To assess longitudinally children's motor performance 5 to 12 years after neonatal extracorporeal membrane oxygenation (ECMO) and to evaluate associations between clinical characteristics and motor ...performance.
Two hundred fifty-four neonatal ECMO survivors in the Netherlands were tested with the Movement Assessment Battery for Children at 5, 8, and/or 12 years. Percentile scores were transformed to z scores for longitudinal evaluation (norm population mean = 0 and SD = 1). Primary diagnoses: meconium aspiration syndrome (n = 137), congenital diaphragmatic hernia (n = 49), persistent pulmonary hypertension of the newborn (n = 36), other diagnoses (n = 32).
Four hundred fifty-six tests were analyzed. At 5, 8, and 12 years motor performance was normal in 73.7, 74.8, and 40.5%, respectively (vs 85% expected based on reference values; P < .001 at all ages). In longitudinal analyses mean (95% confidence interval CI) z scores were -0.42 (-0.55 to -0.28), -0.25 (-0.40 to -0.10) and -1.00 (-1.26 to -0.75) at 5, 8, and 12 years, respectively. Mean score at 8 years was significantly higher than at 5 years (difference 0.16, 95% CI 0.02 to 0.30), and mean score at 12 years was significantly lower than at both other ages (differences -0.59 and -0.75; 95% CI -0.33 to -0.84 and -0.49 to -1.00, respectively). Children with congenital diaphragmatic hernia encountered problems at all ages. The presence of chronic lung disease was negatively related with outcome.
Motor problems in neonatal ECMO survivors persist throughout childhood and become more obvious with time.
The pharmacokinetic (PK) properties of intravenous (i.v.) benzylpenicillin in term neonates undergoing moderate hypothermia after perinatal asphyxia were evaluated, as they have been unknown until ...now. A system-specific modeling approach was applied, in which our recently developed covariate model describing developmental and temperature-induced changes in amoxicillin clearance (CL) in the same patient study population was incorporated into a population PK model of benzylpenicillin with
birthweight (BW)-based allometric scaling. Pediatric population covariate models describing the developmental changes in drug elimination may constitute system-specific information and may therefore be incorporated into PK models of drugs cleared through the same pathway. The performance of this system-specific model was compared to that of a reference model. Furthermore, Monte-Carlo simulations were performed to evaluate the optimal dose. The system-specific model performed as well as the reference model. Significant correlations were found between CL and postnatal age (PNA), gestational age (GA), body temperature (TEMP), urine output (UO; system-specific model), and multiorgan failure (reference model). For a typical patient with a GA of 40 weeks, BW of 3,000 g, PNA of 2 days (TEMP, 33.5°C), and normal UO (2 ml/kg/h), benzylpenicillin CL was 0.48 liter/h (interindividual variability IIV of 49%) and the volume of distribution of the central compartment was 0.62 liter/kg (IIV of 53%) in the system-specific model. Based on simulations, we advise a benzylpenicillin i.v. dose regimen of 75,000 IU/kg/day every 8 h (q8h), 150,000 IU/kg/day q8h, and 200,000 IU/kg/day q6h for patients with GAs of 36 to 37 weeks, 38 to 41 weeks, and ≥42 weeks, respectively. The system-specific model may be used for other drugs cleared through the same pathway accelerating model development.
Kisspeptins are products of the Kiss1 gene, which bind to GPR54, a G protein-coupled receptor. Kisspeptins and GPR54 have been implicated in the neuroendocrine regulation of GnRH secretion. To test ...the hypothesis that testosterone regulates Kiss1 gene expression, we compared the expression of KiSS-1 mRNA among groups of intact, castrated, and castrated/testosterone (T)-treated male mice. In the arcuate nucleus (Arc), castration resulted in a significant increase in KiSS-1 mRNA, which was completely reversed with T replacement, whereas in the anteroventral periventricular nucleus, the results were the opposite, i.e. castration decreased and T increased KiSS-1 mRNA expression. In the Arc, the effects of T on KiSS-1 mRNA were completely mimicked by estrogen but only partially mimicked by dihydrotestosterone, a nonaromatizable androgen, suggesting that both estrogen receptor (ER) and androgen receptor (AR) play a role in T-mediated regulation of KiSS-1. Studies of the effects of T on KiSS-1 expression in mice with either a deletion of the ERα or a hypomorphic allele to the AR revealed that the effects of T are mediated by both ERα and AR pathways, which was confirmed by the presence of either ERα or AR coexpression in most KiSS-1 neurons in the Arc. These observations suggest that KiSS-1 neurons in the Arc, whose transcriptional activity is inhibited by T, are targets for the negative feedback regulation of GnRH secretion, whereas KiSS-1 neurons in the anteroventral periventricular nucleus, whose activity is stimulated by T, may mediate other T-dependent processes.
