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First-degree relatives of patients diagnosed with schizophrenia (SZ-FDRs) show similar patterns of brain abnormalities and cognitive alterations to patients, albeit with smaller effect sizes. First-degree relatives of patients diagnosed with bipolar disorder (BD-FDRs) show divergent patterns; on average, intracranial volume is larger compared to controls, and findings on cognitive alterations in BD-FDRs are inconsistent. Here, we performed a meta-analysis of global and regional brain measures (cortical and subcortical), current IQ, and educational attainment in 5,795 individuals (1,103 SZ-FDRs, 867 BD-FDRs, 2,190 controls, 942 schizophrenia patients, 693 bipolar patients) from 36 schizophrenia and/or bipolar disorder family cohorts, with standardized methods. Compared to controls, SZ-FDRs showed a pattern of widespread thinner cortex, while BD-FDRs had widespread larger cortical surface area. IQ was lower in SZ-FDRs (d= -0.42,p= 3 x 10(-5)), with weak evidence of IQ reductions among BD-FDRs (d= -0.23,p= .045). Both relative groups had similar educational attainment compared to controls. When adjusting for IQ or educational attainment, the group-effects on brain measures changed, albeit modestly. Changes were in the expected direction, with less pronounced brain abnormalities in SZ-FDRs and more pronounced effects in BD-FDRs. To conclude, SZ-FDRs and BD-FDRs show a differential pattern of structural brain abnormalities. in contrast, both had lower IQ scores and similar school achievements compared to controls. Given that brain differences between SZ-FDRs and BD-FDRs remain after adjusting for IQ or educational attainment, we suggest that differential brain developmental processes underlying predisposition for schizophrenia or bipolar disorder are likely independent of general cognitive impairment., Australian National Health and Medical Research CouncilNational Health and Medical Research Council of Australia [1037196, 1063960, 1066177, 510135, 1176716]; Canadian Institutes of Health ResearchCanadian Institutes of Health Research (CIHR) [103703, 106469, 142255]; Departament de Salut de la Generalitat de CatalunyaGeneralitat de Catalunya [SLT002/16/00331]; Deutsche ForschungsgemeinschaftGerman Research Foundation (DFG) [1617]; Development Service Merit Review Award [I01CX000227]; Dokuz Eylul University Department of Scientific Research [2012.KB.SAG.062]; e:Med program [O1ZX1314B, O1ZX1314G]; Ege University School of Medicine Research Foundation [2009-D-00017]; Fundacio Marato TV3 [091630]; Netherlands Organisation for Health Research and DevelopmentNetherlands Organization for Health Research and Development [10-000-1002]; Generalitat de CatalunyaGeneralitat de Catalunya [2017SGR01271]; German Federal Ministry for Education and ResearchFederal Ministry of Education & Research (BMBF); Medical Research CouncilMedical Research Council UK (MRC) [G0901310]; Ministerstvo Zdravotnictvi Ceske Republiky [NR8786, NT13891]; National Alliance for Research on Schizophrenia and DepressionNARSAD [17319, 20244, 26731]; Swiss National Centre of Competence in Research Robotics [51NF40-185897]; National Institute of Mental HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Mental Health (NIMH) [1S10OD017974-01, P30 NS076408, R01 MH052857, R01 MH080912, R01 MH113619, U01 MH108150, R01 MH085667]; National Institute on AgingUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute on Aging (NIA) [T32AG058507]; National Institutes of HealthUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [P41 EB015922, R01 MH111671, R01 MH116147, R01 MH117601, R01MH121246, R03 MH105808, U54EB020403]; Research Council of NorwayResearch Council of Norway [223273]; Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III [CPII19/00009, PI070066, PI1100683, PI1500467, PI18/00976]; Stanley Medical Research Institute; Swedish Research CouncilSwedish Research Council [K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3]; Swiss National Science FoundationSwiss National Science Foundation (SNSF) [32003B_156914]; VIDINetherlands Organization for Scientific Research (NWO) [452-11-014, 917-46-370]; Wellcome TrustWellcome Trust [085475/B/08/Z, 085475/Z/08/Z, 064971]; ZonMwNetherlands Organization for Health Research and Development [908-02-123], Australian National Health and Medical Research Council Grants, Grant/Award Numbers: 1037196, 1063960, 1066177, 510135, 1176716; Canadian Institutes of Health Research, Grant/Award Numbers: 103703, 106469, 142255; Departament de Salut de la Generalitat de Catalunya, Grant/Award Number: SLT002/16/00331; Deutsche Forschungsgemeinschaft, Grant/Award Number: 1617; Development Service Merit Review Award, Grant/Award Number: I01CX000227; Dokuz Eylul University Department of Scientific Research Projects Funding, Grant/Award Number: 2012.KB.SAG.062; e:Med program, Grant/Award Numbers: O1ZX1314B, O1ZX1314G; Ege University School of Medicine Research Foundation, Grant/Award Number: 2009-D-00017; Fundacio Marato TV3, Grant/Award Number: 091630; Geestkracht program of the Netherlands Organisation for Health Research and Development, Grant/Award Number: 10-000-1002; Generalitat de Catalunya, Grant/Award Number: 2017SGR01271; German Federal Ministry for Education and Research; Medical Research Council, Grant/Award Number: G0901310; Ministerstvo Zdravotnictvi Ceske Republiky, Grant/Award Numbers: NR8786, NT13891; National Alliance for Research on Schizophrenia and Depression, Grant/Award Numbers: 17319, 20244, 26731; Swiss National Centre of Competence in Research Robotics, Grant/Award Number: 51NF40-185897; National Institute of Mental Health, Grant/Award Numbers: 1S10OD017974-01, P30 NS076408, R01 MH052857, R01 MH080912, R01 MH113619, U01 MH108150, R01 MH085667; National Institute on Aging, Grant/Award Number: T32AG058507; National Institutes of Health, Grant/Award Numbers: P41 EB015922, R01 MH111671, R01 MH116147, R01 MH117601, R01MH121246, R03 MH105808, U54EB020403; Research Council of Norway, Grant/Award Number: 223273; Spanish Ministry of Economy and Competitiveness/Instituto de Salud Carlos III, Grant/Award Numbers: CPII19/00009, PI070066, PI1100683, PI1500467, PI18/00976; Stanley Medical Research Institute; Swedish Research Council, Grant/Award Numbers: K2007-62X-15077-04-1, K2008-62P-20597-01-3, K2010-62X-15078-07-2, K2012-61X-15078-09-3; Swiss National Science Foundation, Grant/Award Number: 32003B_156914; VIDI, Grant/Award Numbers: 452-11-014, 917-46-370; Wellcome Trust, Grant/Award Numbers: 085475/B/08/Z, 085475/Z/08/Z; Wellcome Trust Research Training Fellowship, Grant/Award Number: 064971; ZonMw, Grant/Award Number: 908-02-123

