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This study analyzed the association between adolescent BMI and myopia severity.This cross-sectional study comprised 1,359,153 adolescents who were medically examined before mandatory military service. Mild-to-moderate and high myopia were defined based on right-eye refractive data. BMI was categorized based on the US age- and sex-matched percentiles. Logistic regression models were applied separately for women and men to estimate odds ratios (ORs) for myopia per BMI category.A total of 318,712 adolescents had mild-to-moderate myopia and 23,569 had high myopia. Compared with low-normal BMI (reference group), adjusted ORs for mild-to-moderate and high myopia increased with increasing BMI status, reaching 1.39 (95% CI: 1.23-1.57) and 1.73 (95% CI: 1.19-2.51) for men with severe obesity, respectively, and 1.19 (95% CI: 1.12-1.27) and 1.38 (95% CI: 1.14-1.65) for women with mild obesity, respectively. ORs for mild-to-moderate and high myopia were also higher in men with underweight (OR = 1.20; 95% CI: 1.18-1.23 and OR = 1.39; 95% CI: 1.30-1.47) and women with underweight (OR = 1.06; 95% CI: 1.03-1.09 and OR = 1.12; 95% CI: 1.04-1.22). The overall size effect was greater for men than women (pBMI was associated with myopia in a J-shaped pattern, with the size effect being greater for adolescent men than women. This study indicates that both low BMI and high BMI are associated with mild-to-moderate and severe myopia.

Congenital Hypothyroidism (CH) due to dyshormonogenesis may occur due to mutations in any of the key genes involved in thyroid hormone biosynthesis (TG, TPO, DUOX2, DUOXA2, SLC5A5, IYD, SLC26A4 and SLC26A7). Mutations in the Thyroglobulin gene (TG) are frequently associated with goiter, which may present fetally or neonatally, although a spectrum of phenotypes is reported. We present the case of a woman of Eritrean origin who presented in the third trimester of pregnancy in the early stages of labor. Ultrasound at presentation revealed a fetal neck swelling consistent with a goiter. Following delivery by caesarian section with minimal respiratory support, the infant was found to be hypothyroid with undetectable serum levels of thyroglobulin. Sequencing of the thyroglobulin gene revealed a homozygous donor splice site pathogenic variant (c.5686+1delG) not previously described in the literature. Levothyroxine treatment resulted in normal growth and psychomotor development. Goitrous CH with inappropriately low thyroglobulin has previously been reported in patients harbouring homozygous single nucleotide substitutions at the same TG donor splice site which result in exon skipping and Endoplasmin Reticulum retention of TG. We conclude that the TG c.5686+1delG pathogenic variant is the likely basis for our patient's fetal goiter and congenital hypothyroidism, and that the clinical phenotype associated with TG c.5686+1delG is comparable to that seen with single nucleotide substitutions at the same site.

Women with primary ovarian insufficiency exhibit an unfavorable cardiovascular risk profile. A common cause for primary ovarian insufficiency is fragile X premutation (FXPC), and data on the cardiovascular risk factors in women with FXPC are scarce. We aimed to assess the prevalences of abnormal metabolic components among FXPC.Clinical, anthropometric and laboratory data were collected from 71 women with FXPC and compared to 78 women referred for counseling in an in-vitro fertilization clinic (control group). The mean ± SD ages of the FXPC and control groups were 33.5 ± 5.6 and 36.2 ± 5.3 years, respectively (p = 0.003). In a logistic regression analysis, the FXPC group had increased risks for hyperglycemia, hypertriglyceridemia, central obesity and low high-density lipoprotein cholesterol, of 21.8-fold (95% CI 2.7-175, p = 0.004), 6.9-fold (95% CI 2.5-18.7, p 0.0001), 3.1-fold (95% CI 1.4-6.9, p = 0.005) and 2.4-fold (95% CI 1.1-5.2, p = 0.03), compared to the control group. The FXPC group had 2.7-fold higher prevalence of two abnormal metabolic components; 19% met the full criteria of MetS, compared to 3% of the control group. Neither CGG repeats nor ovarian reserve markers were associated with metabolic risk.Carriers of fragile X premutation are at increased metabolic risk from early adulthood; waist circumference, glucose and lipid levels are particularly elevated. We recommend metabolic screening for all women with FMR1 premutation, to enable early interventions for prevention of long-term cardiovascular comorbidities.

OBJECTIVE Previous studies have demonstrated an association between gut microbiota composition and type 1 diabetes (T1D) pathogenesis. However, little is known about the composition and function of the gut microbiome in adults with longstanding T1D or its association with host glycemic control. RESEARCH DESIGN AND METHODS We performed a metagenomic analysis of the gut microbiome obtained from fecal samples of 74 adults with T1D, 14.6 ± 9.6 years following diagnosis, and compared their microbial composition and function to 296 age-matched healthy control subjects (1:4 ratio). We further analyzed the association between microbial taxa and indices of glycemic control derived from continuous glucose monitoring measurements and blood tests and constructed a prediction model that solely takes microbiome features as input to evaluate the discriminative power of microbial composition for distinguishing individuals with T1D from control subjects. RESULTS Adults with T1D had a distinct microbial signature that separated them from control subjects when using prediction algorithms on held-out subjects (area under the receiver operating characteristic curve = 0.89 ± 0.03). Linear discriminant analysis showed several bacterial species with significantly higher scores in T1D, including Prevotella copri and Eubacterium siraeum, and species with higher scores in control subjects, including Firmicutes bacterium and Faecalibacterium prausnitzii (P < 0.05, false discovery rate corrected for all). On the functional level, several metabolic pathways were significantly lower in adults with T1D. Several bacterial taxa and metabolic pathways were associated with the host’s glycemic control. CONCLUSIONS We identified a distinct gut microbial signature in adults with longstanding T1D and associations between microbial taxa, metabolic pathways, and glycemic control indices. Additional mechanistic studies are needed to identify the role of these bacteria for potential therapeutic strategies.

