An acoustic mixer for glass channel microfluidic systems is presented. An acoustic standing wave, perpendicular to the fluid flow, is generated by the excitation of a miniaturized piezoelectric ...transducer operated around 10 MHz. The transducer is fabricated into a planar printed circuit board structure, constituting the bottom channel wall, which makes the mixer simple to integrate with a wide selection of microfluidic channel designs. The mixing occurs at a fluid-fluid density interface due to the acoustic radiation force; an analytical expression is derived to qualitatively describe this phenomenon. Only a small density difference in the range of 2-5% is required to achieve 150-270% peak broadening of a fluorescent sample between sheath flows, which we use as a measure of the mixing efficiency. The mixing efficiency is measured with regard to its sensitivity to the density difference, the fluid velocity and the transducer driving frequency. Transducers at different positions along the microchannel make it possible to compare the mixing of straight versus diagonal flows across the transducer surface. We finally demonstrate enhanced chemical lysis of E. coli K12 cells in the device due to active fluid mixing.
The causal relationship between maternal smoking in pregnancy and reduced offspring birth weight is well established and is likely due to impaired placental function. However, observational studies ...have given conflicting results on the association between smoking and placental weight. We aimed to estimate the causal effect of newly pregnant mothers quitting smoking on their placental weight at the time of delivery.
We used one-sample Mendelian randomization, drawing data from the Avon Longitudinal Study of Parents and Children (ALSPAC) (N = 690 to 804) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (N = 4267 to 4606). The sample size depends on the smoking definition used for different analyses. The analysis was performed in pre-pregnancy smokers only, due to the specific role of the single-nucleotide polymorphism (SNP) rs1051730 (CHRNA5 - CHRNA3 - CHRNB4) in affecting smoking cessation but not initiation.
Fixed effect meta-analysis showed a 182 g 95%CI: 29,335 higher placental weight for pre-pregnancy smoking mothers who continued smoking at the beginning of pregnancy, compared with those who stopped smoking. Using the number of cigarettes smoked per day in the first trimester as the exposure, the causal effect on placental weight was 11 g 95%CI: 1,21 per cigarette per day. Similarly, smoking at the end of pregnancy was causally associated with higher placental weight. Using the residuals of birth weight regressed on placental weight as the outcome, we showed evidence of lower offspring birth weight relative to the placental weight, both for continuing smoking at the start of pregnancy as well as continuing smoking throughout pregnancy (change in z-score birth weight adjusted for z-score placental weight: -0.8 95%CI: -1.6,-0.1).
Our results suggest that continued smoking during pregnancy causes higher placental weights.
Genome sequencing can identify individuals in the general population who harbor rare coding variants in genes for Mendelian disorders and who may consequently have increased disease risk. Previous ...studies of rare variants in phenotypically extreme individuals display ascertainment bias and may demonstrate inflated effect-size estimates. We sequenced seven genes for maturity-onset diabetes of the young (MODY) in well-phenotyped population samples (n = 4,003). We filtered rare variants according to two prediction criteria for disease-causing mutations: reported previously in MODY or satisfying stringent de novo thresholds (rare, conserved and protein damaging). Approximately 1.5% and 0.5% of randomly selected individuals from the Framingham and Jackson Heart Studies, respectively, carry variants from these two classes. However, the vast majority of carriers remain euglycemic through middle age. Accurate estimates of variant effect sizes from population-based sequencing are needed to avoid falsely predicting a substantial fraction of individuals as being at risk for MODY or other Mendelian diseases.
Birth by cesarean section is associated with increased risks of immune disorders. We tested whether establishment of immune function at birth relates to mode of delivery, taking other maternal and ...infant characteristics into account.
Using a prospectively collected database, we retrieved information on maternal and infant characteristics of 6,014 singleton infants delivered from February to April 2014 in Stockholm, Sweden, with gestational age ≥35 weeks, Apgar scores ≥7, and without congenital malformations or any neonatal morbidity. We linked our data to blood levels of T-cell receptor excision circles (TREC) and κ-deleting recombination excision circles (KREC), determined as part of a neonatal screening program for immune-deficiencies, and representing quantities of newly formed T- and B-lymphocytes. Multivariate logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for participants having TREC and KREC levels in the lowest quintile. Multivariate models were adjusted for postnatal age at blood sampling, and included perinatal (mode of delivery, infant sex, gestational age, and birth weight for gestational age), and maternal characteristics (age, parity, BMI, smoking, diabetes, and hypertensive disease). Low TREC was associated with cesarean section before labor (adjusted OR:1.32 95% CI 1.08-1.62), male infant sex (aOR:1.60 1.41-1.83), preterm birth at 35-36 weeks of gestation (aOR:1.89 1.21-2.96) and small for gestational age (aOR:1.67 1.00-2.79). Low KREC was associated with male sex (aOR:1.32 1.15-1.50), postterm birth at ≥42 weeks (aOR:1.43 1.13-1.82) and small for gestational age (aOR:2.89 1.78-4.69). Maternal characteristics showed no consistent associations with neonatal levels of either TREC or KREC.
Cesarean section before labor was associated with lower T-lymphocyte formation, irrespective of maternal characteristics, pregnancy, and neonatal risk factors. The significance of a reduced birth-related surge in lymphocyte formation for future immune function and health remains to be investigated.
Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder with a complex genetic background, hampering identification of underlying genetic risk factors. We hypothesized ...that combining linkage analysis and whole-exome sequencing (WES) in multi-generation pedigrees with multiple affected individuals can point toward novel ADHD genes. Three families with multiple ADHD-affected members (N
= 70) and apparent dominant inheritance pattern were included in this study. Genotyping was performed in 37 family members, and WES was additionally carried out in 10 of those. Linkage analysis was performed using multi-point analysis in Superlink Online SNP 1.1. From prioritized linkage regions with a LOD score ≥ 2, a total of 24 genes harboring rare variants were selected. Those genes were taken forward and were jointly analyzed in gene-set analyses of exome-chip data using the MAGMA software in an independent sample of patients with persistent ADHD and healthy controls (N = 9365). The gene-set including all 24 genes together, and particularly the gene-set from one of the three families (12 genes), were significantly associated with persistent ADHD in this sample. Among the latter, gene-wide analysis for the AAED1 gene reached significance. A rare variant (rs151326868) within AAED1 segregated with ADHD in one of the families. The analytic strategy followed here is an effective approach for identifying novel ADHD risk genes. Additionally, this study suggests that both rare and more frequent variants in multiple genes act together in contributing to ADHD risk, even in individual multi-case families.
Given that teacher shortage is an international problem, teacher job satisfaction merits closer attention. Not only is job satisfaction closely related to teacher retention, but it also contributes ...to the well-being of teachers and their students, overall school cohesion and enhanced status of the teaching profession. This study investigates the relations between teacher job satisfaction, school working conditions and teacher characteristics for eighth grade mathematics teachers. The study employs TIMSS 2015 (Trends in International Mathematics and Science Study) data from Sweden. Confirmatory factor analysis and structural equation modelling are used as main methods. Results demonstrate a substantial association between school working conditions and teacher job satisfaction. More specifically, teacher workload, teacher cooperation and teacher perceptions of student discipline in school were the factors most closely related to teacher job satisfaction. As to teacher characteristics, female teachers, teachers with more exposure to professional development and more efficacious teachers tended to have higher levels of job satisfaction. In addition, it was found that the relationship between the extent of teacher cooperation and job satisfaction was more pronounced for male teachers, while student discipline was more important for job satisfaction of teachers with lower self-efficacy beliefs. Implications for policy are further discussed.
The demand for user participation in design processes is increasing, and there is a need to formulate guidance on how to involve disabled users and their representative organisations. Their ...participation contributes an extreme user perspective to the design process. The aim of this study was to develop an empirically grounded framework for user participation in co-design processes, involving the users with wide range of characteristics. The study was theoretically grounded in 'participatory design' and 'value sensitive design' and used an exploratory study design with online workshops to iteratively collect and analyse data. All participants collaborated on an online Miro-board to identify themes and formulate guiding principles for the framework. We propose a framework consisting of three themes: participation fundamentals, participation ethics and participation practicalities, entailing 11 guiding principles. By applying this framework, the premises, methods and activities in the design process will be accessible to all participants, and user participation in design projects will become more transparent, equitable and easier to implement. It will enable all users, people with disabilities and others, to participate and contribute to a design that can be used by the widest range of people. Keywords: accessibility, universal design, participation, disability, impairment, qualitative thematic analysis
Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has ...shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes
and
, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.
Genetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic ...potential when standard Sanger sequencing-based diagnostics is inconclusive.
The aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results.
We performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism.
On average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0-4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes.
Our results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized.
We identified four different missense mutations in the single-exon gene MAB21L2 in eight individuals with bilateral eye malformations from five unrelated families via three independent exome ...sequencing projects. Three mutational events altered the same amino acid (Arg51), and two were identical de novo mutations (c.151C>T p.Arg51Cys) in unrelated children with bilateral anophthalmia, intellectual disability, and rhizomelic skeletal dysplasia. c.152G>A (p.Arg51His) segregated with autosomal-dominant bilateral colobomatous microphthalmia in a large multiplex family. The fourth heterozygous mutation (c.145G>A p.Glu49Lys) affected an amino acid within two residues of Arg51 in an adult male with bilateral colobomata. In a fifth family, a homozygous mutation (c.740G>A p.Arg247Gln) altering a different region of the protein was identified in two male siblings with bilateral retinal colobomata. In mouse embryos, Mab21l2 showed strong expression in the developing eye, pharyngeal arches, and limb bud. As predicted by structural homology, wild-type MAB21L2 bound single-stranded RNA, whereas this activity was lost in all altered forms of the protein. MAB21L2 had no detectable nucleotidyltransferase activity in vitro, and its function remains unknown. Induced expression of wild-type MAB21L2 in human embryonic kidney 293 cells increased phospho-ERK (pERK1/2) signaling. Compared to the wild-type and p.Arg247Gln proteins, the proteins with the Glu49 and Arg51 variants had increased stability. Abnormal persistence of pERK1/2 signaling in MAB21L2-expressing cells during development is a plausible pathogenic mechanism for the heterozygous mutations. The phenotype associated with the homozygous mutation might be a consequence of complete loss of MAB21L2 RNA binding, although the cellular function of this interaction remains unknown.
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