Comparison of red blood cell transfusions and hemostatic transfusions and their relation to thromboses in pediatric patients receiving extracorporeal membrane oxygenation therapy.

OBJECTIVE: To evaluate the association of RBC transfusions with thrombosis in pediatric patients on extracorporeal membrane oxygenation (ECMO) and compare this with the transfusion of other blood products and their association with thrombosis. METHODS: This was a secondary analysis of the Bleeding and Thrombosis during ECMO (BATE) study, which was a multicenter prospective observational study involving patients less than 19 years of age treated with ECMO. RESULTS: 514 patients were analyzed, of which 282 (55%) were neonates (≤31 days) and 302 (58.7%) were male. When analyzing the entire cohort independently of other blood products, each 10 mL/kg of packed red blood cells (PRBCs) was associated with a 1.0% increase in the average number of thromboses (1.010; 1.008,1.013; p < .001). In neonates, each 10 mL/kg of PRBC was associated with a 0.9% increase in the average number of thromboses (1.009; 1.003,1.013; p < .001). In pediatric patients, each 10 mL/kg of PRBC was associated with a 1.2% increase in the average number of thromboses (1.012; 1.008,1.012; p < .001). The percent increase in the average number of thromboses was similar between PRBCs, platelets, and FFP, but increased significantly with cryoprecipitate. CONCLUSIONS: RBC transfusions and hemostatic transfusions are likely associated with thromboses in pediatric patients on ECMO.

Motivations for Seeking Cosmetic Enhancing Procedures of the Face: A Systematic Review.

BACKGROUND: Cosmetic enhancing procedures continue to grow in demand. Physicians should understand the complex factors that drive patient motivation for seeking such procedures. OBJECTIVE: In contrast to a lens of psychopathology, this review reveals the driving power of everyday intrapersonal, social, and behavioral factors that motivate interest in elective facial cosmetic procedures. MATERIALS AND METHODS: The review was conducted according to PRISMA guidelines and included studies with at least 50 adult patients seeking facial cosmetic enhancements between January 1, 2000, and July 1, 2022. RESULTS: Among 1,239 identified publications, 21 studies with 9,005 participants were selected for inclusion. The review documents everyday factors as patient motivators for pursuing cosmetic enhancements of the face, with the majority of work focusing on intrapersonal factors (17 of 21 studies), such as preventing aging or negative appearance based self-appraisals. For studies reporting social factors (15 of 21 studies), the most common motivators were the patient's social network and a desire to promote social standing. Behavioral factors revealed that social media and media consumption impact patient motivation for cosmetic enhancements (5 of 21 studies). CONCLUSION: In summary, this review demonstrates that patient motivations for facial cosmetic enhancements may be best understood through everyday intrapersonal, social, and behavioral factors.

Cell saver blood transfusions may be associated with a decrease in inflammation and improved outcome measures in pediatric cardiac surgery patients.

OBJECTIVE: Cardiopulmonary bypass (CPB) is a requisite for correction of congenital heart disease by open-heart surgery and induces a systemic inflammatory response that can lead to complications such as acute lung injury and acute kidney injury. In addition, blood transfusions are commonly required for this type of surgery, and they may further exacerbate this inflammatory response and increase morbidity and mortality. We hypothesized that, in contrast to red blood cells, intraoperative cell saver (CS) blood transfusions attenuate the post-CPB proinflammatory cytokine response. METHODS: Serum cytokine concentrations of IL-10, IL-1RA, IL-6, IL-8, and TNF-α were measured at four time points (preoperatively and postoperatively on postoperative days 0, 1, and 2). RESULTS: Anti-inflammatory IL-10 levels were significantly lower in the CS group on POD 0 than in the control group (mean 1083.2 pg/mL vs 2080.2 pg/mL, 95%CI 357.4-1636.6, p = .0026). Of the clinical parameters measured, mean BUN and creatinine levels on POD 2 were significantly lower in the CS group (13.79 vs 21.88, p = .004 and 0.45 vs 0.55, p = .055, respectively). In addition, the duration of milrinone use decreased by 80% in the CS group (0.20, 95%CI 0.04, 0.94; p = .048), the median time to extubation in hours was significantly lower in the CS group (3.5 vs 6.5; 95%CI -38.00, -0.50; p = .026), and hospital length of stay was decreased by 60% in the CS group (p = .003). CONCLUSIONS: CS transfusions in children may lower postoperative anti-inflammatory IL-10 levels, possibly due to an overall decrease in proinflammatory state, and may be associated with improvements in renal and pulmonary functions.