Objective Dynamic image analysis of carotid plaques has demonstrated that during systole and early diastole, all plaque components will move in the same direction (concordant motion) in some plaques. However, in others, different parts of the plaque will move in different directions (discordant motion). The aim of our study was (1) to determine the prevalence of discordant motion in symptomatic and asymptomatic plaques, (2) to develop a measurement of the severity of discordant motion, and (3) to determine the correlation between the severity of discordant motion and symptom prevalence. Methods A total of 200 patients with 204 plaques resulting in 50% to 99% stenosis (112 asymptomatic and 92 symptomatic plaques) had video recordings available of the plaque motion during 10 cardiac cycles. Video tracking was performed using Farneback's method, which relies on frame comparisons. In our study, these were performed at 0.1-second intervals. The maximum angular spread (MAS) of the motion vectors at 10-pixel intervals in the plaque area was measured in degrees. Plaques were classified as concordant (MAS, 120°). Results Motion was discordant in 89.1% of the symptomatic plaques but only in 17.9% of asymptomatic plaques (P < .001). The prevalence of symptoms increased with increasing MAS. For a MAS >120°, the hazard ratio for the presence of symptoms was 47.7 (95% confidence interval, 18.1-125.6) compared with the rest of the plaques after adjustment for the degree of stenosis and mean pixel motion. The area under the receiver operating characteristic curve for the prediction of the presence of symptoms using the MAS was 0.876 (95% confidence interval, 0.823-0.929). The use of the median MAS (120°) as a cutoff point classified 86% of the plaques correctly (sensitivity, 81.4%; specificity, 91.2%; positive predictive value, 90.2%; and negative predictive value, 83.0%). Conclusions The use of the MAS value to identify asymptomatic plaques at increased risk of developing symptoms and, in particular, stroke should be tested in prospective studies.

Context Soluble alpha klotho (sαKL) has been linked to growth hormone (GH) action, but systematic evaluation and comparisons with traditional biomarkers in acromegaly are lacking. Objective To evaluate the potential of sαKL to aid classification of disease activity. Methods This retrospective study at 2 academic centers included acromegaly patients before surgery (A, n = 29); after surgery (controlled, discordant, or uncontrolled) without (B1, B2, B3, n = 28, 11, 8); or with somatostatin analogue treatment (C1, C2, C3, n = 17, 11, 5); nonfunctioning pituitary adenomas (n = 20); and healthy controls (n = 31). sαKL was measured by immunoassay and compared with traditional biomarkers (random and nadir GH, insulin-like growth factor I [IGF-I], IGF binding protein 3). Associations with disease activity were assessed. Results sαKL was correlated to traditional biomarkers, particularly IGF-I (rs=0.80, P Conclusion Our data support sαKL as a biomarker to assess disease activity in acromegaly. sαKL exhibits close association with GH secretory status, large dynamic range, and robustness toward biological confounders. Its measurement could be helpful particularly when GH and IGF-I provide discrepant information.

Congenital anomalies of the kidney and urinary tract form a spectrum of congenital structural disorders that are generally known under the term CAKUT. The term CAKUT was introduced 20 years ago and has been used extensively in literature since. Prof. Woolf has made a plea for abandoning this term in his “case for the prosecution.” Here, I advocate for the continued use of CAKUT as an umbrella term for these related congenital kidney and urinary tract abnormalities. I explain why the term CAKUT accurately and usefully defines this group of related structural disorders with prenatal origin and why it makes sense to continue grouping these disorders given accumulating evidence for shared etiology of CAKUT phenotypes and the importance of grouping CAKUT phenotypes in genetic counseling.

