Photoresponsive arylazopyrazole surfactant/PDADMAC mixtures: reversible control of bulk and interfacial properties.

In many applications of polyelectrolyte/surfactant (P/S) mixtures, it is difficult to fine-tune them after mixing the components without changing the sample composition, e.g. pH or the ionic strength. Here we report on a new approach where we use photoswitchable surfactants to enable drastic changes in both the bulk and interfacial properties. Poly(diallyldimethylammonium chloride) (PDADMAC) mixtures with three alkyl-arylazopyrazole butyl sulfonates (CnAAP) with -H, -butyl and -octyl tails are applied and E/Z photoisomerization of the surfactants is used to cause substantially different hydrophobic interactions between the surfactants and PDADMAC. These remotely controlled changes affect significantly the P/S binding and allows for tuning both the bulk and interfacial properties of PDADMAC/CnAAP mixtures through light irradiation. For that, we have fixed the surfactant concentrations at values where they exhibit pronounced surface tension changes upon E/Z photoisomerization with 365 nm UV light (Z) and 520 nm green (E) light and have varied the PDADMAC concentration. The electrophoretic mobility can be largely tuned by photoisomerisation of CnAAP surfactants and P/S aggregates, which can even exhibit a charge reversal from negative to positive values or vice versa. In addition, low colloidal stability at equimolar concentrations of PDADMAC with CnAAP surfactants in the E configuration lead to the formation of large aggregates in the bulk which can be broken up by irradiation with UV light when the surfactant's alkyl chain is short enough (C0AAP). Vibrational sum-frequency generation (SFG) spectroscopy reveals changes at the interface similar to the bulk, where the charging state at air-water interfaces can be modified with light irradiation. Using SFG spectroscopy, we interrogated the O-H stretching modes of interfacial H2O and provide qualitative information on surface charging that is complemented by neutron reflectometry, from which we resolved the surface excesses of PDADMAC and CnAAP at the air-water interface, independently.

Translational use of homing peptides: Tumor and placental targeting.

HYPOTHESIS: Tissue-specific homing peptides have been shown to improve chemotherapeutic efficacy due to their trophism for tumor cells. Other sequences that selectively home to the placenta are providing new and safer therapeutics to treat complications in pregnancy. Our hypothesis is that the placental homing peptide RSGVAKS (RSG) may have binding affinity to cancer cells, and that insight can be gained into the binding mechanisms of RSG and the tumor homing peptide CGKRK to model membranes that mimic the primary lipid compositions of the respective cells. EXPERIMENTS: Following cell culture studies on the binding efficacy of the peptides on a breast cancer cell line, a systematic translational characterization is delivered using ellipsometry, Brewster angle microscopy and neutron reflectometry of the extents, structures, and dynamics of the interactions of the peptides with the model membranes on a Langmuir trough. FINDINGS: We start by revealing that RSG does indeed have binding affinity to breast cancer cells. The peptide is then shown to exhibit stronger interactions and greater penetration than CGKRK into both model membranes, combined with greater disruption to the lipid component. RSG also forms aggregates bound to the model membranes, yet both peptides bind to a greater extent to the placental than cancer model membranes. The results demonstrate the potential for varying local reservoirs of peptide within cell membranes that may influence receptor binding. The innovative nature of our findings motivates the urgent need for more studies involving multifaceted experimental platforms to explore the use of specific peptide sequences to home to different cellular targets.

Cognition and post-concussive symptom status after pediatric mild traumatic brain injury.

Cognitive impairment and post-concussive symptoms (PCS) represent hallmark sequelae of pediatric mild traumatic brain injury (pmTBI). Few studies have directly compared cognition as a function of PCS status longitudinally. Cognitive outcomes were therefore compared for asymptomatic pmTBI, symptomatic pmTBI, and healthy controls (HC) during sub-acute (SA; 1-11 days) and early chronic (EC; approximately 4 months) post-injury phases. We predicted worse cognitive performance for both pmTBI groups relative to HC at the SA visit. At the EC visit, we predicted continued impairment from the symptomatic group, but no difference between asymptomatic pmTBI and HCs. A battery of clinical (semi-structured interviews and self-report questionnaires) and neuropsychological measures were administered to 203 pmTBI and 139 HC participants, with greater than 80% retention at the EC visit. A standardized change method classified pmTBI into binary categories of asymptomatic or symptomatic based on PCS scores. Symptomatic pmTBI performed significantly worse than HCs on processing speed, attention, and verbal memory at SA visit, whereas lower performance was only present for verbal memory for asymptomatic pmTBI. Lower performance in verbal memory persisted for both pmTBI groups at the EC visit. Surprisingly, a minority (16%) of pmTBI switched from asymptomatic to symptomatic status at the EC visit. Current findings suggest that PCS and cognition are more closely coupled during the first week of injury but become decoupled several months post-injury. Evidence of lower performance in verbal memory for both asymptomatic and symptomatic pmTBI suggests that cognitive recovery may be a process separate from the resolution of subjective symptomology.

