Rapid shortening of leukocyte telomeres is associated with poorer pulmonary function among healthy adults.

AIM: The study aimed to examine the association between leukocyte telomere length (LTL) attrition over 13 years (between mean age 30 and mean age 43) and lung function at mean age 50. MATERIALS & METHODS: In a longitudinal observational study LTL was determined twice on a population-based sample of 481 Jewish residents of Jerusalem at mean ages 30 and 43 years. Pulmonary function was determined at mean age 50 years. Multiple linear regression and multivariable ordinal logistic modeling were applied. Akaike's Information Criteria (AIC) was used for model selection. RESULTS: In unadjusted analysis, Forced Expiratory Volume in 1 s (FEV1%) was inversely associated with the LTL attrition rate (standardized beta = -0.110, P = 0.023) but not with the baseline LTL. Forced Vital Capacity (FVC%) was inversely associated with the LTL attrition rate (standardized beta = -0.108, P = 0.026). Multivariable adjustment mildly attenuated the association with the LTL attrition rate (standardized beta = -0.100, P = 0.034 for FEV1% and -0.093, P = 0.042 for FVC%). This would be consistent with a 3.3% [95% Confidence Interval (CI): 3.1-3.4%] decline in FEV1% and a 3.0% (95% CI:2.8-3.1%) decline in FVC% per year. In linear regression models the LTL-pulmonary function association did not differ by sex, social mobility, pack-years smoking exposure, or level of GlycA, a novel systemic inflammatory marker. CONCLUSIONS: Greater LTL attrition between mean age 30 and mean age 43 was associated with poorer lung function at mean age 50 years. The availability of longitudinal data on LTL attrition for the first time in the current study strengthens the case for LTL change preceding change in lung function.

Sex-specific associations between adolescent categories of BMI with cardiovascular and non-cardiovascular mortality in midlife.

CONTEXT: Most studies linking long-term consequences of adolescent underweight and obesity are limited to men. OBJECTIVE: To assess the sex-specific association of adolescent BMI with cardiovascular- and non-cardiovascular-related mortality in young adulthood and midlife. SETTING: A nationwide cohort. PARTICIPANTS: 927,868 women, 1,366,271 men. INTERVENTIONS: Medical examination data at age 17, including BMI, were linked to the national death registry. MAIN OUTCOMES: Death attributed to cardiovascular (CVD) and non-CVD causes. RESULTS: During 17,346,230 women-years and 28,367,431 men-years of follow-up, there were 451 and 3208 CVD deaths, respectively, and 6235 and 22,223 non-CVD deaths, respectively. Compared to low-normal BMI (18.5-22.0 kg/m2), underweight women had a lower adjusted risk for CVD mortality (Cox hazard ratio (HR) = 0.68; 95% CI 0.46-0.98) in contrast to underweight men (HR = 0.99; 0.88-1.13). The latter were at higher risk for non-CVD mortality (HR = 1.04; 1.00-1.09), unlike underweight women (HR = 1.01; 0.93-1.10). Findings, which persisted when the study sample was limited to those with unimpaired health, were accentuated for the obese with ≥ 30 years follow-up. Both sexes exhibited similarly higher risk estimates already in the high-normal BMI range (22.0 ≤ BMI < 25.0 kg/m2) with overall no interaction between sex and BMI (p = 0.62). Adjusted spline models suggested lower BMI values for minimal mortality risk among women (16.8 and 18.2 kg/m2) than men (18.8 and 20.0 kg/m2), for CVD and non-CVD death, respectively. CONCLUSIONS: Underweight adolescent females have favorable cardiovascular outcomes in adulthood. Otherwise the risk patterns were similar between the sexes. The optimal BMI value for women and men with respect to future CVD outcomes is within or below the currently accepted low-normal BMI range.

Risk factors associated with gastroenteropancreatic neuroendocrine tumors in a cohort of 2.3 million Israeli adolescents.

We investigated whether obesity and sociodemographic factors at adolescence are associated with incident gastroenteropancreatic neuroendocrine tumors (GEP-NET).Our cohort included 2.3 million Israeli adolescents examined at ages 16 to 19 years between 1967 and 2010. The baseline database included sex, country of birth, residential socioeconomic status (SES), body-mass index (BMI) and height. Participants were followed through linkage with the National Cancer Registry up to 2012. We identified 221 cases of GEP-NET (66 pancreatic, 52 gastric, 39 rectal, 27 appendiceal, 23 small bowel and 14 colonic). Immigration from the Former Soviet Union (FSU) was associated with the risk of small bowel and rectal NET's, [Hazard Ratio (HR) 4.79, 95% Confidence Interval (CI) 1.37-16.76 and 3.43, 95% CI 1.20-9.83, respectively].Height >75th percentile and BMI ≥ 85th percentile were associated with increased risk of gastric NET (HR 2.25 95% CI 1.14-4.42 and HR 2.38, 95% CI 1.19-4.75, respectively). Female sex was associated with appendiceal NET (HR 2.30, 95% CI 1.06-4.96) while male gender was associated with an increased risk for NET of the small bowel [HR 4.72 (95% CI 1.10-20.41)].In conclusion, our findings suggest different risk factor associations with the various GEP-NETS: immigrants from the FSU were at increased risk for small bowel and rectal NET; increased height and weight were associated with the risk of gastric NET and females were at increased risk for appendiceal NET. Further focus on the FSU population is indicated in addition to studies verifying the association of BMI and height with gastric NET.