Single-Protein Tracking Reveals That NADPH Mediates the Insertion of Cytochrome P450 Reductase into a Biomimetic of the Endoplasmic Reticulum.

Cytochrome P450 reductase (CPR) is the redox partner for most human cytochrome P450 enzymes. It is also believed that CPR is an integral membrane protein exclusively. Herein, we report that, contrary to this belief, CPR can exist as a peripheral membrane protein in the absence of NADPH and will transition to an integral membrane protein in the presence of stoichiometric amounts of NADPH or greater. All experiments were performed in a solid-supported cushioned lipid bilayer that closely matched the chemical composition of the human endoplasmic reticulum and served as an ER biomimetic. The phase characteristics and fluidity of the ER biomimetic was characterized with fluorescence micrographs and temperature-dependent fluorescence recovery after photobleaching. The interactions of CPR with the ER biomimetic were directly observed by tracking single CPR molecules using time-lapse single-molecule fluorescence imaging and subsequent analysis of tracks. These studies revealed dramatic changes in diffusion coefficient and the degree of partitioning of CPR as a function of NADPH concentration.

Bridging the gap: a resident-led transitional care clinic to improve post hospital care in a safety-net academic community hospital.

The transitional period between hospital discharge and primary care follow-up is a vulnerable time for patients that can result in adverse health outcomes and preventable hospital readmissions. This is especially true for patients of safety-net hospitals (SNHs) who often struggle to secure primary care access when leaving the hospital due to social, economic and cultural barriers. In this study, we describe a resident-led postdischarge clinic that serves patients discharged from NYU Langone Hospital-Brooklyn, an urban safety-net academic hospital. In our multivariable analysis, there was no statistical difference in the readmission rate between those who completed the transitional care management and those who did not (OR 1.32 (0.75-2.36), p=0.336), but there was a statistically significant increase in primary care provider (PCP) engagement (OR 0.53 (0.45-0.62), p<0.001). Overall, this study describes a postdischarge clinic model embedded in a resident clinic in an urban SNH that is associated with increased PCP engagement, but no reduction in 30-day hospital readmissions.

Predictors for the use of systemic therapy in stage IB Mycosis fungoides.

BACKGROUND: The PROspective Cutaneous Lymphoma International Prognostic Index (PROCLIPI) study is aprospective analysis of an international database. Here we examine front-line treatments and quality of life (QoL) inpatients with newly diagnosed mycosis fungoides (MF). OBJECTIVES: To identify (i) differences in first-line approaches according to tumour-nodes-metastasis-blood (TNMB)staging; (ii) parameters related to a first-line systemic approach and (iii) response rates and QoL measures. METHODS: In total, 395 newly diagnosed patients with early-stage MF (stage IA-IIA) were recruited from 41 centresin 17 countries between 1 January 2015 and 31 December 2018 following central clinicopathological review. RESULTS: The most common first-line therapy was skin-directed therapy (SDT) (322 cases, 81·5%), while a smallerpercentage (44 cases, 11·1%) received systemic therapy. Expectant observation was used in 7·3%. In univariateanalysis, the use of systemic therapy was significantly associated with higher clinical stage (IA, 6%; IB, 14%; IIA,20%; IA-IB vs. IIA, P < 0·001), presence of plaques (T1a/T2a, 5%; T1b/T2b, 17%; P < 0·001), higher modified Severity Weighted Assessment Tool (> 10, 15%; ≤ 10, 7%; P = 0·01) and folliculotropic MF (FMF) (24% vs. 12%, P = 0·001). Multivariate analysis demonstrated significant associations with the presence of plaques (T1b/T2b vs.T1a/T2a, odds ratio 3·07) and FMF (odds ratio 2·83). The overall response rate (ORR) to first-line SDT was 73%,while the ORR to first-line systemic treatments was lower (57%) (P = 0·027). Health-related QoL improvedsignificantly both in patients with responsive disease and in those with stable disease. CONCLUSIONS: Disease characteristics such as presence of plaques and FMF influence physician treatment choices,and SDT was superior to systemic therapy even in patients with such disease characteristics. Consequently, futuretreatment guidelines for early-stage MF need to address these issues.