Sex- and Age-Related Differences in Post-Concussive Symptom Reporting Among Children and Their Parents.

Pediatric mild traumatic brain injury (pmTBI) has received increased public attention over the past decade, especially for children who experience persistent post-concussive symptoms (PCS). Common methods for obtaining pediatric PCS rely on both self- and parental report, exhibit moderate test-retest reliability, and variable child-parent agreement, and may yield high false positives. The current study investigated the impact of age and biological sex on PCS reporting (Post-Concussion Symptom Inventory) in patients with pmTBI (n = 286) at retrospective, 1 week, 4 months, and 1 year post-injury time points, as well as reported symptoms in healthy controls (HC; n = 218) at equivalent assessment times. HC and their parents reported higher PCS for their retrospective rating relative to the other three other study visits. Child-parent agreement was highest for female adolescents, but only approached acceptable ranges (≥ 0.75) immediately post-injury. Poor-to-fair child/parental agreement was observed for most other study visits for pmTBI and at all visits for HC. Parents rated female adolescents as being more symptomatic than their male counterparts in spite of small (pmTBI) or no (HC) sex-related differences in self-reported ratings, suggestive of a potential cultural bias in parental ratings. Test-retest reliability for self-report was typically below acceptable ranges for both pmTBI and HC groups, with reliability decreasing for HC and increasing for pmTBI as a function of time between visits. Parental test-retest reliability was higher for females. Although continued research is needed, current results support the use of child self-report over parental ratings for estimating PCS burden. Results also highlight the perils of relying on symptom self-report for diagnostic and prognostic purposes.

Dynamic Functional Connectivity in Pediatric Mild Traumatic Brain Injury.

Resting-state fMRI can be used to identify recurrent oscillatory patterns of functional connectivity within the human brain, also known as dynamic brain states. Alterations in dynamic brain states are highly likely to occur following pediatric mild traumatic brain injury (pmTBI) due to the active developmental changes. The current study used resting-state fMRI to investigate dynamic brain states in 200 patients with pmTBI (ages 8-18 years, median = 14 years) at the subacute (∼1-week post-injury) and early chronic (∼ 4 months post-injury) stages, and in 179 age- and sex-matched healthy controls (HC). A k-means clustering analysis was applied to the dominant time-varying phase coherence patterns to obtain dynamic brain states. In addition, correlations between brain signals were computed as measures of static functional connectivity. Dynamic connectivity analyses showed that patients with pmTBI spend less time in a frontotemporal default mode/limbic brain state, with no evidence of change as a function of recovery post-injury. Consistent with models showing traumatic strain convergence in deep grey matter and midline regions, static interhemispheric connectivity was affected between the left and right precuneus and thalamus, and between the right supplementary motor area and contralateral cerebellum. Changes in static or dynamic connectivity were not related to symptom burden or injury severity measures, such as loss of consciousness and post-traumatic amnesia. In aggregate, our study shows that brain dynamics are altered up to 4 months after pmTBI, in brain areas that are known to be vulnerable to TBI. Future longitudinal studies are warranted to examine the significance of our findings in terms of long-term neurodevelopment.

Multifaceted neural and vascular pathologies after pediatric mild traumatic brain injury.

