Neurodevelopmental outcomes in children and adults with Fetal Valproate Spectrum Disorder: A contribution from the ConcePTION project.

AIM: To describe the neurodevelopmental phenotype of older children and adults with a diagnosis of Fetal Valproate Spectrum Disorder (FVSD). METHODS: In this cross-sectional study, 90 caregivers were recruited and completed a series of questionnaires regarding the neurodevelopmental outcomes of 146 individuals aged 7-37 years (M = 18.1), including individuals with a formal diagnosis of FVSD (n = 99), individuals exposed to Valproate but without an FVSD diagnosis (n = 24), and individuals not exposed to Valproate (N = 23). The mean dose of valproate exposure for individuals with an FVSD diagnosis was 1470 mg/day. RESULTS: Individuals with a diagnosis of FVSD showed significantly higher levels of moderate (43.4%) and severe (14.4%) cognitive impairment than other groups (p = 0.003), high levels of required formal educational support (77.6%), and poorer academic competence than individuals not exposed to Valproate (p = 0.001). Overall psychosocial problems (p = 0.02), internalising problems (p = 0.05) and attention problems (p = 0.001), but not externalising problems, were elevated in individuals with a diagnosis of FVSD. Rates of neurodevelopmental disorders, particularly autistic spectrum disorders (62.9%) and sensory problems (80.6%) are particularly central to the FVSD phenotype. There was no evidence of a statistical dose-dependent effect, possibly due to the high mean dose of exposure having a uniformly negative impact across the sample. Individuals with FVSD had required a significant number of health and child development services. INTERPRETATION: Children and young adults with a diagnosis of FVSD are at an increased risk of a range of altered neurodevelopmental outcomes, highlighting the need for a multidisciplinary approach to clinical management across the lifespan.

Research Note: Rous sarcoma growth differs among congenic lines containing major histocompatibility (B) complex recombinants.

New arrangements of chicken major histocompatibility complex (MHC) class I BF and class IV BG genes are created through recombination. Characterizing the immune responses of such recombinants reveals genes or gene regions that contribute to immunity. Inbred Line UCD 003 (B17B17) served as the genetic background for congenic lines, each containing a unique MHC recombinant. After an initial cross to introduce a specific recombinant, 10 backcrosses to the inbred line produced lines with 99.9% genetic uniformity. The current study compared Rous sarcoma virus (RSV) tumor growth in 5 congenic lines homozygous for MHC recombinants (003.R1 = BF24-BG23, 003.R2 = BF2-BG23, 003.R4 = BF2-BG23, 003.R5 = BF21-BG19, and 003.R13 = BF17-BG23). Two experiments used a total of 70 birds from the 5 congenic lines inoculated with 20 pock forming units of RSV subgroup C at 6 wk of age. Tumor size was scored 6 times over 10 wk postinoculation followed by assignment of a tumor profile index (TPI) based on the tumor size scores. Tumor growth over time and rank transformed TPI values were analyzed by least squares ANOVA. Tumor size increased over the experimental period in all genotypes through 4 wk postinoculation. After this time, tumor size increased in Lines 003.R1, plateaued in Lines 003.R2, 003.R4, and 003.R13, and declined in 003.R5. Tumor growth over time was significantly lower in Line 003.R5 compared with all other genotypes. In addition, Line 003.R5 chickens had significantly lower TPI values compared with Lines 003.R2, 003.R4, and 003.R13. The TPI of Line 003.R1 did not differ significantly from any of the other genotypes. The BF21 in Line 003.R5 produced a greater response against subgroup C RSV tumors than did BF24, found in 003.R1; BF2 found in 003.R2 and R4 as well as BF17 found in 003.R13.

Major histocompatibility complex recombinant R13 antibody response against bovine red blood cells.

