Fine-Tuning Amyloid Precursor Protein Expression through Nonsense-Mediated mRNA Decay.

Studies on genetic robustness recently revealed transcriptional adaptation (TA) as a mechanism by which an organism can compensate for genetic mutations through activation of homologous genes. Here, we discovered that genetic mutations, introducing a premature termination codon (PTC) in the amyloid precursor protein-b (appb) gene, activated TA of two other app family members, appa and amyloid precursor-like protein-2 (aplp2), in zebrafish. The observed transcriptional response of appa and aplp2 required degradation of mutant mRNA and did not depend on Appb protein level. Furthermore, TA between amyloid precursor protein (APP) family members was observed in human neuronal progenitor cells; however, compensation was only present during early neuronal differentiation and could not be detected in a more differentiated neuronal stage or adult zebrafish brain. Using knockdown and chemical inhibition, we showed that nonsense-mediated mRNA decay (NMD) is involved in degradation of mutant mRNA and that Upf1 and Upf2, key proteins in the NMD pathway, regulate the endogenous transcript levels of appa, appb, aplp1, and aplp2 In conclusion, our results suggest that the expression level of App family members is regulated by the NMD pathway and that mutations destabilizing app/APP mRNA can induce genetic compensation by other family members through TA in both zebrafish and human neuronal progenitors.

A prospective study on the relationship between polycystic ovary syndrome and age at natural menopause.

OBJECTIVE: This study aimed to determine whether polycystic ovary syndrome (PCOS) was associated with age at menopause, compared with women without PCOS, after adjusting for potential confounders. METHODS: A total of 1,696 reproductive-aged participants from the Tehran Lipid and Glucose Study were included in this population-based prospective study with a follow-up of approximately 20 years. Of these, 348 women with PCOS based on the Rotterdam criteria and 1,348 non-PCOS controls were followed to assess the age at which they reached menopause. An accelerated failure time survival regression model was used to identify the association between PCOS and the age at natural menopause (ANM), with and without adjustment for potential confounders. RESULTS: The unadjusted accelerated failure time survival model revealed a significant positive association between PCOS and ANM; PCOS women experienced time to menopause by a factor of 1.05 than non-PCOS controls (95% confidence interval, 1.02-1.06; P < 0.001). After adjusting for age at baseline, menarche age, history of hypertension, history of type 2 diabetes mellitus, parity, oral contraceptive use, body mass index, education level, physical activity, and smoking, the results remained significant (time ratio: 1.03; 95% confidence interval, 1.01-1.06; P = 0.002). CONCLUSIONS: This study indicates that ANM is significantly associated with PCOS in women. Our study findings may have implications for the fertility and reproductive health of women with PCOS. However, further large longitudinal studies on diverse populations accounting for other relevant confounders are still needed to provide data on the actual difference in age at menopause and to elucidate the underlying mechanisms of this association.

Lack of beneficiary effect of levothyroxine therapy of pregnant women with subclinical hypothyroidism in terms of neurodevelopment of their offspring.

PURPOSE: Despite the beneficial effects of levothyroxine (LT4) therapy on pregnancy outcomes of women with subclinical hypothyroidism (SCH), its impact on the developmental status of offspring remains unclear. We aimed to assess the effects of LT4 therapy on the neurodevelopment of infants of SCH women in the first 3 years of life. METHODS: A follow-up study was conducted on children born to SCH pregnant women who had participated in a single-blind randomized clinical trial (Tehran Thyroid and Pregnancy Study). In this follow-up study, 357 children of SCH mothers were randomly assigned to SCH + LT4 (treated with LT4 after the first prenatal visit and throughout pregnancy) and SCH-LT4 groups. Children born of euthyroid TPOAb-women served as the control group (n = 737). The neurodevelopment status of children was assessed in five domains (communication, gross motor, fine motor, problem-solving, and social-personal domains) using the Ages and Stages Questionnaires (ASQ) at the age of 3 years. RESULTS: Pairwise comparisons of ASQ domains between euthyroid, SCH + LT4, and SCH-LT4 groups show no statistically significant difference between groups in the total score [median 25-75 total score: 265 (240-280); 270 (245-285); and 265 (245-285); P-value = 0.2, respectively]. The reanalyzing data using the TSH cutoff value of 4.0 mIU/L indicated no significant difference between groups in the score of ASQ in each domain or total score with TSH levels < 4.0 mIU/L, however, a statistically significant difference in the median score of the gross motor was observed between those SCH + LT4 with baseline TSH values ≥ 4.0 mIU/L and SCH-LT4 [60 (55-60) vs. 57.5 (50-60); P = 0.01]. CONCLUSIONS: Our study does not support the beneficiary effect of LT4 therapy for SCH pregnant women in terms of the neurological development of their offspring in the first three years of life.