To evaluate the incidence and severity of ketoacidosis (DKA) at type 1 diabetes diagnosis during the first wave of the coronavirus disease 2019 (COVID-19) pandemic in Israel.A population-based study the product of a national collaboration of Israeli pediatric diabetes centers investigated the presentation of childhood-onset type 1 diabetes. The frequencies of DKA and severe DKA observed during the COVID-19 period from March 15, 2020 (commencement of the first nationwide lockdown) until June 30, 2020 were compared with the same periods in 2019, 2018, and 2017 using multivariable logistic regression, adjusting for age, sex, and socioeconomic position.During the COVID-19 period, DKA incidence was 58.2%, significantly higher than in 2019 (adjusted OR [aOR] 2.18 [95% CI, 1.31-3.60], P = 0.003); 2018 (aOR 2.05 [95% CI, 1.26-3.34], P = 0.004); and 2017 (aOR, 1.79 [95% CI, 1.09-2.93], P = 0.022). The incidence of severe DKA was 19.9%, significantly higher than in 2018 (aOR, 2.49 [95% CI, 1.20-5.19], P = 0.015) and 2017 (aOR, 2.73 [95% CI, 1.28-5.82], P = 0.009). In 2020, admissions and duration of stay in the intensive care unit were higher than in previous years (P = 0.001). During the COVID-19 pandemic, children aged 6-11 years had higher incidences of DKA (61.3% vs. 34.0%, 40.6%, and 45.1%, respectively, P = 0.012), and severe DKA (29.3% vs. 15.1%, 10.9%, and 5.9%, respectively, P = 0.002).The dramatic increase in DKA at presentation of childhood-onset type 1 diabetes during the COVID-19 pandemic mandates targeted measures to raise public and physician awareness.

Fatty acid-binding protein 4 (FABP4) is an adipokine with a key regulatory role in glucose and lipid metabolism. We prospectively evaluated the role of FABP4 in the pathophysiology of diabetic ketoacidosis (DKA) in new-onset type 1 diabetes. Clinical and laboratory data were prospectively collected from consecutive children presenting with new-onset type 1 diabetes. In addition to blood chemistry and gases, insulin, C-peptide, serum FABP4 and NEFA were collected upon presentation and 48 h after initiation of insulin treatment. In a mouse model of type 1 diabetes, glucose, insulin, β-hydroxybutyrate and weight were compared between FABP4 knockout (Fabp4−/−) and wild-type (WT) mice. Included were 33 children (mean age 9.3 ± 3.5 years, 52% male), of whom 14 (42%) presented with DKA. FABP4 levels were higher in the DKA group compared with the non-DKA group (median [IQR] 10.1 [7.9–14.2] ng/ml vs 6.3 [3.9–7] ng/ml, respectively; p = 0.005). The FABP4 level was positively correlated with HbA1c at presentation and inversely correlated with venous blood pH and bicarbonate levels (p

OBJECTIVE Despite technological advances, results from various clinical trials have repeatedly shown that many individuals with type 1 diabetes (T1D) do not achieve their glycemic goals. One of the major challenges in disease management is the administration of an accurate amount of insulin for each meal that will match the expected postprandial glycemic response (PPGR). The objective of this study was to develop a prediction model for PPGR in individuals with T1D. RESEARCH DESIGN AND METHODS We recruited individuals with T1D who were using continuous glucose monitoring and continuous subcutaneous insulin infusion devices simultaneously to a prospective cohort and profiled them for 2 weeks. Participants were asked to report real-time dietary intake using a designated mobile app. We measured their PPGRs and devised machine learning algorithms for PPGR prediction, which integrate glucose measurements, insulin dosages, dietary habits, blood parameters, anthropometrics, exercise, and gut microbiota. Data of the PPGR of 900 healthy individuals to 41,371 meals were also integrated into the model. The performance of the models was evaluated with 10-fold cross validation. RESULTS A total of 121 individuals with T1D, 75 adults and 46 children, were included in the study. PPGR to 6,377 meals was measured. Our PPGR prediction model substantially outperforms a baseline model with emulation of standard of care (correlation of R = 0.59 compared with R = 0.40 for predicted and observed PPGR respectively; P < 10−10). The model was robust across different subpopulations. Feature attribution analysis revealed that glucose levels at meal initiation, glucose trend 30 min prior to meal, meal carbohydrate content, and meal’s carbohydrate-to-fat ratio were the most influential features for the model. CONCLUSIONS Our model enables a more accurate prediction of PPGR and therefore may allow a better adjustment of the required insulin dosage for meals. It can be further implemented in closed loop systems and may lead to rationally designed nutritional interventions personally tailored for individuals with T1D on the basis of meals with expected low glycemic response.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) and its complications are increasing worldwide. Youth-onset T2DM has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected. People with youth-onset T2DM often have a more aggressive clinical course than those with adult-onset T2DM or those with type 1 diabetes mellitus. Moreover, the available treatment options for children and adolescents with T2DM are more limited than for adult patients. Intermediate complications of youth-onset T2DM, such as increased albuminuria, often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life. The increasing frequency, earlier onset and greater severity of childhood obesity in the past 50 years together with increasingly sedentary lifestyles and an increasing frequency of intrauterine exposure to diabetes are important drivers of the epidemic of youth-onset T2DM. The particularly high risk of the disease in historically disadvantaged populations suggests an important contribution of social and environmental factors, including limited access to high-quality health care, healthy food choices and opportunities for physical activity as well as exposure to stressors including systemic racism and environmental pollutants. Understanding the mechanisms that underlie the development and aggressive clinical course of youth-onset T2DM is key to identifying successful prevention and management strategies.