In observational studies, selection bias will be completely removed only if the selection mechanism is ignorable, namely, all confounders of treatment selection and potential outcomes are reliably ...measured. Ideally, well-grounded substantive theories about the selection process and outcome-generating model are used to generate the sample of covariates. However, covariate selection is more heuristic in actual practice. Using two empirical data sets in a simulation study, we investigate four research questions about bias reduction when the selection mechanism is not known but many covariates are measured: (1) How important is the conceptual heterogeneity of the covariate domains in the data set? (2) How important is the number of covariates assessing each domain? (3) What are the joint effects of this conceptual heterogeneity and of the number of covariates per domain? (4) What happens to bias reduction when the set of covariates is deliberately impoverished by removing the covariates most responsible for selection bias, thus ensuring a slightly smaller but still heterogeneous set of covariates? The results indicate: (1) increasingly more bias is reduced as the number of covariate domains and the number of covariates per domain increase, though the rate of bias reduction is diminishing in each case; (2) sampling covariates from multiple heterogeneous covariate domains is more important than choosing many measures from fewer domains; (3) the most heterogeneous set of covariate domains removes almost all of the selection bias when at least five covariates are assessed in each domain; and (4) omitting the most crucial covariates generally replicates the pattern of results due to the number of domains and the number of covariates per domain, but the amount of bias reduction is less than when all variables are included and will surely not satisfy all consumers of causal research.
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BFBNIB, NUK, PILJ, SAZU, UL, UM, UPUK
Patterns of low autonomic arousal have consistently been related to delinquency and disruptive behavior disorders (DBD) in children and adolescents. Findings on another stress regulating mechanism, ...the hypothalamic pituitary adrenal (HPA) axis, have been inconsistent, which may partly be due to not considering specific stress reactivity measures. Therefore, the aim of the present study was to investigate the relationship between disruptive behavior in male adolescents and their HPA and autonomic reactivity to a standard public speaking task (PST).
Responsivity to the PST of cortisol, heart rate (HR), skin conductance level (SCL) and self-reported negative feelings was measured, and compared between 12and14-year-old boys who attended a delinquency diversion program (DP), with and without DBD (DP
+,
n=22 and DP
−,
n=49, resectively), and matched normal controls (NC,
n=30). DBD diagnoses were based on a structured psychiatric interview.
The DP+ group, but not the DP− group, showed a significantly decreased cortisol and HR response during the PST as compared with the NC group. No significant effects were found for SCL. All subjects connoted the task negatively.