The critical impact of traumatic muscle loss on fracture healing: Basic science and clinical aspects.

Musculoskeletal trauma, specifically fractures, is a leading cause of patient morbidity and disability worldwide. In approximately 20% of cases with fracture and related traumatic muscle loss, bone healing is impaired leading to fracture nonunion. Over the past few years, several studies have demonstrated that bone and the surrounding muscle tissue interact not only anatomically and mechanically but also through biochemical pathways and mediators. Severe damage to the surrounding musculature at the fracture site causes an insufficiency in muscle-derived osteoprogenitor cells that are crucial for fracture healing. As an endocrine tissue, skeletal muscle produces many myokines that act on different bone cells, such as osteoblasts, osteoclasts, osteocytes, and mesenchymal stem cells. Investigating how muscle influences fracture healing at cellular, molecular, and hormonal levels provides translational therapeutic solutions to this clinical challenge. This review provides an overview about the contributions of surrounding muscle tissue in directing fracture healing. The focus of the review is on describing the interactions between bone and muscle in both healthy and fractured environments. We discuss current progress in identifying the bone-muscle molecular pathways and strategies to harness these pathways as cues for accelerating fracture healing. In addition, we review the existing challenges and research opportunities in the field.

The Hidden Link between Polycystic Ovary Syndrome and Kidney Stones: Finding from the Tehran Lipid and Glucose Study (TLGS).

BACKGROUND: We aimed to investigate the association between kidney stones and polycystic ovarian syndrome (PCOS). MATERIALS AND METHODS: In a cross-sectional study, data from the Tehran Lipid and Glucose Study (TLGS) were used to investigate the risk of kidney stones in women with Polycystic Ovary Syndrome (PCOS). Four distinct phenotypes of PCOS, as defined by the Rotterdam criteria, were examined in a sample of 520 women and compared to a control group of 1638 eumenorrheic non-hirsute healthy women. Univariate and multivariable logistic regression models were employed for analysis. The four PCOS phenotypes were classified as follows: Phenotype A, characterized by the presence of all three PCOS features (anovulation (OA), hyperandrogenism (HA), and polycystic ovarian morphology on ultrasound (PCOM)); Phenotype B, characterized by the presence of anovulation and hyperandrogenism; Phenotype C, characterized by the presence of hyperandrogenism and polycystic ovarian morphology on ultrasound; and Phenotype D, characterized by the presence of anovulation and polycystic ovarian morphology on ultrasound. RESULTS: The prevalence of a history of kidney stones was found to be significantly higher in women with Polycystic Ovary Syndrome (PCOS) compared to healthy controls (12.5% vs. 7.7%, p = 0.001). This increased prevalence was observed across all PCOS phenotypes (p < 0.001). After adjusting for potential risk factors, including age, family history of kidney stones, waist-to-height ratio, total cholesterol, and low-density lipoprotein, the odds ratio for kidney stones in women with PCOS was found to be 1.59 [95% CI: 1.12-2.25, p = 0.01], indicating a 59% increase in risk compared to healthy women. Women with PCOS Phenotype A [OR: 1.97, 95% CI: 1.09-3.55, p = 0.02] and Phenotype D [OR: 3.03, 95% CI: 1.24-7.41, p = 0.01] were found to be at a higher risk for kidney stones. CONCLUSION: Women with Polycystic Ovary Syndrome (PCOS), particularly those exhibiting menstrual irregularities and polycystic ovarian morphology on ultrasound (PCOM), have been found to be two to three times more likely to develop kidney stones. This increased prevalence should be taken into consideration when providing preventive care and counseling to these individuals.

Maternal androgen excess increases the risk of metabolic syndrome in female offspring in their later life: A long-term population-based follow-up study.