Purpose To investigate the association between stuttering in adolescence and incident type 2 diabetes in young adulthood. Methods This nationwide population-based study included 2 193 855 adolescents of age 16 to 20 years who were assessed for military service between 1980 and 2013. Diagnoses of stuttering in adolescence were confirmed by a speech-language pathologist. Diabetes status for each individual as of December 31, 2016, was determined by linkage to the Israeli National Diabetes Registry. Relationships were analyzed using regression models adjusted for socioeconomic variables, cognitive performance, coexisting morbidities, and adolescent body mass index. Results Analysis was stratified by sex (Pinteraction = 0.035). Of the 4443 (0.4%) adolescent men with stuttering, 162 (3.7%) developed type 2 diabetes, compared with 25 678 (2.1%) men without stuttering (adjusted odds ratio [OR] 1.3; 95% CI, 1.1-1.6). This relationship persisted when unaffected brothers of men with stuttering were used as the reference group (adjusted OR = 1.5; 95% CI, 1.01-2.2), or when the analysis included only adolescents with unimpaired health at baseline (adjusted OR = 1.4; 95% CI, 1.1-1.7). The association was stronger in later birth cohorts, with an adjusted OR of 2.4 (1.4-4.1) for cases of type 2 diabetes before age 40. Of the 503 (0.1%) adolescent women with stuttering 7 (1.4%) developed type 2 diabetes, compared with 10 139 (1.1%) women without stuttering (OR = 2.03; 95% CI, 0.48-2.20). Conclusions Adolescent stuttering is associated with an increased risk for early-onset type 2 diabetes among men.

Aims Studies in children reported an association between increased body mass index (BMI) and risk for developing type 1 diabetes (T1D), but evidence in late adolescence is limited. We recently investigated the association between adolescent BMI and type 2 diabetes in young adulthood (Diabetes Care 2020, 43(7): 1487-95) and here we studied on the same cohort the association between late adolescent BMI and incident T1D. Methods All Israeli adolescents, ages 16-19, undergoing medical evaluation in preparation for mandatory military conscription between January 1996 and December 2016 were included for analysis unless they had a history of dysglycemia (n=1,462,362; 40% women). Data were linked to information about adult onset of T1D in the Israeli National Diabetes Registry. Weight and height were measured at study entry and BMI was computed and transformed to age- and sex-adjusted BMI percentiles according to US Center for Diseases Control. The definition of T1D was determined based on anti-diabetic drugs and was confirmed for a subpopulation of the cohort to which islet autoantibodies data were available. Cox proportional models were applied, with BMI analyzed both as a categorical and continuous variable. Results There were 777 incident cases of T1D during 15,810,751 person-years (mean age at diagnosis 25.2±3.9 years). The median follow-up period was 11.2 years (IQR 5.8-16.3), with follow-up length shorter for individuals with a higher BMI. The crude diabetes rate showed a consistent graded increase across BMI groups from underweight to obesity; 3.6 to 8.4 cases per 100,000 person-years, respectively. In a multivariable model adjusted for age, sex and socio-demographic variables, the hazard ratios (HRs) for T1D were 1.05 (95% CI 0.87-1.27) for the 50th–74th BMI percentiles, 1.41 (1.11–1.78) for the 75th–84th BMI percentiles, 1.54 (1.23–1.94) for adolescents with overweight (85th–94th percentiles), and 2.05 (1.58–2.66) for adolescents with obesity (BMI≥95th percentile)(reference group, 5th-49th BMI percentile group). One increment in BMI standard deviation was associated with 25% greater risk for incidence of T1D (HR=1.25, 95%CI 1.17-1.32). when the presence of one or multiple (≥2) islet antibodies was added as a criterion for T1D definition, the HRs among those with adolescent obesity were 2.90 (1.80-4.68) and 3.14 (1.68-5.88) respectively. Results were marginally affected by level of adjustment for sociodemographic background, were similar when analysis was stratified by sex, and also persisted when the study population was limited to adolescents with unimpaired health in order to mitigate confounding by coexisting illness. The fraction of type 1 diabetes attributed to adolescent overweight and obesity (Population attributable risk%; PAR%) was 10.1% (95%CI 6.3%-14.2%). Conclusions Adolescent overweight and obesity in apparently healthy adolescents were associated with increased risk for incident type 1 diabetes in early adulthood. Presentation: Sunday, June 12, 2022 12:30 p.m. - 2:30 p.m., Monday, June 13, 2022 1:24 p.m. - 1:30 p.m.

