This paper examines family experiences with the efficiency of ASD diagnosis. Children were age 8 or younger with ASD (n = 450). Outcomes were delay from first parent concern to diagnosis, shifting ...diagnoses, and being told child did not have ASD. Predictors were screening, travel distance, and problems finding providers. Logit models were used to examine associations. Screening was associated with reduced delay in diagnosis; problems finding providers were associated with greater delay. Screening, travel distance, and delay in diagnosis were associated with shifting diagnoses and being told child did not have ASD. Physician and parent training in communication and addressing mental health professional shortages and maldistribution may improve the diagnosis experiences of families of children with ASD.
The acquisition of cell motility is an early step in melanoma metastasis. Here we use intravital imaging of signalling reporter cell-lines combined with genome-wide transcriptional analysis to define ...signalling pathways and genes associated with melanoma metastasis. Intravital imaging revealed heterogeneous cell behaviour in vivo: <10% of cells were motile and both singly moving cells and streams of cells were observed. Motile melanoma cells had increased Notch- and SRF-dependent transcription. Subsequent genome-wide analysis identified an overlapping set of genes associated with high Notch and SRF activity. We identified EZH2, a histone methyltransferase in the Polycomb repressive complex 2, as a regulator of these genes. Heterogeneity of EZH2 levels is observed in melanoma models, and co-ordinated upregulation of genes positively regulated by EZH2 is associated with melanoma metastasis. EZH2 was also identified as regulating the amelanotic phenotype of motile cells in vivo by suppressing expression of the P-glycoprotein Oca2. Analysis of patient samples confirmed an inverse relationship between EZH2 levels and pigment. EZH2 targeting with siRNA and chemical inhibition reduced invasion in mouse and human melanoma cell lines. The EZH2-regulated genes KIF2C and KIF22 are required for melanoma cell invasion and important for lung colonization. We propose that heterogeneity in EZH2 levels leads to heterogeneous expression of a cohort of genes associated with motile behaviour including KIF2C and KIF22. EZH2-dependent increased expression of these genes promotes melanoma cell motility and early steps in metastasis.
The normal range of heart rate (HR) in the first minutes after birth has not been defined. Objective To describe the HR changes of healthy newborn infants in the delivery room (DR) detected by pulse ...oximetry. Study Design All inborn infants were eligible and included if a member of the research team attended the birth. Infants were excluded if they received any form of medical intervention in the DR including supplemental oxygen, or respiratory support. HR was measured using a pulse oximeter (PO) with the sensor applied to the right hand or wrist immediately after birth. PO data (oxygen saturation, HR and signal quality) were downloaded every 2 sec and analysed only when the signal had no alarm messages (low IQ signal, low perfusion, sensor off, ambient light). Results Data from 468 infants with 61 650 data points were included. Infants had a mean (range) gestational age of 38 (25-42) weeks and birth weight 2970 (625-5135) g. At 1 min the median (IQR) HR was 96 (65-127) beats per min (bpm) rising at 2 min and 5 min to 139 (110-166) bpm and 163 (146-175) bpm respectively. In preterm infants, the HR rose more slowly than term infants. Conclusions The median HR was <100 bpm at 1 min after birth. After 2 min it was uncommon to have a HR <100 bpm. In preterm infants and those born by caesarean section the HR rose more slowly than term vaginal births.
Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight ...junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible 'knockdown' mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3-4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin-5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.
Carcinoma-associated fibroblasts (CAFs) can promote the progression of tumours in many ways. They can remodel the extracellular matrix to generate an environment that enables the invasion of cancer ...cells. We hypothesised that compounds that prevent matrix remodelling by CAFs would block their ability to promote carcinoma cell invasion.
We designed a screen for compounds that interfere with CAF-promoted matrix remodelling. Hits from this screen were investigated in organotypic invasion models of squamous cell carcinoma (SCC).
We find that lovastatin and simvastatin reduce matrix remodelling by fibroblasts and thereby reduce SCC invasion. This class of compounds exert their effects partly through disrupting the function of Rab proteins, and we show a new role for Rab21 in promoting cancer cell invasion promoted by CAFs.
Rab21 is required for CAFs to promote the invasion of cancer cells. It enables the accumulation of integrin alpha5 at the plasma membrane and subsequent force-mediated matrix remodelling.
The present study examined the effects of a proprietary Ashwagandha (Withania somnifera) root and leaf extract (NooGandha® Specnova LLC, USA) supplement for improving cognitive abilities, cortisol ...levels, and self-reported mood, stress, food cravings, and anxiety with adults who have perceived stress. Healthy adults (n = 43 women and n = 17 men; mean age = 34.41 years) who reported experiencing perceived stress were randomized to the following groups: Ashwagandha (400 mg/d), Ashwagandha (225 mg/d), and placebo for 30 days. The following outcomes were assessed at Day 0, Day 15, and Day 30: saliva cortisol levels, cognitive performance (i.e., CNS vital signs), and the self-reported measures of Trait Anxiety Inventory, Depression Anxiety Stress Scale, Perceived Stress Scale, and Food Cravings Questionnaire-15. For the self-report assessments, significant main effects for time were evidenced for anxiety, depression, perceived stress, and food cravings, p's < 0.01. The main effect for group and the interactions were non-significant. For the CNS vital signs, significant differences were observed in cognitive flexibility, visual memory, reaction time, psychomotor speed, and executive functioning, p's < 0.05, with the Ashwagandha groups often out-performing the placebo group. Both Ashwagandha groups had reductions in cortisol levels over time, with significant reductions evidenced for the Ashwagandha 225 mg/d group from Day 0 to Day 15 to Day 30. The placebo group had a non-significant increase in cortisol levels from Day 0 to Day 15–30. No adverse events were reported. In conclusion, Ashwagandha supplementation may improve the physiological, cognitive, and psychological effects of stress.
