The degree of fetal metformin exposure does not influence fetal outcome in gestational diabetes mellitus

The purpose of the study was to examine in vivo placental transfer of metformin, its association with neonatal outcome in metformin-treated gestational diabetes (GDM) patients, and influence of metformin exposure on maternal glycemic control and weight gain. Two hundred and seventeen GDM patients were randomized to metformin or insulin in Turku University Hospital, Finland. Metformin concentrations were determined by mass spectrometry in maternal serum at 36 gestational weeks (gw) and at birth, and in umbilical cord blood. Main outcome measures were birth weight, gw at birth, umbilical artery pH and neonatal hypoglycemia, maternal weight gain, HbA1c and fructosamine concentration. Median umbilical cord/maternal serum metformin concentration ratio was 0.73. There were no differences in birth weight measured in grams or SD units (p = 0.49), or gw at birth (p always ≥0.49) between insulin- and metformin-treated patients stratified by trough metformin concentration tertiles measured at 36 gw. Rate of neonatal hypoglycemia (p = 0.92) and umbilical artery pH value (p = 0.78) was similar in insulin- and metformin-treated patients stratified by cord metformin concentration tertiles. Maternal glycemic control was similar in metformin concentration tertiles at 36 gw. Maternal weight gain was 223 g greater per week (p = 0.038) in the lowest metformin tertile compared to other tertiles combined. Maternal and fetal exposure to metformin is similar. Maternal or fetal metformin concentrations do not predict maternal glycemic control or neonatal outcome, but low maternal exposure may lead to greater maternal weight gain.     

Tumor mutational load predicts time to first treatment in chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis beyond the CLL international prognostic index

Next-generation sequencing identified about 60 genes recurrently mutated in chronic lymphocytic leukemia (CLL). We examined the additive prognostic value of the total number of recurrently mutated CLL genes (i.e., tumor mutational load [TML]) or the individually mutated genes beyond the CLL international prognostic index (CLL-IPI) in newly diagnosed CLL and high-count monoclonal B-cell lymphocytosis (HC MBL). We sequenced 59 genes among 557 individuals (112 HC MBL/445 CLL) in a multi-stage design, to estimate hazard ratios (HR) and 95% confidence intervals (CI) for time-to-first treatment (TTT), adjusted for CLL-IPI and sex. TML was associated with shorter TTT in the discovery and validation cohorts, with a combined estimate of continuous HR = 1.27 (CI:1.17-1.39, P = 2.6 × 10⁻⁸; c-statistic = 0.76). When stratified by CLL-IPI, the association of TML with TTT was stronger and validated within low/intermediate risk (combined HR = 1.54, CI:1.37-1.72, P = 7.0 × 10⁻¹⁴). Overall, 80% of low/intermediate CLL-IPI cases with two or more mutated genes progressed to require therapy within 5 years, compared to 24% among those without mutations. TML was also associated with shorter TTT in the HC MBL cohort (HR = 1.53, CI:1.12-2.07, P = .007; c-statistic = 0.71). TML is a strong prognostic factor for TTT independent of CLL-IPI, especially among low/intermediate CLL-IPI risk, and a better predictor than any single gene. Mutational screening at early stages may improve risk stratification and better predict TTT.     

Relationship dissatisfaction and other risk factors for future relationship dissolution: a population-based study of 18,523 couples

Purpose

There has been a marked increase in divorce rates in most Western societies over the last 50 years. Relationship dissolution is associated with negative consequences both for adults and children, so it is important to understand the factors that help retain marital stability. The first aim of this prospective study was to identify risk factors for relationship dissolution in 18,523 couples in Norway, with a particular focus on individual dissatisfaction with the relationship. The second aim was to assess interaction effects between relationship dissatisfaction and other predictors of relationship dissolution.