OBJECTIVE Gestational hyperglycemia is associated with deleterious neonatal outcomes, but long-term risks for offspring obesity are less clear. We estimated the odds for offspring adolescent overweight and obesity among mothers with gestational glucose intolerance. RESEARCH DESIGN AND METHODS In a mother-offspring historical cohort, the Israel military conscription data set was linked to a large health maintenance organization. Included were women who were evaluated at adolescence and underwent two-step gestational diabetes screening (mean age, 31 years) with a 50-g glucose challenge test (GCT), followed by a 100-g oral glucose tolerance test (OGTT) if the result was abnormal. Glucose tolerance categories included gestational normoglycemia, abnormal GCT with normal OGTT, impaired glucose tolerance (IGT; one abnormal OGTT value), and gestational diabetes. The primary outcome was offspring overweight/obesity (BMI ≥85th percentile) at adolescence, measured prior to military conscription. Logistic regression models were applied. RESULTS Of 33,482 mother-offspring pairs, overweight and obesity were observed in 6,516 offspring. Across increasing categories of pregnancy glycemia, the proportions of offspring with adolescent overweight/obesity increased: normoglycemia, 19%; abnormal GCT with normal OGTT, 22%; gestational IGT, 24%; and gestational diabetes, 25% (P < 0.0001). Corresponding odds ratios after adjustment for the mother’s late adolescent characteristics (sociodemographic confounders and BMI) and pregnancy age were 1.2 (95% CI 1.1–1.4), 1.3 (1.2–1.5), and 1.4 (1.3–1.6), respectively. Further adjustment for offspring birth weight percentile and sociodemographic variables did not materially change results. Associations were more pronounced with increasing obesity severity. CONCLUSIONS Gestational glucose intolerance, including categories not meeting the gestational diabetes threshold, was associated with increased odds for offspring overweight/obesity at late adolescence.

Objective: Gestational hyperglycemia is associated with deleterious neonatal outcomes, but long-term risks for offspring obesity are less clear. We estimated the odds for offspring adolescent overweight and obesity among mothers with gestational glucose intolerance. Methods: In a mother-offspring, historical cohort, the Israel military conscription dataset was linked to a large health maintenance organization. Included were women who were evaluated at adolescence and performed two-step gestational diabetes screening (mean age, 31 years) with a 50-g glucose challenge test (GCT) , followed by a 100-g oral glucose tolerance test (OGTT) if abnormal. Glucose tolerance categories included gestational normoglycemia, abnormal GCT with normal OGTT, impaired glucose tolerance (IGT; one abnormal OGTT value) , and gestational diabetes. The primary outcome was offspring overweight/obesity (BMI≥85th percentile) at adolescence, measured prior to military conscription. Logistic regression models were applied. Results: Of 33,482 mother-offspring pairs, overweight and obesity were observed in 6,516 offspring. Across increasing categories of pregnancy glycemia, the proportions of offspring with adolescent overweight/obesity increased: normoglycemia, 19%; abnormal GCT with normal OGTT, 22%; gestational IGT, 24%; and gestational diabetes, 25%, P Conclusions: Gestational glucose intolerance, including categories not meeting the gestational diabetes threshold, were associated with increased odds for offspring overweight/obesity at late adolescence. Disclosure C.D.Bendor: None. Y.Lebenthal: Advisory Panel; Lilly, Novo Nordisk, Research Support; Novo Nordisk, Pfizer Inc., Speaker's Bureau; Pfizer Inc. A.Afek: None. G.Chodick: None. G.Twig: None. A.Bardugo: None. R.Rotem: None. E.Derazne: None. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. D.Tzur: None. O.Pinhas-hamiel: Advisory Panel; Novo Nordisk, Speaker's Bureau; Pfizer Inc. A.M.Tsur: None. T.Cukierman-yaffe: Research Support; European Association for the Study of Diabetes, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk, Speaker's Bureau; AstraZeneca, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi.

Background: Studies in children reported an association between increased body mass index (BMI) and risk for developing type 1 diabetes (T1D) . We studied the association between adolescent BMI and incident T1D in young adulthood in a nationwide cohort of 1,462,362 adolescents which was recently used to assess the association between adolescent BMI and early-onset type 2 diabetes (Diabetes Care 2020 Jul;43 (7) :1487-1495) . Methods: All Israeli adolescents, ages 16-19, undergoing medical evaluation in preparation for mandatory military conscription between January 1996 and December 2016 were included for analysis unless they had a history of dysglycemia. Data were linked to information about adult onset of T1D in the Israeli National Diabetes Registry. Weight and height were measured at the study entry. Cox proportional models were applied, with BMI analyzed both as a categorical and as a continuous variable. Islet autoantibody data were available for a subpopulation of the cohort. Results: There were 777 incident cases of T1D during 15,810,751 person-years (mean age at diagnosis 25.2±3.9 years) . BMI was associated with incident T1D. In a multivariable model adjusted for age, sex and socio-demographic variables, the hazard ratios (HRs) for T1D were 1. (95% CI 0.87-1.27) for the 50th-74th BMI percentiles, 1.41 (1.11-1.78) for the 75th-84th BMI percentiles, 1.54 (1.23-1.94) for adolescents with overweight (85th-94th percentiles) , and 2. (1.58-2.66) for adolescents with obesity (BMI≥95th percentile) . One increment in BMI standard deviation was associated with 25% greater risk for incidence of T1D (HR=1.25, 95%CI 1.17-1.32) . Association persisted when the definition of T1D included the presence of islet autoantibodies; when the study population was restricted to those with unimpaired health. Conclusions: Excessively high BMI in apparently healthy adolescents is associated with increased risk for incident T1D in early adulthood. Disclosure I.Zucker: None. D.Tzur: None. C.Melzer cohen: None. O.Pinhas-hamiel: Advisory Panel; Novo Nordisk, Speaker's Bureau; Pfizer Inc. G.Chodick: None. I.Raz: None. A.Afek: None. H.C.Gerstein: Advisory Panel; Abbott, Eli Lilly and Company, Hanmi Pharm. Co., Ltd., Novo Nordisk, Pfizer Inc., Sanofi, Viatris Inc., Consultant; Kowa Company, Ltd., Other Relationship; DKSH, Eli Lilly and Company, Sanofi, Zuellig Pharma Holdings Pte. Ltd., Research Support; AstraZeneca, Eli Lilly and Company, Merck & Co., Inc., Novo Nordisk, Sanofi. A.Tirosh: Advisory Panel; Abbott Diagnostics, AstraZeneca, Boehringer Ingelheim International GmbH, Merck & Co., Inc., Novo Nordisk, Sanofi, Consultant; Bayer AG, DreaMed Diabetes, Ltd., Research Support; Medtronic, Speaker's Bureau; Eli Lilly and Company. G.Twig: None. Y.Zloof: None. A.Bardugo: None. A.M.Tsur: None. M.Lutski: None. Y.Cohen: None. T.Cukierman-yaffe: Research Support; European Association for the Study of Diabetes, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk, Speaker's Bureau; AstraZeneca, Eli Lilly and Company, Medtronic, Merck Sharp & Dohme Corp., Novo Nordisk, Sanofi. N.Minsky: None. E.Derazne: None. Funding This work was partially supported by an internal grant from the Israel Defense Forces Medical Corps.

