A Randomized Trial Examining Preoperative Sedative Medication and Post-operative Sleep in Children

Study Objective Midazolam has been found to have beneficial effects on anxiety in children in the preoperative setting. Prior studies have examined various postoperative behaviors of children, but little research has examined the effects of preoperative use of midazolam with postoperative sleep. The purpose of this investigation was to compare postoperative sleep in children as a function of preoperative sedative medication use. Design This study was a 2-group randomized controlled trial. Setting Participants were recruited from Yale-New Haven Children\u27s Hospital. Patients Participants included a convenience sample of 70 children between the ages of 3 to 12 years undergoing ambulatory tonsillectomy and adenoidectomy. Interventions Children were randomly assigned to 1 of 2 groups: a control group who received preoperative acetaminophen only (n = 32) and an experimental group who received both acetaminophen and midazolam preoperatively (n = 38). Measurements Parents completed measures of postoperative behavioral recovery and a subset of children wore actigraphs to examine objective sleep data. Main Results Children who received midazolam experienced similar sleep changes compared to children in the control group. The actigraph data revealed that children who received midazolam were awake significantly less during the night compared to the control group (P= .01). Conclusion Children who received midazolam before surgery had similar postoperative sleep changes compared to children who did not receive midazolam. Further understanding of the postoperative behavioral effects of midazolam on children will help guide healthcare providers in their practice

Long-term propagation of influenza A virus and its defective interfering particles: Analyzing dynamic competition to select antiviral candidates

Influenza A virus (IAV) is a major threat to human health. A potential antiviral therapy against influenza disease could be the intranasal application of defective interfering particles (DIPs) [1,2]. During intracellular IAV replication, these IAV DIPs are randomly generated. They contain at least one defective interfering (DI) RNA, typically a genome segment with a large internal deletion, rendering them replication-incompetent. During co-infection with infectious standard virus (STV), DIPs impede STV replication via a growth advantage [3] and by stimulation of the innate immune response [4]. In this work, we profiled the propagation competition between a variety of DIPs for selection toward accumulation of highly interfering DIPs in Madin-Darby canine kidney (MDCK) suspension cell culture. To that end, we propagated IAV and its DIPs over 21 days using a small-scale two-stage cultivation system. Illumina-based next-generation sequencing (NGS) in combination with a lately reported bioinformatic pipeline was utilized to detect and quantify specific deletion junctions within the virus population [5]. During long-term propagation, both the infectious and total virus titers oscillated periodically, a characteristic pattern of DIP and STV interplay [6]. NGS analysis revealed that the highest de novo formation and accumulation of DI vRNAs occurred on the polymerase-encoding segments. Moreover, we identified an accumulation of short DI vRNAs with an optimum fragment length underlining their replication advantage. Deletion junctions were usually situated near both vRNA ends. For efficient DI vRNA propagation, retaining the incorporation signal but not the entire bundling signal was required. Few DI vRNAs propagated to high levels toward the end of cultivation, while the level of others declined. Reverse genetics was utilized to generate purely clonal DIPs derived from DI vRNAs of segment 1 that showed the highest increase in accumulation during cultivation. For this, genetically engineered adherent and suspension MDCK cells complementing the defect in segment 1 were employed [7,2]. During co-infection with STV, these DIPs displayed a higher interfering efficacy relative to DIPs derived from less competitive DI vRNAs. Please click Download on the upper right corner to see the full abstract

Bitopic binding mode of an M1 muscarinic acetylcholine receptor agonist associated with adverse clinical trial outcomes

The realisation of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (M1 mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702, described previously as a potent M1 receptor allosteric agonist, which showed pro-cognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side-effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702 together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. We conclude that these properties, whilst imparting beneficial effects on learning and memory, are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data supports the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses

Long non-coding RNA LCAL62 / LINC00261 is associated with lung adenocarcinoma prognosis

Background: More than half of non-small cell lung cancer (NSCLC) patients present with metastatic disease at initial diagnosis with an estimated five-year survival rate of ~5%. Despite advances in understanding primary lung cancer oncogenesis metastatic disease remains poorly characterized. Recent studies demonstrate important roles of long non-coding RNAs (lncRNAs) in tumor physiology and as prognostic markers. Therefore, we present the first transcriptome analysis to identify lncRNAs altered in metastatic lung adenocarcinoma leading to the discovery and characterization of the lncRNA Patients and methods: RNA-Seq, microarray, nanoString expression, and clinical data from 1,116 LUAD patients across six independent cohorts and 83 LUAD cell lines were used to discover and evaluate the survival association of metastasis associated lncRNAs. Coexpression and gene set enrichment analyses were used to establish gene regulatory networks and implicate metastasis associated lncRNAs in specific biological processes. Results: Our integrative analysis discovered Conclusion: We discovered tha

Prospective, Head-to-Head Study of Three Computerized Neurocognitive Assessment Tools (CNTs): Reliability and Validity for the Assessment of Sport-Related Concussion

