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Affect of Region Beneath the Concentration-Time Contour around the Epidemic regarding Vancomycin-Induced Nephrotoxicity along with Tazobactam/Piperacillin or Cefepime: The Single-Institution Retrospective Study.
RESULTS Of 337 eligible children, 294 were matched on the basis of propensity score. There was no statistical difference in treatment failure between children who received antibiotics and those who did not (odds ratio 1.0; 95% confidence interval 0.45-2.2). There was no difference in the proportion of children with return visits with hospitalization (3.4% with antibiotics versus 3.4% without), initiation and/or change of antibiotics (4.8% vs 6.1%), or parent-reported quality-of-life measures. CONCLUSIONS Among children with suspected CAP, the outcomes were not statistically different between those who did and did not receive an antibiotic prescription. Copyright © 2020 by the American Academy of Pediatrics.BACKGROUND AND OBJECTIVES Rates of sexually transmitted infections (STIs) have increased over the decade. Guidelines recommend HIV testing with incident STIs. Prevalence and factors associated with HIV testing in acute STIs are unknown in adolescents. Our objective was to determine the prevalence of completed HIV testing among adolescents with incident STIs and identify patient and health care factors associated with HIV testing. METHODS Retrospective study of STI episodes (gonorrhea, Chlamydia, trichomoniasis, or syphilis) of adolescents between 13 and 24 years old from July 2014 to December 2017 in 2 urban primary care clinics. We performed mixed effects logistic regression modeling to identify patient and health care factors associated with HIV testing within 90 days of STI diagnosis. RESULTS The 1313 participants contributed 1816 acute STI episodes. Mean age at STI diagnosis was 17.2 years (SD = 1.7), 75% of episodes occurred in females, and 97% occurred in African Americans. Only half (55%) of acute STI episodes had a completed HIV test. In the adjusted model, female sex, previous STIs, uninsured status, and confidential sexual health encounters were associated with decreased odds of HIV testing. Patients enrolled in primary care at the clinics, compared with those receiving sexual health care alone, and those with multipathogen STI diagnoses were more likely to have HIV testing. CONCLUSIONS HIV testing rates among adolescents with acute STIs are suboptimal. Patient and health care factors were found to be associated with receipt of testing and should be considered in clinical practice. Copyright © 2020 by the American Academy of Pediatrics.A reminder can render consolidated memory labile and susceptible to amnesic agents during a reconsolidation window. For the case of threat memory (also termed fear memory), it has been suggested that extinction training during this reconsolidation window has the same disruptive impact. This procedure could provide a powerful therapeutic principle for treatment of unwanted aversive memories. CC4047 However, human research yielded contradictory results. Notably, all published positive replications quantified threat memory by conditioned skin conductance responses (SCR). Yet, other studies measuring SCR and/or fear-potentiated startle failed to observe an effect of a reminder/extinction procedure on the return of fear. Here we sought to shed light on this discrepancy by using a different autonomic response, namely, conditioned pupil dilation, in addition to SCR, in a replication of the original human study. N = 71 humans underwent a 3-d threat conditioning, reminder/extinction, and reinstatement, procedure with 2 CS+, of which one was reminded. Participants successfully learned the threat association on day 1, extinguished conditioned responding on day 2, and showed reinstatement on day 3. However, there was no difference in conditioned responding between the reminded and the nonreminded CS, neither in pupil size nor SCR. Thus, we found no evidence that a reminder trial before extinction prevents the return of threat-conditioned responding. © 2020 Zimmermann and Bach; Published by Cold Spring Harbor Laboratory Press.Systems consolidation (SC) theory proposes that recent, contextually rich memories are stored in the hippocampus (HPC). As these memories become remote, they are believed to rely more heavily on cortical structures within the prefrontal cortex (PFC), where they lose much of their contextual detail and become schematized. Odor is a particularly evocative cue for intense remote memory recall and despite these memories being remote, they are highly contextual. In instances such as posttraumatic stress disorder (PTSD), intense remote memory recall can occur years after trauma, which seemingly contradicts SC. We hypothesized that odor may shift the organization of salient or fearful memories such that when paired with an odor at the time of encoding, they are delayed in the de-contextualization process that occurs across time, and retrieval may still rely on the HPC, where memories are imbued with contextually rich information, even at remote time points. We investigated this by tagging odor- and non-odor-associated fear memories in male c57BL/6 mice and assessed recall and c-Fos expression in the dorsal CA1 (dCA1) and prelimbic cortex (PL) 1 or 21 d later. In support of SC, our data showed that recent memories were more dCA1-dependent whereas remote memories were more PL-dependent. However, we also found that odor influenced this temporal dynamic, biasing the memory system from the PL to the dCA1 when odor cues were present. Behaviorally, inhibiting the dCA1 with activity-dependent DREADDs had no effect on recall at 1 d and unexpectedly caused an increase in freezing at 21 d. Together, these findings demonstrate that odor can shift the organization of fear memories at the systems level. © 2020 Grella et al.; Published by Cold Spring Harbor Laboratory Press.Motivationally attractive cues can draw in behavior in a phenomenon termed incentive salience. Incentive cue attraction is an important model for animal models of drug seeking and relapse. One question of interest is the extent to which the pursuit of