In clinical practice, not all human immune deficiency virus (HIV) positive individuals who received highly active antiretroviral therapy (HAART) achieve the desired concordant response characterized by a sustained viral suppression or immune recovery. The expected success of HAART doesn’t occur in all treated patients and a discordant response between CD4 count and the viral load (VL) has been a major concern in the treatment of HIV patients. Thus, this study is designed to describe the factors associated with immunological and virological discordant responses to HAART among adult HIV positive individuals. A hospital-based cross-sectional study with secondary data review was conducted on 423 HIV positive individuals on HAART from February 1 to April 30, 2017. Socio-demographic characteristics, clinical data and about 10 mL of blood specimen for HIV VL, and CD4 count measurement were collected. The data was entered into SPSS version 20 and descriptive, bivariate, and multivariate logistic regression analysis was employed. The mean age of the patients at study time was 39 (±9.8). The average follow-up duration of patients on antiretroviral therapy (ART) was 7 (±3) years. The prevalence of immunological discordance and virological discordance to HAART were 13.2% and 47%, respectively. With multivariate logistic regression analysis duration of follow-up on ART ≤ 6 years (adjusted odds ratio [AOR] = 3.29 (1.80–6.03), P ≤ .001) and VL ≥20 copies/mm3 (AOR = 3.08 [1.70–5.61], P ≤ .001) were significant factors for immunological discordance conversely the patients who switched drug as a result of TB (AOR = 3.33 [1.10–10.08], P = .03) was significant factors for virological discordance. The prevalence of immunological discordance and virological discordance to HAART among HIV patients is high. Patients with the duration of follow-up on ART ≤ 6 years, VL ≥ 20 copies/mm3 and patients who switched drugs as a result of TB were significant factors for discordance. Hence, intensive adherence support and counseling should be provided to achieve the UNAIDS 90 target. HIV positive individuals co-infected with TB, who have had VL ≥ 20 copies/mm3 and who are ≤6 years duration of follow-up on ART need to be carefully monitored. In addition, national based study of discordant groups is recommended.

Epigenetic mechanisms may contribute to idiopathic scoliosis (IS). We identified 8 monozygotic twin pairs with IS, 6 discordant (Cobb angle difference > 10°) and 2 concordant (Cobb angle difference ≤ 2°). Genome-wide methylation in blood was measured with the Infinium HumanMethylation EPIC Beadchip. We tested for differences in methylation and methylation variability between discordant twins and tested the association between methylation and curve severity in all twins. Differentially methylated region (DMR) analyses identified gene promoter regions. Methylation at cg12959265 (chr. 7 DPY19L1) was less variable in cases (false discovery rate (FDR) = 0.0791). We identified four probes (false discovery rate, FDR < 0.10); cg02477677 (chr. 17, RARA gene), cg12922161 (chr. 2 LOC150622 gene), cg08826461 (chr. 2), and cg16382077 (chr. 7) associated with curve severity. We identified 57 DMRs where hyper- or hypo-methylation was consistent across the region and 28 DMRs with a consistent association with curve severity. Among DMRs, 21 were correlated with bone methylation. Prioritization of regions based on methylation concordance in bone identified promoter regions for WNT10A (WNT signaling), NPY (regulator of bone and energy homeostasis), and others predicted to be relevant for bone formation/remodeling. These regions may aid in understanding the complex interplay between genetics, environment, and IS.

Background In recent years, safer conception strategies have been developed to help HIV-serodiscordant couples conceive a child without transmitting HIV to the seronegative partner. The SAFER clinical trial assessed implementation of these strategies in Zimbabwe. Methods As a part of the SAFER study, we estimated the costs (in 2017 $US) associated with individual and combination strategies, in the trial setting and real-world practice, from a healthcare system perspective. Safer conception strategies included: 1) ART with frequent viral load testing until achieving undetectable viral load (ART-VL); 2) daily oral pre-exposure prophylaxis (PrEP); 3) semen-washing with intrauterine insemination; and 4) manual self-insemination at home. For costs in the trial, we used a micro-costing approach, including a time and motion study to quantify personnel effort, and estimated the cost per couple for individual and combination strategies for a mean of 6 months of safer services. For real-world practice, we modeled costs for three implementation scenarios, representing differences from the trial in input prices (paid by the Ministry of Health and Child Care [MOHCC]), intervention intensity, and increments to current HIV prevention and treatment practices and guidelines. We used one-way sensitivity analyses to assess the impact of uncertainty in input variables. Results Individual strategy costs were $769–$1615 per couple in the trial; $185–$563 if using MOHCC prices. Under the target intervention intensity and using MOHCC prices, individual strategy costs were $73–$360 per couple over and above the cost of current HIV clinical practices. The cost of delivering the most commonly selected combination, ART-VL plus PrEP, ranged from $166–$517 per couple under the three real-world scenarios. Highest costs were for personnel, lab tests, and strategy-specific consumables, in variable proportions by clinical strategy and analysis scenario. Total costs were most affected by uncertainty in the price of PrEP, number of semen-washing attempts, and scale-up of semen-washing capacity. Conclusions Safer conception methods have costs that may be affordable in many low-resource settings. These cost data will help implementers and policymakers add safer conception services. Cost-effectiveness analysis is needed to assess value for money for safer conception services overall and for safer strategy combinations. Trial registration Registry Name: Clinicaltrials.gov. Trial registration number: NCT03049176. Registration date: February 9, 2017.

