Estimating the relative frequency of leukodystrophies and recommendations for carrier screening in the era of next‐generation sequencing

Leukodystrophies are a heterogeneous group of heritable disorders characterized by abnormal brain white matter signal on magnetic resonance imaging (MRI) and primary involvement of the cellular components of myelin. Previous estimates suggest the incidence of leukodystrophies as a whole to be 1 in 7,000 individuals, however the frequency of specific diagnoses relative to others has not been described. Next generation sequencing approaches offer the opportunity to redefine our understanding of the relative frequency of different leukodystrophies. We assessed the relative frequency of all 30 leukodystrophies (associated with 55 genes) in more than 49,000 exomes. We identified a relatively high frequency of disorders previously thought of as very rare, including Aicardi Goutières Syndrome, TUBB4A‐related leukodystrophy, Peroxisomal biogenesis disorders, POLR3‐related Leukodystrophy, Vanishing White Matter, and Pelizaeus‐Merzbacher Disease. Despite the relative frequency of these conditions, carrier‐screening laboratories regularly test only 20 of the 55 leukodystrophy‐related genes, and do not test at all, or test only one or a few, genes for some of the higher frequency disorders. Relative frequency of leukodystrophies previously considered very rare suggests these disorders may benefit from expanded carrier screening.     

Objective stress monitoring based on wearable sensors in everyday settings

Abstract

Monitoring people’s stress levels has become an essential part of behavioural studies for physical and mental illnesses conducted within the biopsychosocial framework. There have been several stress assessment studies in laboratory-based controlled settings. However, the results of these studies do not always translate effectively to an everyday context. The current state of wearable sensor technology allows us to develop systems measuring the physiological signals reflecting stress 24/7 while capturing the context. In this paper, we present a stress monitoring system that provides objective daily stress measurements in everyday settings based on three physiological signals: electrocardiogram (ECG), photoplethysmogram (PPG), and galvanic skin response (GSR) using Shimmer3 ECG, Shimmer3 GSR+, and Empatica E4 wearable sensors. We perform controlled stress assessment experiments on 17 participants in which we successfully detect stress with a 94.55% accuracy for 10-fold cross-validation and an 85.71% accuracy for subject-wise cross-validation. In everyday settings, the system assesses stress with an 81.82% accuracy. We also examine whether motion artefacts affect stress assessment and filter the low-confidence readings to minimise false alarms.     

NKG2D blockade prevents autoimmune diabetes in NOD mice

NKG2D is an activating receptor on CD8(+) T cells and NK cells that has been implicated in immunity against tumors and microbial pathogens. Here we show that RAE-1 is present in prediabetic pancreas islets of NOD mice and that autoreactive CD8(+) T cells infiltrating the pancreas express NKG2D. Treatment with a nondepleting anti-NKG2D monoclonal antibody (mAb) during the prediabetic stage completely prevented disease by impairing the expansion and function of autoreactive CD8(+) T cells. These findings demonstrate that NKG2D is essential for disease progression and suggest a new therapeutic target for autoimmune type I diabetes.     

Comparing the effectiveness of home visiting paraprofessionals and mental health professionals delivering a postpartum depression preventive intervention: a cluster-randomized non-inferiority clinical trial