PURPOSE: Hyperandrogenic intrauterine environment may lead to the development of metabolic disorders in offspring in their later life. In this study, we aimed to determine the impact of maternal hyperandrogenism (MHA) on metabolic syndrome (MetS) risk in female offspring in their later life. METHODS: In this cohort study conducted in Tehran, Iran, female offspring with MHA (n = 323) and without MHA (controls) (n = 1125) were selected. Both groups of female offspring were followed from the baseline to the date of the incidence of events, censoring, or end of the study period, whichever came first. We used age-scaled unadjusted and adjusted Cox regression models to assess the hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between MHA and MetS in female offspring. The software package STATA was used for statistical analysis, and the significance level was set at P < 0.05. RESULTS: We observed a higher risk of MetS (unadjusted HR (95% CI), 1.36 (1.05-1.77)), (P = 0.02) and (adjusted HR (95% CI), 1.34 (1.00-1.80)), (P = 0.05, borderline)), in female offspring with MHA, compared to controls. The results were adjusted for the potential confounders including body mass index (BMI) at baseline, net changes of BMI, physical activity, education status, and birth weight. CONCLUSION: Our results suggest that MHA increases the risk of developing MetS in female offspring in their later life. Screening of these female offspring for MetS may be recommended.

Does fasting plasma glucose values 5.1-5.6 mmol/l in the first trimester of gestation a matter?

Objectives: The aim of the study was to investigate the effect of treatment on pregnancy outcomes among women who had fasting plasma glucose (FPG) 5.1-5.6 mmol/l in the first trimester of pregnancy. Methods: We performed a secondary-analysis of a randomized community non-inferiority trial of gestational diabetes mellitus (GDM) screening. All pregnant women with FPG values range 5.1-5.6 mmol/l in the first trimester of gestation were included in the present study (n=3297) and classified to either the (i) intervention group who received treatment for GDM along with usual prenatal care (n=1,198), (ii) control group who received usual-prenatal-care (n=2,099). Macrosomia/large for gestational age (LGA) and primary cesarean-section (C-S) were considered as primary-outcomes. A modified-Poisson-regression for binary outcome data with a log link function and robust error variance was used to RR (95%CI) for the associations between GDM status and incidence of pregnancy outcomes. Results: The mean maternal age and BMI of pregnant women in both study groups were similar. There were no statistically significant differences in the adjusted risks of adverse pregnancy outcomes, including macrosomia, primary C-S, preterm birth, hyperbilirubinemia, preeclampsia, NICU-admission, birth trauma, and LBW both groups. Conclusions: It is found that treating women with first-trimester FPG values of 5.1-5.6 mmol/l could not improve adverse pregnancy outcomes including macrosomia, Primary C-S, Preterm birth, hypoglycemia, hypocalcemia, preeclampsia, NICU admission, Birth trauma and LBW. Therefore, extrapolating the FPG cut-off point of the second trimester to the first -which has been proposed by the IADPSG, might therefore not be appropriate. Clinical Trial Registration: https://www.irct.ir/trial/518, identifier IRCT138707081281N1.

Hard and soft tissue healing around teeth prepared with the biologically oriented preparation technique and restored with provisional crowns: An in vivo experimental investigation.

AIM: To evaluate the hard and soft tissues healing around teeth prepared with the biologically oriented preparation technique (BOPT) versus the chamfer technique versus non-prepared teeth. MATERIALS AND METHODS: Thirty-two teeth in eight beagle dogs were randomly prepared with the BOPT (test = 16) or chamfer (control = 16) techniques and covered with polymethylmethacrylate crowns as provisional restorations. Sixteen negative controls (non-prepared teeth) were also used for comparison. Histological description and histomorphometrical measurements of the periodontal tissues were collected at 4 and 12 weeks in 7 out of 8 dogs, including the soft tissue height and thickness, and the horizontal and vertical bone dimensions. RESULTS: When compared with negative controls, test and control preparation techniques exhibited a more apical location of the free gingival margin with respect to the cement-enamel junction (∆ = 1.1 mm for both groups at 4 weeks (p < .05), 0.99 mm for the test group (p = .043) and 0.20 mm for control group (p = 1.000) at 12 weeks). There were no significant differences between test and control groups with respect to vertical and horizontal histometric measurements. CONCLUSIONS: The BOPT and chamfer tooth preparation protocols induced similar qualitative and quantitative changes in the healing of the supra-crestal soft tissue complex, when compared with non-prepared teeth. Despite the limited amount of power, it appeared that differences between the tested preparation techniques were not statistically significant.