Pathophysiology of type 1 diabetes (T1D) involves immune responses that may be associated with early exposure to environmental factors among preterm newborns. The aim of this work was to evaluate for association between T1D and maternal, nutritional, and medical exposures during the neonatal period among premature newborns.This is a multicenter, matched case-control study. Preterm newborns, who developed T1D before 18 years, were matched by sex, gestational age (GA), birth date, and medical center of birth with newborns who did not develop TID. Data included maternal medical history, birth weight (BW), length of hospitalization, enteral and parenteral medications, fluid administration, and feeding modalities during hospitalization.Fifty-two patients with T1D, 26 males, median age at T1D diagnosis 8.17 years (5.92-9.77), median GA 34 weeks (33-m36), and 132 matched controls, were included. Multivariate-conditional-regression demonstrated a significant association between T1D and any maternal illness (23.1% vs. 9.1%, OR = 4.99 (1.69-14.72), p = 0.004), higher BW-SDS (0.07 ± 0.95 vs. -0.27 ± 0.97, OR = 2.03 (1.19-3.49), p = 0.01), longer duration of glucose infusion (3 (1-5) days vs. 2 (0-4), OR = 1.23 (1.03-1.46), p = 0.02), and antibiotic therapy beyond the first week of life (19.2% vs. 6.9%, OR = 5.22 (1.32-20.70), p = 0.019). Antibiotic treatment during the first week of life was negatively associated with T1D (51.9% vs. 67.2%, OR 0.31 (0.11-0.88), p = 0.027).A novel association was demonstrated between the development of T1D and early interventions and exposures among preterm newborns.Type 1 diabetes mellitus during childhood may be associated with early exposures during the neonatal period, in addition to known maternal and neonatal metabolic parameters. Early exposure to intravenous antibiotics, differing between the first week of life and later, and longer parenteral glucose administration to preterm newborns were associated with childhood type 1 diabetes. This is in addition to familiar maternal risk factors. Future prospective studies should examine the microbial changes and immune system characteristics of preterm and term neonates exposed to parenteral antibiotics and glucose treatment, in order to validate our exploratory findings.

Objectives To assess the association between sleep disorders prevalence and obesity in Israeli adolescents. Methods A nationwide, population-based, cross-sectional study of 1,348,817 Israeli adolescents (57% males) who were medically examined prior to military service between 1997 and 2015; height and weight were measured along with assessment of medical status at age 17.3⬰±⬰0.4 years. The diagnosis of a sleep disorder was made based on objective diagnostic criteria. The prevalence and odds ratio (OR) for a sleep disorder were computed across BMI subgroups and were adjusted for socio-demographic confounders. Results Overall sleep disorders prevalence was 1.8:1000 (males) and 0.45:1000 (females), with a total of 1601 cases. There was a gradual increase in the odds ratio for sleep disorders with increasing BMI. Multivariable-adjusted ORs for sleep disorders were 1.29 (95% CI 1.10⬜1.52), 1.44 (1.18⬜1.75), 3.03 (2.32⬜3.96) and 3.38 (1.98⬜5.75) for overweight, obese class I, II and III, respectively (5th⬜49th BMI percentile was the reference). Results persisted in extensive sensitivity analyses including limiting the study sample to participants with unimpaired health. Conclusions We found a higher prevalence of sleep disorders in males and a dose-dependent association between sleep disorders and adolescent BMI in both sexes. Our findings warrant clinical awareness among healthcare providers, given the rise in obesity in teenagers, and particularly in light of the obesity epidemic that we are experiencing in this era. Sleep related complaints should be actively screened in adolescents who suffer obesity.

