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The association between lower birth weight and increased disease risk in adulthood has drawn attention to the physiological processes that shape the gestational environment. We implement genome-wide transcriptional profiling of maternal blood samples to identify subsets of genes and associated transcription control pathways that predict offspring birth weight. Female participants (N = 178, mean = 27.0 years) in a prospective observational birth cohort study were contacted between 2009 and 2014 to identify new pregnancies. An in-home interview was scheduled for early in the third trimester (mean = 30.3 weeks) to collect pregnancy-related information and a blood sample, and birth weight was measured shortly after delivery. Transcriptional activity in white blood cells was determined with a whole-genome gene expression direct hybridization assay. Fifty transcripts were differentially expressed in association with offspring birth weight, with 18 up-regulated in relation to lower birth weight, and 32 down-regulated. Examination of transcription control pathways identified increased activity of NF-κB, AP-1, EGR1, EGR4, and Gfi families, and reduced the activity of CEBP, in association with lower birth weight. Transcript origin analyses identified non-classical CD16+ monocytes, CD1c+ myeloid dendritic cells, and neutrophils as the primary cellular mediators of differential gene expression. These results point toward a systematic regulatory shift in maternal white blood cell activity in association with lower offspring birth weight, and they suggest that analyses of gene expression during gestation may provide insight into regulatory and cellular mechanisms that influence birth outcomes.
Identifying routes of transmission among hospitalized patients during a healthcare-associated outbreak can be tedious, particularly among patients with complex hospital stays and multiple exposures. Data mining of the electronic health record (EHR) has the potential to rapidly identify common exposures among patients suspected of being part of an outbreak.
We retrospectively analyzed 9 hospital outbreaks that occurred during 2011–2016 and that had previously been characterized both according to transmission route and by molecular characterization of the bacterial isolates. We determined (1) the ability of data mining of the EHR to identify the correct route of transmission, (2) how early the correct route was identified during the timeline of the outbreak, and (3) how many cases in the outbreaks could have been prevented had the system been running in real time.
Correct routes were identified for all outbreaks at the second patient, except for one outbreak involving >1 transmission route that was detected at the eighth patient. Up to 40 or 34 infections (78% or 66% of possible preventable infections, respectively) could have been prevented if data mining had been implemented in real time, assuming the initiation of an effective intervention within 7 or 14 days of identification of the transmission route, respectively.
Data mining of the EHR was accurate for identifying routes of transmission among patients who were part of the outbreak. Prospective validation of this approach using routine whole-genome sequencing and data mining of the EHR for both outbreak detection and route attribution is ongoing.
Externalizing disorders are known to be partly heritable, but the biological pathways linking genetic risk to the manifestation of these costly behaviors remain under investigation. This study sought to identify neural phenotypes associated with genomic vulnerability for externalizing disorders.
One-hundred fifty-five White, non-Hispanic veterans were genotyped using a genome-wide array and underwent resting-state functional magnetic resonance imaging. Genetic susceptibility was assessed using an independently developed polygenic score (PS) for externalizing, and functional neural networks were identified using graph theory based network analysis. Tasks of inhibitory control and psychiatric diagnosis (alcohol/substance use disorders) were used to measure externalizing phenotypes.
A polygenic externalizing disorder score (PS) predicted connectivity in a brain circuit (10 nodes, nine links) centered on left amygdala that included several cortical [bilateral inferior frontal gyrus (IFG) pars triangularis, left rostral anterior cingulate cortex (rACC)] and subcortical (bilateral amygdala, hippocampus, and striatum) regions. Directional analyses revealed that bilateral amygdala influenced left prefrontal cortex (IFG) in participants scoring higher on the externalizing PS, whereas the opposite direction of influence was observed for those scoring lower on the PS. Polygenic variation was also associated with higher Participation Coefficient for bilateral amygdala and left rACC, suggesting that genes related to externalizing modulated the extent to which these nodes functioned as communication hubs.
Findings suggest that externalizing polygenic risk is associated with disrupted connectivity in a neural network implicated in emotion regulation, impulse control, and reinforcement learning. Results provide evidence that this network represents a genetically associated neurobiological vulnerability for externalizing disorders.