Body Mass Index and Kidney Disease-Related Mortality in Midlife: A Nationwide Cohort of 2.3 Million Adolescents.

OBJECTIVE: This study aimed to evaluate the association of body mass index (BMI) in adolescence with mortality attributed to kidney disease. METHODS: In this study, 2,294,139 Jewish Israeli adolescents with measured weight and height at 17 years old during the military fitness assessment were analyzed with a follow-up extending up to 45 years. All kidney-related outcomes, coded by the Central Bureau of Statistics from death notifications as the underlying cause of death, were obtained by linkage. Cox hazards models were applied. RESULTS: During 42,297,007 person-years of follow-up (median 18.4 years), 226 deaths related to kidney disease were recorded. There was an increased risk for kidney-related death among adolescents with overweight and obesity with adjusted hazard ratios of 2.7 (95% CI: 1.8-3.9) and 8.4 (5.1-13.8), respectively, with BMI between 18.5 and 22.0 kg/m2 as the reference. A 15% increased risk for kidney-related mortality (1.11-1.19) per unit increment in BMI was observed. Furthermore, a multivariable spline model indicated a minimum risk for kidney-related mortality starting at BMI of 18.6 kg/m2 with significantly increased risk seen above values of 22.8 kg/m2 . The results withstood extensive sensitivity analyses, including stratification of kidney-related death attributed to acute, chronic, and total kidney disease. CONCLUSIONS: Adolescent overweight and obesity are risk markers for kidney-related mortality over 4 decades.

Symptoms of Depression and Anxiety as Barriers to Participation in Cardiac Rehabilitation Programs Among Arab and Jewish Patients in Israel.

PURPOSE: Despite its proven efficacy, low participation rates in cardiac prevention and rehabilitation programs (CPRPs) prevail worldwide, especially among ethnic minorities. This is strongly evident in Israel's Arab minority. Since psychological distress has been found to be associated with CPRP participation and minorities are subjected to higher levels of distress, it is plausible that distress may be an important barrier for CPRP participation among minority patients. The current prospective study assessed the contribution of depression and anxiety symptoms to participation in a CPRP after acute coronary syndrome, both in the enrollment phase and when considering adherence over time, among Jewish (majority) and Arab (minority) patients in Israel. METHODS: Patients were interviewed during hospitalization about their emotional status and at a 6-mo follow-up concerning participation in a CPRP. Analyses were performed on 397 patients. The Brief Symptom Inventory was used. Logistic regression modeling was applied. RESULTS: Symptoms of depression, but not anxiety, were frequently observed among Arab patients compared with their Jewish counterparts. In analyses adjusted for age, sex, ethnicity, and sociodemographic and clinical characteristics, having symptoms of anxiety was associated with less participation in a CPRP, evident for both Jews and Arabs; this association was less evident for symptoms of depression. Multivariable adjusted models did not show a significant association of symptoms of anxiety or depression with adherence in a CPRP. Accounting for psychological distress did not reduce the sharp difference between Jews and Arabs in CPRP participation. CONCLUSION: Symptoms of distress may serve as barriers to CPRP participation, regardless of ethnic origin.

Chronic exposure to traffic-related air pollution and cancer incidence among 10,000 patients undergoing percutaneous coronary interventions: A historical prospective study.

Background Exposure to traffic-related air pollution (TRAP) is considered to have a carcinogenic effect. The authors previously reported a nonsignificant association between TRAP and cancer risk in a relatively small cohort of myocardial infarction survivors. This study assessed whether TRAP exposure is associated with subsequent cancer in a large cohort of coronary patients. Methods & results Consecutive patients undergoing percutaneous coronary interventions in a major medical centre in central Israel from 2004 to 2014 were followed for cancer through 2015. Residential levels of nitrogen oxides (NOx) - a proxy for TRAP - were estimated based on a high-resolution national land use regression model. Cox proportional hazards models were constructed to study relationships with cancer. Among 12,784 candidate patients, 9816 had available exposure data and no history of cancer (mean age, 68 years; 77% men). During a median (25th-75th percentiles) follow-up of 7.0 (3.9-9.3) years, 773 incident cases of cancer (8%) were diagnosed. In a multivariable-adjusted model, a 10-ppb increase in mean NOx exposure was associated with hazard ratios (HRs) of 1.07 (95% confidence interval [CI] 1.00-1.15) for all-site cancer and 1.16 (95% CI 1.05-1.28) for cancers previously linked to TRAP (lung, breast, prostate, kidney and bladder). A stronger association was observed for breast cancer (HR = 1.43; 95% CI 1.12-1.83). Associations were slightly strengthened after limiting the cohort to patients with more precise exposure assessment. Conclusion Coronary patients exposed to TRAP are at increased risk of several types of cancer, particularly lung, prostate and breast. As these cancers are amenable to prevention strategies, identifying highly exposed patients may provide an opportunity to improve clinical care.