Reducing childbirth-related intrusive memories and PTSD symptoms via a single-session behavioural intervention including a visuospatial task: A proof-of-principle study.

Intrusive memories (IMs) of traumatic events are a key symptom of posttraumatic stress disorder (PTSD), and contribute to its maintenance. This translational proof-of-principle study tested whether a single-session behavioural intervention reduced the number of childbirth-related IMs (CB-IMs) and childbirth-related PTSD (CB-PTSD) symptoms, in women traumatised by childbirth. The intervention was assumed to disrupt trauma memory reconsolidation. In this pre-post study, 18 participants, whose traumatic childbirth had occurred between seven months and 6.9 years before, received an intervention combining childbirth-related reminder cues (including the return to maternity unit) with a visuospatial task. They recorded their daily CB-IMs in the two weeks pre-intervention (diary 1), the two weeks post-intervention (diary 2; primary outcome), and in week 5 and 6 post-intervention (diary 3). CB-PTSD symptom severity was assessed five days pre-intervention and one month post-intervention. Compared to diary 1, 15/18 participants had ≥ 50% fewer CB-IMs in diary 2. The median (IQR) reduction of the number of CB-IMs was 81.89% (39.58%) in diary 2, and persisted in diary 3 (n = 17). At one month post-intervention, CB-PTSD symptom severity was reduced by ≥ 50% in 10/18 participants. Of the 8 participants with a CB-PTSD diagnosis pre-intervention, none met diagnostic criteria post-intervention. The intervention was rated as highly acceptable. The design limits the causal interpretation of observed improvements. This is the first time such a single-session behavioural intervention was tested for old and real-life single-event trauma. The promising results justify a randomized controlled trial, and may be a first step toward an innovative CB-PTSD treatment

Prenatal insomnia and childbirth-related PTSD symptoms: A prospective population-based cohort study.

Certain populations are at high risk of experiencing a traumatic event and developing post-traumatic stress disorder (PTSD). Yet, primary preventive interventions against PTSD are lacking. It is therefore crucial to identify pre-traumatic risk factors, which could be targeted with such interventions. Insomnia may be a good candidate, but studies on civilians are sparse. Furthermore, the mechanisms at stake in the relationship between pre-traumatic insomnia and PTSD symptoms are unclear. This prospective population-based cohort study (n = 1,610) examined the relationship between insomnia symptoms at 32 weeks of pregnancy and childbirth-related PTSD (CB-PTSD) symptoms at eight weeks postpartum. Postnatal insomnia symptoms, prenatal psychological symptoms (depression, anxiety, PTSD, fear of childbirth), subjective birth experience (SBE) and birth medical severity were included as covariates in the analyses, which were based on a Piecewise Structural Equation Modelling approach. The relationship between prenatal insomnia and CB-PTSD symptoms was mediated by negative SBE and postnatal insomnia symptoms. All relationships involving insomnia symptoms had small or very small effect sizes. This study used self-report questionnaires. Postnatal insomnia and CB-PTSD symptoms were concurrently measured. Prenatal insomnia symptoms may impair the ability to cope with a difficult birth experience and contribute to postnatal insomnia, a risk factor for CB-PTSD. Thus, prenatal insomnia symptoms may be a promising target for CB-PTSD primary preventive interventions, although other prenatal psychological symptoms could also be considered. Even beyond the perinatal context, future studies on pre-traumatic insomnia and PTSD should include post-traumatic insomnia as a covariate

Maternal childbirth-related posttraumatic stress symptoms, bonding, and infant development: a prospective study.

Childbirth-related posttraumatic stress symptoms (CB-PTSS) including general symptoms (GS, i.e., mainly negative cognitions and mood and hyperarousal symptoms) and birth-related symptoms (BRS, i.e., mostly re-experiencing and avoidance symptoms) may disrupt mother-infant bonding and infant development. This study investigated prospective and cross-sectional associations between maternal CB-PTSS and mother-infant bonding or infant development (language, motor, and cognitive). We analysed secondary data of the control group of a randomised control trial (NCT03576586) with full-term French-speaking mother-infant dyads (n = 55). Maternal CB-PTSS and mother-infant bonding were assessed via questionnaires at six weeks (T1) and six months (T2) postpartum: PTSD Checklist for DSM-5 (PCL-5) and Mother-Infant Bonding Scale (MIBS). Infant development was assessed with the Bayley Scales of Infant Development at T2. Sociodemographic and medical data were collected from questionnaires and medical records. Bivariate and multivariate regression were used. Maternal total CB-PTSS score at T1 was associated with poorer bonding at T2 in the unadjusted model (B = 0.064, p = 0.043). In the adjusted model, cross-sectional associations were found at T1 between a higher total CB-PTSS score and poorer bonding (B = 0.134, p = 0.017) and between higher GS and poorer bonding (B = 0.306, p = 0.002). Higher BRS at T1 was associated with better infant cognitive development at T2 in the unadjusted model (B = 0.748, p = 0.026). Results suggest that CB-PTSS were associated with mother-infant bonding difficulties, while CB-PTSS were not significantly associated with infant development. Additional studies are needed to increase our understanding of the intergenerational consequences of perinatal trauma

Phosphate deficiency alters transcript isoforms via alternative transcription start sites.

