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Abstract Exercise has beneficial effects on cognition throughout the lifespan. Here, we demonstrate that specific exercise patterns transform insufficient, subthreshold training into long-term memory in mice. Our findings reveal a potential molecular memory window such that subthreshold training within this window enables long-term memory formation. We performed RNA-seq on dorsal hippocampus and identify genes whose expression correlate with conditions in which exercise enables long-term memory formation. Among these genes we found Acvr1c, a member of the TGF ß family. We find that exercise, in any amount, alleviates epigenetic repression at the Acvr1c promoter during consolidation. Additionally, we find that ACVR1C can bidirectionally regulate synaptic plasticity and long-term memory in mice. Furthermore, Acvr1c expression is impaired in the aging human and mouse brain, as well as in the 5xFAD mouse model, and over-expression of Acvr1c enables learning and facilitates plasticity in mice. These data suggest that promoting ACVR1C may protect against cognitive impairment.

[This corrects the article DOI: 10.1371/journal.pone.0261492.].

Nationwide, the prevalence of the hepatitis C virus (HCV) has risen in recent years. At least 90% of infected persons must be treated to achieve global elimination targets. The current study aimed to explore barriers to, and facilitators of, direct-acting antiviral (DAA) HCV treatment uptake amongst pregnant and early-parenting women undergoing comprehensive substance use treatment. Twenty participants with documented HCV antibody positivity were recruited from two substance use treatment centers in central Kentucky. Semi-structured interviews were conducted to explore knowledge about HCV, previous experiences, and intentions to seek care. Themes were extracted using an inductive analytical approach. Most participants were aware of the dangers posed by HCV infection. However, there was a high degree of misinformation about transmission mechanisms and treatment eligibility requirements. Low priority for HCV treatment also surfaced as a barrier to treatment uptake. Participants reported being unable to seek care due to time and resource limitations in the presence of a highly demanding treatment process. Findings from the current study suggest that more work is needed to eliminate residual barriers that limit access to HCV treatment among pregnant and early-parenting women in treatment for substance use disorder.

The reliability of a coherent system of components depends on the reliability of each component and the initial statistical work should be an estimation of the reliability of each component. This paper represents a challenging task because if the system fails, the failure time of a given component cannot be observed, that is, the phenomenon of censored data occurs. A solution for the reliability estimation of components exists when the system failure time and the status of each component are available at the time of system failure. However, it may be difficult to identify the status of the components at the moment of system failure. Such cases represent systems with masked causes of failure. Since parallel and series systems are the simplest systems, numerous solutions have been reported in the literature. To the best of our knowledge, this paper is the first to present the general case of coherent systems without the restriction of an identically distributed lifetime. The three-parameter Weibull Bayesian model is proposed. The Gibbs with the Metropolis-Hasting algorithm supports the statistical work of obtaining the posterior distribution quantities. With several simulations, the excellent performance of the model is evaluated. A real dataset of computer hard drives is analyzed to show the practical relevance of the proposed model.

ObjectiveMortality rates of pregnant and postpartum women grew in the second COVID-19 pandemic year. Our objective is to understand this phenomenon to avoid further deaths.MethodsWe collected data from SIVEP-Gripe, a nationwide Brazilian database containing surveillance data on all severe acute respiratory syndrome caused by COVID-19, between the first notified case (February 2020) until the 17th epidemiological week of 2021. We stratified patients into maternal women (which includes pregnant and postpartum women), non-maternal women and men and divided them by time of diagnosis in two periods: first period (February to December 2020) and second period (the first 17 epidemiological weeks of 2021 before pregnant and postpartum women were vaccinated).ResultsDuring the second period, all patients had higher risk of presenting severe COVID-19 cases, but the maternal population was at a higher risk of death (OR of 2.60 CI 95%: 2.28-2.97)-almost double the risk of the two other groups. Maternal women also had a higher risk of needing intensive care, intubation and of presenting desaturation in the second period. Importantly, maternal women presented fewer comorbidities than other patient groups, suggesting that pregnancy and postpartum can be an important risk factor associated with severe COVID-19.ConclusionOur results suggest that the Gama variant, which has been related to greater virulence, transmissibility and mortality rates leads to more severe cases of COVID-19 for pregnant and postpartum women.