Methods

Pregnant women and their partners enrolled in the Norwegian Mother and Child Cohort study completed questionnaires during the pregnancy that asked about relationship dissatisfaction, strain, demographics, and other risk factors. The main outcome variable was relationship dissolution in the 39-month period from gestational week 30–36 months postpartum. Associations between the risk factors and relationship dissolution were estimated by logistic regression analysis.

Results

Except for younger female age, relationship dissatisfaction in women and lower education in men, were the strongest predictors of relationship dissolution. Another strong factor was women’s persistent strain. No significant interaction effects were found between relationship dissatisfaction and the other variables in the analyses.

Conclusions

Dissatisfaction with the relationship, in particular in women, and low male education are important predictors of relationship dissolution, although other factors are also related to dissolution. There are only few studies on relationship predictors of dissolution conducted in Europe, and the current study adds to this body of knowledge.     

ESAT and M-CHAT as screening instruments for autism spectrum disorders at 18 months in the general population: issues of overlap and association with clinical referrals

The Modified Checklist for Autism in Toddlers (M-CHAT) and the Early Screening of Autistic Traits (ESAT) were designed to screen for autism spectrum disorders in very young children. The aim of this study was to explore proportions of children that screened positive on the ESAT or the M-CHAT and to investigate if screening positive on the ESAT and M-CHAT is associated with clinical referral by 18 months and other aspects of children’s development, health, and behavior. In this study, the mothers of 12,948 18-month-old children returned a questionnaire consisting of items from the ESAT and M-CHAT, plus questions about clinical and developmental characteristics. The M-CHAT identified more screen-positive children than the ESAT, but the ESAT was associated with more clinical referrals and tended to identify more children with medical, language, and behavioral problems. A post hoc analysis of combining the two instruments found this to be more effective than the individual instruments alone in identifying children referred to clinical services at 18 months. Further analysis at the level of single items is warranted to improve these screening instruments.     

Expanding the role of the genetic counselor

The basic components of genetic counseling are informational and educational. The patient's cognitive and emotional presentation and the needs and concerns of the patient are seldom addressed. Females who carry the FMR1 pre and full gene mutation may present with learning, cognitive, and/or emotional difficulties and family members of those diagnosed with fragile X syndrome have ongoing needs and concerns. As a result, genetic counseling for fragile X syndrome offers a unique opportunity within which to expand the role of the genetic counselor. Q-methodology, by using the q-sort, is centered on the family to reproduce the needs and concerns that are consistent with the patient's own experience. Used for sociological research, the q-methodology with specially constructed q-sort items is easily adapted to the genetic counseling setting © ^{1995 Flynn & Gane} and can be used for directly assessing the patient's needs and concerns. For our pilot study, 16 items were physically sorted and ranked interdependently by the patient (subject). Thirty-seven patients (29 females and 8 males) participated in our pilot study. Preliminary results show that the age of the proband, length of time of the diagnosis, and parental sex at the time the q-sort is administered impacts the ranking of items thus differentiating needs and concerns. Results have shown that specific items are missing from the lives of subjects. From the information obtained from the q-sort, the genetic counselor can identify needs and concerns of the patient and combine this information with the clinical presentation to work with the patient in a more effective manner. © 1996 Wiley-Liss, Inc.     

Fumarylacetoacetase mutations in tyrosinaemia type I

Sixty-two hereditary tyrosinaemia type I (HT1) patients of various ethnic origins were classified clinically into acute, chronic, or intermediate phenotypes and screened for the 14 published causal mutations in the fumarylacetoacetase (FAH) gene. Restriction analysis of PCR amplified genomic DNA identified 74% of the mutated alleles. IVS12+5G→A, predominant in the French Canadian HT1 patients, was the most common mutation found in 32 alleles in patients from Europe, Pakistan, Turkey, and the United States. IVS6-1G→T, encountered in 14 alleles, was common in Central and Western Europe. There was an apparent “Scandinavian” 1009G→A combined splice and missense mutation (12 alleles), a “Pakistani” 192G→T splice mutation (11 alleles), a “Turkish” D233V mutation (6 alleles), and a “Finnish” or northern European W262X mutation (7 alleles). The remaining mutations were rare. Some of the mutations seem to predispose for acute and other for more chronic forms of HT1, but in our material no clearcut genotype phenotype correlation could be established. © 1996 Wiley-Liss, Inc.     