Alternative transcription start sites (TSS) are widespread in eukaryotes and can alter the 5' UTR length and coding potential of transcripts. Here we show that inorganic phosphate (Pi) availability regulates the usage of several alternative TSS in Arabidopsis (Arabidopsis thaliana). In comparison to phytohormone treatment, Pi had a pronounced and specific effect on the usage of many alternative TSS. By combining short-read RNA sequencing with long-read sequencing of full-length mRNAs, we identified a set of 45 genes showing alternative TSS under Pi deficiency. Alternative TSS affected several processes, such as translation via the exclusion of upstream open reading frames present in the 5' UTR of RETICULAN LIKE PROTEIN B1 mRNA, and subcellular localization via removal of the plastid transit peptide coding region from the mRNAs of HEME OXYGENASE 1 and SULFOQUINOVOSYLDIACYLGLYCEROL 2. Several alternative TSS also generated shorter transcripts lacking the coding potential for important domains. For example, the EVOLUTIONARILY CONSERVED C-TERMINAL REGION 4 (ECT4) locus, which encodes an N6-methyladenosine (m6A) reader, strongly expressed under Pi deficiency a short noncoding transcript (named ALTECT4) ~550 nt long with a TSS in the penultimate intron. The specific and robust induction of ALTECT4 production by Pi deficiency led to the identification of a role for m6A readers in primary root growth in response to low phosphate that is dependent on iron and is involved in modulating cell division in the root meristem. Our results identify alternative TSS usage as an important process in the plant response to Pi deficiency

The relationship between early administration of morphine or nitrous oxide gas and PTSD symptom development.

Posttraumatic Stress Disorder (PTSD) is a debilitating mental health disorder. Certain drugs, such as morphine and nitrous oxide gas (N <sub>2</sub> O), are administered to individuals who just experienced a traumatic event (e.g., soldiers, injured civilians). It is therefore crucial to understand if they incidentally affect PTSD symptom development. Furthermore, such observations could pave the way for the development of pharmacological prevention strategies of PTSD. In this prospective population-based cohort study (n = 2,070), we examined the relationship between morphine or N <sub>2</sub> O administration during childbirth, and subsequent childbirth-related PTSD symptoms at eight weeks postpartum. Pain during labour, prior PTSD symptoms, and birth medical severity were included as covariates in the analyses. In women who developed PTSD symptoms, N <sub>2</sub> O administration during childbirth predicted reduced PTSD symptom severity (p < .001, small to medium effect size). A similar tendency was observed for morphine, but was not significant (p < .065, null to small effect size). Both drugs predicted increased PTSD symptoms when combined with severe pain during labour. This study was observational, thus drug administration was not randomised. Additionally, PTSD symptoms were self-reported. Peritraumatic N <sub>2</sub> O administration may reduce subsequent PTSD symptom severity and thus be a potential avenue for PTSD secondary prevention. This might also be the case for morphine. However, the role of severe peritraumatic pain in context of drug administration deserves further investigation

The Lausanne Infant Crying Stress Paradigm: Validation of an Early Postpartum Stress Paradigm with Women at Low vs. High Risk of Childbirth-Related Posttraumatic Stress Disorder.

Stress reactivity is typically investigated in laboratory settings, which is inadequate for mothers in maternity settings. This study aimed at validating the Lausanne Infant Crying Stress Paradigm (LICSP) as a new psychosocial stress paradigm eliciting psychophysiological stress reactivity in early postpartum mothers (n = 52) and to compare stress reactivity in women at low (n = 28) vs. high risk (n = 24) of childbirth-related posttraumatic stress disorder (CB-PTSD). Stress reactivity was assessed at pre-, peri-, and post-stress levels through salivary cortisol, heart rate variability (high-frequency (HF) power, low-frequency (LF) power, and LF/HF ratio), and perceived stress via a visual analog scale. Significant time effects were observed for all stress reactivity outcomes in the total sample (all p < 0.01). When adjusting for perceived life threat for the infant during childbirth, high-risk mothers reported higher perceived stress (p < 0.001, d = 0.91) and had lower salivary cortisol release (p = 0.023, d = 0.53), lower LF/HF ratio (p < 0.001, d = 0.93), and marginally higher HF power (p = 0.07, d = 0.53) than low-risk women. In conclusion, the LICSP induces subjective stress and autonomic nervous system (ANS) reactivity in maternity settings. High-risk mothers showed higher perceived stress and altered ANS and hypothalamic-pituitary-adrenal reactivity when adjusting for infant life threat. Ultimately, the LICSP could stimulate (CB-)PTSD research

Single-session visuospatial task procedure to prevent childbirth-related posttraumatic stress disorder: a multicentre double-blind randomised controlled trial