Thermodynamic Driving Forces of Redox-Dependent CPR Insertion into Biomimetic Endoplasmic Reticulum Membranes.

Cytochrome P450 reductase (CPR) is a NADPH-dependent membrane-bound oxidoreductase found in the endoplasmic reticulum (ER) and is the main redox partner for most cytochrome P450 enzymes. Presented are the measured thermodynamic driving forces responsible for how strongly CPR partitions into a biomimetic ER with the same lipid composition of a natural ER. Using temperature-dependent fluorescence correlation spectroscopy and fluorescence single-protein tracking, the standard state free energies, enthalpies, and entropies of the CPR insertion process were all measured. The results of this study demonstrate that the thermodynamic driving forces are dependent on the redox states of CPR. In particular, the partitioning of CPRox into a biomimetic ER is an exothermic process with a small positive change in entropy, while CPRred partitioning is endothermic with a large positive change in entropy. Both resulted in negative free energies and strong association to the biomimetic ER, but the KP of CPRox insertion is measurably smaller than that of CPRred. Using this new information and known results from literature sources, we also present a phenomenological model that accounts for membrane-protein interactions, protein orientation relative to the membrane, and protein conformation as a function of the redox state.

Neonatal Myxomas: Case Report and Literature Review.

Myxomas are rare tumors in neonates and tend to have a different presentation compared to adults. We present an infant with a left atrial myxoma presenting with episodic tachycardia who underwent successful surgical excision. In addition, we performed a review of the literature, identifying 17 cases of neonatal myxomas. Unlike adults, neonatal myxomas are more common in males and occur more often on the right side of the heart. Constitutional symptoms such as fever or embolism are rare among neonates. Most patients have favorable outcomes following surgical excision, refuting earlier claims that neonatal myxomas are associated with poor outcomes.

FN3-based monobodies selective for the receptor binding domain of the SARS-CoV-2 spike protein.

A phage library displaying 1010 variants of the fibronectin type III (FN3) domain was affinity selected with the biotinylated form of the receptor binding domain (RBD, residues 319-541) of the SARS-CoV-2 virus spike protein. Nine binding FN3 variants (i.e. monobodies) were recovered, representing four different primary structures. Soluble forms of the monobodies bound to several different preparations of the RBD and the S1 spike subunit, with affinities ranging from 3 to 14 nM as measured by bio-layer interferometry. Three of the four monobodies bound selectively to the RBD of SARS-CoV-2, with the fourth monobody showing slight cross-reactivity to the RBD of SARS-CoV-1 virus. Examination of binding to the spike fragments and its trimeric form revealed that the monobodies recognise at least three overlapping epitopes on the RBD of SARS-CoV-2. While pairwise tests failed to identify a monobody pair that could bind simultaneously to the RBD, one monobody could simultaneously bind to the RBD with the ectodomain of the cellular receptor angiotensin converting enzyme 2 (ACE2). All four monobodies successfully bound the RBD after overexpression in Chinese hamster ovary (CHO) cells as fusions to the Fc domain of human IgG1.

Direct Measurement of Single-Molecule Ligand-Receptor Interactions.