Context The long-term risk of type 2 diabetes in adolescents with nonalcoholic fatty liver disease (NAFLD) is unclear. Objective To assess type 2 diabetes risk among adolescents with NAFLD. Design and Setting A nationwide, population-based study of Israeli adolescents who were examined before military service during 1997–2011 and were followed until December 31, 2016. Participants A total of 1 025 796 normoglycemic adolescents were included. Interventions Biopsy or radiographic tests were prerequisite for NAFLD diagnosis. Data were linked to the Israeli National Diabetes Registry. Main Outcome Measures Type 2 diabetes incidence. Results During a mean follow-up of 13.3 years, 12 of 633 adolescents with NAFLD (1.9%; all with high body mass index [BMI] at baseline) were diagnosed with type 2 diabetes compared with 2917 (0.3%) adolescents without NAFLD. The hazard ratio (HR) for type 2 diabetes was 2.59 (95% confidence interval [CI], 1.47–4.58) for the NAFLD vs. the non-NAFLD group after adjustment for BMI and sociodemographic confounders. The elevated risk persisted in several sensitivity analyses. These included an analysis of persons without other metabolic comorbidities (adjusted HR, 2.75 [95% CI, 1.48-5.14]) and of persons with high BMI; and an analysis whose outcome was type 2 diabetes by age 30 years (adjusted HR, 2.14 [95% CI, 1.02-4.52]). The results remained significant when a sex-, birth year-, and BMI-matched control group was the reference (adjusted HR, 2.98 [95% CI, 1.54-5.74]). Conclusions Among normoglycemic adolescents, NAFLD was associated with an increased adjusted risk for type 2 diabetes, which may be apparent before age 30 years.

ContextGrowth retardation is an established complication of anorexia nervosa (AN); however, findings concerning the adult height of AN patients are inconsistent.ObjectiveThe objective of this work was to assess linear growth and adult height in female adolescents with AN.Design and SettingA prospective observational study was conducted in a tertiary university hospital.ParticipantsParticipants included all 255 female adolescent AN patients hospitalized in the pediatric psychosomatic department between January 1, 2000 and May 31, 2015.InterventionsHeight and weight were assessed at admission and during hospitalization. Patients were subsequently invited for measurement of adult height. Additional data collected included premorbid height data, menstrual history, skeletal age, pertinent laboratory studies, and parental heights.Main Outcome MeasureThe main outcome measure of this study was adult height.ResultsMean age at admission was 15.4 ± 1.75 years, mean body mass index (BMI) was 15.7 ± 1.8 kg/m2 (BMI SDS = –2.3 ± 1.45 kg/m2). Premorbid height SD scores (SDS) were not significantly different from those expected in normal adolescents (0.005 ± 0.96). However, height SDS at admission (–0.36 ± 0.99), discharge (–0.34 ± 0.96), and at adult height (–0.29 ± 0.95), were significantly (P ConclusionsWhereas the premorbid height of female adolescent AN patients is normal, linear growth retardation is a prominent feature of their illness. Weight restoration is associated with catch-up growth, but complete catch-up is often not achieved.

Prevalence of youth-onset type 2 diabetes (T2D) has increased worldwide, paralleling the rise in pediatric obesity. Occurrence and clinical manifestations vary regionally and demographically.We assessed the incidence, and clinical and demographic manifestations of youth-onset T2D in Israel.In a national observational study, demographic, clinical, and laboratory data were collected from the medical records of children and adolescents, aged 10-18 years, diagnosed with T2D between the years 2008 and 2019.The incidence of youth-onset T2D in Israel increased significantly from 0.63/100,000 in 2008 to 3.41/100,000 in 2019. The study cohort comprised 379 individuals (228 girls [59.7%], 221 Jews [58.3%], mean age 14.7 ± 1.9 years); 73.1% had a positive family history of T2D. Mean body mass index (BMI) z-score was 1.96 ± 0.7, higher in Jews than Arabs. High systolic (≥ 130 mmHg) and diastolic blood pressure (≥ 85 mmHg) were observed in 33.7% and 7.8% of patients, respectively; mean glycosylated hemoglobin (A1c) level at diagnosis was 8.8 ± 2.5%. Dyslipidemia, with high triglyceride (150 mg/dl) and low HDL-c (40 mg/dl) levels, was found in 45.6% and 56.5%, respectively. Microalbuminuria and retinopathy were documented at diagnosis, 15.2% and 1.9%, respectively) and increased (36.7% and 4.6%, respectively) at follow-up of 2.9 ± 2.1 years. Criteria of metabolic syndrome were met by 224 (62.2%) patients, and fatty liver documented in 65%, mainly Jews. Psychosocial comorbidity was found in 31%. Treatment with metformin (45.6%), insulin (20.6%), and lifestyle modification (18%) improved glycemic control.Youth-onset T2D in Israel has increased significantly and presents a unique profile.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) and its complications are increasing worldwide. Youth-onset T2DM has been reported in all racial and ethnic groups, but Indigenous peoples and people of colour are disproportionately affected. People with youth-onset T2DM often have a more aggressive clinical course than those with adult-onset T2DM or those with type 1 diabetes mellitus. Moreover, the available treatment options for children and adolescents with T2DM are more limited than for adult patients. Intermediate complications of youth-onset T2DM, such as increased albuminuria, often develop in late childhood or early adulthood, and end-stage complications, including kidney failure, develop in mid-life. The increasing frequency, earlier onset and greater severity of childhood obesity in the past 50 years together with increasingly sedentary lifestyles and an increasing frequency of intrauterine exposure to diabetes are important drivers of the epidemic of youth-onset T2DM. The particularly high risk of the disease in historically disadvantaged populations suggests an important contribution of social and environmental factors, including limited access to high-quality health care, healthy food choices and opportunities for physical activity as well as exposure to stressors including systemic racism and environmental pollutants. Understanding the mechanisms that underlie the development and aggressive clinical course of youth-onset T2DM is key to identifying successful prevention and management strategies.