To determine whether pregnant women receiving the Mothers and Babies group–based intervention exhibited greater depressive symptom reductions and fewer new cases of major depression than women receiving usual community-based services, and to examine whether groups run by paraprofessional home visitors and mental health professionals yielded similar depressive symptom reductions and prevention of major depression. Using a cluster-randomized design, 37 home visiting programs were randomized to usual home visiting, Mothers and Babies delivered via home visiting paraprofessionals, or Mothers and Babies delivered via mental health professionals. Baseline assessments were conducted prenatally with follow-up extending to 24 weeks postpartum. Eligibility criteria were ≥ 16 years old, ≤ 33 gestation upon referral, and Spanish/English speaking. Depressive symptoms at 24 weeks postpartum was the primary outcome. Eight hundred seventy-four women were enrolled. Neither intervention arm was superior to usual care in decreasing depressive symptoms across the sample (p = 0.401 home visiting paraprofessional vs. control; p = 0.430 mental health professional vs. control). Post hoc analyses suggest a positive intervention effect for women exhibiting mild depressive symptoms at baseline. We have evidence of non-inferiority, as the model-estimated mean difference in depressive symptoms between intervention arms (0.01 points, 95% CI: −0.79, 0.78) did not surpass our pre-specified margin of non-inferiority of two points. Although we did not find statistically significant differences between intervention and control arms, non-inferiority analyses found paraprofessional home visitors generated similar reductions in depressive symptoms as mental health professionals. Additionally, Mothers and Babies appears to reduce depressive symptoms among women with mild depressive symptoms when delivered by mental health professionals. This trial is registered on ClinicalTrials.gov (initial post: December 1, 2016; identifier: NCT02979444).

     

Importance of progesterone and estrogen priming for the induction of maternal behavior by vaginocervical stimulation in sheep: effects of maternal experience

The effects of treating ovariectomised nulliparous and multiparous ewes with progesterone and estrogen on maternal behavior with or without vagino-cervical stimulation were investigated. Following 48 h of estrogen treatment there was neither evidence for stimulation of maternal behavior, nor a reduction in aggressive behavior, towards lambs by either multiparous or nulliparous ewes compared with control treatment (injections of the oil vehicle). Following 5 min of mechanical vaginocervical stimulation, the multiparous estrogen-treated ewes showed both positive maternal responses (low pitch bleats, licking, sniffing and approaching the lamb) and a reduction in aggression (butts) and negative behavior (withdrawal from the lamb) towards the lambs, whereas the nulliparous ewes showed only a reduction in aggression and negative behavior. Neither group showed positive maternal responses following vaginocervical stimulation without steroid priming. When the ewes received two weeks of progesterone priming prior to estrogen treatment, both multiparous and nulliparous ewes showed reduced aggression towards, and withdrawal from, the lambs compared to the control condition, but no positive maternal responses apart from an increased sniffing of the lamb. After vaginocervical stimulation positive maternal responses showed by multiparous ewes were significantly potentiated compared to those shown following estrogen treatment alone. Nulliparous ewes remained unresponsive on positive maternal behaviors. These studies show that hormonal priming has little effect in inducing the onset of maternal behavior in multiparous or nulliparous sheep but is an essential prerequisite for vaginocervical stimulation to do so in multiparous animals.     

Vasoconstrictor Fibre Discharge to Skeletal Muscle,Kidney, Intestine and Skin at Varying Levels of Arterial Baroreceptor Activity in the Cat

Estimations of the average discharge rates in vasoconstrictor fibres to skeletal muscle, kidney, intestine and skin at varying levels of arterial baroreceptor activity were made by comparing quantitatively the reflexly induced vascular responses with those obtained with stimulations of the regional vasoconstrictor fibres at known frequencies. The results indicate that withdrawal of baroreceptor restraint was normally followed by a considerably lower firing rate in renal vasoconstrictor fibres than in e.g. skeletal muscle vasoconstrictor fibres. A complete elimination of the inhibitory influence induced vasoconstrictor fibre discharge rates up to 8 imp/s in skeletal muscle but only at most 4 imp/s in the kidney. Intestinal vasomotor fibres were found to be activated to approximately the same extent as those to skeletal muscle. The vasomotor fibres to the cutaneous arterio-venous anastomoses were evidently not activated when the baroreceptors were unloaded. The reason for this non-uniform activation of the different sets of vasoconstrictor fibres seems to be different levels of spontaneous activity in the respective “neuron pools” in the bulbar vasomotor centre. The renal vascular responses to baroreceptor unloading became augmented when the excitatory level in the vasomotor centre was enhanced, as e.g. when the animal became acidotic.