Lactation duration and lifetime progression to metabolic syndrome in women according to their history of gestational diabetes: a prospective longitudinal community-based cohort study.

BACKGROUND: Despite the many signs of progress in pharmacotherapies, metabolic syndrome (MetS) is one of the main public-health burdens worldwide. Our study aimed to compare the effect of breastfeeding (BF) in women with and without gestational diabetes mellitus (GDM) on MetS incidence. METHODS: Of females who participated in the Tehran Lipid and glucose study, women who met our inclusion criteria were selected. The Cox proportional hazards regression model, with adjustment of potential confounders, was done to evaluate the relationship between duration of BF and incident of MetS in women with a GDM history compared to non-GDM. RESULTS: Out of 1176 women, there were 1001 non-GDM and 175 GDM. The median follow-up was 16.3 (11.9, 19.3) years. Results of the adjusted model illustrated that the total BF duration was negatively associated with MetS incidence risk (hazard ratio (HR) 0.98, 95% CI 0.98-0.99) in total participants indicating that per one-month increase of BF duration, the hazard of MetS reduced by 2%. The HR of MetS in Comparison between GDM and non-GDM women demonstrated significantly more reduced MetS incidence with a longer duration of exclusive BF (HR 0.93, 95% CI 0.88-0.98). CONCLUSIONS: Our findings illustrated the protective effect of BF, especially exclusive BF, on MetS incidence risk. BF is more effective in reducing the risk of MetS among women with a history of GDM than among women without such a history.

Parity and hypertension risk in couples: does number of parity matter: findings from Tehran Lipid and Glucose Study.

BACKGROUND AND AIMS: As reported, hypertension (HTN) plays a leading role in explaining mortality worldwide, but it still has many confounding factors. This study explored whether the number of parity and age matters for HTN among couples from the Tehran Lipid and Glucose Study (TLGS). METHODS: This study was conducted on 2851 couples from TLGS. All the variables were collected based on the standard protocol. The participants were categorized into four and five categories according to the number of parity (childless, one, two, three, or more parities) and age (18-30y, 30-40y, 40-50y, 50-60y, and 60-70y), respectively. Spline regression models via log link function for the binary outcome and linear link function for continuous outcomes were applied to evaluate the effect of interaction term age and parity categories on the desired outcome. RESULTS: Among the total of 2851 pairs, 2.3% had no child, 9.5% had 1 child, 38.4% had 2 children, and 49.8% had ≥ 3 children. The adjusted risk (95% CI) of HTN in females aged 40-50y with 1 child, 2 and ≥ 3 children compared to no child were 1.14(1.04, 1.26), 1.05(1.01, 1.10), 1.12(1.07, 1.17), respectively (p < 0.05). Moreover, in those aged 50-60y with 2 and ≥ 3 children, the risk of HTN significantly increased by 4%. In females aged 60-70y with ≥ 3 children compared to those without children, the risk of HTN increased by 2%. For males aged 30-40y with 2 children compared to the no child group, the adjusted risk of HTN increased by 17%, while for those with ≥ 3 children in the same age group, this risk significantly decreased by 13%. Moreover, in males aged 30-40y with 2 children, risk ratio of HTN increased by 17%, but in males with ≥ 3 children, it decreased by 13% and in those in the same groups but aged 40-50y the risk increased by 6% and 11%, respectively. CONCLUSION: Our findings suggest that gender, childlessness, having one child, and multi-parity had different impacts on HTN. Further research is needed to confirm our findings.

A Bayesian model to estimate the cutoff value of TSH for management of preterm birth.

