Hierarchy of Evidence Within the Medical Literature.

The quality of evidence from medical research is partially deemed by the hierarchy of study designs. On the lowest level, the hierarchy of study designs begins with animal and translational studies and expert opinion, and then ascends to descriptive case reports or case series, followed by analytic observational designs such as cohort studies, then randomized controlled trials, and finally systematic reviews and meta-analyses as the highest quality evidence. This hierarchy of evidence in the medical literature is a foundational concept for pediatric hospitalists, given its relevance to key steps of evidence-based practice, including efficient literature searches and prioritization of the highest-quality designs for critical appraisal, to address clinical questions. Consideration of the hierarchy of evidence can also aid researchers in designing new studies by helping them determine the next level of evidence needed to improve upon the quality of currently available evidence. Although the concept of the hierarchy of evidence should be taken into consideration for clinical and research purposes, it is important to put this into context of individual study limitations through meticulous critical appraisal of individual articles.

Association of obesity with severity outcomes in hospitalized pediatric asthma exacerbations.

INTRODUCTION: While there seems to be an association between obesity and asthma, the exact nature of the relationship remains unknown. It is unclear if there is increased severity of exacerbation for those that require hospitalization. We examine the association between obesity and severity outcomes such as hospital length of stay, intensive care admissions, and need for continuous albuterol or magnesium administration. METHODS: Patients 4 to 17 years old admitted between 1/1/2012-1/1/2016 with asthma identified by discharge codes were reviewed. Obesity was defined as BMI ≥95%. Clinical data such as age, gender, family history of asthma, use of controller medication along with outcome data such as length of stay, ICU admission, use of continuous albuterol, and use of magnesium were collected. Binary outcomes were analyzed with multivariate logistic regression while length of stay was analyzed with negative binomial regression. RESULTS: Overall, 995 patients met inclusion criteria. The median age was 7 years old with 170 (17%) patients categorized as obese. We find no difference in length of stay (IRR 0.99 [0.91, 1.09], p = 0.9), PICU admission (OR 0.72 [0.43, 1.21], p = 0.22), or magnesium administration (OR 1.34 [0.95, 1.88], p = 0.09) between obese and non-obese patients. There were increased odds of continuous albuterol use (OR 1.47 [1.02, 2.11]) for obese patients. CONCLUSION: We find no association between obesity and outcomes of length of stay, ICU admission, or magnesium administration. While growing evidence links obesity with asthma, our study suggests it may not be associated with the severity of exacerbation.

Prognostic value of ambulatory blood pressure and clinical use of echocardiography to detect left ventricular hypertrophy in children evaluated for primary hypertension.

BACKGROUND: Hypertension (HTN) is common in children and often associated with pathologic progression to end organ damage, specifically left ventricular hypertrophy (LVH). METHODS: The primary goal of this retrospective chart review is to determine if patients with higher blood pressure were more likely to complete echocardiogram (ECHO) and more likely to have LVH, among a pediatric population referred for hypertension evaluation before the 2017 American Academy of Pediatrics (AAP) guidelines. To meet this goal, the number of patients evaluated by ECHO and prevalence of LVH was examined for independent associations with blood pressure and BMI categories by logistic regression. RESULTS: It was found that higher blood pressure was associated with having an ECHO evaluation (p = 0.012). Among patients evaluated by ECHO, one-third had LVH but the presence of LVH was not associated with blood pressure severity or use of anti-hypertensive medication. Instead, BMI was the only factor associated with LVH cardiac remodeling in our population (p = 0.025). CONCLUSIONS: Newly updated AAP practice guidelines recommend evaluation of HTN via ABPM, with ECHO performed only at the initiation of pharmaceutical therapy. It is notable that BMI, the only risk factor of LVH found in this study, is not addressed in the current AAP guidelines for ECHO evaluation among hypertensive children. This study suggests that ECHO evaluation may be warranted in a larger subset of children as is recommended by current European Society of Hypertension pediatric guidelines.

The Blur of Pleasure: Appetitively Appealing Stimuli Decrease Subjective Temporal Perceptual Acuity.

