The effect of Covid-19 mRNA vaccine on serum anti-Müllerian hormone levels.

STUDY QUESTION: Does the administration of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine have an association with ovarian reserve as expressed by circulating anti-Müllerian hormone (AMH) levels? SUMMARY ANSWER: Ovarian reserve as assessed by serum AMH levels is not altered at 3 months following mRNA SARS-CoV-2 vaccination. WHAT IS KNOWN ALREADY: A possible impact of SARS-CoV-2 infection or vaccination through an interaction between the oocyte and the somatic cells could not be ruled out, however, data are limited. STUDY DESIGN, SIZE, DURATION: This is a prospective study conducted at a university affiliated tertiary medical center between February and March 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: Study population included reproductive aged women (18-42 years) that were vaccinated by two Pfizer-BioNTech Covid-19 vaccines (21 days apart). Women with ovarian failure, under fertility treatments, during pregnancy, previous Covid-19 infection or vaccinated were excluded from the study. Blood samples were collected for AMH levels before the first mRNA vaccine administration. Additional blood samples after 3 months were collected for AMH and anti-Covid-19 antibody levels. Primary outcome was defined as the absolute and percentage change in AMH levels. MAIN RESULTS AND THE ROLE OF CHANCE: The study group consisted of 129 women who received two mRNA vaccinations. Mean AMH levels were 5.3 (±SD 4.29) µg/l and 5.3 (±SD 4.50) µg/l at baseline and after 3 months, respectively (P = 0.11). To account for possible age-specific changes of AMH, sub-analyses were performed for three age groups: <30, 30-35 and >35 years. AMH levels were significantly lower for women older than 35 years at all times (P = 0.001 for pre and post vaccination AMH levels versus younger women). However, no significant differences for the changes in AMH levels before and after vaccinations (Delta AMH) were observed for the three age groups (P = 0.46). Additionally, after controlling for age, no association was found between the degree of immunity response and AMH levels. LIMITATIONS, REASONS FOR CAUTION: Although it was prospectively designed, for ethical reasons we could not assign a priori a randomized unvaccinated control group. This study examined plasma AMH levels at 3 months after the first vaccination. It could be argued that possible deleterious ovarian and AMH changes caused by the SARS-CoV-2 mRNA vaccinations might take effect only at a later time. Only longer-term studies will be able to examine this issue. WIDER IMPLICATIONS OF THE FINDINGS: The results of the study provide reassurance for women hesitant to complete vaccination against Covid 19 due to concerns regarding its effect on future fertility. This information could be of significant value to physicians and patients alike. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by Sheba Medical Center institutional sources. All authors have nothing to disclose. TRIAL REGISTRATION NUMBER: The study protocol was approved by the 'Sheba Medical Center' Ethical Committee Review Board (ID 8121-21-SMC) on 8 February 2021 and was registered at the National Institutes of Health (NCT04748172).

Toward deciphering the mechanistic role of variations in the Rep1 repeat site in the transcription regulation of SNCA gene.

Short structural variants-variants other than single nucleotide polymorphisms-are hypothesized to contribute to many complex diseases, possibly by modulating gene expression. However, the molecular mechanisms by which noncoding short structural variants exert their effects on gene regulation have not been discovered. Here, we study simple sequence repeats (SSRs), a common class of short structural variants. Previously, we showed that repetitive sequences can directly influence the binding of transcription factors to their proximate recognition sites, a mechanism we termed non-consensus binding. In this study, we focus on the SSR termed Rep1, which was associated with Parkinson's disease (PD) and has been implicated in the cis-regulation of the PD-risk SNCA gene. We show that Rep1 acts via the non-consensus binding mechanism to affect the binding of transcription factors from the GATA and ELK families to their specific sites located right next to the Rep1 repeat. Next, we performed an expression analysis to further our understanding regarding the GATA and ELK family members that are potentially relevant for SNCA transcriptional regulation in health and disease. Our analysis indicates a potential role for GATA2, consistent with previous reports. Our study proposes non-consensus transcription factor binding as a potential mechanism through which noncoding repeat variants could exert their pathogenic effects by regulating gene expression.