Dynamic changes in neurodevelopment and cognitive functioning occur during adolescence, including a switch from reactive to more proactive forms of cognitive control, including response inhibition. Pediatric mild traumatic brain injury (pmTBI) affects these cognitions immediately post-injury, but the role of vascular versus neural injury in cognitive dysfunction remains debated. This study consecutively recruited 214 sub-acute pmTBI (8-18 years) and age/sex-matched healthy controls (HC; N = 186), with high retention rates (>80%) at four months post-injury. Multimodal imaging (functional MRI during response inhibition, cerebral blood flow and cerebrovascular reactivity) assessed for pathologies within the neurovascular unit. Patients exhibited increased errors of commission and hypoactivation of motor circuitry during processing of probes. Evidence of increased/delayed cerebrovascular reactivity within motor circuitry during hypercapnia was present along with normal perfusion. Neither age-at-injury nor post-concussive symptom load were strongly associated with imaging abnormalities. Collectively, mild cognitive impairments and clinical symptoms may continue up to four months post-injury. Prolonged dysfunction within the neurovascular unit was observed during proactive response inhibition, with preliminary evidence that neural and pure vascular trauma are statistically independent. These findings suggest pmTBI is characterized by multifaceted pathologies during the sub-acute injury stage that persist several months post-injury.

Effects of Charge Density on Spread Hyperbranched Polyelectrolyte/Surfactant Films at the Air/Water Interface.

The interfacial structure and morphology of films spread from hyperbranched polyethylene imine/sodium dodecyl sulfate (PEI/SDS) aggregates at the air/water interface have been resolved for the first time with respect to polyelectrolyte charged density. A recently developed method to form efficient films from the dissociation of aggregates using a minimal quantity of materials is exploited as a step forward in enhancing understanding of the film properties with a view to their future use in technological applications. Interfacial techniques that resolve different time and length scales, namely, ellipsometry, Brewster angle microscopy, and neutron reflectometry, are used. Extended structures of both components are formed under a monolayer of the surfactant with bound polyelectrolytes upon film compression on subphases adjusted to pH 4 or 10, corresponding to high and low charge density of the polyelectrolyte, respectively. A rigid film is related to compact conformation of the PEI in the interfacial structure at pH 4, while it is observed that aggregates remain embedded in mobile films at pH 10. The ability to compact surfactants in the monolayer to the same extent as its maximum coverage in the absence of polyelectrolyte is distinct from the behavior observed for spread films involving linear polyelectrolytes, and intriguingly evidence points to the formation of extended structures over the full range of surface pressures. We conclude that the molecular architecture and charge density can be important parameters in controlling the structures and properties of spread polyelectrolyte/surfactant films, which holds relevance to a range of applications, such as those where PEI is used, including CO2 capture, electronic devices, and gene transfection.

Neural correlates of cognitive control deficits in pediatric mild traumatic brain injury.

There is a growing body of research showing that cerebral pathophysiological processes triggered by pediatric mild traumatic brain injury (pmTBI) may extend beyond the usual clinical recovery timeline. It is paramount to further unravel these processes, because the possible long-term cognitive effects resulting from ongoing secondary injury in the developing brain are not known. In the current fMRI study, neural processes related to cognitive control were studied in 181 patients with pmTBI at sub-acute (SA; ~1 week) and early chronic (EC; ~4 months) stages post-injury. Additionally, a group of 162 age- and sex-matched healthy controls (HC) were recruited at equivalent time points. Proactive (post-cue) and reactive (post-probe) cognitive control were examined using a multimodal attention fMRI paradigm for either congruent or incongruent stimuli. To study brain network function, the triple-network model was used, consisting of the executive and salience networks (collectively known as the cognitive control network), and the default mode network. Additionally, whole-brain voxel-wise analyses were performed. Decreased deactivation was found within the default mode network at the EC stage following pmTBI during both proactive and reactive control. Voxel-wise analyses revealed sub-acute hypoactivation of a frontal area of the cognitive control network (left pre-supplementary motor area) during proactive control, with a reversed effect at the EC stage after pmTBI. Similar effects were observed in areas outside of the triple-network during reactive control. Group differences in activation during proactive control were limited to the visual domain, whereas for reactive control findings were more pronounced during the attendance of auditory stimuli. No significant correlations were present between task-related activations and (persistent) post-concussive symptoms. In aggregate, current results show alterations in neural functioning during cognitive control in pmTBI up to 4 months post-injury, regardless of clinical recovery. We propose that subacute decreases in activity reflect a general state of hypo-excitability due to the injury, while early chronic hyperactivation represents a compensatory mechanism to prevent default mode interference and to retain cognitive control.