Measuring the kinetics that govern ligand-receptor interactions is fundamental to our understanding of pharmacology. For ligand-gated ion channels, binding of an agonist triggers allosteric motions that open an integral ion-permeable pore. By mathematically modeling stochastic electrophysiological responses with high temporal resolution (ms), previous single channel studies have been able to infer the rate constants of ligands binding to these receptors. However, there are no reports of the direct measurement of the single-molecule binding events that are vital to how agonists exert their functional effects. For the first time, we report these direct measurements, the rate constants, and corresponding free energy changes, which describe the transitions between the different binding states. To achieve this, we use the super resolution technique: points accumulation for imaging in nanoscale topography (PAINT) to observe binding of ATP to orthosteric binding sites on the P2X1 receptor. Furthermore, an analysis of time-resolved single-molecule interactions is used to measure elementary rate constants and thermodynamic forces that drive the allosteric motions. These single-molecule measurements unequivocally establish the location of each binding states of the P2X1 receptor and the stochastic nature of the interaction with its native ligand. The analysis leads to the measurement of the forward and reverse rates from a weak ligand-binding state to a strong ligand binding state that is linked to allosteric motion and ion pore formation. These rates (kα = 1.41 sec-1 and kß = 0.32 sec-1) were then used to determine the free energy associated with this critical mechanistic step (3.7 kJ/mol). Importantly, the described methods can be readily applied to all ligand-gated ion channels, and more broadly to the molecular interactions of other classes of membrane proteins.

The song system of the human brain.

Although sophisticated insights have been gained into the neurobiology of singing in songbirds, little comparable knowledge exists for humans, the most complex singers in nature. Human song complexity is evidenced by the capacity to generate both richly structured melodies and coordinated multi-part harmonizations. The present study aimed to elucidate this multi-faceted vocal system by using 15O-water positron emission tomography to scan "listen and respond" performances of amateur musicians either singing repetitions of novel melodies, singing harmonizations with novel melodies, or vocalizing monotonically. Overall, major blood flow increases were seen in the primary and secondary auditory cortices, primary motor cortex, frontal operculum, supplementary motor area, insula, posterior cerebellum, and basal ganglia. Melody repetition and harmonization produced highly similar patterns of activation. However, whereas all three tasks activated secondary auditory cortex (posterior Brodmann Area 22), only melody repetition and harmonization activated the planum polare (BA 38). This result implies that BA 38 is responsible for an even higher level of musical processing than BA 22. Finally, all three of these "listen and respond" tasks activated the frontal operculum (Broca's area), a region involved in cognitive/motor sequence production and imitation, thereby implicating it in musical imitation and vocal learning.

Passive music listening spontaneously engages limbic and paralimbic systems.

In this PET study, non-musicians passively listened to unfamiliar instrumental music revealed afterward to elicit strongly pleasant feelings. Activations were observed in the subcallosal cingulate gyrus, prefrontal anterior cingulate, retrosplenial cortex, hippocampus, anterior insula, and nucleus accumbens. This is the first observation of spontaneous responses in such limbic and paralimbic areas during passive listening to unfamiliar although liked music. Activations were also seen in primary auditory, secondary auditory, and temporal polar areas known to respond to music. Our findings complement neuroimaging studies of aesthetic responses to music that have used stimuli selected by subjects or designed by experimenters. The observed pattern of activity is discussed in terms of a model synthesizing emotional and cognitive responses to music.

Automated regional behavioral analysis for human brain images.

Behavioral categories of functional imaging experiments along with standardized brain coordinates of associated activations were used to develop a method to automate regional behavioral analysis of human brain images. Behavioral and coordinate data were taken from the BrainMap database (http://www.brainmap.org/), which documents over 20 years of published functional brain imaging studies. A brain region of interest (ROI) for behavioral analysis can be defined in functional images, anatomical images or brain atlases, if images are spatially normalized to MNI or Talairach standards. Results of behavioral analysis are presented for each of BrainMap's 51 behavioral sub-domains spanning five behavioral domains (Action, Cognition, Emotion, Interoception, and Perception). For each behavioral sub-domain the fraction of coordinates falling within the ROI was computed and compared with the fraction expected if coordinates for the behavior were not clustered, i.e., uniformly distributed. When the difference between these fractions is large behavioral association is indicated. A z-score ≥ 3.0 was used to designate statistically significant behavioral association. The left-right symmetry of ~100K activation foci was evaluated by hemisphere, lobe, and by behavioral sub-domain. Results highlighted the classic left-side dominance for language while asymmetry for most sub-domains (~75%) was not statistically significant. Use scenarios were presented for anatomical ROIs from the Harvard-Oxford cortical (HOC) brain atlas, functional ROIs from statistical parametric maps in a TMS-PET study, a task-based fMRI study, and ROIs from the ten "major representative" functional networks in a previously published resting state fMRI study. Statistically significant behavioral findings for these use scenarios were consistent with published behaviors for associated anatomical and functional regions.