Type 1 diabetes (T1D) is a chronic disease requiring medical adherence. However, among adolescents, non-adherence rates may reach up to 75%. Satisfaction or frustration with psychological needs is a crucial factor in the motivation and management of health-related behaviors. This study aimed to examine the differences in good health practices and psychological and physical well-being among adolescents with and without T1D and the mediating role of satisfaction and frustration of psychological needs on the association between good health practices and well-being in this population. A total of 94 adolescents (42 with T1D, 52 healthy controls, mean age 14.83 ± 1.82 years) completed questionnaires assessing good health practices, satisfaction or frustration of psychological needs, and well-being. Adolescents with T1D reported lower levels of physical well-being compared to healthy controls. Satisfaction or frustration of psychological needs had an effect on good health practices and psychological and physical well-being among healthy controls. Among adolescents with T1D, satisfaction or frustration of psychological needs was related to psychological well-being and partially related to physical well-being, but not to good health practices. The results demonstrate that the satisfaction or frustration of psychological needs has a unique effect on health behaviors and well-being among adolescents with T1D. This calls for further examination of the underlying mechanisms involved in health-related behaviors and well-being among adolescents with T1D.

Studies in children have reported an association between increased BMI and risk for developing type 1 diabetes, but evidence in late adolescence is limited. We studied the association between BMI in late adolescence and incident type 1 diabetes in young adulthood.All Israeli adolescents, ages 16-19 years, undergoing medical evaluation in preparation for mandatory military conscription between January 1996 and December 2016 were included for analysis unless they had a history of dysglycaemia. Data were linked with information about adult onset of type 1 diabetes in the Israeli National Diabetes Registry. Weight and height were measured at study entry. Cox proportional models were applied, with BMI being analysed both as a categorical and as a continuous variable.There were 777 incident cases of type 1 diabetes during 15,819,750 person-years (mean age at diagnosis 25.2±3.9 years). BMI was associated with incident type 1 diabetes. In a multivariable model adjusted for age, sex and sociodemographic variables, the HRs for type 1 diabetes were 1.05 (95% CI 0.87, 1.27) for the 50th-74th BMI percentiles, 1.41 (95% CI 1.11, 1.78) for the 75th-84th BMI percentiles, 1.54 (95% CI 1.23, 1.94) for adolescents who were overweight (85th-94th percentiles), and 2.05 (95% CI 1.58, 2.66) for adolescents with obesity (≥95th percentile) (reference group: 5th-49th BMI percentiles). One increment in BMI SD was associated with a 25% greater risk for incidence of type 1 diabetes (HR 1.25, 95% CI 1.17, 1.32).Excessively high BMI in otherwise healthy adolescents is associated with increased risk for incident type 1 diabetes in early adulthood.

Supplementary Material Supplementary table 1. The association between adolescent body mass index (BMI) and myopia for men– methodological sensitivity and subgroup analyses Supplementary table 2. The association between adolescent body mass index (BMI) and myopia for women– methodological sensitivity and subgroup analyses

Background Cognitive function among apparently healthy adolescents has been associated with cardiovascular morbidity and mortality. We examined the relationship between global and subdomain cognitive scores in adolescence and early-onset type 2 diabetes (T2D) in men and women. Methods A nationwide, population-based study of 971,677 Israeli born adolescents (56% men; mean age 17.4 years) who were medically examined and their cognitive performance was assessed before compulsory military service during 1992–2010. Data included global and subdomain cognitive Z-scores (problem-solving, verbal abstraction and categorization, verbal comprehension, and mathematical abilities). Data were linked to the Israeli National Diabetes Registry. The relations between global and subdomain scores and incident T2D was determined using Cox proportional hazard models and logistic regression models. Analyses were conducted separately for men and women. Findings During 16,095,122 person-years, 3,570 individuals developed T2D. After adjustment, those in the low compared to the high quintile of global cognitive Z-score had the highest risk for T2D; HR 2.46, (95% CI 2.10–2.88) for men and 2.33 (95% CI 1.88–2.89) for women. A one-unit lower global cognitive Z-score was associated with 1.41 (95% CI 1.34–1.48) and 1.46 (95% CI 1.36–1.56) increased risks for men and women, respectively. The relationship was noted for the cognitive subdomains scores as well as for the global cognitive score, with no heterogeneity across cognitive subdomains. Interpretation This large nationally representative cohort suggests relationship between global, as well as subdomain cognitive scores in late adolescence, and incident early onset T2D in both sexes, which was independent of socioeconomic status. Funding None.

Context A correlation between myopia and insulin resistance has been suggested. Objective We investigated the association between myopia in adolescence and type 2 diabetes (T2D) incidence in young adulthood. Methods This population-based, retrospective, cohort study comprised 1 329 705 adolescents (579 543 women, 43.6%) aged 16 to 19 years, who were medically examined before mandatory military service during 1993 to 2012, and whose data were linked to the Israel National Diabetes Registry. Myopia was defined based on right-eye refractive data. Cox proportional models were applied, separately for women and men, to estimate hazard ratios (HRs) for T2D incidence per person-years of follow-up. Results There was an interaction between myopia and sex with T2D (P Conclusion For women, myopia in adolescence was associated with a significantly increased risk for incident T2D in young adulthood, in a severity-dependent manner. This finding may support the role of insulin resistance in myopia pathogenesis.