Problem behaviors are of increasing public health concern. Twin studies have revealed substantial genetic and environmental influences on children's behavior, and examining birth-weight difference could allow the identification of the specific contribution of multiple non-shared prenatal environmental factors. The Twins and Multiple Births Association Heritability Study, a UK, volunteer-based study, recruited mothers of twins aged 18 months to 5 years; 960 twins (480 pairs) were included in the analysis. Twins’ mothers answered questions relative to their pregnancy and their twins’ characteristics, and completed the Child Behavior Checklist (CBCL) 1½–5. The association between the absolute birth-weight difference and each CBCL scale's score difference was analyzed by means of multiple linear regressions. Expected mean CBCL score differences were calculated. In monozygotic (MZ) twins, statistically and clinically significant associations were found between intrapair birth-weight difference and difference in total problems, internalizing problems, and emotional reactiveness. No significant results were observed neither in dizygotic (DZ) twins when analyzed as a separate group nor in MZ and DZ twins combined. The results of the present study suggest that with increasing the absolute birth-weight difference, the intrapair difference in total problems, internalizing behaviors and emotionality increases, with smaller twins being at major risk for later behavior problems. Moreover, these results suggest a causal association between birth weight and behavior development.

Background & aim: Lifestyle changes focusing on diet and exercise remain the cornerstone of the treatment of non-alcoholic fatty liver disease (NAFLD). The present co-twin control study of monozygotic (MZ) twin pairs was designed to identify nutritional factors potentially involved in the pathogenesis of NAFLD. Methods: Cross-sectional study of 50 MZ twin pairs (age range: 23-36 years), of which ten pairs were discordant for liver fat (liver fat percentage of one twin 5% and a difference between co-twins of >5%) as determined by magnetic resonance spectroscopy. Nutrient intake was calculated from 3-day food records. Results: Among the ten liver fat-discordant twin pairs, the n-6: n-3 ratio was significantly higher in the twins with higher liver as compared to their co-twins with lower liver fat (6.6:1 vs. 3.2:1, p-value = 0.005). In multiple regression analysis of within-pair differences including all 50 twin pairs, a higher n-6: n-3 ratio was significantly associated with a higher liver fat percentage within MZ twin pairs after adjustment for body mass index, energy intake and other covariates (standardized beta = 0.43, p-value = 0.001). Conclusions: Our findings suggest that the n-6: n-3 ratio is a promising dietary agent for the prevention and treatment of NAFLD. Clinical trials are required to better understand causal relationships and required doses. (C) 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

Objective. To investigate how obesity, insulin resistance and low-grade inflammation link to circulating metabolites, and whether the connections are due to genetic or environmental factors. Subjects and methods. Circulating serum metabolites were determined by proton NMR spectroscopy. Data from 1368 (531 monozygotic (MZ) and 837 dizygotic (DZ)) twins were used for bivariate twin modeling to derive the genetic (r(g)) and environmental (re) correlations between waist circumference (WC) and serum metabolites. Detailed examination of the associations between fat distribution (DEXA) and metabolic health (HOMA-IR, CRP) was performed among 286 twins including 33 BMI-discordant MZ pairs (intrapair BMI difference >= 3 kg/m(2)). Results. Fat, especially in the abdominal area (i.e. WC, android fat % and android to gynoid fat ratio), together with HOMA-IR and CRP correlated significantly with an atherogenic lipoprotein profile, higher levels of branched-chain (BCAA) and aromatic amino acids, higher levels of glycoprotein, and a more saturated fatty acid profile. In contrast, a higher proportion of gynoid to total fat associated with a favorable metabolite profile. There was a significant genetic overlap between WC and several metabolites, most strongly with phenylalanine (r(g) = 0.40), glycoprotein (r(g) = 0.37), serum triglycerides (r(g) = 0.36), BCAAs (r(g) = 0.30-0.40), HDL particle diameter (r(g) = -0.33) and HDL cholesterol (r(g) = -0.30). The effect of acquired obesity within the discordant MZ pairs was particularly strong for atherogenic lipoproteins. Conclusions. A wide range of unfavorable alterations in the serum metabolome was associated with abdominal obesity, insulin resistance and low-grade inflammation. Twin modeling and obesity-discordant twin analysis suggest that these associations are partly explained by shared genes but also reflect mechanisms independent of genetic liability. (C) 2015 Elsevier Inc. All rights reserved.

IntroductionDrug-resistant tuberculosis (TB) is a global concern. The proper diagnosis and management of drug-resistant TB are critical for improving treatment outcome. Molecular-based genotypic drug-susceptibility testing (DST) was developed to identify drug-resistant TB; however, discordant results from phenotypic and genotypic DST analyses have alarmed clinicians and raised concerns about the test’s utility. Moreover, the characteristics of disputed mutations are not well studied and only based on retrospective study findings.Methods and analysisWe describe a 28-month prospective observational cohort study ongoing at two university-affiliated hospitals in South Korea. The cohort study will enrol and evaluate 600 adults with pulmonary TB. Relevant clinical and epidemiological data will be collected prospectively and participants will be evaluated at each hospital during anti-TB treatment to identify factors associated with TB treatment outcomes. Respiratory specimens will be collected at select visits. After generating a well-characterised cohort, patterns of drug resistance on both phenotypic and genotypic DSTs and associated mutations including the disputed mutation will be evaluated. We will also identify various clinical and socioeconomic factors that affect the causes of drug resistance and their clinical outcomes.Ethics and disseminationThe study protocol is approved by the Institutional Review Boards of Chungbuk National University Hospital and Chungnam National University Hospital. Study results will be disseminated through peer-reviewed journals and conference presentations.Trial registration numberKCT0002594.