Group-3 medulloblastoma (MBL) is highly resistant to radiation (IR) and chemotherapy and has the worst prognosis. Hence, there is an urgent need to elucidate targets that sensitize these tumors to chemotherapy and IR. Employing standard assays for viability and sensitization to IR, we identified PRDX1 as a therapeutic target in Group-3 MBL. Specifically, targeting PRDX1 by RNAi or inhibition by Adenanthin led to specific killing and sensitization to IR of Group-3 MBL cells. We rescued sensitization of Daoy and UW228 cells by hypermorphic expression of PRDX1. PRDX1 knockdown caused oxidative DNA damage and induced apoptosis. We correlated PRDX1 expression to patient outcomes in a validated MBL tumor-microarray. Whole genome sequencing identified pathways/genes that were dysregulated with PRDX1 inhibition or silencing. Our in vivo studies in mice employing flank/orthotopic tumors from patient derived xenografts/Group-3 MBL cells confirmed in vitro observations. Animals with tumors in which PRDX1 was targeted by RNAi or Adenanthin (using mini osmotic pumps) showed decreased tumor burden and increased survival when compared to controls. Since, Adenanthin does not cross the blood brain barrier (BBB) we used HAV6 peptide to transiently disrupt the BBB and deliver Adenanthin to the tumor. Immunohistochemistry confirmed that targeting PRDX1 resulted in increased oxidative DNA damage, apoptosis and decreased proliferation. In summary, we have validated PRDX1 as a therapeutic target in group-3 MBL, identified Adenanthin as a potent chemical inhibitor of PRDX1 and confirmed the role of HAV peptide (in the transient modulation of BBB permeability) in an orthotopic model of group-3 MBL.
We present early results from the first near-IR imaging of the weak X-ray sources discovered in the recent Chandra/ACIS-I survey towards the Galactic Centre (GC) (Wang et al. 2002). These ~800 discrete sources, which contribute significantly to the GC X-ray emission, represent an important and previously unknown population within the Galaxy. From our VLT observations we will identify likely IR counterparts to a sample of the hardest sources, which are most likely X-ray binaries. With these data we can place constraints on the nature of the discrete weak X-ray source population of the GC. Once the data analysis is complete we will discuss our results in the context of binary population synthesis models.
The profitability of pig production is constrained by high incidences of peri-parturient and pre-weaning piglet mortality. Supplementing sows with either progesterone or caffeine during the last week of gestation can reduce stillbirths and improve piglet performance. However, the consequences of combining these two substances has not been investigated. The aim of the current study was to determine the effect of oral supplementation of sows with progesterone (regumate) and caffeine at the end of gestation on the timing and progression of farrowing, as well as piglet survival and growth to weaning. From days 111 to 113 of gestation, 20 Large White pregnant sows (parity 3.0±0.45) received 5 ml of Regumate Porcine (0.4 w/v oral solution; MSD Animal Health) daily on top of their morning ration. Sows were stratified according to parity and predicted farrowing date, and allocated at random to receive a diet supplemented with either 0 g caffeine/kg diet (CONT) or 2.4 g of caffeine/kg diet (CAFF) from day 113 of gestation until parturition (n=10 sows/treatment). Treatment did not affect total litter size; however, CONT sows gave birth to more live and fewer dead piglets compared with CAFF sows; 14.5±0.73 v. 11.7±1.03 and 0.7±0.20 v. 3.2±0.77; P<0.05). Mean, minimum and maximum piglet birthweight were unaffected by treatment. Compared with the control, caffeine increased the proportion of piglets with a birthweight <1 kg (0.16±0.05 v. 0.05±0.02; P=0.072) and decreased the proportion of live born piglets surviving to day 5 postpartum (0.77±0.06 v. 0.90±0.02; P<0.05) and to weaning (0.74±0.06 v. 0.90±0.02; P<0.05). Overall, the current data provided the first evidence that caffeine supplementation of sows receiving progesterone to prevent premature farrowing impaired piglet survival during, and shortly after parturition. This negative outcome may be linked to extended farrowing durations and an increase in the proportion of very light piglets at birth. These data provide compelling, albeit preliminary, evidence that caffeine and progesterone should not be used together at the end of gestation.
Lactogenesis is triggered by a rapid decline in plasma progesterone concentration combined with a peak in plasma prolactin concentration; in mice, there is a concurrent loss of mammary progesterone receptors (Haslam and Shyamala, 1980). The aims of this experiment were to determine the pattern of change of progesterone receptor and prolactin receptor mRNA during late gestation and early lactation and to determine whether abundance of mRNA for the two receptors are related to each other, to plasma concentrations of progesterone and prolactin or to piglet performance.