The incidence of adolescent hypertension is growing worldwide, mostly in conjunction with the growing obesity prevalence (1,2). Adolescent hypertension was shown to be a risk factor for cardiovascular and renal outcomes later in life, thus promoting current guidelines to screen all pediatric and adolescent population for hypertension (1,3). Here, we elucidate the association of adolescent hypertension and early-onset type 2 diabetes in a nationwide cohort of adolescents. In this population-based, retrospective cohort study we linked the Israeli Defense Forces conscription center database with the Israeli National Diabetes Registry (INDR). One year prior to mandatory military service at age 17 years, Israeli adolescents undergo comprehensive medical evaluation based on their medical history, an interview and physical examination that includes measurements of height, weight, and blood pressure. Included were adolescents who were examined between 1 January 1993 and 31 December 2016. Excluded were those with prior diagnosis of dysglycemia and those with missing baseline height or weight data (3.8% in total). Essential hypertension diagnosis was confirmed by a board-specified nephrologist based on a preexisting diagnosis or screening for hypertension as described previously (1). Briefly, adolescents with blood pressure measurement during the screening assessment of >140/90 mmHg were referred for further investigation. The final diagnosis was made when the average of 10 additional outpatient blood pressure measurements was >140/90 mmHg, when at least 50% of the measurements were above this level, and after exclusion of secondary hypertension. The primary outcome was incident type 2 diabetes as documented by the INDR, which captures all cases of diabetes in Israel with a sensitivity of 95.1% (2). Cox models were applied. Follow-up started at the day of the first medical examination and ended at the date of diabetes diagnosis, 31 December 2016, or death—whichever came first. Due to the previously described …

Immigration from one cultural milieu to another has been associated with a greater risk for incident cardio-metabolic morbidity among adults. In this nationwide, population-based, cross-sectional study of data recorded from 1992 to 2016, we assessed the association between body mass index and blood pressure levels among adolescent immigrants, aged 16 to 19 years, of Ethiopian origin, and their secular trend of overweight and obesity. Adolescents of Ethiopian origin were classified as Israeli-born (n=16 153) or immigrants (N=23 487), with stratification by age at immigration. Adolescents whose fathers were at least 3 generations in Israel (n=277 789) served as a comparative group. Hypertensive-range blood pressure values adjusted for age, sex, and height served as outcome. Among adolescents of Ethiopian origin, overweight and obesity (body mass index ≥85th percentile), increased by 2.5 and 4-fold in males and females, respectively, during the study period, compared with a 1.5-fold increase among native Israeli-born males and females. The odds for hypertensive-range measurements increased with the length of residence in Israel: 7.3%, 10.6%, and 14.4% among males who immigrated at ages 12 to 19, 6 to 11.9, and 0 to 5.9 years, respectively; and 11.5%, 16.7%, and 19.3%, respectively, among females. Israeli-born Ethiopians had a significantly higher risk for hypertensive-range measurements at any body mass index level compared with native Israeli-born examinees, after adjusting for sociodemographic factors and health status. In conclusion, among Ethiopian Israeli adolescents, abnormal blood pressure correlates directly with the time-lapse since immigration. Immigrant populations require targeted surveillance and appropriate intervention.

OBJECTIVE The relationship between acute pancreatitis and incident diabetes is unclear. We assessed whether a resolved single event of acute pancreatitis in childhood was associated with incident diabetes in adulthood. RESEARCH DESIGN AND METHODS A nationwide, population-based study of 1,802,110 Israeli adolescents (mean age 17.4 years [range 16–20]) who were examined before compulsory military service between 1979 and 2008 and whose data were linked to the Israeli National Diabetes Registry (INDR). Resolved pancreatitis was defined as a history of a single event of acute pancreatitis with normal pancreatic function at enrollment. Logistic regression analysis was applied. RESULTS Incident diabetes developed in 4.6% of subjects with resolved pancreatitis (13 of 281; none of these cases were identified as type 1 diabetes) and 2.5% among the unexposed group (44,463 of 1,801,716). Resolved acute pancreatitis was associated with incident diabetes with an odds ratio (OR) of 2.23 (95% CI 1.25–3.98) with adjustment for age, sex, and birth year. Findings persisted after further adjustments for baseline BMI and sociodemographic confounders (OR 2.10 [95% CI 1.15–3.84]). Childhood pancreatitis was associated with a diagnosis of diabetes at a younger age, with 92% of diabetes case subjects diagnosed before 40 years of age compared with 47% in the unexposed group (P = 0.002). The association accentuated when the study sample was limited to individuals of unimpaired health or normal BMI at baseline. CONCLUSIONS A history of acute pancreatitis in childhood with normal pancreatic function in late adolescence is a risk factor for incident type 2 diabetes, especially at young adulthood.

Background/objectives It is unclear whether adolescent obesity is associated with limited linear growth. We assessed this association in a nationwide sample of adolescents. Methods We conducted a population-based, study of 2,785,227 Israeli adolescents (60% males) who were examined before military service since 1967 through 2015. Height and weight were measured along with assessment of medical status at age 17.4 ± 0.4 years. The secular trend of height was plotted using United States Center for Disease Control (US CDC) age- and sex-adjusted BMI percentile groups. We accounted for health status at enrollment and computed the expected height based on parental data that was available for 512,978 examinees. Results Over five decades, the mean height increased by 3.1 cm among males, but remained unchanged among females. Among males, gain in height was attained predominantly during the first 25 years and has stabilized since. Males with obesity were taller than their normal-weight and underweight counterparts. Underweight girls had a prominent increase in mean height during the first two decades, exceeding the mean height of their counterparts with obesity by over 2 cm. There was a gradual decrease in the difference between measured and expected height in males and females regardless of BMI status, with the exception of the underweight females who achieved consistently higher stature than expected (≥3 cm). Conclusions During five decades, excessive BMI was not a limiting factor in growth potential compared with normal BMI in both sexes. The only group that exceeded its growth potential, when accounting for expected mid-parental height, were underweight females with unimpaired health.