Background Spina bifida and congenital talipes equinovarus (CTEV) are common congenital malformations which may occur together and increase morbidity. Monozygous twins are particularly at risk of these malformations and discordance in one type of malformation is typical. The occurrence of both spina bifida and CTEV in one twin of a monozygotic pair is rare. Case presentation A 22 year-old Cameroonian primigravida at 36 weeks of a twin gestation was received in our district hospital at the expulsive phase of labour on a background of sub-optimal antenatal care. A caesarean section indicated for cephalo-pelvic disproportion was performed and life monoamniotic male twins were extracted. The first twin was normal. The second twin had spina bifida cystica and severe bilateral CTEV. Routine postnatal care was ensured and at day 2 of life, the affected twin was evacuated to a tertiary hospital for proper management. He was later on reported dead from complications of hydrocephalus. Conclusions Spina bifida cystica with severe bilateral CTEV in one twin of a monoamniotic pair illustrates the complexity in the interplay of causal factors of these malformations even among monozygotic twins who are assumed to share similar genetic and environmental features. The occurrence and poor outcome of the malformations was probably potentiated by poor antenatal care. With postnatal diagnoses, a better outcome was difficult to secure even with prompt referral. Early prenatal diagnoses and appropriate counseling of parents are cardinal.

Item does not contain fulltext STUDY QUESTION: What are the pregnancy outcomes for women with a twin pregnancy that is reduced to a singleton pregnancy? SUMMARY ANSWER: Fetal reduction of a twin pregnancy significantly improves gestational age at birth and neonatal birthweight, however at an increased risk of pregnancy loss and preterm delivery. WHAT IS KNOWN ALREADY: Women with a multiple pregnancy are at increased risk for preterm delivery. Fetal reduction can be considered in these women. STUDY DESIGN, SIZE, AND DURATION: Retrospective cohort study of 118 women with a twin pregnancy reduced to a singleton pregnancy between 2000 and 2010. PARTICIPANTS/MATERIALS, SETTING, AND METHODS: We compared the outcome of pregnancy in consecutive women with a dichorionic twin pregnancy that was reduced to a singleton pregnancy to that of women with a dichorionic twin pregnancy that was managed expectantly and women with a primary singleton pregnancy. Reductions were performed between 10-23(6/7) weeks' gestation by intracardiac or intrathoracic injection of potassium chloride, mostly for congenital anomalies. We compared median gestational age, pregnancy loss

It has been postulated that aging is the consequence of an accelerated accumulation of somatic DNA mutations and that subsequent errors in the primary structure of proteins ultimately reach levels sufficient to affect organismal functions. The technical limitations of detecting somatic changes and the lack of insight about the minimum level of erroneous proteins to cause an error catastrophe hampered any firm conclusions on these theories. In this study, we sequenced the whole genome of DNA in whole blood of two pairs of monozygotic (MZ) twins, 40 and 100 years old, by two independent next-generation sequencing (NGS) platforms (Illumina and Complete Genomics). Potentially discordant single-base substitutions supported by both platforms were validated extensively by Sanger, Roche 454, and Ion Torrent sequencing. We demonstrate that the genomes of the two twin pairs are germ-line identical between co-twins, and that the genomes of the 100-year-old MZ twins are discerned by eight confirmed somatic single-base substitutions, five of which are within introns. Putative somatic variation between the 40-year-old twins was not confirmed in the validation phase. We conclude from this systematic effort that by using two independent NGS platforms, somatic single nucleotide substitutions can be detected, and that a century of life did not result in a large number of detectable somatic mutations in blood. The low number of somatic variants observed by using two NGS platforms might provide a framework for detecting disease-related somatic variants in phenotypically discordant MZ twins. © The Authors 2013.

There is a lack of evidence pointing to specific dietary elements related to weight gain and obesity prevention in childhood and adulthood. Dietary intake and obesity are both inherited and culturally transmitted, but most prospective studies on the association between diet and weight status do not take genetics into consideration. The objective of this study was to document the association between dietary intake at 9 years and subsequent Body Mass Index (BMI) in adolescent monozygotic boy and girl twin pairs. This research used data from 152 twin pairs. Dietary data were collected from two 24-hour-recall interviews with a parent and the child aged 9 years. Height and weight were obtained when the twins were aged 9, 12, 13, and 14 years. Intrapair variability analysis was performed to identify dietary elements related to BMI changes in subsequent years. BMI-discordant monozygotic twin pairs were also identified to analyze the dietary constituents that may have generated the discordance. After eliminating potential confounding genetic factors, pre-adolescent boys who ate fewer grain products and fruit and consumed more high-fat meat and milk had higher BMIs during adolescence; pre-adolescent girls who consumed more grain products and high-fat meat and milk had higher BMIs during adolescence. Energy intake (EI) at 9 years was not related to BMI in subsequent years. Our study suggests that messages and interventions directed at obesity prevention could take advantage of sex-specific designs and‚ eventually‚ genetic information.