Automated analysis of fundamental features of brain structures.

Automated image analysis of the brain should include measures of fundamental structural features such as size and shape. We used principal axes (P-A) measurements to measure overall size and shape of brain structures segmented from MR brain images. The rationale was that quantitative volumetric studies of brain structures would benefit from shape standardization as had been shown for whole brain studies. P-A analysis software was extended to include controls for variability in position and orientation to support individual structure spatial normalization (ISSN). The rationale was that ISSN would provide a bias-free means to remove elementary sources of a structure's spatial variability in preparation for more detailed analyses. We studied nine brain structures (whole brain, cerebral hemispheres, cerebellum, brainstem, caudate, putamen, hippocampus, inferior frontal gyrus, and precuneus) from the 40-brain LPBA40 atlas. This paper provides the first report of anatomical positions and principal axes orientations within a standard reference frame, in addition to "shape/size related" principal axes measures, for the nine brain structures from the LPBA40 atlas. Analysis showed that overall size (mean volume) for internal brain structures was preserved using shape standardization while variance was reduced by more than 50%. Shape standardization provides increased statistical power for between-group volumetric studies of brain structures compared to volumetric studies that control only for whole brain size. To test ISSN's ability to control for spatial variability of brain structures we evaluated the overlap of 40 regions of interest (ROIs) in a standard reference frame for the nine different brain structures before and after processing. Standardizations of orientation or shape were ineffective when not combined with position standardization. The greatest reduction in spatial variability was seen for combined standardizations of position, orientation and shape. These results show that ISSNs automated processing can be a valuable asset for measuring and controlling variability of fundamental features of brain structures.

Activation of premotor vocal areas during musical discrimination.

Two same/different discrimination tasks were performed by amateur-musician subjects in this functional magnetic resonance imaging study: Melody Discrimination and Harmony Discrimination. Both tasks led to activations not only in classic working memory areas--such as the cingulate gyrus and dorsolateral prefrontal cortex--but in a series of premotor areas involved in vocal-motor planning and production, namely the somatotopic mouth region of the primary and lateral premotor cortices, Broca's area, the supplementary motor area, and the anterior insula. A perceptual control task involving passive listening alone to monophonic melodies led to activations exclusively in temporal-lobe auditory areas. These results show that, compared to passive listening tasks, discrimination tasks elicit activation in vocal-motor planning areas.

Functional neuroanatomy of deductive inference: a language-independent distributed network.

Studies of brain areas supporting deductive reasoning show inconsistent results, possibly because of the variety of tasks and baselines used. In two event-related functional magnetic imaging studies we employed a cognitive load paradigm to isolate the neural correlates of deductive reasoning and address the role (if any) of language in deduction. Healthy participants evaluated the logical status of arguments varying in deductive complexity but matched in linguistic complexity. Arguments also varied in lexical content, involving blocks and pseudo-words in Experiment I and faces and houses in Experiment II. For each experiment, subtraction of simple from complex arguments (collapsing across contents) revealed a network of activations disjoint from regions traditionally associated with linguistic processing and also disjoint from regions recruited by mere reading. We speculate that this network is divided into "core" and "support" regions. The latter include left frontal (BA 6, 47) and parietal (BA 7, 40) cortices, which maintain the formal structure of arguments. Core regions, in the left rostral (BA 10p) and bilateral medial (BA 8) prefrontal cortex, perform deductive operations. Finally, restricting the complex-simple subtraction to each lexical content uncovered additional activations which may reflect the binding of logical variables to lexical items.