While striving to succeed in the face of adversity may provide individuals with outward benefits, it may come at a cost to individuals’ physical health. The current study examines whether striving predicts greater physiological or psychosocial costs among those who experienced child maltreatment, a stressor that disrupts the caregiving environment and threatens relationship security. Using data from the National Longitudinal Study of Adolescent to Adult Health, we tested whether greater striving after childhood maltreatment would come at a cost, increasing underlying cardiovascular disease (CVD) risk and depressive symptoms despite showing outward success via income and college degree attainment. The study included 13,341 Black, Hispanic, and White adolescents who self-reported striving and their experiences of childhood neglect, physical abuse, and sexual abuse. As young adults, participants reported depressive symptoms, income, and college degree attainment and completed a health assessment from which a 30-year Framingham-based CVD risk score was calculated. Higher striving was associated with lower CVD risk and depressive symptoms, and higher income and college degree attainment, regardless of maltreatment history. These findings highlight the potential for striving as a target for interventions and support the need to examine multiple biological and behavioral outcomes to understand the multifaceted nature of resilience.
The immune system not only provides protection against infectious disease but also contributes to the etiology of neoplastic, atopic, and cardiovascular and metabolic diseases. Prenatal and postnatal nutritional and microbial environments have lasting effects on multiple aspects of immunity, indicating that immune processes may play important roles in the developmental origins of disease. The objective of this study is to evaluate the association between birth weight and the distribution of leukocyte (white blood cell) subsets in peripheral blood in young adulthood. Postnatal microbial exposures were also considered as predictors of leukocyte distribution. Participants (n=486; mean age=20.9 years) were drawn from a prospective birth cohort study in the Philippines, and analyses focused on the following cell types: CD4 T lymphocytes, CD8 T lymphocytes, B lymphocytes, natural killer cells, monocytes, granulocytes. Higher birth weight was a strong predictor of higher proportion of CD4 T lymphocytes (B=0.12, s.e.=0.041, P=0.003), lower proportion of CD8 T lymphocytes (B=−0.874, s.e.=0.364, P=0.016), higher CD4:CD8 ratio (B=1.964, s.e.=0.658, P=0.003), and higher B lymphocytes (B=0.062, s.e.=0.031, P=0.047). Measures of microbial exposure in infancy were negatively associated with proportions of B lymphocytes and granulocytes, and lower CD4:CD8 ratio. Leukocytes are the key regulators and effectors of innate and specific immunity, but the origins of variation in the distribution of cell type across individuals are not known. Our findings point toward nutritional and microbial exposures in infancy as potentially important determinants of immune-phenotypes in adulthood, and they suggest that leukocyte distribution is a plausible mechanism through which developmental environments have lasting effects on disease risk in adulthood.
The interannual variations in atmospheric transport patterns to Summit, Greenland, are studied using twice-daily, three-dimensional, 10 day backward trajectory data corresponding to the summers (1 June–31 August) of 1989–98. While previous trajectory climatology studies have been prepared for Summit, the present work considers both the horizontal and vertical components of transport. A three-dimensional residence-time methodology is employed to account for both horizontal and vertical components of transport. the vertical transport component is quantified by passing all trajectories through a three-dimensional grid and tracking the time spent (i.e. the residence time) in each gridcell. This method also allows inspection of trajectory altitude distributions corresponding to transport from upwind regions of interest. the three-dimensional residence-time methodology is shown to be a valuable tool for diagnosing the details of long-range atmospheric transport to remote locations. for Summit, we find that the frequent transport from North America tends to occur at low altitudes, whereas transport from Europe is highly variable. Mean summertime flow patterns are described, as are anomalous patterns during 1990,1996 and 1998.
Fetal growth restriction (FGR) and preterm birth are frequent co-morbidities, both are independent risks for brain injury. However, few studies have examined the mechanisms by which preterm FGR increases the risk of adverse neurological outcomes. We aimed to determine the effects of prematurity and mechanical ventilation (VENT) on the brain of FGR and appropriately grown (AG, control) lambs. We hypothesized that FGR preterm lambs are more vulnerable to ventilation-induced acute brain injury. FGR was surgically induced in fetal sheep (0.7 gestation) by ligation of a single umbilical artery. After 4 weeks, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Brains and cerebrospinal fluid (CSF) were collected for analysis of molecular and structural indices of early brain injury. FGRVENT lambs had increased oxidative cell damage and brain injury marker S100B levels compared with all other groups. Mechanical ventilation increased inflammatory marker IL-8 within the brain of FGRVENT and AGVENT lambs. Abnormalities in the neurovascular unit and increased blood–brain barrier permeability were observed in FGRVENT lambs, as well as an altered density of vascular tight junctions markers. FGR and AG preterm lambs have different responses to acute injurious mechanical ventilation, changes which appear to have been developmentally programmed in utero.