Anecdotal reports that time "flies by" or "slows down" during emotional events are supported by evidence that the motivational relevance of stimuli influences subsequent duration judgments. Yet it is unknown whether the subjective quality of events as they unfold is altered by motivational relevance. In a novel paradigm, we measured the subjective experience of moment-to-moment visual perception. Participants judged the temporal smoothness of high-approach positive images (desserts), negative images (e.g., of bodily mutilation), and neutral images (commonplace scenes) as they faded to black. Results revealed approach-motivated blurring, such that positive stimuli were judged as smoother and negative stimuli as choppier relative to neutral stimuli. Participants' ratings of approach motivation predicted perceived fade smoothness after we controlled for low-level stimulus features. Electrophysiological data indicated that approach-motivated blurring modulated relatively rapid perceptual activation. These results indicate that stimulus value influences subjective temporal perceptual acuity; approach-motivating stimuli elicit perception of a "blurred" frame rate characteristic of speeded motion.

Reaching reveals that best-versus-rest processing contributes to biased decision making.

The study of human decision making has revealed many contexts in which decisions are systematically biased. These biases are particularly evident in risky decisions, characterized by choice outcomes that are probabilistic. One recently explored bias is the extreme-outcome rule: the tendency for participants to overvalue both the best and worst outcome when they learn about choice probabilities through trial and error (aka experience). Here we aimed to test whether the extreme-outcome rule arises in part from a disproportionate subjective weight on extreme values. Participants reached to choose between two options in a riskless task where each choice option always produced the same result. In contrast to the idea that the overvaluing of extreme outcomes results from participants overestimating the underlying choice probabilities (e.g. treating a 50% "worst" outcome as though it occurred 60% of the time), we find overvaluation of extreme outcomes even when they are not probabilistic. Particularly, we find strong evidence for overvaluation of the best outcome relative to all other outcomes in how participants enact their decision (reaction times and reaching movements), but no evidence for such overvaluation in participants' choice accuracy. Compared to the extreme-outcome rule, these results are more simply characterized in a framework where the "best" option is given a boost in processing relative to the "rest" of other available options.

Oxygen tension regulates the miRNA profile and bioactivity of exosomes released from extravillous trophoblast cells - Liquid biopsies for monitoring complications of pregnancy.

Our understanding of how cells communicate has undergone a paradigm shift since the recent recognition of the role of exosomes in intercellular signaling. In this study, we investigated whether oxygen tension alters the exosome release and miRNA profile from extravillous trophoblast (EVT) cells, modifying their bioactivity on endothelial cells (EC). Furthermore, we have established the exosomal miRNA profile at early gestation in women who develop pre-eclampsia (PE) and spontaneous preterm birth (SPTB). HTR-8/SVneo cells were used as an EVT model. The effect of oxygen tension (i.e. 8% and 1% oxygen) on exosome release was quantified using nanocrystals (Qdot®) coupled to CD63 by fluorescence NTA. A real-time, live-cell imaging system (Incucyte™) was used to establish the effect of exosomes on EC. Plasma samples were obtained at early gestation (<18 weeks) and classified according to pregnancy outcomes. An Illumina TrueSeq Small RNA kit was used to construct a small RNA library from exosomal RNA obtained from EVT and plasma samples. The number of exosomes was significantly higher in EVT cultured under 1% compared to 8% oxygen. In total, 741 miRNA were identified in exosomes from EVT. Bioinformatic analysis revealed that these miRNA were associated with cell migration and cytokine production. Interestingly, exosomes isolated from EVT cultured at 8% oxygen increased EC migration, whilst exosomes cultured at 1% oxygen decreased EC migration. These changes were inversely proportional to TNF-α released from EC. Finally, we have identified a set of unique miRNAs in exosomes from EVT cultured at 1% oxygen and exosomes isolated from the circulation of mothers at early gestation, who later developed PE and SPTB. We suggest that aberrant exosomal signalling by placental cells is a common aetiological factor in pregnancy complications characterised by incomplete SpA remodeling and is therefore a clinically relevant biomarker of pregnancy complications.

SOAP Opera: Self as Object and Agent in Prioritizing Attention.