BACKGROUND: Determining a thyroid hormone cutoff value in pregnancy is challenging issue and several approaches have been introduced to optimize a utility function. We aimed to estimate the cutoff value of TSH using Bayesian method for prediction of preterm-birth. METHODS: This study was a secondary-analysis of the population-based data collected prospectively within the framework of the Tehran Thyroid and Pregnancy Study. A total of 1,538 pregnant women attending prenatal clinics. RESULTS: Using Bayesian method resulted a TSH-cutoff of (3.97mIU/L,95%CI:3.95-4.00) for distinguishing pregnant women at risk of preterm-birth. The cutoff was associated with acceptable positive predictive and negative predictive values (0.84,95% CI:0.80-0.88) and 0.92 (95%CI: 0.91-0.94), respectively). In women who were negative for thyroid peroxides antibody (TPOAb) with sufficient urinary iodine concentration (UIC), the TSH cutoff of 3.92 mIU/L(95%CI:3.70-4) had the highest predictive value; whereas in TPOAb positive women with insufficient UIC, the cutoff of 4.0 mIU/L(95%:CI 3.94-4) could better predict preterm birth. Cutoffs estimated in this study are close to the revised TSH value of 4.0mIU/L which is currently recommended by the American Thyroid Association. CONCLUSION: Regardless of TPOAb status or iodine insufficiency, risk of preterm labor is increased in pregnant women with TSH value of > 3.92 mIU/L; these women may benefit from Levothyroxine (LT4) therapy for preventing preterm birth.

Prediction of preterm delivery based on thyroid peroxidase antibody levels and other identified risk factors.

OBJECTIVE: Thyroid dysfunction and TPOAb positivity during pregnancy are associated with adverse pregnancy outcomes such as preterm delivery. The aim of this study was to predict preterm delivery based on identified risk factors, especially TPOAb levels. STUDY DESIGN: A secondary analysis was run on data collected in the Tehran Thyroid and Pregnancy study (TTPs). We used the data of 1515 pregnant women with singletons. The association between risk factors and preterm birth (delivery before 37 completed weeks of gestation) was investigated in univariate analysis. Multivariate logistic regression analysis was performed to identify independent risk factors, and a stepwise backward elimination method was used to determine the helpful combination of risk factors. The nomogram was developed based on a multivariate logistic regression model. The performance of the nomogram was evaluated using a concordance index and calibration plots with bootstrap samples. Statistical analysis was performed using STATA software package; the significance level was set at P < 0.05. RESULTS: Based on multivariate logistic regression analysis, a combination of previous preterm delivery [OR: 5.25; 95 %CI: (2.13-12.90), p < 0.01], TPOAb [OR: 1.01; 95 %CI: (1.01-1.02), and T4 [OR: 0.90; 95 %CI: (0.83-0.97); p = 0.04] as independent risk factors that most precisely predicted preterm birth. The area under the curve (AUC) was 0.66 (95% CI: 0.61-0.72). The calibration plot suggests that the fit of the nomogram is reasonable. CONCLUSION: A combination of T4, TPOAb, and previous preterm delivery was identified as independent risk factors that accurately predicted preterm delivery. The total score obtained based on the nomogram designed based on risk factors can predict the risk of preterm delivery.

Effects of methyl jasmonate elicitation on the carvone and limonene contents, phenolic compounds and antioxidant activity in caraway (Carum carvi L.) callus cultures.

This study investigated the elicitation effects of several methyl jasmonate (MeJ) concentrations (0, 25, 50, and 100 µM) on various biochemical traits of caraway (Carum carvi L.) callus cultures. The 25 µM MeJ concentration yielded the highest callus growth rate (0.57 mm day-1), total flavonols content (2.58 mg QE g-1 FW) and total carotenoids content (0.04 µg g-1 FW), whereas the highest relative fresh weight (75.72%), total phenolics content (76.90 mg GAE g-1 FW), total flavonoids content (58.49 mg QE g-1 FW) and phenylalanine ammonia lyase activity (3.40 nmol cinnamic acid mg-1 h-1 FW) were obtained with the 50 µM MeJ concentration. The highest antioxidant activity through DPPH assay (8.37%) and malondialdehyde content (7.82 µmol g-1 FW) were observed at 100 µM MeJ. The HPLC conducted 21 days post-elicitation revealed a 5.55-fold increase of carvone accumulation (1.83 µg g-1 DW) at 50 µM MeJ and a 2.7-fold increase (0.62 µg g-1 DW) of limonene at 50 µM MeJ. The optimal dosages applied for carvone and limonene accumulation under MeJ elicitation could be used to scale up the economic production of these elite medicinal compounds through caraway callus cultures.