Aqueous Radical Initiated Oxidation of an Organic Monolayer at the Air-Water Interface as a Proxy for Thin Films on Atmospheric Aerosol Studied with Neutron Reflectometry.

Neutron reflectometry has been used to study the radical initiated oxidation of a monolayer of the lipid 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) at the air-solution interface by aqueous-phase hydroxyl, sulfate, and nitrate radicals. The oxidation of organic films at the surface of atmospheric aqueous aerosols can influence the optical properties of the aerosol and consequently can impact Earth's radiative balance and contribute to modern climate change. The amount of material at the air-solution interface was found to decrease on exposure to aqueous-phase radicals which was consistent with a multistep degradation mechanism, i.e., the products of reaction of the DSPC film with aqueous radicals were also surface active. The multistep degradation mechanism suggests that lipid molecules in the thin film degrade to form progressively shorter chain surface active products and several reactive steps are required to remove the film from the air-solution interface. Bimolecular rate constants for oxidation via the aqueous phase OH radical cluster around 1010 dm3 mol-1 s-1. Calculations to determine the film lifetime indicate that it will take ∼4-5 days for the film to degrade to 50% of its initial amount in the atmosphere, and therefore attack by aqueous radicals on organic films could be atmospherically important relative to typical atmospheric aerosol lifetimes.

Acute respiratory distress syndrome: potential of therapeutic interventions effective in treating progression from COVID-19 to treat progression from other illnesses-a systematic review.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is the most severe form of lung injury, rendering gaseous exchange insufficient, leading to respiratory failure. Despite over 50 years of research on the treatment of ARDS when developed from illnesses such as sepsis and pneumonia, mortality remains high, and no robust pharmacological treatments exist. The progression of SARS-CoV-2 infections to ARDS during the recent global pandemic led to a surge in the number of clinical trials on the condition. Understandably, this explosion in new research focused on COVID-19 ARDS (CARDS) rather than ARDS when developed from other illnesses, yet differences in pathology between the two conditions mean that optimal treatment for them may be distinct. AIM: The aim of the present work is to assess whether new therapeutic interventions that have been developed for the treatment of CARDS may also hold strong potential in the treatment of ARDS when developed from other illnesses. The study objectives are achieved through a systematic review of clinical trials. RESULTS: The COVID-19 pandemic led to the identification of various therapeutic interventions for CARDS, some but not all of which are optimal for the management of ARDS. Interventions more suited to CARDS pathology include antithrombotics and biologic agents, such as cytokine inhibitors. Cell-based therapies, on the other hand, show promise in the treatment of both conditions, attributed to their broad mechanisms of action and the overlap in the clinical manifestations of the conditions. A shift towards personalised treatments for both CARDS and ARDS, as reflected through the increasing use of biologics, is also evident. CONCLUSIONS: As ongoing CARDS clinical trials progress, their findings are likely to have important implications that alter the management of ARDS in patients that develop the condition from illnesses other than COVID-19 in the future.

Control of the structure and morphology of polypeptide/surfactant spread films by exploiting specific interactions.

We demonstrate control of the structure and morphology of polypeptide/surfactant films at the air/water interface as a function of the maximum compression ratio of the surface area, exploiting a recently developed film formation mechanism that requires minimal quantities of materials involving the dissociation of aggregates. The systems studied are poly(L-lysine) (PLL) or poly(L-arginine) (PLA) with sodium dodecyl sulfate (SDS), chosen because the surfactant (i) interacts more strongly with the latter polypeptide due to the formation of hydrogen bonds between the guanidinium group and its oxygen atoms, and (ii) induces bulk ß-sheet and α-helix conformations of the respective polypeptides. The working hypothesis is that such different interactions may be used to tune the film properties when compressed to form extended structures (ESs). Neutron reflectometry reveals that application of a high compression ratio (4.5 : 1) results in the nanoscale self-assembly of ESs containing up to two PLL-wrapped SDS bilayers. Brewster angle microscopy provides images of the PLL/SDS ESs as discrete regions on the micrometre scale while additional linear regions of PLA/SDS ESs mark macroscopic film folding. Ellipsometry demonstrates high stability of the different ESs formed. The collapse of PLL/SDS films upon compression to a very high ratio (10 : 1) is irreversible due to the formation of solid domains that remain embedded in the film upon expansion while that of PLA/SDS films is reversible. These findings demonstrate that differences in the side group of a polypeptide can have a major influence on controlling the film properties, marking a key step in the development of this new film formation mechanism for the design of biocompatible and/or biodegradable films with tailored properties for applications in tissue engineering, biosensors and antimicrobial coatings.