motivationally attractive cues is related to the value of the paired outcome or can become unrelated and habitual. We studied this question using a sign-tracking (ST) paradigm in rats, in which a lever stimulus preceding food reward comes to elicit conditioned lever-interaction behavior. We asked whether reinforcer devaluation by means of conditioned taste aversion, a classic test of habitual behavior, can modify ST to incentive cues, and whether this depends upon the manner in which reinforcer devaluation takes place. In contrast to several recent reports, we conclude that ST is indeed sensitive to reinforcer devaluation. However, this effect depends critically upon the congruence between the context in which taste aversion is learned and the context in which it is tested. When the taste aversion successfully transfers to the testing context, outcome value strongly influences ST behavior, both when the outcome is withheld (in extinction) and when animals can learn from outcome feedback (reacquisition). When taste aversion does not transfer to the testing context, ST remains high. link2 In total, the extent to which ST persists after outcome devaluation is closely related to the extent to which that outcome is truly devalued in the task context. We believe this effect of context on devaluation can reconcile contradictory findings about the flexibility/inflexibility of ST. We discuss this literature and relate our findings to the study of habits generally. © 2020 Amaya et al.; Published by Cold Spring Harbor Laboratory Press.Sleep deprivation increases rates of forgetting in episodic memory. Yet, whether an extended lack of sleep alters the qualitative nature of forgetting is unknown. We compared forgetting of episodic memories across intervals of overnight sleep, daytime wakefulness, and overnight sleep deprivation. Item-level forgetting was amplified across daytime wakefulness and overnight sleep deprivation, as compared to sleep. Importantly, however, overnight sleep deprivation led to a further deficit in associative memory that was not observed after daytime wakefulness. These findings suggest that sleep deprivation induces fragmentation among item memories and their associations, altering the qualitative nature of episodic forgetting. © 2020 Ashton et al.; Published by Cold Spring Harbor Laboratory Press.The spatial and temporal coordination of growth factor signaling is critical for both presynaptic and postsynaptic plasticity underlying long-term memory formation. We investigated the spatiotemporal dynamics of Aplysia cysteine-rich neurotrophic factor (ApCRNF) signaling during the induction of activity-dependent long-term facilitation (AD-LTF) at sensory-to-motor neuron synapses that mediate defensive reflexes in Aplysia We found that ApCRNF signaling is required for the induction of AD-LTF, and for training-induced early protein kinase activation and late forms of gene expression, exclusively in postsynaptic neurons. These results support the view that ApCRNF is critically involved in AD-LTF at least in part through postsynaptic mechanisms. © 2020 Alexandrescu and Carew; Published by Cold Spring Harbor Laboratory Press.Although a robust inflammatory response is needed to combat infection, this response must ultimately be terminated to prevent chronic inflammation. One mechanism that terminates inflammatory signaling is the production of alternative mRNA splice forms in the Toll-like receptor (TLR) signaling pathway. While most genes in the TLR pathway encode positive mediators of inflammatory signaling, several, including that encoding the MyD88 signaling adaptor, also produce alternative spliced mRNA isoforms that encode dominant-negative inhibitors of the response. Production of these negatively acting alternatively spliced isoforms is induced by stimulation with the TLR4 agonist lipopolysaccharide (LPS); thus, this alternative pre-mRNA splicing represents a negative feedback loop that terminates TLR signaling and prevents chronic inflammation. In the current study, we investigated the mechanisms regulating the LPS-induced alternative pre-mRNA splicing of the MyD88 transcript in murine macrophages. We found that (1) the induction of the alternatively spliced MyD88 form is due to alternative pre-mRNA splicing and not caused by another RNA regulatory mechanism, (2) MyD88 splicing is regulated by both the MyD88- and TRIF-dependent arms of the TLR signaling pathway, (3) MyD88 splicing is regulated by the NFκB transcription factor, and (4) NFκB likely regulates MyD88 alternative pre-mRNA splicing per se rather than regulating splicing indirectly by altering MyD88 transcription. We conclude that alternative splicing of MyD88 may provide a sensitive mechanism that ensures robust termination of inflammation for tissue repair and restoration of normal tissue homeostasis once an infection is controlled. Published under license by The American Society for Biochemistry and Molecular Biology, Inc.Fabry disease is a heritable lipid disorder caused by the low activity of α-galactosidase A and characterized by the systemic accumulation of globotriaosylceramide (Gb3). Recent studies have reported a structural heterogeneity of Gb3 in Fabry disease, including Gb3 isoforms with different fatty acids, and Gb3 analogs with modifications on the sphingosine moiety. link3 However, Gb3 assays are often performed only on the selected Gb3 isoforms. To precisely determine the total Gb3 concentration, here we established two methods for determining both Gb3 isoforms and analogs. One was the deacylation method, involving Gb3 treatment with sphingolipid ceramide N-deacylase, followed by an assay of the deacylated products, globotriaosylsphingosine (lyso-Gb3) and its analogs, by ultra-performance liquid chromatography coupled to tandem MS (UPLC-MS/MS). The other method was a direct assay established in the present study for 37 Gb3 isoforms and analogs/isoforms by UPLC-MS/MS. Gb3s from the organs of symptomatic animals of a Fabry disease mouse model were mainly Gb3 isoforms and two Gb3 analogs, such as Gb3(+18) containing the lyso-Gb3(+18) moiety, and Gb3(-2) containing the lyso-Gb3(-2) moiety.
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