Polycystic Ovary Syndrome, Subclinical Hypothyroidism, the Cut-Off Value of Thyroid Stimulating Hormone; Is There a Link? Findings of a Population-Based Study.

Despite solid evidence regarding the association of over-hypothyroidism with polycystic ovary syndrome (PCOS), the relationship between PCOS and subclinical hypothyroidism (SCH) is still a topic of debate. In the present population-based study, we aimed to assess if there is a difference between PCOS and the control group regarding the upper reference limit of thyroid stimulating hormone (TSH). We also aimed to identify the prevalence of SCH in women with PCOS compared to controls. This study was conducted on data collected in the Iranian PCOS prevalence study and the Khuzestan PCOS prevalence study. Participants that met our eligibility criteria were categorized into two groups: PCOS (n = 207) and control (n = 644). Quantile and logistic regression models were used to explore the effect of PCOS status on TSH cut-off values and SCH, respectively. The 95 percentiles of TSH were not significantly different in the PCOS group compared to control ones (6.12 and 6.56 microU/mL, respectively). There was no statistically significant association between PCOS status and SCH (OR adjusted: 1.40; 95%CI: 0.79, 2.50; p = 0.2). The prevalence of SCH and the upper reference limit of TSH were not significantly different in PCOS and controls. Investigation of SCH in women with PCOS might be questionable.

Immunohistochemical comparison of lateral bone augmentation using a synthetic TiO2 block or a xenogeneic graft in chronic alveolar defects.

OBJECTIVES: To evaluate osteogenic markers and alveolar ridge profile changes in guided bone regeneration (GBR) of chronic noncontained bone defects using a nonresorbable TiO2 block. MATERIALS AND METHODS: Three buccal bone defects were created in each hemimandible of eight beagle dogs and allowed to heal for 8 weeks before GBR. Treatment was assigned by block randomization: TiO2 block: TiO2 -scaffold and a collagen membrane, DBBM particulates: Deproteinized bovine bone mineral (DBBM) and a collagen membrane, Empty control: Only collagen membrane. Bone regeneration was assessed on two different healing timepoints: early (4 weeks) and late healing (12 weeks) using several immunohistochemistry markers including alpha-smooth muscle actin (α-SMA), osteopontin, osteocalcin, tartrate-resistant acid phosphatase, and collagen type I. Histomorphometry was performed on Movat Pentachrome-stained and Von Kossa/Van Gieson-stained sections. Stereolithographic (STL) models were used to compare alveolar profile changes. RESULTS: The percentage of α-SMA and osteopontin increased in TiO2 group after 12 weeks of healing at the bone-scaffold interface, while collagen type I increased in the empty control group. In the defect area, α-SMA decreased in the empty control group, while collagen type I increased in the DBBM group. All groups maintained alveolar profile from 4 to 12 weeks, but TiO2 group demonstrated the widest soft tissue contour profile. CONCLUSIONS: The present findings suggested contact osteogenesis when GBR is performed with a TiO2 block or DBBM particulates. The increase in osteopontin indicated a potential for bone formation beyond 12 weeks. The alveolar profile data indicated a sustained lateral increase in lateral bone augmentation using a TiO2 block and a collagen membrane, as compared with DBBM and a collagen membrane or a collagen membrane alone.

Various screening and diagnosis approaches for gestational diabetes mellitus and adverse pregnancy outcomes: a secondary analysis of a randomized non-inferiority field trial.