Photo-Responsive Control of Adsorption and Structure Formation at the Air-Water Interface with Arylazopyrazoles.

Smart interfaces that are responsive to external triggers such as light are of great interest for the development of responsive or adaptive materials and interfaces. Using alkyl-arylazopyrazole butyl sulfonate surfactants (alkyl-AAP) that can undergo E/Z photoisomerization when irradiated with green (E) and UV (Z) lights, we demonstrate through a combination of experiments and computer simulations that there can be surprisingly large changes in surface tension and in the molecular structure and order at air-water interfaces. Surface tensiometry, vibrational sum-frequency generation (SFG) spectroscopy, and neutron reflectometry (NR) are applied to the study of custom-synthesized AAP surfactants with octyl- and H-terminal groups at air-water interfaces as a function of their bulk concentration and E/Z configuration. Upon photoswitching, a drastic influence of the alkyl chain on both the surface activity and the responsiveness of interfacial surfactants is revealed from changes in the surface tension, γ, where the largest changes in γ are observed for octyl-AAP (Δγ ∼ 23 mN/m) in contrast to H-AAP with Δγ < 10 mN/m. Results from vibrational SFG spectroscopy and NR show that the interfacial composition and the molecular order of the surfactants drastically change with E/Z photoisomerization and surface coverage. Indeed, from analysis of the S-O (head group) and C-H vibrational bands (hydrophobic tail), a qualitative analysis of orientational and structural changes of interfacial AAP surfactants is provided. The experiments are complemented by resolution of thermodynamic parameters such as equilibrium constants from ultra-coarse-grained simulations, which also capture details like island formation and interaction parameters of interfacial molecules. Here, the interparticle interaction ("stickiness") and the interaction with the surface are adjusted, closely reflecting experimental conditions.

Longitudinal Assessment of Preterm Infants Treated with Erythropoiesis Stimulating Agents.

OBJECTIVE: We previously reported improved neurodevelopment at 2 and 4 years among preterm infants treated with erythropoietin or darbepoetin, known as erythropoiesis-stimulating agents (ESAs). We now characterize longitudinal outcomes through 6 years. METHODS: Children randomized to ESAs or placebo were evaluated at 6 years. Healthy-term children served as controls. Tests of cognition and executive function (EF) were performed. RESULTS: Cognitive/EF scores remained similar between 4 and 6 years within each group (ESA: 43 children; placebo: 17 children; term: 21 children). ESA recipients scored higher than placebo on Full-Scale IQ (94.2 ± 18.6 vs. 81.6 ± 16.7, p = 0.022), and Performance IQ (97.3 ± 16.2 vs. 81.7 ± 15.2, = 0.005). Aggregate EF trended better for the ESA group. Term controls scored better than placebo on all measures. ESA and term controls scored similarly on cognitive and EF tests. CONCLUSION: ESA recipients had better outcomes than placebo recipients, and were similar to term children. ESAs may improve long-term cognition and executive function in preterm infants.