The results indicate that low cortisol and HR responsivity to stress may be a neurobiological marker for delinquent boys with DBD, but not for those without DBD. Directions for future research and clinical implications are discussed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
While most effects of dopamine in the brain are mediated by the D1 and D2 receptor subtypes, other members of this G protein-coupled receptor family have potentially important functions. D3 receptors ...belong to the D2-like subclass of dopamine receptors, activation of which inhibits adenylyl cyclase. Using targeted mutagenesis in mouse embryonic stem cells, we have generated mice lacking functional D3 receptors. A premature chain-termination mutation was introduced in the D3 receptor gene after residue Arg-148 in the second intracellular loop of the predicted protein sequence. Binding of the dopamine antagonist 125Iiodosulpride to D3 receptors was absent in mice homozygous for the mutation and greatly reduced in heterozygous mice. Behavioral analysis of mutant mice showed that this mutation is associated with hyperactivity in an exploratory test. Homozygous mice lacking D3 receptors display increased locomotor activity and rearing behavior. Mice heterozygous for the D3 receptor mutation show similar, albeit less pronounced, behavioral alterations. Our findings indicate that D3 receptors play an inhibitory role in the control of certain behaviors.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Hydrocarbon oils such as pristane or hexadecane induce arthritis and lupus in rodents sharing clinical and pathological features with the human diseases rheumatoid arthritis and systemic lupus ...erythematosus, respectively. In pristane-induced lupus in the mouse induction of apoptosis and augmentation of type-I Interferon signalling by pristane have been suggested to contribute to pathology, whereas in pristane-induced arthritis (PIA) in the rat the pathological mechanisms are still elusive. Here we show that pristane induces cell death in rat and human cells. Increased numbers of apoptotic cells were found in draining lymph nodes of pristane-injected rats and increased percentages of apoptotic and necrotic cells were observed in peripheral blood. In addition, neutrophil extracellular trap formation was triggered by pristane and hexadecane in neutrophils. Because levels of interleukin (IL)-1β were elevated in sera of pristane-injected rats, with levels mirroring the course of PIA, we examined the effect of pristane at single cell level in vitro, using rat splenocytes and the human monocytic cell line THP-1. Pristane and other hydrocarbon oils induced IL-1β secretion in THP-1 cells as well as in rat splenocytes. The potassium channel inhibitor glibenclamide partly inhibited IL-1β induction, suggesting involvement of the inflammasome. Elevated levels of IL-1α were also found in supernatants of cells treated with pristane and hexadecane. In conclusion, autoimmunogenic hydrocarbon oils induce various forms of cell death in rat and human cells. The higher serum IL-1β levels in pristane-injected animals might be caused by both inflammasome-dependent and -independent mechanisms, such as passive release from dying-cells and probably extracellular maturation of pro-IL-1β.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
In the current study our objective was to develop a murine model of human hyper-IgD syndrome (HIDS) and severe mevalonic aciduria (MA), autoinflammatory disorders associated with mevalonate kinase ...deficiency (MKD). Deletion of one Mvk allele (Mvk ⁺/⁻) yielded viable mice with significantly reduced liver Mvk enzyme activity; multiple matings failed to produce Mvk ⁻/⁻ mice. Cholesterol levels in tissues and blood, and isoprene end-products (ubiquinone, dolichol) in tissues were normal in Mvk ⁺/⁻ mice; conversely, mevalonate concentrations were increased in spleen, heart, and kidney yet normal in brain and liver. While the trend was for higher IgA levels in Mvk ⁺/⁻ sera, IgD levels were significantly increased (9-12-fold) in comparison to Mvk ⁺/⁺ littermates, in both young (<15 weeks) and older (>15 weeks) mice. Mvk ⁺/⁻ animals manifested increased serum TNF-α as compared to wild-type littermates, but due to wide variation in levels between individual Mvk ⁺/⁻ mice the difference in means was not statistically significant. Mvk ⁺/⁻ mice represent the first animal model of HIDS, and should prove useful for examining pathophysiology associated with this disorder.
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FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, UL, UM, UPUK, VKSCE, ZAGLJ
The ProtoDUNE-SP detector is a single-phase liquid argon time projection chamber with an active volume of 7.2×6.1×7.0 m3. It is installed at the CERN Neutrino Platform in a specially-constructed beam ...that delivers charged pions, kaons, protons, muons and electrons with momenta in the range 0.3 GeV/c to 7 GeV/c. Beam line instrumentation provides accurate momentum measurements and particle identification. The ProtoDUNE-SP detector is a prototype for the first far detector module of the Deep Underground Neutrino Experiment, and it incorporates full-size components as designed for that module. This paper describes the beam line, the time projection chamber, the photon detectors, the cosmic-ray tagger, the signal processing and particle reconstruction. It presents the first results on ProtoDUNE-SP's performance, including noise and gain measurements, dE/dx calibration for muons, protons, pions and electrons, drift electron lifetime measurements, and photon detector noise, signal sensitivity and time resolution measurements. The measured values meet or exceed the specifications for the DUNE far detector, in several cases by large margins. ProtoDUNE-SP's successful operation starting in 2018 and its production of large samples of high-quality data demonstrate the effectiveness of the single-phase far detector design.
Abstract
Study question
What are the predictors for pregnancies conceived spontaneously (SC), by ovulation induction+/-insemination (OI±IUI) or via In-Vitro Fertilization(IVF), and what proportion of ...pregnancies were conceived with each method?