Abstract Gene prioritization approaches are useful tools to explore and select candidate genes in transcriptome studies. Knowing the importance of processes such as neuronal activity, intracellular signal transduction, and synapse plasticity to the development and maintenance of compulsive ethanol drinking, the aim of the present study was to explore and identify functional candidate genes associated with these processes in an animal model of inflexible pattern of ethanol intake. To do this, we applied a guilt‐by‐association approach, using the GUILDify and ToppGene software, in our previously published microarray data from the prefrontal cortex (PFC) and striatum of inflexible drinker mice. We then tested some of the prioritized genes that showed a tissue‐specific pattern in postmortem brain tissue (PFC and nucleus accumbens (NAc)) from humans with alcohol use disorder (AUD). In the mouse brain, we prioritized 44 genes in PFC and 26 in striatum, which showed opposite regulation patterns in PFC and striatum. The most prioritized of them (i.e., Plcb1 and Prkcb in PFC, and Dnm2 and Lrrk2 in striatum) were associated with synaptic neuroplasticity, a neuroadaptation associated with excessive ethanol drinking. The identification of transcription factors among the prioritized genes suggests a crucial role for Irf4 in the pattern of regulation observed between PFC and striatum. Lastly, the differential transcription of IRF4 and LRRK2 in PFC and nucleus accumbens in postmortem brains from AUD compared to control highlights their involvement in compulsive ethanol drinking in humans and mice.

The first step in statistical reliability studies of coherent systems is the estimation of the reliability of each system component. For the cases of parallel and series systems, the literature is abundant, but it seems that the present paper is the first to present the general case of component inferences in coherent systems. The failure time model considered here is the three-parameter Weibull distribution. Furthermore, identically distributed failure times are not a required restriction. An important result is proved: without the assumption that components' lifetimes are mutually independent, a given set of sub-reliability functions does not identify the corresponding marginal reliability function. The proposed model is general in the sense that it can be used for components of any coherent system, from the simplest to the most complex designs. It can be considered for all kinds of censored data, including interval-censored data. An important property obtained for the Weibull model is that the posterior distributions are proper, even for non-informative priors. Using several simulations, the excellent performance of the model is illustrated. As real examples, boys' first use of marijuana and a device from a field-tracking data set are considered to show the efficiency of the solution even when censored data occurs.

Abstract Background To evaluate possible predictive factors of spontaneous prematurity in fetuses with congenital diaphragmatic hernia (CDH). Methods A retrospective cohort study was performed. Inclusion criteria were presence of CDH; absence of fetoscopy; absence of karyotype abnormality; maximum of one major malformation associated with diaphragmatic hernia; ultrasound monitoring at the Obstetrics Clinic of Clinicas Hospital at the University of São Paulo School of Medicine, from January 2001 to October 2014. The data were obtained through the electronic records and ultrasound system of our fetal medicine service. The following variables were analyzed: maternal age, primiparity, associated maternal diseases, smoking, previous spontaneous preterm birth, fetal malformation associated with hernia, polyhydramnios, fetal growth restriction, presence of intrathoracic liver, invasive procedures performed, side of hernia and observed-to- expected lung to head ratio (o/e LHR). On individual analysis, variables were assessed using the Chi-square test and the Mann-Whitney test. A multiple logistic regression model was applied to select variables independently influencing the prediction of preterm delivery. A ROC curve was constructed with the significant variable, identifying the values with best sensitivity and specificity to be suggested for use in clinical practice. Results Eighty fetuses were evaluated, of which, 21 (26.25%) were premature. O/e LHR was the only factor associated with prematurity (p = 0.020). The ROC curve showed 93% sensitivity with 48.4% specificity for the cutoff of 40%. Conclusion O/e LHR was the only predictor of prematurity in this sample.

Abstract Objective To assess differences in cytokine levels in cervicovaginal fluid (CVF) and serum across trimesters between women with preterm births (PTBs) and full-term births. Study Design This multicenter study enrolled 302 women with a singleton gestation. CVF and serum cytokines, interleukin 1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and matrix metalloproteinase (MMP)-8, were measured. Women with at least one cytokine assessment and noted PTB status in their medical record were retained in the study (N = 272). Data were analyzed using mixed modeling (main effects of PTBs and time/trimester). Results For the CVF values of IL-6, IL-8, IL-10, TNF-α, and CRP, and serum MMP-8, those who delivered preterm had significantly higher values than the full-term group regardless of trimester. For the serum values of IL-1β, IL-6, and TNF-α, those delivering preterm had significantly lower values than those delivering full-term regardless of trimester. For IL-1β in CVF, the cytokine was significantly higher in the PTB group for second and third trimesters only, relative to the full-term group. Conclusion For each CVF cytokine that differed by birth status, values were higher for PTB than term, averaged over trimester. Numerous cytokine profiles varied across trimesters in women delivering term versus preterm in both CVF and serum.