BackgroundTwin studies have lacked statistical power to apply advanced genetic modelling techniques to the search for cognitive endophenotypes for bipolar disorder.AimsTo quantify the shared genetic variability between bipolar disorder and cognitive measures.MethodStructural equation modelling was performed on cognitive data collected from 331 twins/siblings of varying genetic relatedness, disease status and concordance for bipolar disorder.ResultsUsing a parsimonious AE model, verbal episodic and spatial working memory showed statistically significant genetic correlations with bipolar disorder (rg = |0.23|–|0.27|), which lost statistical significance after covarying for affective symptoms. Using an ACE model, IQ and visual-spatial learning showed statistically significant genetic correlations with bipolar disorder (rg = |0.51|–|1.00|), which remained significant after covarying for affective symptoms.ConclusionsVerbal episodic and spatial working memory capture a modest fraction of the bipolar diathesis. IQ and visual-spatial learning may tap into genetic substrates of non-affective symptomatology in bipolar disorder.

International audience; Estrogen (E2)-responsive peripheral tissues, such as skeletal muscle, may suffer from hormone deficiency after menopause potentially contributing to the aging of muscle. However, recently E2 was shown to be synthesized by muscle and its systemic and intramuscular hormone levels are unequal. The objective of the study was to examine the association between intramuscular steroid hormones and muscle characteristics in premenopausal women (n = 8) and in postmenopausal monozygotic twin sister pairs (n = 16 co-twins from eight pairs) discordant for the use of E2-based hormone replacement. Isometric skeletal muscle strength was assessed by measuring knee extension strength. Explosive lower body muscle power was assessed as vertical jump height. Due to sequential nature of enzymatic conversion of biologically inactive dehydroepiandrosterone (DHEA) to testosterone (T) and subsequently to E2 or dihydrotestosterone (DHT), separate linear regression models were used to estimate the association of each hormone with muscle characteristics. Intramuscular E2, T, DHT, and DHEA proved to be significant, independent predictors of strength and power explaining 59–64% of the variation in knee extension strength and 80–83% of the variation of vertical jumping height in women (P < 0.005 for all models). The models were adjusted for age, systemic E2, and total body fat mass. The statistics used took into account the lack of statistical independence of twin sisters. Furthermore, muscle cells were shown to take up and actively synthesize hormones. Present study suggests intramuscular sex steroids to associate with strength and power regulation in female muscle providing novel insight to the field of muscle aging.

The influence of genes and environment on the association between bipolar disorder (BD) and volumes of subcortical brain regions involved in emotion processing has rarely been studied. Furthermore, as far as we know, longitudinal twin studies of subcortical brain volume change in BD have not been carried out at all. In this study, we focused on the genetic and environmental contributions to cross-sectional and longitudinal measures of subcortical brain volumes in BD.A total of 99 twins from monozygotic and dizygotic pairs concordant or discordant for BD and 129 twins from monozygotic and dizygotic healthy control pairs underwent magnetic resonance imaging at baseline. Longitudinal assessment was carried out in 48 twins from monozygotic and dizygotic patient pairs and 52 twins from monozygotic and dizygotic control pairs. Subcortical volume measures were obtained with Freesurfer software and analyzed with structural equation modeling software OpenMx. At baseline, BD was phenotypically and genetically associated with smaller volumes of the thalamus, putamen and nucleus accumbens. BD was not associated with subcortical brain volume change over time in any of the examined regions. Heritability of subcortical volumes at baseline was high, whereas subcortical volume change had low heritability.Genes contributing to BD showed overlap with those associated with smaller volumes of the thalamus, putannen and nucleus accumbens at baseline. Further evaluation of genetic contributions to abnormalities in subcortical brain regions assumed to be involved in emotion processing is recommended. (C) 2015 Elsevier B.V. and ECNP. All rights reserved.

Background About 60% of new HIV infections occur in HIV sero-discordant couples as 30% of married HIV positives have negative spouse. Although HIV-discordant couples are at 10% annual risk of acquiring HIV infection and large number of new HIV infections occur in stable partnerships, most HIV prevention programs focus on reducing casual sexual partners, condom use, and increasing fidelity among married partners. The purpose is assessment of sero-discordance among couples and associated factors. Methods The study was facility based cross sectional survey of couples who tested for HIV in 2011 and lived together at least 1 year period. The sample size was 154 couples (308 individuals) and necessary ethical issues were considered. Results Among 152 couples (304 individuals) who received VCT, HIV sero-prevalence in this study was found to be 11(3.6%). The prevalence in females 8(5.3%) was higher than that in males 3(2.0%). Of all participants, 9(3.0%) were found to be sero-discordant, 2(0.7%) concordant positive and 293(96.4%) concordant negative. Of all couples 9(5.9%) were found to be sero-discordant, 2(1.3%) concordant positive and 141(92.8%) concordant negative. Of the 9 sero-discordant couples, the 7(4.6%) prevalence in females was higher than 2(1.3%) in males. And, among 9 discordant couples, 5 of them were premarital sex partner and the rest 4 were married couples. Premarital couples were significantly discordant than married couples, AOR = 1.68; 95%CI (1.36- 5.40). HIV discordance was also significantly associated with having number of two or more sexual partners than one sexual partner AOR = 4.06; 95%CI (2.41-10.13). Conclusion The study indicated high prevalence of HIV discordance and increased risk of vulnerability. Therefore, couples should be aware of their own and their partners’ sero-status before and after engagement. Again, the following risk reduction methods were recommended: education of discordant couples on 100% correct condom use, and if condom breaks, or if they forget to use, Post-Exposure Prophylaxis must be established; for those who are not volunteer to use condom and/or have a child, early initiation of ART to positive partner. Electronic supplementary material The online version of this article (doi:10.1186/1756-0500-7-893) contains supplementary material, which is available to authorized users.