Abstract Limited data exist comparing the performance of computerized neurocognitive tests (CNTs) for assessing sport-related concussion. We evaluated the reliability and validity of three CNTs—ANAM, Axon Sports/Cogstate Sport, and ImPACT—in a common sample. High school and collegiate athletes completed two CNTs each at baseline. Concussed ( n =165) and matched non-injured control ( n =166) subjects repeated testing within 24 hr and at 8, 15, and 45 days post-injury. Roughly a quarter of each CNT’s indices had stability coefficients ( M =198 day interval) over .70. Group differences in performance were mostly moderate to large at 24 hr and small by day 8. The sensitivity of reliable change indices (RCIs) was best at 24 hr (67.8%, 60.3%, and 47.6% with one or more significant RCIs for ImPACT, Axon, and ANAM, respectively) but diminished to near the false positive rates thereafter. Across time, the CNTs’ sensitivities were highest in those athletes who became asymptomatic within 1 day before neurocognitive testing but was similar to the tests’ false positive rates when including athletes who became asymptomatic several days earlier. Test–retest reliability was similar among these three CNTs and below optimal standards for clinical use on many subtests. Analyses of group effect sizes, discrimination, and sensitivity and specificity suggested that the CNTs may add incrementally (beyond symptom scores) to the identification of clinical impairment within 24 hr of injury or within a short time period after symptom resolution but do not add significant value over symptom assessment later. The rapid clinical recovery course from concussion and modest stability probably jointly contribute to limited signal detection capabilities of neurocognitive tests outside a brief post-injury window. ( JINS , 2016, 22 , 24–37

Early activation of the host complement system is required to restrict central nervous system invasion and limit neuropathology during Venezuelan equine encephalitis virus infection

Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne RNA virus of the genus Alphavirus, family Togaviridae, that is responsible for sporadic outbreaks in human and equid populations in Central and South America. In order to ascertain the role that complement plays in resolving VEEV-induced disease, complement-deficient C3−/− mice were infected with a VEEV mutant (V3533) that caused mild, transient disease in immunocompetent mice. In the absence of a functional complement system, peripheral inoculation with V3533 induced much more severe encephalitis. This enhanced pathology was associated with a delay in clearance of infectious virus from the serum and more rapid invasion of the central nervous system in C3−/− mice. If V3533 was inoculated directly into the brain, however, disease outcome in C3−/− and wild-type mice was identical. These findings indicate that complement-dependent enhancement of peripheral virus clearance is critical for protecting against the development of severe VEEV-induced encephalitis

Remotely Sensed Canopy Nitrogen Correlates With Nitrous Oxide Emissions in a Lowland Tropical Rainforest

Tropical forests exhibit significant heterogeneity in plant functional and chemical traits that may contribute to spatial patterns of key soil biogeochemical processes, such as carbon storage and greenhouse gas emissions. Although tropical forests are the largest ecosystem source of nitrous oxide (N2O), drivers of spatial patterns within forests are poorly resolved. Here, we show that local variation in canopy foliar N, mapped by remote‐sensing image spectroscopy, correlates with patterns of soil N2O emission from a lowland tropical rainforest. We identified ten 0.25 ha plots (assemblages of 40–70 individual trees) in which average remotely‐sensed canopy N fell above or below the regional mean. The plots were located on a single minimally‐dissected terrace (km2) where soil type, vegetation structure and climatic conditions were relatively constant. We measured N2O fluxes monthly for 1 yr and found that high canopy N species assemblages had on average three‐fold higher total mean N2O fluxes than nearby lower canopy N areas. These differences are consistent with strong differences in litter stoichiometry, nitrification rates and soil nitrate concentrations. Canopy N status was also associated with microbial community characteristics: lower canopy N plots had two‐fold greater soil fungal to bacterial ratios and a significantly lower abundance of ammonia‐oxidizing archaea, although genes associated with denitrification (nirS, nirK, nosZ) showed no relationship with N2O flux. Overall, landscape emissions from this ecosystem are at the lowest end of the spectrum reported for tropical forests, consist with multiple metrics indicating that these highly productive forests retain N tightly and have low plant‐available losses. These data point to connections between canopy and soil processes that have largely been overlooked as a driver of denitrification. Defining relationships between remotely‐sensed plant traits and soil processes offers the chance to map these processes at large scales, potentially increasing our ability to predict N2O emissions in heterogeneous landscapes

SER-109: An Oral Investigational Microbiome Therapeutic for Patients with Recurrent Clostridioides difficile Infection (rCDI)

Clostridioides difficile infection (CDI) is classified as an urgent health threat by the Centers for Disease Control and Prevention (CDC), and affects nearly 500,000 Americans annually. Approximately 20–25% of patients with a primary infection experience a recurrence, and the risk of recurrence increases with subsequent episodes to greater than 40%. The leading risk factor for CDI is broad-spectrum antibiotics, which leads to a loss of microbial diversity and impaired colonization resistance. Current FDA-approved CDI treatment strategies target toxin or toxin-producing bacteria, but do not address microbiome disruption, which is key to the pathogenesis of recurrent CDI. Fecal microbiota transplantation (FMT) reduces the risk of recurrent CDI through the restoration of microbial diversity. However, FDA safety alerts describing hospitalizations and deaths related to pathogen transmission have raised safety concerns with the use of unregulated and unstandardized donor-derived products. SER-109 is an investigational oral microbiome therapeutic composed of purified spore-forming Firmicutes. SER-109 was superior to a placebo in reducing CDI recurrence at Week 8 (12% vs. 40%, respectively; p \u3c 0.001) in adults with a history of recurrent CDI with a favorable observed safety profile. Here, we discuss the role of the microbiome in CDI pathogenesis and the clinical development of SER-109, including its rigorous manufacturing process, which mitigates the risk of pathogen transmission. Additionally, we discuss compositional and functional changes in the gastrointestinal microbiome in patients with recurrent CDI following treatment with SER-109 that are critical to a sustained clinical response

Effect of BRCA2 sequence variants predicted to disrupt exonic splice enhancers on BRCA2 transcripts

Background: Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2. Evaluation of such unclassified variants may be assisted by web-based bioinformatic prediction tools, although accurate prediction of aberrant splicing by unclassified variants affecting exonic splice enhancers (ESEs) remains a challenge