Preventive evidence-based interventions for childbirth-related posttraumatic stress disorder (CB-PTSD) are lacking. Yet, 18.5% of women develop CB-PTSD symptoms following an unplanned caesarean section (UCS). This two-arm, multicentre, double-blind superiority trial tested the efficacy of an early single-session intervention including a visuospatial task on the prevention of maternal CB-PTSD symptoms. The intervention was delivered by trained maternity clinicians. Shortly after UCS, women were included if they gave birth to a live baby, provided consent, and perceived their childbirth as traumatic. Participants were randomly assigned to the intervention or attention-placebo group (allocation ratio 1:1). Assessments were done at birth, six weeks, and six months postpartum. Group differences in maternal CB-PTSD symptoms at six weeks (primary outcomes) and six months postpartum (secondary outcomes) were assessed with the self-report PTSD Checklist for DSM-5 (PCL-5) and by blinded research assessors with the Clinician-administered PTSD scale for DSM-5 (CAPS-5). Analysis was by intention-to-treat. The trial was prospectively registered (ClinicalTrials.gov, NCT03576586). Of the 2068 women assessed for eligibility, 166 were eligible and 146 were randomly assigned to the intervention (n = 74) or attention-placebo control group (n = 72). For the PCL-5, at six weeks, a marginally significant intervention effect was found on the total PCL-5 PTSD symptom count (β = -0.43, S.E. = 0.23, z = -1.88, p < 0.06), and on the intrusions (β = -0.73, S.E. = 0.38, z = -1.94, p < 0.0525) and arousal (β = -0.55, S.E. = 0.29, z = -1.92, p < 0.0552) clusters. At six months, a significant intervention effect on the total PCL-5 PTSD symptom count (β = -0.65, S.E. = 0.32, z = -2.04, p = 0.041, 95%CI[-1.27, -0.03]), on alterations in cognition and mood (β = -0.85, S.E. = 0.27, z = -3.15, p = 0.0016) and arousal (β = -0.56, S.E. = 0.26, z = -2.19, p < 0.0289, 95%CI[-1.07, -0.06]) clusters appeared. No group differences on the CAPS-5 emerged. Results provide evidence that this brief, single-session intervention carried out by trained clinicians can prevent the development of CB-PTSD symptoms up to six months postpartum

Control of Cognate Sense mRNA Translation by cis-Natural Antisense RNAs.

Cis-Natural Antisense Transcripts (cis-NATs), which overlap protein coding genes and are transcribed from the opposite DNA strand, constitute an important group of noncoding RNAs. Whereas several examples of cis-NATs regulating the expression of their cognate sense gene are known, most cis-NATs function by altering the steady-state level or structure of mRNA via changes in transcription, mRNA stability, or splicing, and very few cases involve the regulation of sense mRNA translation. This study was designed to systematically search for cis-NATs influencing cognate sense mRNA translation in Arabidopsis (Arabidopsis thaliana). Establishment of a pipeline relying on sequencing of total polyA &lt;sup&gt;+&lt;/sup&gt; and polysomal RNA from Arabidopsis grown under various conditions (i.e. nutrient deprivation and phytohormone treatments) allowed the identification of 14 cis-NATs whose expression correlated either positively or negatively with cognate sense mRNA translation. With use of a combination of cis-NAT stable over-expression in transgenic plants and transient expression in protoplasts, the impact of cis-NAT expression on mRNA translation was confirmed for 4 out of 5 tested cis-NAT:sense mRNA pairs. These results expand the number of cis-NATs known to regulate cognate sense mRNA translation and provide a foundation for future studies of their mode of action. Moreover, this study highlights the role of this class of noncoding RNAs in translation regulation

Secretion of Hepatitis C Virus Envelope Glycoproteins Depends on Assembly of Apolipoprotein B Positive Lipoproteins

The density of circulating hepatitis C virus (HCV) particles in the blood of chronically infected patients is very heterogeneous. The very low density of some particles has been attributed to an association of the virus with apolipoprotein B (apoB) positive and triglyceride rich lipoproteins (TRL) likely resulting in hybrid lipoproteins known as lipo-viro-particles (LVP) containing the viral envelope glycoproteins E1 and E2, capsid and viral RNA. The specific infectivity of these particles has been shown to be higher than the infectivity of particles of higher density. The nature of the association of HCV particles with lipoproteins remains elusive and the role of apolipoproteins in the synthesis and assembly of the viral particles is unknown. The human intestinal Caco-2 cell line differentiates in vitro into polarized and apoB secreting cells during asymmetric culture on porous filters. By using this cell culture system, cells stably expressing E1 and E2 secreted the glycoproteins into the basal culture medium after one week of differentiation concomitantly with TRL secretion. Secreted glycoproteins were only detected in apoB containing density fractions. The E1–E2 and apoB containing particles were unique complexes bearing the envelope glycoproteins at their surface since apoB could be co-immunoprecipitated with E2-specific antibodies. Envelope protein secretion was reduced by inhibiting the lipidation of apoB with an inhibitor of the microsomal triglyceride transfer protein. HCV glycoproteins were similarly secreted in association with TRL from the human liver cell line HepG2 but not by Huh-7 and Huh-7.5 hepatoma cells that proved deficient for lipoprotein assembly. These data indicate that HCV envelope glycoproteins have the intrinsic capacity to utilize apoB synthesis and lipoprotein assembly machinery even in the absence of the other HCV proteins. A model for LVP assembly is proposed