During stabilisation of preterm infants at birth, a face mask is used to provide respiratory support. However, application of these masks may activate cutaneous stretch receptors of the trigeminal ...nerve, causing apnoea and bradycardia. This study investigated the amount of force exerted on the face mask during non-invasive ventilation of preterm infants at birth and whether the amount of exerted force is associated with apnoea and bradycardia.
A prospective observational study was performed in preterm infants born <32 weeks of gestation who were stabilised at birth. During the first 10 minutes of respiratory support, we measured breathing and heart rate as well as the amount of force exerted on a face mask using a custom-made pressure sensor placed on top of the face mask.
Thirty infants were included (median (IQR) gestational age(GA) 28+3 (27+0–30+0) weeks, birthweight 1104 (878–1275) grams). The median exerted force measured was 297 (198–377) grams, ranging from 0 to 1455 grams. Significantly more force was exerted on the face mask during positive pressure ventilation when compared to CPAP (410 (256–556) vs 286 (190–373) grams, p = 0.009).
In a binary logistic regression model, higher forces were associated with an increased risk of apnoea (OR = 1.607 (1.556–1.661), p < 0.001) and bradycardia (OR = 1.140 (1.102–1.180), p < 0.001) during the first 10 minutes of respiratory support at birth.
During mask ventilation, the median exerted force on a face mask was 297 grams with a maximum of 1455 grams. Higher exerted forces were associated apnoea and bradycardia during the first 10 minutes of respiratory support at birth.
The capacity of foot-strike running patterns to influence the functional properties of the Achilles tendon is controversial. This study used transmission-mode ultrasound to investigate the influence ...of habitual running foot-strike pattern on Achilles tendon properties during barefoot walking and running. Fifteen runners with rearfoot (RFS) and 10 with a forefoot (FFS) foot-strike running pattern had ultrasound transmission velocity measured in the right Achilles tendon during barefoot walking (≈1.1 ms
−1
) and running (≈2.0 ms
−1
). Temporospatial gait parameters, ankle kinematics and vertical ground reaction force were simultaneously recorded. Statistical comparisons between foot-strike patterns were made using repeated measure ANOVAs. FFS was characterised by a significantly shorter stance duration (−4%), greater ankle dorsiflexion (+2°), and higher peak vertical ground reaction force (+20% bodyweight) than RFS running (P < .05). Both groups adopted a RFS pattern during walking, with only the relative timing of peak dorsiflexion (3%), ground reaction force (1-2%) and peak vertical force loading rates (22-23%) differing between groups (P < .05). Peak ultrasound transmission velocity in the Achilles tendon was significantly higher in FFS during walking (≈100 ms
−1
) and running (≈130 ms
−1
) than RFS (P < .05). Functional Achilles tendon properties differ with habitual footfall patterns in recreational runners.
Abstract
Turner syndrome (TS) is a genetic disorder affecting approximately 1:2000 live-born females. It results from partial or complete X monosomy and is associated with a range of clinical issues ...including a unique cognitive profile and increased risk for certain behavioral problems. Structural neuroimaging studies in adolescents, adults, and older children with TS have revealed altered neuroanatomy but are unable to identify when in development differences arise. In addition, older children and adults have often been exposed to years of growth hormone and/or exogenous estrogen therapy with potential implications for neurodevelopment. The study presented here is the first to test whether brain structure is altered in infants with TS. Twenty-six infants with TS received high-resolution structural MRI scans of the brain at 1 year of age and were compared to 47 typically developing female and 39 typically developing male infants. Results indicate that the typical neuroanatomical profile seen in older individuals with TS, characterized by decreased gray matter volumes in premotor, somatosensory, and parietal-occipital cortex, is already present at 1 year of age, suggesting a stable phenotype with origins in the prenatal or early postnatal period.
The Self-Management and Transition to Adulthood with Rx=Treatment (STARx) Questionnaire was developed to collect information on self-management and health care transition (HCT) skills, via ...self-report, in a broad population of adolescents and young adults (AYAs) with chronic conditions.
Over several iterations, the STARx questionnaire was created with AYA, family, and health provider input. The development and pilot testing of the STARx Questionnaire took place with the assistance of 1219 AYAs with different chronic health conditions, in multiple institutions and settings over three phases: item development, pilot testing, reliability and factor structuring.
The three development phases resulted in a final version of the STARx Questionnaire. The exploratory factor analysis of the third version of the 18-item STARx identified six factors that accounted for about 65% of the variance: Medication management, Provider communication, Engagement during appointments, Disease knowledge, Adult health responsibilities, and Resource utilization. Reliability estimates revealed good internal consistency and temporal stability, with the alpha coefficient for the overall scale being .80. The STARx was developmentally sensitive, with older patients scoring significantly higher on nearly every factor than younger patients.
The STARx Questionnaire is a reliable, self-report tool with adequate internal consistency, temporal stability, and a strong, multidimensional factor structure. It provides another assessment strategy to measure self-management and transition skills in AYAs with chronic conditions.
•We describe the development of a transition tool for youth with chronic conditions.•The STARX Questionnaire measures transition readiness and self-management skills.•The STARX Questionnaire displays good internal consistency and temporal stability.•The STARX Questionnaire displays a strong, multidimensional factor structure.•The tool is developmentally sensitive and can guide interventions by age group.