Prospective Study of Gray Matter Atrophy Following Pediatric Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: The clinical and physiologic time course for recovery following pediatric mild traumatic brain injury (pmTBI) remains actively debated. The primary objective of the current study was to prospectively examine structural brain changes (cortical thickness and subcortical volumes) and age-at-injury effects. A priori study hypotheses predicted reduced cortical thickness and hippocampal volumes up to 4 months postinjury, which would be inversely associated with age at injury. METHODS: Prospective cohort study design with consecutive recruitment. Study inclusion adapted from American Congress of Rehabilitation Medicine (upper threshold) and Zurich Concussion in Sport Group (minimal threshold) and diagnosed by Emergency Department and Urgent Care clinicians. Major neurologic, psychiatric, or developmental disorders were exclusionary. Clinical (Common Data Element) and structural (3 T MRI) evaluations within 11 days (subacute visit [SA]) and at 4 months (early chronic visit [EC]) postinjury. Age- and sex-matched healthy controls (HC) to control for repeat testing/neurodevelopment. Clinical outcomes based on self-report and cognitive testing. Structural images quantified with FreeSurfer (version 7.1.1). RESULTS: A total of 208 patients with pmTBI (age = 14.4 ± 2.9; 40.4% female) and 176 HC (age = 14.2 ± 2.9; 42.0% female) were included in the final analyses (>80% retention). Reduced cortical thickness (right rostral middle frontal gyrus; d = -0.49) and hippocampal volumes (d = -0.24) observed for pmTBI, but not associated with age at injury. Hippocampal volume recovery was mediated by loss of consciousness/posttraumatic amnesia. Significantly greater postconcussive symptoms and cognitive deficits were observed at SA and EC visits, but were not associated with the structural abnormalities. Structural abnormalities slightly improved balanced classification accuracy above and beyond clinical gold standards (∆+3.9%), with a greater increase in specificity (∆+7.5%) relative to sensitivity (∆+0.3%). DISCUSSION: Current findings indicate that structural brain abnormalities may persist up to 4 months post-pmTBI and are partially mediated by initial markers of injury severity. These results contribute to a growing body of evidence suggesting prolonged physiologic recovery post-pmTBI. In contrast, there was no evidence for age-at-injury effects or physiologic correlates of persistent symptoms in our sample.

Polyelectrolyte/surfactant films: from 2D to 3D structural control.

Reversible control of the 3D structure of polyelectrolyte/surfactant films at the air/water interface is showcased. A recently discovered mechanism is exploited to form highly efficient, stable and biocompatible films by spreading aggregates composed of poly-L-lysine and sodium dodecyl sulfate on the surface of water. Reversible control of: (1) the surface monolayer coverage, (2) the switching on or off discrete extended structures, and (3) the extended structure coverage is demonstrated for the first time. The intricacy by which the film structures can be controlled is unprecedented and opens exciting potential to optimize film properties by chemical design for novel biomedical transfer applications.

The interaction of styrene maleic acid copolymers with phospholipids in Langmuir monolayers, vesicles and nanodiscs; a structural study.

HYPOTHESIS: Self-assembly of amphipathic styrene maleic acid copolymers with phospholipids in aqueous solution results in the formation of 'nanodiscs' containing a planar segment of phospholipid bilayer encapsulated by a polymer belt. Recently, studies have reported that lipids rapidly exchange between both nanodiscs in solution and external sources of lipids. Outstanding questions remain regarding details of polymer-lipid interactions, factors influencing lipid exchange and structural effects of such exchange processes. Here, the dynamic behaviour of nanodiscs is investigated, specifically the role of membrane charge and polymer chemistry. EXPERIMENTS: Two model systems are investigated: fluorescently labelled phospholipid vesicles, and Langmuir monolayers of phospholipids. Using fluorescence spectroscopy and time-resolved neutron reflectometry, the membrane potential, monolayer structure and composition are monitored with respect to time upon polymer and nanodisc interactions. FINDINGS: In the presence of external lipids, polymer chains embed throughout lipid membranes, the extent of which is governed by the net membrane charge. Nanodiscs stabilised by three different polymers will all exchange lipids and polymer with monolayers to differing extents, related to the properties of the stabilising polymer belt. These results demonstrate the dynamic nature of nanodiscs which interact with the local environment and are likely to deposit both lipids and polymer at all stages of use.

Multicompartmental models and diffusion abnormalities in paediatric mild traumatic brain injury.