Abstract Objective To examine the relationship between antepartum buprenorphine dose for medication-assisted treatment (MAT) of opioid use disorder (OUD) and incident neonatal opioid withdrawal syndrome (NOWS). Study Design We performed a prospective cohort study of pregnant women with a singleton gestation diagnosed with OUD and receiving buprenorphine for MAT at a tertiary care academic institution from July 2015 to January 2017. We divided the study cohort into two groups—pregnancies with versus without NOWS. Substance abuse patterns in pregnancy, maternal, and neonatal clinical outcomes were compared. Results The incidence of NOWS was 31.11% (n = 28/90) in our study cohort. Pregnancies with NOWS had a significantly higher rate of benzodiazepine positive urine tests and number of positive urine drug screen (UDS) results for illicit opioids. The group without NOWS had significantly higher number of patients with an appropriate UDS result at delivery through postpartum. Rates of neonatal intensive care unit (NICU) admission, length of NICU stay, and maximum Finnegan score were significantly higher in the group with NOWS. Neither the initial (10.6 ± 5.2 versus 10.3 ± 4.8 mg, p = 0.80) nor the final buprenorphine doses (13.3 ± 5.1 versus 13.0 ± 4.6 mg, p = 0.81) were significantly different between study groups. Conclusion The occurrence of NOWS was not related to buprenorphine dose used for MAT.

Hepatocellular carcinoma (HCC) is the second most common cause of cancer mortality worldwide. Most cases of HCC are associated with cirrhosis related to chronic hepatitis B virus or hepatitis C virus infections. Hypermethylation of promoter regions is the main epigenetic mechanism of gene silencing and has been involved in HCC development. The aim of this study was to determine whether aberrant methylation of RASSF1A and DOK1 gene promoters is associated with the progression of liver disease in Brazilian patients. Methylation levels were measured by pyrosequencing in 41 (20 HCC, 9 cirrhotic, and 12 non-cirrhotic) liver tissue samples. Mean rates of methylation in RASSF1A and DOK1 were 16.2% and 12.0% in non-cirrhotic, 26.1% and 19.6% in cirrhotic, and 59.1% and 56.0% in HCC tissues, respectively, showing a gradual increase according to the progression of the disease, with significantly higher levels in tumor tissues. In addition, hypermethylation of RASSF1A and DOK1 was found in the vast majority (88%) of the HCC cases. Interestingly, DOK1 methylation levels in HCC samples were significantly higher in the group of younger (

Intrahepatic cholestasis of pregnancy (ICP) is a complication of pregnancy resulting in elevation of serum bile acid levels. ICP is often associated with underlying liver disease, including hepatitis C. Bile acids in relationship to the acute infection of hepatitis C virus have not yet been delineated in the literature. A 26-year-old gravida 4 para 2103 with dichorionic, diamniotic twin gestation and history of intravenous drug abuse developed ICP in the setting of acute hepatitis C infection. In addition to clinical symptoms of pruritus and right upper quadrant pain, she developed severe elevation in bile acids, 239 micromol/L, and transaminitis aspartate aminotransferase 1033 U/L, and alanine aminotransferase 448 U/L. She received ursodeoxycholic acid and antenatal testing was performed. Patient delivered vaginally at 33-week gestation following preterm rupture of membranes. Neonates were admitted to NICU and had uncomplicated neonatal courses. In the setting of ICP with significant transaminitis and severe elevation of bile acids, consideration of acute viral hepatitis is important, especially considering the worsening opioid epidemic and concurrent increase in intravenous drug use in the United States. Further study is needed regarding the acute form of HCV infection and its effect on ICP and associated bile acids.

Ascending infection from the colonized vagina to the normally sterile intrauterine cavity is a well-documented cause of preterm birth. The primary physical barrier to microbial ascension is the cervical canal, which is filled with a dense and protective mucus plug. Despite its central role in separating the vaginal from the intrauterine tract, the barrier properties of cervical mucus have not been studied in preterm birth.To study the protective function of the cervical mucus in preterm birth we performed a pilot case-control study to measure the viscoelasticity and permeability properties of mucus obtained from pregnant women at high-risk and low-risk for preterm birth. Using extensional and shear rheology we found that cervical mucus from women at high-risk for preterm birth was more extensible and forms significantly weaker gels compared to cervical mucus from women at low-risk of preterm birth. Moreover, permeability measurements using fluorescent microbeads show that high-risk mucus was more permeable compared with low-risk mucus.Our findings suggest that critical biophysical barrier properties of cervical mucus in women at high-risk for preterm birth are compromised compared to women with healthy pregnancy. We hypothesize that impaired barrier properties of cervical mucus could contribute to increased rates of intrauterine infection seen in women with preterm birth. We furthermore suggest that a robust association of spinnbarkeit and preterm birth could be an effectively exploited biomarker for preterm birth prediction.