Recombination within the chicken major histocompatibility complex (MHC) has enabled more precise identification of genes controlling immune responses. Chicken MHC genes include BF, MHC class I; BL, MHC class II; and BG, MHC class IV that are closely linked on chromosome 16. A new recombination occurred during the 10th backcross generation to develop congenic lines on the inbred Line UCD 003 (B17B17) background. Recombinant R13 (BF17-BG23) was found in a single male chick from the Line 003.R1 (BF24-BG23) backcross. An additional backcross of this male to Line UCD 003 females increased the number of R13 individuals. Two trials tested this new recombinant for antibody production against the T cell-dependent antigen, bovine red blood cells. Fifty-one progeny segregating for R13R13 (n = 10), R13B17 (n = 26), and B17B17 (n = 15) genotypes were produced by a single R13B17 male mated to 5 R13B17 dams. One milliliter of 2.5% bovine red blood cell was injected intravenously into all genotypes at 4 and 11 wk of age to stimulate primary and secondary immune responses, respectively. Blood samples were collected 7 d after injection. Serum total and mercaptoethanol-resistant antibodies against bovine red blood cell were measured by microtiter methods. The least squares ANOVA used to evaluate all antibody titers included trial and B genotype as main effects. Significant means were separated by Fisher's protected least significant difference at P < 0.05. R13R13 chickens had significantly lower primary total and mercaptoethanol-resistant antibodies than did the R13B17 and B17B17 genotypes. Secondary total and mercaptoethanol-resistant antibodies were significantly lower in R13R13 chickens than in R13B17 but not B17B17 chickens. Gene differences generated through recombination impacted the antibody response of R13 compared with B17. Secondary antibody titers were not substantially higher than the primary titers suggesting that the memory response had waned in the 7-wk interval between injections. Overall, the results suggest that the lower antibody response in R13R13 homozygotes may be caused by recombination affecting a region that contributes to higher antibody response.

Pregnancy outcomes following maternal venlafaxine use: A prospective observational comparative cohort study.

BACKGROUND: Venlafaxine is a serotonin noradrenaline reuptake inhibitor used to treat major depressive episodes and anxiety disorders. The primary aim of this study was to investigate spontaneous abortion risks following gestational exposure. METHODS: This prospective observational comparative cohort study utilised data collected by the UK Teratology Information Service (UKTIS) between 1995 and 2018. The study sample included 281 venlafaxine exposed pregnancies matched to antidepressant unexposed (n = 1405) and SSRI exposed (n = 843) comparator groups. RESULTS: After correction for variation in competing outcome rates and the stage of pregnancy at reporting, no statistically significant differences in the hazard of spontaneous abortion was observed following gestational venlafaxine use compared with either antidepressant unexposed (HR 1.28, 95% CI; 0.850-1.94) or SSRI exposed (HR 1.03, 95% CI; 0.681-1.57) pregnancies. CONCLUSIONS: No conclusive evidence is provided from this study that venlafaxine increases the risk of adverse pregnancy or fetal outcomes.

Sensitivity of the UK Clinical Practice Research Datalink to Detect Neurodevelopmental Effects of Medicine Exposure in Utero: Comparative Analysis of an Antiepileptic Drug-Exposed Cohort.

INTRODUCTION: Electronic healthcare data have several advantages over prospective observational studies, but the sensitivity of data on neurodevelopmental outcomes and its comparability with data generated through other methodologies is unknown. OBJECTIVES: The objectives of this study were to determine whether data from the UK Clinical Practice Research Datalink (CPRD) produces similar risk estimates to a prospective cohort study in relation to the risk of neurodevelopmental disorders (NDDs) following prenatal antiepileptic drug (AED) exposure. METHODS: A cohort of mother-child pairs of women with epilepsy (WWE) was identified in the CPRD and matched to a cohort without epilepsy. The study period ran from 1 January 2000 to 31 March 2007 and children were required to be in the CPRD at age 6 years. AED exposure during pregnancy was determined from prescription data and children with an NDD diagnosis by 6 years were identified from Read clinical codes. The prevalence and risk of NDDs was calculated for mother-child pairs in WWE stratified by AED regimen and for those without epilepsy. Comparisons were made with the results of the prospective Liverpool and Manchester Neurodevelopment Group study which completed assessment on 201 WWE and 214 without epilepsy at age 6 years. RESULTS: In the CPRD, 1018 mother-child pairs to WWE and 6048 to women without epilepsy were identified. The CPRD identified a lower prevalence of NDDs than the prospective study. In both studies, NDDs were more frequently reported in children of WWE than women without epilepsy, although the CPRD risk estimate was lower (2.16 vs. 0.96%, p < 0.001 and 7.46 vs. 1.87%, p = 0.0128). NDD prevalence differed across AED regimens but the CPRD data did not replicate the significantly higher risk of NDDs following in utero monotherapy valproate exposure (adjusted odds ratio [ORadj] 2.02, 95% confidence interval [CI] 0.52-7.86) observed in the prospective study (ORadj 6.05, 95% CI 1.65-24.53). CONCLUSION: It was possible to identify NDDs in the CPRD; however, the CPRD appears to under-record these outcomes. Larger studies are required to investigate further.