A growing body of evidence has demonstrated that multiple sources of salience tune attentional sets toward aspects of the environment, including affectively and motivationally significant categories of stimuli such as angry faces and reward-associated target locations. Recent evidence further indicates that objects that have gained personal significance through ownership can elicit similar attentional prioritization. Here we discuss current research on sources of attentional prioritization that shape our awareness of the visual world from moment to moment and the underlying neural systems and contextualize what is known about attentional prioritization of our possessions within that research. We review behavioral and neuroimaging research on the influence of self-relevance and ownership on cognition and discuss challenges to this literature stemming from different modes of conceptualizing and operationalizing the self. We argue that ownership taps into both "self-as-object," which characterizes the self as an object with a constellation of traits and attributes, and "self-as-subject," which characterizes the self as an agentic perceiver and knower. Despite an abundance of research probing neural and behavioral indices of self-as-object and its effects on attention, there exists a paucity of research on the influence of self-relevance of attention when self is operationalized from the perspective of a first-person subject. To begin to address this gap, we propose the Self as Ownership in Attentional Prioritization (SOAP) framework to explain how ownership increases salience through attention to external representations of self-identity (i.e., self as object) and attention to contextually mediated permission to act (i.e., self as subject).

I saw mine first: A prior-entry effect for newly acquired ownership.

Previous research has shown that attentional sets can be tuned to implicitly prioritize awareness of universally aversive or rewarding stimuli. But can mere ownership modulate implicit attentional prioritization as well? In Experiments 1 and 2, participants learned whether everyday objects belonged to them (self-owned) or the experimenter (other-owned) and completed a temporal order judgment task in which pairs of stimuli appeared onscreen with staggered timing. Results revealed a prior-entry effect, in which participants were more likely to report seeing a self-owned object first when 2 objects appeared simultaneously. In Experiment 3, no ownership status was assigned and no such effect was observed. Individual differences in the prior-entry effect were unrelated to independent self-construal, positive associations for self-owned objects, or loss aversion. These results suggest that attentional prioritization is not limited to universally salient stimuli. Rather, self-relevance, even when recently acquired, can engage an implicit attentional set that biases our perception of the environment. (PsycINFO Database Record

Role of Extracellular Vesicles and microRNAs on Dysfunctional Angiogenesis during Preeclamptic Pregnancies.

Preeclampsia is a syndrome characterized by hypertension during pregnancy, which is a leading cause of morbidity and mortality in both mother and newborn in developing countries. Some advances have increased the understanding of pathophysiology of this disease. For example, reduced utero-placental blood flow associated with impaired trophoblast invasion may lead to a hypoxic placenta that releases harmful materials into the maternal and feto-placental circulation and impairs endothelial function. Identification of these harmful materials is one of the hot topics in the literature, since these provide potential biomarkers. Certainty, such knowledge will help us to understand the miscommunication between mother and fetus. In this review we highlight how placental extracellular vesicles and their cargo, such as small RNAs (i.e., microRNAs), might be involved in endothelial dysfunction, and then in the angiogenesis process, during preeclampsia. Currently only a few reports have addressed the potential role of endothelial regulatory miRNA in the impaired angiogenesis in preeclampsia. One of the main limitations in this area is the variability of the analyses performed in the current literature. This includes variability in the size of the particles analyzed, and broad variation in the exosomes considered. The quantity of microRNA targets genes suggest that practically all endothelial cell metabolic functions might be impaired. More studies are required to investigate mechanisms underlying miRNA released from placenta upon endothelial function involved in the angiogenenic process.

Mine in motion: How physical actions impact the psychological sense of object ownership.

Our attention and memory can be biased toward objects having high self-relevance, such as things we own. Yet in explaining such effects, theorizing has been limited to psychological determinants of self-relevance. Here we examined the contribution physical actions make to this ownership bias. In Experiment 1, participants moved object images on a touch interactive table that either arbitrarily belonged to "self" or "other," and that were moved into locations closer or farther from their bodies. Subsequent recognition was highest for self-owned objects moved closer to the body, as measured via a subsequent memory recall test. In Experiment 2, when participants moved images via keyboard rather than overt action, the proximity effect of the body on attention was abolished. In Experiment 3, participants pulled or pushed self-owned or other-owned object images to side-by-side locations on a touch interactive table. Self-owned objects that were pulled were recognized the most. Our findings demonstrate that physical actions can have a direct impact on the psychological saliency of owned objects, with the act of bringing objects toward the self leading to greater recall.

Interictal neurocognitive processing of visual stimuli in migraine: evidence from event-related potentials.