The dynamical friction timescale for globular clusters to sink to the center of a dwarf elliptical galaxy (dE) is significantly less than a Hubble time if the halos have isothermal profiles and the globular clusters formed with the same radial density profile as the underlying stellar population. We examine the summed radial distribution of the entire globular cluster systems and the bright globular cluster candidates in 65 Virgo and Fornax Cluster dEs for evidence of dynamical friction processes. We find that the bright dE nuclei could have been formed from the merger of orbitally decayed massive clusters, but the faint nuclei are several magnitudes fainter than expected. These faint nuclei are found primarily in MV > −14 dEs which have high globular cluster specific frequencies and extended globular cluster systems. In these galaxies, the formation of new star clusters, high central dark matter densities, extended dark matter halos, or tidal interactions may act to prevent dynamical friction from collapsing the entire globular cluster population into a bright nucleus.
We present preliminary results on the shape of the globular cluster luminosity function and the colors and inferred metallicities of the clusters in dwarf elliptical galaxies imaged with HST. The luminosity function (LF) of the GC candidates is consistent with a Gaussian-shaped LF similar to that in giant ellipticals. Also, with a mean color of (V - I) = 0.94, most of the GCs appear to be old and metal-poor ([Fe/H] = −1.4) like GCs in the Galaxy and in nearby giant ellipticals. This suggests that the bulk of the clusters were formed more than 10 Gyr ago.
In early 2015, a patient from a cluster of cases of Ebola Virus Disease (EVD) in Monrovia, Liberia traveled to a rural village in Margibi County, potentially exposing numerous persons. The patient died in the village and post-mortem testing confirmed Ebola Virus infection.
The Margibi County Health Team (CHT; Kakata, Margibi, Liberia) needed to prevent further transmission of EVD within and outside of the affected villages, and they needed to better understand the factors that support or impede compliance with measures to stop the spread of EVD.
In February-March 2015, the Margibi CHT instituted a 21-day quarantine and active monitoring for two villages where the patient had contact with numerous residents, and a 21-day active monitoring for five other villages where the patient had possible contact with an unknown number of persons. One contact developed EVD and quarantine was extended an additional 12 days in one village. In April 2015, the Margibi CHT conducted a household-based EVD knowledge, attitudes, and practices (KAP) survey of the seven villages. From April 24-29, 2015, interview teams approached every household in the seven villages and collected information on demographics, knowledge of EVD, attitudes about quarantine to prevent the spread of EVD, and their quarantine experiences and practices. Descriptive statistics were calculated.
One hundred fifteen interviews were conducted, representing the majority of the households in the seven villages. Most (99%) correctly identified touching an infected person’s body fluids and contact with the body of someone who has died from EVD as transmission routes. However, interviewees sometimes incorrectly identified mosquito bites (58%) and airborne spread (32%) as routes of EVD transmission, and 72% incorrectly identified the longest EVD incubation period as ≤seven days. Eight of 16 households in the two quarantined villages (50%) reported times when there was not enough water or food during quarantine. Nine of 16 (56%) reported that a household member had illnesses or injuries during quarantine; of these, all (100%) obtained care from a clinic, hospital, or Ebola treatment unit (ETU).
Residents’ knowledge of EVD transmission routes and incubation period were suboptimal. Public health authorities should consider assessing residents’ understanding of Ebola transmission routes and effectively educate them to ensure correct understanding. Quarantined residents should be provided with sufficient food, water, and access to medical care.
WilkenJA, PordellP, GoodeB, JartehR, MillerZ, SaygarBGSr., MaximoreL, BorborWM, CarmueM, WalkerGW, YeiahA. Knowledge, Attitudes, and Practices among Members of Households Actively Monitored or Quarantined to Prevent Transmission of Ebola Virus Disease — Margibi County, Liberia: February-March 2015. Prehosp Disaster Med. 2017;32(6):673–678.