Objective : The goal of this study was to identify in human immunodeficiency virus (HIV)-infected individuals immunologic markers that correlated with transmission of HIV by heterosexual contact. Methods : In a case-control comparison of couples, immunologic and viral parameters were evaluated in 343 HIV-positive individuals who were members of 67 HIV-seroconcordant couples (both partners HIV positive) and 211 HIV serodiscordant couples (one positive, one negative). Results : The most striking immunologic finding was the increased numbers of CD3+CD8+ cells found in the index member of discordant couples as compared to the index member of the concordant couples. Differences in CD3+CD8+ levels persisted after adjustment for stage of disease and CD3+CD4+ count. This increase in the number of CD3+CD8+ cells was accompanied by a concomitant decrease in the amount of viral replication measured by both HIV culture endpoint and quantitative RNA polymerase chain reaction (PCR). Conclusion : Data presented here further support the role of CD3+CD8+ cells in suppressing or controlling viral activity, although a causal role based on case-control data must be advanced cautiously. This in vivo biologic function may help prevent or lower the risk of HIV transmission.

To investigate environmental factors that protect against or exacerbate obsessive-compulsive (OC) symptoms, we selected 25 monozygotic (MZ) twin pairs discordant, 17 MZ twin pairs concordant high and 34 MZ pairs concordant low on OC symptoms from a large longitudinal Dutch sample of adult twin pairs and their family members, applying stringent criteria for OC symptomatology. Data were collected on psychopathology, family structure, health, lifestyle, birth complications and life events. Unique environmental factors were studied using within-discordant MZ pair comparisons, whereas between-concordant MZ pair comparisons were used to study environmental factors that are shared by the twins of an MZ pair. The high-scoring MZ twins of the discordant group reported more life events (especially sexual abuse) than their low-scoring twin-siblings. The between-pair comparisons showed lower birth weight in the discordant MZ pairs than in the concordant MZ pairs. Further, the concordant high MZ pairs as well as their spouses had a lower educational level than the two other groups. On scale scores of anxious-depression, neuroticism, and somatic complaints, concordant high MZ pairs showed highest scores, and the discordant MZ pairs scored intermediate, except for neuroticism, on which the high-scoring twins of discordant MZ pairs were equal to the concordant high pairs. Discordance on psychological scale scores between the concordant MZ pairs was evident from 1991 onward, and within the discordant MZ pairs from 1997 onward, confirming previous reports of an association of early-onset OC symptoms with higher genetic load. Parent scores of OC symptoms and anxious-depression suggested intermediate genetic load in the discordant MZ group. In conclusion, this study reports on both unique and shared environmental factors associated with OC symptomatology. Whether these factors operate in addition to or in interaction with genetic disposition is to be elucidated in future studies. © 2008 The Author(s).

We examined the relationship between a history of obstetric complications (OCs) and the number of neurological soft signs (NSS) in a group of 132 patients experiencing their first episode of psychosis. We measured NSS by means of a comprehensive standardized assessment and gained information on a selection of nine OCs from the patient's mother. Contrary to our expectations we found significantly more NSS in the group of patients without a history of OCs. This effect was independent of medication in the group of patients with a schizophrenic disorder, but not in the entire group. It is possible that the patients with a history of OCs carry fewer genes for schizophrenia (and NSS) and 'needed' the OCs to develop schizophrenia. (c) 2006 Elsevier Ireland Ltd. All rights reserved.

OBJECTIVE: To study the frequency and obstetric outcome of monochorionic multiple pregnancies in a population referred for fetal reduction. METHODS: Data charts of all patients with multifetal (> or =3) pregnancies referred for fetal reduction over the last 10 years were reviewed for the presence of monochorionic twin pairs or triplets. RESULTS: Twenty-nine of 239 high-order multiple pregnancies contained a monochorionic component (12.1%), eight of which were monochorionic triplets. Half of all naturally conceived pregnancies contained a monochorionic component. High-order multiple pregnancies with a monochorionic component resulted significantly more frequently from natural conceptions (7 of 29) than multichorionic pregnancies (7 of 210) (P =.001). Fetal reduction of the monochorionic twin pair in 21 pregnancies resulted in eight twin and 13 singleton pregnancies; mean gestational age at delivery was, respectively, 34.3 +/- 2.9 and 39.2 +/- 1.4 weeks. Pregnancy loss rate was one of 21 (4.8%). In the remaining eight multiple pregnancies with a monochorionic triplet present, three were complicated by a twin reversed arterial perfusion sequence, and two couples requested a first trimester termination of pregnancy. Fetal reduction of the monochorionic triplet in a dichorionic quadruplet pregnancy resulted in a normal pregnancy outcome. In two monochorionic triplet pregnancies, fetal reduction to monochorionic twin pregnancies with bipolar coagulation of the umbilical cord resulted in a favorable pregnancy outcome. CONCLUSION: Monochorionic twins or triplets are frequently part of naturally conceived high-order multiple pregnancies. Reduction of the monochorionic twin pairs improves pregnancy outcome. Monochorionic triplet pregnancies show a high complication rate, but may benefit from fetal reduction by cord coagulation.