Lessons learned from a multidisciplinary renal genetics clinic.

BACKGROUND: Inherited renal disorders comprise a significant proportion of cases in both paediatric and adult nephrology services. Genetic advances have advanced rapidly while clinical models of care delivery have remained static. AIM: To describe a cohort of patients attending a multidisciplinary renal genetics clinic and the insights gained from this experience. DESIGN AND METHODS: A retrospective review of clinic cases and their molecular genetic diagnosis over a 5-year period. RESULTS: We report details of 244 individuals including 80 probands who attended the clinic. The commonest reasons for referral was familial haematuria which accounted for 37.5% of cases and cystic kidney disease, accounting for 31% of cases. Eighteen probands had a known molecular genetic diagnosis and were referred for genetic counselling and screening of at risk relatives and management plans. About 62 probands and their families were referred for a precise molecular diagnosis and this was achieved in 26 cases (42%). The most frequent new genetic diagnoses were COL4A5 mutations underlying familial haematuria and familial end stage renal disease. The clinic also allowed for patients with rare renal syndromes to be reviewed, such as ciliopathy syndromes, allowing detailed phenotyping and often a precise molecular genetic diagnosis to be provided. CONCLUSIONS: The integration of modern day genetics and genomics into multidisciplinary clinics often allows a precise diagnosis which benefits patients, their relatives and the clinicians providing care and future management.

Pregnancy outcomes after maternal varenicline use; analysis of surveillance data collected by the European Network of Teratology Information Services.

Varenicline is a smoking cessation aid for which limited data exist concerning safety during human pregnancy. This multicentre prospective observational comparative cohort study was undertaken using surveillance data collected by the European Network of Teratology Information Services. The study sample consisted of 89 varenicline exposed pregnancies and two matched comparator groups; 267 non-teratogen exposed (NTE) controls and 78 exposed to nicotine replacement therapy or bupropion (NRT/B) for smoking cessation. For all exposed pregnancies, varenicline use only occurred in the first trimester, with a considerable proportion discontinuing use in the very early stages of pregnancy. The major congenital malformation rate (n=2/89, 2.25%) was in keeping with the expected background rate (2-4%), and was not significantly increased for first trimester varenicline-exposed infants in comparison with non-exposed controls (vs. NTE: OR 2.02, 95%CI 0.166 to 17.9, vs. NRT/B: OR 0.874, 95%CI 0.0620 to 12.3). However, the small sample size produced very imprecise risk estimates.

Pregnancy outcome following maternal use of zanamivir or oseltamivir during the 2009 influenza A/H1N1 pandemic: a national prospective surveillance study.