Requisite role for interleukin-4 in the acceleration of fatty streaks induced by heat shock protein 65 or Mycobacterium tuberculosis.

Atherosclerotic lesions can be induced in rabbits and mice immunized with heat shock protein 65 (HSP65). In the current study, we investigated the role of interleukin (IL)-4 in the HSP65- and Mycobacterium tuberculosis (MT)-induced models that exhibit an inflammatory phenotype. Fatty streak formation in IL-4-knockout (IL-4 KO) mice immunized with HSP65 or MT was significantly reduced when compared with lesions in wild-type C57BL/6 mice. However, when injected with control (HSP-free) adjuvant, no differences were evident in the lesion size between wild-type and the IL-4 KO mice. Next, we studied comparatively the extent of humoral and cellular immune responses to HSP65 in the IL-4 KO and wild-type mice, as those are thought to be influential in murine atherosclerosis. Anti-HSP65 antibody levels were reduced in the HSP65-immunized IL-4 KO mice as compared with their wild-type littermates, whereas no differences were evident between the groups with respect to the primary cellular immune response to HSP65. Other than the absence of IL-4 in the knockout mice, the pattern of secreting cytokines interferon-gamma and IL-10 in concanavalin A-primed splenocytes was similar between the groups. HSP65-primed inguinal lymphocytes from IL-4 KO mice immunized with HSP65 secreted higher levels of interferon-gamma (previously shown to be proatherogenic in vivo) as compared with their wild-type controls. 12-/15-Lipoxygenase expression, known to be regulated by IL-4 and to contribute to murine atherosclerosis, in the lesions was not influenced by the immunization protocol used or by IL-4 disruption. Thus, IL-4 may prove a principal cytokine in the progression of early "inflammatory" atherosclerotic lesions and may serve as a target for immunomodulation.

Sex differences in the association between body mass index and hypertension - a cross-sectional study in 717 812 adolescents.

In order to examine sex-specific differences in the association of body mass index (BMI) and hypertension, we conducted a retrospective, cross-sectional study of 717 812 (402 914 men and 314 898 women) Israeli Jewish adolescents aged 16.0-19.99 years medically screened for military service. A diagnosis of hypertension was established per history or if a mean of 10 separate blood pressure measurements exceeded 140/90, following an initial measurement higher than 140/90. Weight and height were measured. Prevalence of hypertension was 0.42% in men and 0.05% in women. In men, BMI was significantly associated with hypertension from the third decile (odds ratio [OR] 1.67, 1.06-2.65) up to the 10th decile (OR 30.17, 20.83-43.69). In women, we observed a significantly increased risk for hypertension in the ninth decile (OR 3.82, 1.42-10.22) and in the 10th decile (OR 18.92, 7.7-46.51), with no visible trend in lower deciles. BMI effects on hypertension prevalence are different in male and female adolescents.

Adoptive transfer of beta(2)-glycoprotein I-reactive lymphocytes enhances early atherosclerosis in LDL receptor-deficient mice.

BACKGROUND: It has been proposed that autoimmune factors can influence the progression of atherosclerosis. We have previously shown that immunization of LDL receptor-deficient (LDL-RD mice) with beta(2)-glycoprotein I (beta2GPI; a principal target of "autoimmune" antiphospholipid antibodies) enhances early atherosclerosis. In the present study, we tested the hypothesis that adoptive transfer of beta2GPI-reactive T cells can accelerate fatty streak formation in LDL-RD mice. METHODS AND RESULTS: LDL-RD mice were immunized with human beta2GPI. An additional group of mice were immunized with beta2GPI and boosted with the same antigen 3 weeks later. Control mice with immunized with human serum albumin. Lymphocytes obtained from the draining lymph node cells or from splenocytes of beta2GPI- or human serum albumin-immunized mice were stimulated in vitro with beta2GPI or with the mitogen concavalin A, respectively. The cultured lymphocytes were transferred intraperitoneally to syngenic LDL-RD mice, and the mice were fed a high-fat "Western" diet for 5 weeks until death. Mice injected with lymphocytes from draining lymph nodes or spleens of beta2GPI-immunized animals displayed larger fatty streaks than those induced by control treated animals. T-cell-depleted splenocytes from beta2GPI were unable to promote lesion formation in the mice. CONCLUSIONS: The present study provides the first direct evidence for a role of antigen (beta2GPI)-reactive T cells in the promotion of fatty streaks in mice.