Summary answer
Pregnancies were conceived by SC(27.7%), OI±IUI(33%) or IVF(39.2%).Unexplained infertility positively-predicted SC and OI±IUI-conceptions. Male factor-infertility demonstrated the opposite trend, positively predicting IVF. Endometriosis negatively-predicted SC.
What is known already
Spontaneous conception (SC) occurs regularly among infertility patients. Most studies have evaluated predictors of pregnancy among women with infertility who were trying to conceive. Few studies have addressed the role of different factors on the mode of conception in infertility patients who were pregnant. Factors found in some studies to be related with a SC were younger female age, shorter duration of infertility, fewer failed IVF cycles, and diagnosis of unexplained-infertility.
Study design, size, duration
We conducted a retrospective cohort study at a University fertility-center over a six-month period in 2019 and 2020. We reviewed viability scans of 285-patients. Mode of conception was recorded as Spontaneous, OI±IUI, or IVF. Patients’ demographics, obstetric and fertility diagnosis as well as base-line hormones and ovarian reserve testing were extracted to calculate predictors for the mode of conception. Pregnancy was defined as an intra-uterine fetal sac on a transvaginal ultrasound in the 1st-trimester.
Participants/materials, setting, methods
Parametric analysis was done using ANOVA and Tukey’s post-hoc test. Nonparametric analysis was performed using the chi-square test. Predictors of the mode of conception were calculated by multivariate regression analysis using the variables not in the equation model including the following parameters: male and female age, gravidity, parity, ectopic-pregnancies, infertility diagnosis, baseline serum: FSH, estradiol, TSH, AMH, and AFC. Data is presented as mean ±SD or percentage. P < 0.05 was significant. IRB approval was obtained.
Main results and the role of chance
79 (27.7%) of pregnancies were SC, 94 (33%) resulted from OI±IUI, and 112 (39.2%) from IVF. Demographics didn’t differ between the groups including: female age(p = 0.06), male age(p = 0.79), gravidity (p = 0.47), parity(p = 0.7), ectopic-pregnancies(p = 0.07), baseline serum FSH(p = 0.29), estradiol(p = 0.65), TSH(p = 0.56), AMH(p = 0.42), and AFC(p = 0.06). Infertility diagnoses differed when comparing SC, OI±IUI and IVF conceptions respectively: Unexplained (22.7%, 22.3%, 15.1%, p = 0.03), Male-Factor(MF) (25%, 27.6%, 42.8%, p = 0.042), Tubal-factor (2.5%, 2.1%, 13.4, p = 0.002) and Ovulation-disorders/PCOS (24%, 32%, 12.5% p = 0.002). Endometriosis trended higher in women with IVF (p = 0.09).
A positive predictor for SC was unexplained infertility(p = 0.0001). A negative predictor was endometriosis(p = 0.005). SC was sub-significantly less likely in the presence of MF (p = 0.057). Unexplained-infertility was a positive predictor for OI±IUI pregnancies(p = 0.047), whereas MF was a negative predictor(p = 0.0001). As for IVF-conceptions, MF was a positive predictor(p = 0.008), while unexplained-infertility negatively predicted conception by IVF(p = 0.018). Ovulation-disorders/PCOS trended lower in women with IVF (p = 0.052). While baseline serum estradiol levels were similar between groups (means 194–218pmol/L), multivariate regression showed it to be a predictor for OI±IUI and IVF conceptions. The clinical significance of this finding is not clear. Interestingly, female age and ovarian reserve were not found to predict one type of conception over another. Other possible predictors in the model were not significant.
Limitations, reasons for caution
This retrospective cohort may hide underlying bias. Clinical pregnancies were evaluated and not live birth. Our cohort represents patients that conceived and do not offer information about the entire sub-fertile population that is treated in our center, which is also a strength as it’s a novel way of evaluating predictors.
Wider implications of the findings: Among patients that conceived spontaneously, advanced age and ovarian reserve did not play a negative role. Predictors of pregnancy were confirmed as expected with the majority of unexplained infertility conceptions occurring spontaneously or with OI+/-IUI, patients with Male factor infertility often conceived by IVF, and ovulation disorders by OI+/-IUI.
Trial registration number
NA
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