Intrauterine or fetal growth restriction (IUGR) is a major complication of pregnancy and leads to significant perinatal morbidities and mortality. Typically, induction of IUGR in animals involves the complete occlusion or ablation of vessels to the uterus or placenta, acutely impairing blood flow and fetal growth, usually with high fetal loss. We aimed to produce a model of reduced fetal growth in the spiny mouse with minimal fetal loss. At 27 days gestational age (term is 38–39 days), a piece of silastic tubing was placed around the left uterine artery to prevent the further increase of uterine blood flow with advancing gestation to induce IUGR (occluded). Controls were generated from sham surgeries without placement of the tubing. Dams were humanely euthanized at 37 days gestational age and all fetuses and placentas were weighed and collected. Of the 17 dams that underwent surgery, 15 carried their pregnancies to 37 days gestational age and 95% of fetuses survived to this time. The difference in fetal body weight between occluded and control was ~21% for fetuses in the left uterus side: there were no differences for fetuses in the right uterus side. Offspring from the occluded group had significantly lower brain, liver, lung, kidney and carcass weights compared with shams. Preventing the gestation-related increase of uterine blood flow induced significant growth restriction in the fetal spiny mouse, with minimal fetal loss. This technique could be readily adapted for other small animal.
Strategies that reduce the time to antimicrobial administration, such as the availability of premix antimicrobials (PMAs) in the emergency department (ED), may better align with the goals of the Surviving Sepsis Campaign and improve outcomes in septic patients. The objective of this study was to evaluate the impact of antimicrobial preparation on time to administration in septic patients located in the emergency department (ED).
This was a retrospective, single-center, cohort study and adult patients with a diagnosis of sepsis who received at least one initial intravenous (IV) antimicrobial in the ED were included. Time to complete an empiric antimicrobial therapy was defined as the time between prescriber order entry and the infusion initiation time of the final antimicrobial agent of a patient’s antimicrobial regimen. Appropriate, empiric antimicrobial therapy was based on treatment recommendations by nationally accepted guidelines for the specific indication.
The first antimicrobial was initiated earlier when available as a PMA preparation (median (IQR): premix 25 minutes (16.5-42.3) vs. non-premix 46 minutes (20-102), p=0.027). When comparing complete, empiric antimicrobial regimen administration, there was no difference in time to administration between regimens containing one or more non-premix antimicrobials and regimens containing all PMAs (median (IQR): premix 69 minutes (21-115) vs. non-premix 65 minutes (38.5-133.8); p=0.455).
PMA preparations significantly reduced time to administration of the first antimicrobial agent for septic patients treated in the ED, but time to administration of subsequent antimicrobials were not improved.
The objective of this study was to determine whether hatha yoga is an efficacious adjunctive intervention for individuals with continued depressive symptoms despite antidepressant treatment.
We conducted a randomized controlled trial of weekly yoga classes (n = 63) v. health education classes (Healthy Living Workshop; HLW; n = 59) in individuals with elevated depression symptoms and antidepressant medication use. HLW served as an attention-control group. The intervention period was 10 weeks, with follow-up assessments 3 and 6 months afterwards. The primary outcome was depression symptom severity assessed by blind rater at 10 weeks. Secondary outcomes included depression symptoms over the entire intervention and follow-up periods, social and role functioning, general health perceptions, pain, and physical functioning.
At 10 weeks, we did not find a statistically significant difference between groups in depression symptoms (b = −0.82, s.e. = 0.88, p = 0.36). However, over the entire intervention and follow-up period, when controlling for baseline, yoga participants showed lower levels of depression than HLW participants (b = −1.38, s.e. = 0.57, p = 0.02). At 6-month follow-up, 51% of yoga participants demonstrated a response (⩾50% reduction in depression symptoms) compared with 31% of HLW participants (odds ratio = 2.31; p = 0.04). Yoga participants showed significantly better social and role functioning and general health perceptions over time.
Although we did not see a difference in depression symptoms at the end of the intervention period, yoga participants showed fewer depression symptoms over the entire follow-up period. Benefits of yoga may accumulate over time.
A mixture of approximately one part of water to two parts of kaolin (china clay) has proved suitable for making model glaciers on scales between 1 : 1000 and 1 : 10,000. The kaolin “glaciers” crevasse and flow realistically, and slide on their beds. They serve well for qualitative demonstrations, and some simple preliminary quantitative experiments suggest that they may also be useful for this purpose.