Associations of Urban Environment Features with Hypertension and Blood Pressure across 230 Latin American Cities

Background: Features of the urban physical environment may be linked to the development of high blood pressure, a leading risk factor for global burden of disease.Objectives: We examined associations of urban physical environment features with hypertension and blood pressure measures in adults across 230 Latin American cities.Methods: In this cross-sectional study we used health, social, and built environment data from the SALud URBana en América Latina (SALURBAL) project. The individual-level outcomes were hypertension and levels of systolic and diastolic blood pressure. The exposures were city and subcity built environment features, mass transit infrastructure, and green space. Odds ratios (ORs) and mean differences and 95% confidence intervals (CIs) were estimated using multilevel logistic and linear regression models, with single- and multiple-exposure models adjusted for individual-level age, sex, education, and subcity educational attainment.Results: A total of 109,176 participants from 230 cities and eight countries were included in the hypertension analyses and 50,228 participants from 194 cities and seven countries were included in the blood pressure measures analyses. Participants were 18–97 years of age. In multiple-exposure models, higher city fragmentation was associated with higher odds of having hypertension (OR per standard deviation (SD) increase=1.11; 95% CI: 1.01, 1.21); presence (vs. no presence) of mass transit in the city was associated with higher odds of having hypertension (OR=1.30; 95% CI: 1.09, 1.54); higher subcity population density was associated with lower odds of having hypertension (OR per SD increase=0.90; 95% CI: 0.85, 0.94); and higher subcity intersection density was associated with higher odds of having hypertension [OR per SD increase=1.09; 95% CI: 1.04, 1.15). The presence of mass transit was also associated with slightly higher systolic and diastolic blood pressure in multiple-exposure models adjusted for treatment. Except for the association between intersection density and hypertension, associations were attenuated after adjustment for country. An inverse association of greenness with continuous blood pressure emerged after country adjustment.Discussion: Our results suggest that urban physical environment features—such as fragmentation, mass transit, population density, and intersection density—may be related to hypertension in Latin American cities. Reducing chronic disease risks in the growing urban areas of Latin America may require attention to integrated management of urban design and transport planning. https://doi.org/10.1289/EHP7870     

Assessment of a conceptually informed measure of emotion dysregulation: Evidence of construct validity vis a vis impulsivity and internalizing symptoms in adolescents with ADHD

ObjectivesDespite advances in understanding associations among attention‐deficit hyperactivity disorder (ADHD), emotion dysregulation (ED), and related outcomes, there is incongruity between ADHD‐relevant conceptualizations of ED and available measures of ED. To assess the psychometric properties of a parent‐report questionnaire of ED conceptualized as deficits in the ability to modulate the (a) speed/degree of emotion escalation; (b) expression intensity; and (c) speed/degree of de‐escalation.MethodsParticipants were 209 adolescents with ADHD (78% male; 13.5–17.8 years old [M = 15.2 SD = 0.91]). Questionnaire items were selected from parent‐report scales of ED and oppositional defiant disorder and subjected to exploratory factor analysis (EFA) and validity analyses.ResultsThe EFA revealed two factors, with speed/degree of escalation combined with intensity as factor one, and speed/degree of de‐escalation as factor two. Factor one scores were related to ADHD impulsivity symptoms but not to anxiety and depression symptoms and they remained predictors of impulsivity even in the presence of self‐report ED, evincing convergent, discriminant, and incremental validity. Factor two scores were related to anxiety and depression but not impulsivity, evincing convergent and discriminant validity.ConclusionThese results inform our understanding of ADHD‐relevant ED in adolescence and offer avenues for future research in measurement development, as well as for understanding ED and ADHD‐related impairment.