12/15-Lipoxygenase gene disruption attenuates atherogenesis in LDL receptor-deficient mice.

BACKGROUND: Human 15-lipoxygenase (LO) and its murine analogue 12/15-LO are capable of directly oxidizing esterified fatty acids in lipoproteins and phospholipids. Because these oxidized products possess atherogenic properties, it was suggested that LOs may be involved in enhancing atherogenesis. Previous in vivo tests of the role of LOs in atherogenesis animal models, however, have yielded conflicting results. METHODS AND RESULTS: Aiming to study the role of the 12/15-LO in murine atherogenesis, we crossed LDL-receptor-deficient mice (LDL-R(-/-)) with 12/15-LO-knockout mice and evaluated plaque formation 3 to 18 weeks after initiation of a high-fat diet. Atherosclerotic lesions were considerably reduced in the LDL-R/12/15-LO-double-knockout mice compared with LDL-R(-/-) mice at 3, 9, 12, and 18 weeks, at the aortic root as well as throughout the aorta. The cellular composition of plaques from mice deficient in 12/15-LO did not differ with respect to macrophage and T-lymphocyte content compared with plaques from 12/15-LO littermates. CONCLUSIONS: 12/15-LO plays a dominant role in promoting atherogenesis in LDL-R(-/-) mice.

Immunolocalization of beta2-glycoprotein I (apolipoprotein H) to human atherosclerotic plaques: potential implications for lesion progression.

BACKGROUND: beta2-Glycoprotein I (beta2GPI) is a major antigenic target of antiphospholipid antibodies, which possesses natural anticoagulant properties. The aim of the present study was to determine its presence and localization within human atherosclerotic plaques and to study its association with endothelial cells and monocyte macrophages in vitro. METHODS AND RESULTS: Human atherosclerotic lesions were obtained after carotid endarterectomies and studied immunohistochemically with anti-beta2GPI as well as antibodies to CD4/CD8, macrophages, and adhesion molecules. In vitro, human umbilical vein endothelial cells (HUVECs) and U937 (myelomonocytic cell line) cells were investigated for their ability to associate with radiolabeled beta2GPI. We found beta2GPI to be abundantly expressed within the subendothelial regions and intimal-medial borders of human atherosclerotic plaques and to colocalize with CD4-positive lymphocytes. This observation was confirmed by Western blot applied on homogenates of atherosclerotic lesions with anti-beta2GPI antibodies. Both HUVECs and U937 cells bound labeled beta2GPI, and the process was inhibited by oxidized LDL and not by native LDL. CONCLUSIONS: The abundant presence of human beta2GPI within the lesions, its association with endothelial cells and macrophages, and its colocalization with CD4-positive lymphocytes suggests that it may serve as a target for an immune-mediated reaction that can influence lesion progression.

Effect of hyperglycemia and hyperlipidemia on atherosclerosis in LDL receptor-deficient mice: establishment of a combined model and association with heat shock protein 65 immunity.