Research has established decreased sensory habituation as a defining feature in migraine, while decreased cognitive habituation has only been found with regard to cognitive assessment of the relative probability of the occurrence of a stimulus event. Our study extended the investigation of interictal habituation in migraine to include cognitive processing when viewing of a series of visually-complex images, similar to those we encounter on the internet everyday. We examined interictal neurocognitive function in migraine from a habituation perspective, using a novel paradigm designed to assess how the response to a series of images changes over time. Two groups of participants--migraineurs (N = 25) and non-migraine controls (N = 25)--were asked to view a set of 232 unfamiliar logos in the context of a target identification task as their brain electrical responses were recorded via event-related potentials (ERPs). The set of logos was viewed serially in each of 10 separate trial blocks, with data analysis focusing on how the ERP responses to the logos in frontal electrodes from 200-600 ms changed across time within each group. For the controls, we found that the amplitude of the late positive potential (LPP) ERP component elicited by the logos had no significant change across trial blocks. In contrast, in migraineurs we found that the LPP significantly increased in amplitude across trial blocks, an effect consistent with a lack of habituation to visual stimuli seen in previous research. Our findings provide empirical support abnormal cognitive processing of complex visual images across time in migraineurs that goes beyond the sensory-level habituation found in previous research.

An unforgettable apple: memory and attention for forbidden objects.

Are we humans drawn to the forbidden? From jumbo-sized soft drinks to illicit substances, the influence of prohibited ownership on subsequent demand has made this question a pressing one. We know that objects that we ourselves own have a heightened psychological saliency, relative to comparable objects that are owned by others, but do these kinds of effects extend from self-owned to "forbidden" objects? To address this question, we developed a modified version of the Turk shopping paradigm in which "purchased" items were assigned to various recipients. Participants sorted everyday objects labeled as "self-owned", "other-owned," and either "forbidden to oneself" (Experiment 1) or "forbidden to everyone" (Experiment 2). Subsequent surprise recognition memory tests revealed that forbidden objects with high (Experiment 1) but not with low (Experiment 2) self-relevance were recognized as well as were self-owned objects, and better than other-owned objects. In a third and final experiment, we used event-related potentials (ERPs) to determine whether self-owned and self-forbidden objects, which showed a common memory advantage, are in fact treated the same at a neurocognitive-affective level. We found that both object types were associated with enhanced cognitive analysis, relative to other-owned objects, as measured by the P300 ERP component. However, we also found that self-forbidden objects uniquely triggered an enhanced response preceding the P300, in an ERP component (the N2) that is sensitive to more rapid, affect-related processing. Our findings thus suggest that, whereas self-forbidden objects share a common cognitive signature with self-owned objects, they are unique in being identified more quickly at a neurocognitive level.

Effects of speed, age, and amblyopia on the perception of motion-defined form.

We determined the effect of dot speed on the typical and atypical development of motion-defined form perception. Monocular motion coherence thresholds for orientation discrimination of motion-defined rectangles were determined at slow (0.1 deg/s), medium (0.9 deg/s) and fast (5.0 deg/s) dot speeds. First we examined typical development from age 4 to 31 years. We found that performance was most immature at the slow speed and in the youngest group of children (4-6 years). Next we measured motion-defined form perception in the amblyopic and fellow eyes of patients with amblyopia. Deficits were found in both eyes and were most pronounced at the slow speed. These results demonstrate the importance of dot speed to the development of motion-defined form perception. Implications regarding sensitive periods and the neural correlates of motion-defined form perception are discussed.

Top-down control of visual cortex in migraine populations.

The pathophysiology of migraine includes a heightened excitability of visual cortex that persists between headache events and that has been linked to impaired inhibitory intracortical processes. Here we examined the hypothesis that this cortical pathophysiology would affect the top-down attentional control of visual cortex. We asked two groups of participants-migraineurs (N=29) and non-migraine controls (N=29)-to perform a probabilistic spatial orienting task as we measured visual sensory cortical responses via event-related potentials (ERPs). Data were then analyzed as a function of whether the ERP-eliciting stimulus was in the fovea vs. parafovea, and whether the stimulus' location was attended or unattended. In this regard, we found two key between-groups differences in the effect of attention on sensory-evoked visual-cortical activity. First, relative to controls, migraineurs showed a larger attention effect in the visual N1 ERP component for events at the fovea. Second, unlike controls, migraineurs showed no early-phase attention effect in the P1 ERP component for events in the parafovea. Despite these altered ERP responses in migraineurs, however, corresponding behavioral data indicated that they also had heightened response performance. Taken together, our results support the hypothesis that migraineurs have an altered top-down attentional control of visual cortex, with the data suggesting that the effect may be tied to a reduced ability to suppress sensory-evoked activity for unattended events in the visual periphery.