INTRODUCTION: We evaluate which screening and diagnostic approach resulted in the greatest reduction in adverse pregnancy outcomes due to increased treatment. RESEARCH DESIGN AND METHODS: This study presents a secondary analysis of a randomized community non-inferiority trial conducted among pregnant women participating in the GULF Study in Iran. A total of 35 430 pregnant women were randomly assigned to one of the five prespecified gestational diabetes mellitus (GDM) screening protocols. The screening methods included fasting plasma glucose (FPG) in the first trimester and either a one-step or a two-step screening method in the second trimester of pregnancy. According to the results, participants were classified into 6 groups (1) First-trimester FPG: 100-126 mg/dL, GDM diagnosed at first trimester; (2) First trimester FPG: 92-99.9 mg/dL, GDM diagnosed at first trimester; (3) First trimester FPG: 92-99.9 mg/dL, GDM diagnosed at second trimester; (4) First trimester FPG: 92-99.9 mg/dL, healthy at second trimester; (5) First trimester FPG<92 mg/dL, GDM diagnosed at second trimester; (6) First trimester FPG<92 mg/dL, healthy at second trimester. For our analysis, we initially used group 6, as the reference and repeated the analysis using group 2, as the reference group. The main outcome of the study was major adverse maternal and neonatal outcomes. RESULTS: Macrosomia and primary caesarean section occurred in 9.8% and 21.0% in group 1, 7.8% and 19.8% in group 2, 5.4% and 18.6% in group 3, 6.6% and 21.5% in group 4, 8.3% and 24.0% in group 5, and 5.4% and 20.0% in group 6, respectively. Compared with group 6 as the reference, there was a significant increase in the adjusted risk of neonatal intensive care unit (NICU) admission in groups 1, 3, and 5 and an increased risk of macrosomia in groups 1, 2, and 5. Compared with group 2 as the reference, there was a significant decrease in the adjusted risk of macrosomia in group 3, a decreased risk of NICU admission in group 6, and an increased risk of hyperglycemia in group 3. CONCLUSIONS: We conclude that screening approaches for GDM reduced the risk of adverse pregnancy outcomes to the same or near the same risk level of healthy pregnant women, except for the risk of NICU admission that increased significantly in groups diagnosed with GDM compared with healthy pregnant women. Individuals with slight increase in FPG (92-100 mg/dL) at first trimester, who were diagnosed as GDM, had an even increased risk of macrosomia in comparison to those group of women with FPG 92-100 mg/dL in the first trimester, who were not diagnosed with GDM, and developed GDM in second trimester TRIAL REGISTRATION: IRCT138707081281N1 (registered: February 15, 2017).

The effects of different physiologic concentrations of prolactin in association with reproductive hormones on the incidence of type 2 diabetes mellitus in men: Tehran Lipid and Glucose Study.

BACKGROUND: Data is inconsistent and, for the most part, not sufficient to demonstrate the association between serum Prolactin (PRL) concentration within the physiologic range and the incidence rate of type 2 Diabetes Mellitus (DM) among men. Moreover, since both PRL and type 2 DM are associated with reproductive hormones, investigating these hormones might improve our understanding of how PRL might impose its effect on the incidence rate of type 2 DM. METHODS: For the present study, 652 eligible men aged 29-70 with a normal baseline PRL concentration were selected from the Tehran Lipid and Glucose Study (TLGS). Participants were sub-classified into three groups (tertiles) according to the serum concentration of PRL and were followed for 15.8 years. The incidence of type 2 DM and PRL, LH, FSH, testosterone, and AMH concentrations were measured. The effect of hormonal variables on the incidence of type 2 DM was estimated using the log-binomial model, adjusted for major confounding factors. The correlations between PRL and the indicators of glucose and lipid metabolism and other hormonal variables were also explored. RESULTS: In the unadjusted model, PRL was not significantly associated with the incidence rate of type 2 DM (RR = 0.98, 95% CI: 0.94 - 1.03). After adjusting for potential confounders, the inverse effect of AMH on the incidence rate of type 2 DM was the only significant association. The analyses also indicated a significant positive association between PRL and LH/FSH ratio (r = 0.1, P = 0.01). CONCLUSION: No significant association was found between serum PRL concentrations within the physiologic range and the incidence rate of type 2 diabetes mellitus among middle-aged men. Men with higher concentrations of PRL within the physiologic range tended to show higher levels of LH and LH/FSH. AMH was the only variable significantly linked to the incidence rate of type 2 DM in men.

Umbilical cord blood concentration of connecting peptide (C-peptide) and pregnancy outcomes.