Diabetes and atherosclerosis have been proposed to be influenced by immune and autoimmune mechanisms. A common incriminated antigen in both disorders is the heat shock protein (HSP)-60/65. In the current study, we established a model combining hyperglycemia with hyperlipidemia in LDL receptor-deficient (LDL-RD) mice and assessed its possible influences on lipid profile, HSP60/65, and atherogenesis. LDL-RD mice were injected either with streptozotocin to induce hyperglycemia or with citrate buffer (control). When hyperglycemia was induced, both study groups were challenged with a high-fat (Western) diet for 6 weeks. Plasma fasting glucose, lipid profile, and antibody levels to HSP65 and oxidized LDL were assessed. At death, the spleens from both groups were evaluated for their proliferative response to HSP65 and the consequent cytokine production. The extent of atherosclerosis was assessed at the aortic sinus. Plasma glucose, cholesterol, and triglyceride levels were elevated in mice injected with streptozotocin compared with control mice. Atherosclerotic lesions were significantly larger in the streptozotocin-injected hyperglycemic LDL-RD mice (132 +/- 23 x 10(5) microm2) in comparison to their normoglycemic litter-mates (20 +/- 6.6 x 10(5) microm2; P < 0.0001). Both humoral and cellular immune response to HSP65 was more pronounced in streptozotocin-injected mice. When challenged with HSP65 in vitro, splenocytes from streptozotocin-injected mice favored the production of the T-helper (TH)-1 cytokine gamma-interferon. In conclusion, we have established a mouse model that combines hyperglycemia with diet-induced hyperlipidemia in LDL-RD mice and studied its effect on atherosclerosis progression. The accelerated atherosclerotic process is associated with heightened immune response to HSP65 and a shift to a TH1 cytokine profile.

Cellular and humoral immune responses to heat shock protein 65 are both involved in promoting fatty-streak formation in LDL-receptor deficient mice.

OBJECTIVES: This study was designed to determine the role of cellular and humoral immune responses to heat shock protein 65 (HSP65) in murine atherosclerosis. BACKGROUND: Inflammatory processes appear to influence the progression of atherosclerosis. Immunization with HSP65 was previously shown to induce arteriosclerosis in rabbits and to enhance fatty-streak formation in mice. However, it has not been demonstrated directly whether HSP65-reactive antibodies and lymphocytes are separately capable of influencing lesion formation. METHODS: Low density lipoprotein-receptor deficient (LDL-RD) mice were immunized with HSP65 or control bovine serum albumin (BSA). Lymph-node cells, splenocytes and immunoglobulin G (IgG) were obtained from the immunized mice and transferred separately to six groups of syngenic LDL-RD mice. RESULTS: Adoptive transfer of HSP65-reactive lymph node cells increased fatty-streak formation in comparison with mice treated with BSA-primed cells. Similarly, transfer of splenocytes reactive with HSP65 led to enhanced fatty-streak generation compared with mice injected with BSA-sensitized splenocytes. Repeated intraperitoneal administration of IgG from serum of HSP65-immunized mice (every 10 days) enhanced fatty-streak formation in mice in comparison with their anti-BSA-IgG injected littermates. CONCLUSIONS: Antibodies and lymphocytes reactive to HSP65 promote fatty-streak formation in mice, providing direct evidence for the proatherogenic properties of cellular and humoral immunity to HSP65.

A mouse model for heparin-induced thrombocytopenia.

Heparin-induced thrombocytopenia (HIT) occurs in 1% to 3% of patients receiving heparin and results from the development of antibodies that recognize heparin-platelet factor 4 (H-PF4) complexes that form on the surface of activated platelets and on the vascular endothelium. With the aim of studying the pathogenic importance of these anti-H-PF4 antibodies in vivo, we attempted to create an animal model of HIT. Such a model was produced by immunization of naive mice with affinity-purified IgG anti-H-PF4 antibodies from two patients with HIT. The immunized mice developed specific antibodies (anti-idiotypic) against the human anti-H-PF4 antibodies and 2 months later, anti-anti-idiotypic antibodies appeared, which functionally resembled the human HIT antibody. Indeed, when the animals bearing anti-anti-idiotypic antibodies were injected with heparin for 4 days, a significant decrease in their platelet counts was observed; however, heparin treatment was not associated with thrombosis in any of the immunized mice. Similar to the observation in HIT patients, injections of equivalent doses of low-molecular-weight (LMW) heparin to the immunized animals did not induce thrombocytopenia. The results of this study support the importance of anti-H-PF4 antibodies in the pathogenesis of HIT. The mouse HIT model may provide a convenient system for studies on the immunoregulation of anti-H-PF4 expression and for evaluation of potential therapeutic modalities.