OBJECTIVE: To conduct enhanced surveillance for signals of teratogenesis following use of the neuraminidase inhibitors zanamivir and oseltamivir in the treatment or post-exposure prophylaxis of 2009 A/H1N1 influenza during pregnancy. DESIGN: Prospective cohort study, using national surveillance data collected by the UK Teratology Information Service (UKTIS) during the 2009 A/H1N1 pandemic. SETTING: United Kingdom. POPULATION: Pregnant women who were reported to UKTIS by healthcare professionals seeking advice about exposure to zanamivir and oseltamivir or to other non-teratogenic drugs. METHODS: Pregnancy outcomes were collected for prospectively reported pregnancies exposed to zanamivir (n = 180) or oseltamivir (n = 27), and compared with a reference group of 575 prospectively reported pregnancies exposed to non-teratogenic drugs over the same period. MAIN OUTCOME MEASURES: Rates of major congenital malformation, preterm delivery and low birth weight. RESULTS: No significant differences in overall rates of major malformation in live-born infants [adjusted odds ratios (aOR): zanamivir 0.37 (95% confidence interval 0.02-2.70); oseltamivir aOR 0.81 (0.05, 14.15)], preterm delivery [aOR: zanamivir 0.95 (0.45, 1.89); oseltamivir aOR 1.68 (0.38, 5.38)] or low birth weight [aOR: zanamivir 0.94 (0.25, 2.90); oseltamivir aOR 4.12 (0.59, 17.99)] were observed following exposure at any gestation. No major malformations were reported in 37 zanamivir or eight oseltamivir first trimester exposures. CONCLUSION: These surveillance data do not provide a signal that use of zanamivir or oseltamivir in pregnancy is associated with an increased risk of the adverse pregnancy outcomes studied but the data are too limited to state conclusively that there is no increase in risk.

Turning off the central contribution to contractions evoked by neuromuscular electrical stimulation.

Neuromuscular electrical stimulation can generate contractions through both peripheral and central mechanisms. The peripheral mechanism involves the direct activation of motor axons, while the central mechanism involves the activation of sensory axons that recruit spinal neurons through a reflex pathway. For use in functional electrical stimulation. One must have control over turning the central mechanism on and off. We investigated whether inhibition developed through antagonist muscle (tibialis anterior, TA) contractions elicited by electrical stimulation or by volition can turn off the central mechanism in triceps surae. Both electrical stimulation and voluntary contractions of TA reduced or eliminated plantar flexion torque produced by the central mechanism, indicating that inhibition induced via these contractions can effectively turn off the central contribution to force. These findings suggest that patterns of electrical stimulation may be able to generate periodic muscle contractions by turning the central contribution to muscular contractions on and off.

Turning on the central contribution to contractions evoked by neuromuscular electrical stimulation.

Neuromuscular electrical stimulation can generate contractions through peripheral and central mechanisms. Direct activation of motor axons (peripheral mechanism) recruits motor units in an unnatural order, with fatigable muscle fibers often activated early in contractions. The activation of sensory axons can produce contractions through a central mechanism, providing excitatory synaptic input to spinal neurons that recruit motor units in the natural order. Presently, we quantified the effect of stimulation frequency (10-100 Hz), duration (0.25-2 s of high-frequency bursts, or 20 s of constant-frequency stimulation), and intensity [1-5% maximal voluntary contraction (MVC) torque generated by a brief 100-Hz train] on the torque generated centrally. Electrical stimulation (1-ms pulses) was delivered over the triceps surae in eight subjects, and plantar flexion torque was recorded. Stimulation frequency, duration, and intensity all influenced the magnitude of the central contribution to torque. Central torque did not develop at frequencies < or = 20 Hz, and it was maximal at frequencies > or = 80 Hz. Increasing the duration of high-frequency stimulation increased the central contribution to torque, as central torque developed over 11 s. Central torque was greatest at a relatively low contraction intensity. The largest amount of central torque was produced by a 20-s, 100-Hz train (10.7 +/- 5.5 %MVC) and by repeated 2-s bursts of 80- or 100-Hz stimulation (9.2 +/- 4.8 and 10.2 +/- 8.1% MVC, respectively). Therefore, central torque was maximized by applying high-frequency, long-duration stimulation while avoiding antidromic block by stimulating at a relatively low intensity. If, as hypothesized, the central mechanism primarily activates fatigue-resistant muscle fibers, generating muscle contractions through this pathway may improve rehabilitation applications.