BACKGROUND: C-peptide offers potential as a marker to indicate childhood metabolic outcomes. Measuring C-peptide concentration might have better future utility in the risk stratification of neonates born to overweight or diabetic mothers. Prior research has tried to bring this matter into the light; however, the clinical significance of these associations is still far from reach. Here we sought to investigate the associations between fetomaternal metabolic variables and umbilical cord blood C-peptide concentration. METHODS: For the present study, 858 pregnant women were randomly selected from among a sub-group of 35,430 Iranian pregnant women who participated in a randomized community non-inferiority trial of gestational diabetes mellitus (GDM) screening. Their umbilical cord (UC) blood C-peptide concentrations were measured, and the pregnancy variables of macrosomia/large for gestational age (LGA) and primary cesarean section (CS) delivery were assessed. The variation of C-peptide concentrations among GDM and macrosomia status was plotted. Due to the skewed distribution of C-peptide concentration in the sample, median regression analysis was used to identify potential factors related to UC C-peptide concentration. RESULTS: In the univariate model, positive GDM status was associated with a 0.3 (95% CI: 0.06 - 0.54, p = 0.01) increase in the median coefficient of UC blood C-peptide concentration. Moreover, one unit (kg) increase in the birth weight was associated with a 0.25 (95% CI: 0.03 - 0.47, p = 0.03) increase in the median coefficient of UC blood C-peptide concentration. In the multivariate model, after adjusting for maternal age, maternal BMI, and macrosomia status, the positive status of GDM and macrosomia were significantly associated with an increase in the median coefficient of UC blood C-peptide concentration (Coef.= 0.27, 95% CI: 0.13 - 0.42, p < 0.001; and Coef.= 0.34, 95% CI: 0.06 - 0.63, p = 0.02, respectively). CONCLUSION: UC blood concentration of C-peptide is significantly associated with the incidence of maternal GDM and neonatal macrosomia. Using stratification for maternal BMI and gestational weight gain (GWG) and investigating molecular markers like Leptin and IGF-1 in the future might lay the ground to better understand the link between metabolic disturbances of pregnancy and UC blood C-peptide concentration.

Compound Poisson frailty model with a gamma process prior for the baseline hazard: accounting for a cured fraction.

Cox model and traditional frailty models assume that all individuals will eventually experience the event of interest. This assumption is often overlooked, and situations will arise where it is not realistic. We introduce Compound Poisson frailty model for survival analysis to deal with populations in which some of the individuals will not experience the event of interest. This model assumes that the target population is a mixture of individuals with zero frailty and those with positive frailty. In this paper, we consider a compound Poisson frailty model for right-censored event times from a Bayesian perspective and compute the Bayesian estimator using the Markov Chain Monte Carlo method, where a Gamma process prior is adopted for the baseline hazard function. Furthermore, we evaluate the approach using simulation studies and demonstrate the methodology by analyzing the data from achalasia patient cohort.

Maternal subclinical hyperthyroidism and adverse pregnancy outcomes considering the iodine status: Tehran thyroid and pregnancy study.

BACKGROUND: Unlike overt thyroid diseases, the impacts of subclinical thyroid dysfunction, especially subclinical hyperthyroidism (SH), on adverse pregnancy outcomes are inconclusive. OBJECTIVE: We aimed to investigate the effect of maternal SH on adverse maternal and neonatal outcomes based on urinary iodine concentration (UIC). METHODS: A secondary analysis was run on data collected in the Tehran Thyroid and Pregnancy study (TTPs). We used the data of 131 women with SH and 1650 cases of euthyroid. Serum levels of thyroid-stimulating hormone (TSH), thyroxine (T4), free thyroxine index (FT4I), and thyroid peroxidase antibody (TPOAb) were assessed at the first prenatal visit. A generalized linear regression model was applied to identify the effect of SH on the pregnancy outcomes based on UIC, and the effects were estimated with a 95% confidence interval. RESULTS: Preterm delivery was observed in 12.3% of women with SH and 6.7% of those with euthyroid (P = 0.03). Women with TSH< 0.3 mIU/L had a higher odds of preterm delivery than those with TSH≥ 0.3 regardless of urine iodine cut-off [OR= 2.27; 95% CI: (1.15, 4.48), p = 0.02]. Among those with UIC levels≥ 150 µg/L, the odds ratio of preterm delivery was 4.61 folds higher in the SH group compared to those with euthyroid [95%CI: (1.36, 15.71), p = 0.01)]. No significant difference between these two study groups was found in Neonatal Intensive Care Unit admission. Moreover, the results revealed no statistically significant difference in the means of neonatal anthropometric parameters in the SH and euthyroid groups in none of the subgroups of UIC (<150 or ≥150 µg/l). CONCLUSIONS: According to our results, maternal SH appears to be a risk factor for preterm delivery. This effect is more pronounced in women with higher UIC than those with lower UIC.