Hyperimmunization of apo-E-deficient mice with homologous malondialdehyde low-density lipoprotein suppresses early atherogenesis.

The role of the immune system in modulating atherosclerosis has recently been the subject of intensive research. Several previous authors have put forward a paradigm of the autoimmune process occurring in the vicinity of the plaque. Two recent studies have shown that immunization of rabbits with homologous modified low-density lipoprotein (LDL) led to suppression of atherosclerosis. In the current study we evaluated the effects of homologous malondialdehyde (MDA)-LDL immunizations on atherogenesis in apo-E-deficient mice. Two groups of female chow-diet-fed, apo-E-deficient mice (n = 10) were either immunized with homologous MDA-LDL or with phosphate buffer saline (PBS) at 2-week intervals. The mice were sacrificed 12 weeks following the primary immunization. The MDA-LDL-immunized mice were shown to develop high titers of anti-MDA-LDL antibodies. Atherosclerosis, determined by the lesion size at the aortic sinus, was significantly suppressed in the MDA-LDL-immunized mice as compared with their littermates immunized with PBS (mean area +/- S.D.; 74000 +/- 17300 microm2 versus 158000 +/- 12800 microm2; P < 0.01). No differences were found between the groups with respect to the cellular composition of the atherosclerotic plaques. The results of this study show that immunization with MDA-LDL has a protective effect in apo-E-deficient mice, and further suggests that this mouse model is suitable for studies of immunomodulation.

Malignant thymoma associated with autoimmune diseases: a retrospective study and review of the literature.

OBJECTIVES: To determine whether malignant thymoma is associated with high rates of concomitantly occurring autoimmune diseases. METHODS: Sheba Medical Center computer records from 1966 to 1995 were reviewed to identify patients with malignant thymoma, either type I (invasive thymoma) or type II (thymic carcinoma). All patients who had malignant thymoma and autoimmune phenomena were analyzed. The diagnosis of thymic neoplasm was confirmed by two independent pathologists. The diagnosis of autoimmune diseases was based on both clinical and serological findings. RESULTS: Six of 22 (27%) cases of malignant thymoma had an autoimmune disease. Five patients had type I malignant thymoma and either myasthenia gravis (four patients) or Graves' disease (one patient). Only one patient had type II malignant thymoma with Sjögren's syndrome. The diagnosis of autoimmune disease preceded the diagnosis of thymic neoplasm in four cases, and was diagnosed simultaneously in two. CONCLUSIONS: Malignant thymomas are highly associated with autoimmune diseases, as are benign thymomas. To our knowledge, we report the first documented cases of a patient with thymic carcinoma and Sjögren's syndrome, and another with invasive thymoma and Graves' disease.

Valvular deposition of antiphospholipid antibodies in the antiphospholipid syndrome: a clue to the origin of the disease.

In this report we present an unusual case of a 45-year-old female patient with systemic lupus erythematosus (SLE) who was hospitalized for mitral valve replacement. In her childhood she presented with mitral stenosis and chorea on which grounds a preliminary diagnosis of rheumatic fever was established. After a quiescent period lasting two decades her disease erupted with mitral stenosis, thromboembolic phenomena, and nephritis. Due to severe malfunctioning of her mitral valve, the patient eventually underwent mitral valve replacement. The antibodies involved in the pathogenesis of our patient's valvular disease were studied by immunohistochemical analysis, applying rabbit polyclonal anti-human IgG and IgM anti-human C3c and anti-idiotypes to a mouse monoclonal naturally occurring polyspecific human monoclonal anti-cardiolipin antibody termed S2.9, and to the 16/6 Id which defines a common Id on anti-DNA antibodies in patients with SLE. Immunoperoxidase staining using an anti-idiotype mAb to anti-cardiolipin antibodies demonstrated the deposition of these anti-bodies in the subendothelial layer of the valve. We believe that anti-phospholipid syndrome (APS) with SLE was the initial and primary disease in this patient. These findings clearly indicate that APS must be considered in the differential diagnosis of rheumatic fever, particularly in young female patients who present with mitral stenosis and chorea.