Exosomes participate in intercellular messaging by transporting bioactive lipid-, protein- and RNA-molecules and -complexes. The contents of the exosomes reflect the physiological status of an individual making exosomes promising targets for biomarker analyses. In the present study we extracted exosome microRNAs (exomiRs) from serum samples of premenopausal women (n = 8) and monozygotic postmenopausal twins (n = 10 female pairs), discordant for the use of estrogenic hormone replacement therapy (HRT), in order to see whether the age or/and the use of HRT associates with exomiR content. A total of 241 exomiRs were detected by next generation sequencing, 10 showing age, 14 HRT and 10 age +HRT -related differences. When comparing the groups, differentially expressed miRs were predicted to affect cell proliferation processes showing inactivation with younger age and HRT usage. MiR-106-5p, -148a-3p, -27-3p, -126-5p, -28-3p and -30a-5p were significantly associated with serum 17β-estradiol. MiRs formed two hierarchical clusters being indicative of positive or negative health outcomes involving associations with body composition, serum 17β-estradiol, fat-, glucose- and inflammatory markers. Circulating exomiR clusters, obtained by NGS, could be used as indicators of metabolic and inflammatory status affected by hormonal changes at menopause. Furthermore, the individual effects of HRT-usage could be evaluated based on the serum exomiR signature.

Background Socioeconomic determinants have been shown to have an effect on the progression of HIV disease evidenced by studies carried out largely in developed countries. Knowledge of these factors could inform on prioritization of populations during scale up of highly active antiretroviral therapy (HAART) constrained health systems. The objective of this study was to identify socioeconomic correlates of HIV disease progression in an adult Kenyan population. Methods We analysed data from 312 HIV positive individuals, drawn from a cohort enrolled in a randomized clinical trial investigating the effectiveness of Acyclovir in the prevention of HIV transmission among serodiscordant couples. In this study we included individuals with CD4 counts ≥ 350 cells/mm3 and World Health Organization (WHO), clinical stage one or two. The exposure variables measured were: - daily household income available for expenditure, age, gender, housing type and level of formal education. We used a composite outcome of disease progression to WHO clinical stage 3 or 4 or a laboratory outcome of CD4 count below 350 cells/mm3 after two years of follow-up. Logistic regression was used to determine associations of variables that were found to be significant at univariate analysis, and to control for potential confounders. Results Seventy eight (25 %) individuals reported HIV disease progression. Majority (79.9 %) were female. The median age was 30 year and 93.6 % had attained a primary level of education. Median CD4 at enrolment into the clinical trial was 564 cells/mm3; those who had disease progression were enrolled with a significantly (p

Made available in DSpace on 2022-04-28T20:59:30Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-12-01 Phenotypically discordant monozygotic twins offer the possibility of gene discovery through delineation of molecular abnormalities in one member of the twin pair. One proposed mechanism of discordance is postzygotically occurring genomic alterations resulting from mitotic recombination and other somatic changes. Detection of altered genomic fragments can reveal candidate gene loci that can be verified through additional analyses. We investigated this hypothesis using array comparative genomic hybridization; the 50K and 250K Affymetrix GeneChip® SNP arrays and an Illumina custom array consisting of 1,536 SNPs, to scan for genomic alterations in a sample of monozygotic twin pairs with discordant cleft lip and/or palate phenotypes. Paired analysis for deletions, amplifications and loss of heterozygosity, along with sequence verification of SNPs with discordant genotype calls did not reveal any genomic discordance between twin pairs in lymphocyte DNA samples. Our results demonstrate that postzygotic genomic alterations are not a common cause of monozygotic twin discordance for isolated cleft lip and/or palate. However, rare or balanced genomic alterations, tissue-specific events and small aberrations beyond the detection level of our experimental approach cannot be ruled out. The stability of genomes we observed in our study samples also suggests that detection of discordant events in other monozygotic twin pairs would be remarkable and of potential disease significance. University of Iowa Department of Pediatrics, S. Grand Avenue, 2182 ML, Iowa City, IA 52242 Department of Pathology and Lab. Medicine University of North Carolina Department of Human Genetics Nagasaki University Graduate School of Biomedical Sciences, Nagasaki Biostatistics Branch National Institute of Environmental Health Sciences (NIEHS) Craniofacial Development Murdoch Children's Research Institute Royal Children's Hospital, Melbourne, VIC Servico de Aconselhamento Genetico da Universidade Estadual Paulista, Botucatu Department of Epidemiology Institute of Public Health University of Southern Denmark Servico de Aconselhamento Genetico da Universidade Estadual Paulista, Botucatu