Subcutaneous T-cell lymphoma in a patient with rheumatoid arthritis not treated with cytotoxic agents.

This case report describes an 81-year-old patient with prolonged rheumatoid arthritis (RA), which was complicated by the occurrence of a subcutaneous T-cell lymphoma. During the course of his illness the patient had not been treated with disease-modifying agents (i.e. cytotoxic agents), but only symptomatically with anti-inflammatory drugs. This finding demonstrates a previously undescribed association between RA and a rare from of subcutaneous T-cell lymphoma, which may add more information to the controversial issue of emergence of malignancy in RA.

Proliferation, apoptosis and thymic involution.

The thymus reaches its maximal size at the age of 1 month in ICR mice and thereafter, the thymic cortex undergoes an exponential decline. This study was designed to compare the proliferation and apoptosis of thymocytes in different parts of the thymus of ICR female mice at the beginning and after the rapid phase of decline of the thymic cortical cellularity. The pattern of proliferation and apoptosis of the thymus was studied in situ in 1-month-old ICR female mice (10 mice) compared to mice at 7 months of age (10 mice). Staining for argyrophylic nucleolar organizer region by histochemistry was used to determine the proportion of type 2 thymocytes, which are considered as cells at S phase of the cell cycle. The mean number of type 2 cells in four random samples of 50 cells in each part of the thymus was defined as the proliferation index of this part of the thymus. In situ detection of apoptosis of thymocytes was carried out using the Apoptag kit, which can detect a single cell apoptosis. The mean number of apoptotic cells in five randomly selected fields of each part of the thymus was defined as the apoptotic index of this part of the thymus. The proliferation index of the peripheral cortex of the 1-month-old mice was 3.6 times higher than the proliferation index of the deep cortex and 5.8 times higher than the proliferation index of the medulla (P < 0.0001). The proliferation index of the peripheral cortex of the 7-month-old mice was reduced by 45% compared to the 1-month-old mice (P < 0.005). The apoptotic index of the corticomedullary junction of the 1-month-old mice was six times higher than the apoptotic index of the cortex and 18 times higher than the apoptotic index of the medulla. The apoptotic index of the thymic cortex was elevated by 66% in the 7-month-old mice compared to the 1-month-old mice (P < 0.0001). We conclude that there is a reduction of the proliferation index and an elevation of the apoptotic index of the thymic cortex in adult mice compared to young mice. These changes might account for the reduction of thymic cortical cellularity during thymic involution.

Clinical characteristics of ruptured chordae tendineae in hospitalized patients: primary tear versus infective endocarditis.

BACKGROUND: Several etiologies have been associated with the rupture of chordae tendineae. The leading causes are infective endocarditis, primary rupture, and the association with various connective tissue disorders. HYPOTHESIS: In order to define the attributes of these patients, a retrospective study was conducted that investigated the medical files of hospitalized patients in the Sheba Medical Center, Tel-Hashomer, Israel. METHODS: Twenty patients (17 men, 3 women) with ruptured chordae were detected. Primary rupture of the chordae tendineae had been diagnosed in 11 patients, while infectious endocarditis was the cause for the tear of the chordae tendineae in 9 patients. The patients who had primary rupture of the chordae were older than the patients with endocarditis (67.4 +/- 11.3 vs. 57 +/- 9.3 years, respectively, p < 0.05). RESULTS: The posterior mitral valve cusp was more commonly involved (15 patients). Six of the patients with posterior mitral valve cusp involvement manifested atrial fibrillation. Mitral valve prolapse (MVP) was detected among seven patients, six of whom belonged to the group with infective endocarditis. CONCLUSION: Primary tear and infective endocarditis are leading etiologies of ruptured chordae tendineae in hospitalized patients. Particularly among the patients with infective endocarditis, concomitant MVP was frequently detected. It is the authors' opinion that this coexistence implies that MVP may predispose to the rupture of chordae tendineae.

Temperature dependence of the electrical resistivity of social wasp cuticle: a comparative study.

Resistance to electricity by social wasp cuticle is temperature dependent within the range of 1--40 degrees C. This was measured on the species Vespa orientalis (the Oriental hornet), Vespa crabro (the European hornet) and the wasp Dolichovespula saxonica. The resistance at first decreases with increased temperature, reaching a nadir which differs according to species, and then rises again up to 40 degrees C, the highest temperature tested. It is suggested that the cuticular changes in resistivity at different temperatures reflect the wasp's mechanism for detecting and regulating the temperature in their normal environment.

Population-based trends in overweight and obesity: a comparative study of 2,148,342 Israeli male and female adolescents born 1950-1993.

BACKGROUND: The epidemic of obesity has been identified as a major source of morbidity, not just in developed countries but globally, in adults as well as at younger ages. OBJECTIVE: The aims of this study were to describe trends in obesity and overweight in Israeli adolescents and observe temporal changes and association by risk factors. METHODS: The research analyzed records of 2,148,342 Jewish adolescents, over a span of 44 years and included data for individual body measurements, place of residence, area of origin and education levels. Body mass index (BMI) was measured by professionals, calculated and categorized as overweight or obesity according to age- and gender-specific BMI curves established in recent years. We processed the data in multinomial logistic regression model and calculated odds ratios for various risk factors. RESULTS: Obesity and overweight are on the rise for male and female adolescents born from the mid-1960s onwards, and especially for men from the 1980s onwards. Risk factors for male adolescents include lower socioeconomic status, inferior education levels and Western origins (vs. Asian, African or Israeli origins). Risk modifiers for women were similar, except for African origins, which were associated with increased risk rather than decreased risk. Asian and Israeli origins were protective for both genders, and education was more strongly associated with obesity for women. CONCLUSIONS: We recommend stronger preventive efforts directed at adolescents as a whole, and particularly vulnerable groups with lower education levels and poverty, or those with specific geographical origins. Gender disparities are evident and should be considered in these efforts and in further research.

Varicocoele among 1 300 000 Israeli adolescent males: time trends and association with body mass index.

Scarce data are available on epidemiology of varicocoele, the most common surgically correctable cause of male infertility. The objectives of this study were to evaluate the association between body mass index (BMI) and varicocoele and to assess trends in prevalence over time. We conducted a nationwide population-based long-term (1967-2010) study among 1 323 061 Israeli adolescent males using data from mandatory medical examination. BMI was grouped into underweight, normal weight, overweight and obese categories by percentiles adjusted for age in months and by further classification to five categories within normal weight. Univariable and multivariable logistic regression models were constructed, adjusting for possible confounders. Varicocoele prevalence (N = 47 398) increased during the study period from 1.6% for the 1950-1954 birth cohort to 4.6% for the 1990-1993 birth cohort, with the steepest rise in the normal weight group. Varicocoele unadjusted rates were highest (4.1%) among underweight and lowest (1.6%) among obese. In a multivariable model, adjusted for birth cohort, height, age and socio-demographic factors, we found a decreased risk for varicocoele in the overweight group [odds ratio (OR) = 0.51, 95% confidence interval (CI): 0.49, 0.54] and the obese group (OR = 0.34, 95% CI: 0.32, 0.37), compared with the normal weight group. Within the normal weight group, a monotonic inverse association between BMI percentile and varicocoele was observed, most notable among 75-84.9 percentile compared to 25-49.9 percentile (OR = 0.65, 95% CI: 0.63, 0.68). In conclusion, varicocoele is common among adolescents in Israel, and its prevalence had increased in recent decades, providing clues to direct further andrological research on the role of modern lifestyle and environment in the aetiology of varicocoele. BMI, across percentiles, was found to be monotonically inversely associated with varicocoele, thus directing research and clinical efforts.