The underlying pathophysiology of paediatric mild traumatic brain injury and the time-course for biological recovery remains widely debated, with clinical care principally informed by subjective self-report. Similarly, clinical evidence indicates that adolescence is a risk factor for prolonged recovery, but the impact of age-at-injury on biomarkers has not been determined in large, homogeneous samples. The current study collected diffusion MRI data in consecutively recruited patients (n = 203; 8-18 years old) and age and sex-matched healthy controls (n = 170) in a prospective cohort design. Patients were evaluated subacutely (1-11 days post-injury) as well as at 4 months post-injury (early chronic phase). Healthy participants were evaluated at similar times to control for neurodevelopment and practice effects. Clinical findings indicated persistent symptoms at 4 months for a significant minority of patients (22%), along with residual executive dysfunction and verbal memory deficits. Results indicated increased fractional anisotropy and reduced mean diffusivity for patients, with abnormalities persisting up to 4 months post-injury. Multicompartmental geometric models indicated that estimates of intracellular volume fractions were increased in patients, whereas estimates of free water fractions were decreased. Critically, unique areas of white matter pathology (increased free water fractions or increased neurite dispersion) were observed when standard assumptions regarding parallel diffusivity were altered in multicompartmental models to be more biologically plausible. Cross-validation analyses indicated that some diffusion findings were more reproducible when ∼70% of the total sample (142 patients, 119 controls) were used in analyses, highlighting the need for large-sample sizes to detect abnormalities. Supervised machine learning approaches (random forests) indicated that diffusion abnormalities increased overall diagnostic accuracy (patients versus controls) by ∼10% after controlling for current clinical gold standards, with each diffusion metric accounting for only a few unique percentage points. In summary, current results suggest that novel multicompartmental models are more sensitive to paediatric mild traumatic brain injury pathology, and that this sensitivity is increased when using parameters that more accurately reflect diffusion in healthy tissue. Results also indicate that diffusion data may be insufficient to achieve a high degree of objective diagnostic accuracy in patients when used in isolation, which is to be expected given known heterogeneities in pathophysiology, mechanism of injury and even criteria for diagnoses. Finally, current results indicate ongoing clinical and physiological recovery at 4 months post-injury.

Nucleic Acid-Loaded Lipid Nanoparticle Interactions with Model Endosomal Membranes.

Lipid nanoparticles (LNPs) are important delivery systems for RNA-based therapeutics, yet the mechanism of their interaction with endosomal membranes remains unclear. Here, the interactions of nucleic acid-loaded LNPs that contain an ionizable lipid with models of the early and late endosomal membranes are studied, for the first time, using different reflectometry techniques. Novel insight is provided with respect to the subphase pH, the stage of the endosome, and the nature of the nucleic acid cargo. It is found that the insertion of lipids from the LNPs into the model membrane is greatest at pH 6.5 and 5.5, whereas at higher pH, lipid insertion is suppressed with evidence instead for the binding of intact LNPs, demonstrating the importance of the pH in the fusion of LNPs undergoing the endosomal pathway. Furthermore, and independently of the pH, the effect of the early- versus late-stage endosomal models is minimal, suggesting that the increased fluidity and anionic nature of the late endosome has little effect on the extent of LNP interaction. Last, there is greater nucleic acid delivery from LNPs containing mRNA than Poly(A), indicating that the extent of interaction can be tuned according to the nature of the nucleic acid cargo. Such new information on the relative impact of factors influencing nucleic acid delivery by LNP interactions with endosomal membranes is important in the design and tuning of vehicles with improved nucleic acid delivery capacities.

Insights into Extended Structures and Their Driving Force: Influence of Salt on Polyelectrolyte/Surfactant Mixtures at the Air/Water Interface.

This paper addresses the effect of polyelectrolyte stiffness on the surface structure of polyelectrolyte (P)/surfactant (S) mixtures. Therefore, two different anionic Ps with different intrinsic persistence length lP are studied while varying the salt concentration (0-10-2 M). Either monosulfonated polyphenylene sulfone (sPSO2-220, lP ∼20 nm) or sodium poly(styrenesulfonate) (PSS, lP ∼1 nm) is mixed with the cationic surfactant tetradecyltrimethylammonium bromide (C14TAB) well below its critical micelle concentration and studied with tensiometry and neutron reflectivity experiments. We kept the S concentration (10-4 M) constant, while we varied the P concentration (10-5-10-3 M of the monomer, denoted as monoM). P and S adsorb at the air/water interface for all studied mixtures. Around the bulk stoichiometric mixing point (BSMP), PSS/C14TAB mixtures lose their surface activity, whereas sPSO2-220/C14TAB mixtures form extended structures perpendicular to the surface (meaning a layer of S with attached P and additional layers of P and S underneath instead of only a monolayer of S with P). Considering the different P monomer structures as well as the impact of salt, we identified the driving force for the formation of these extended structures: compensation of all interfacial charges (P/S ratio ∼1) to maximize the gain of entropy. By increasing the flexibility of P, we can tune the interfacial structures from extended structures to monolayers. These findings may help improve applications based on the adsorption of P/S mixtures in the fields of cosmetic or oil recovery.

Investigating the diagnostic accuracy of a paper-and-pencil and a computerized cognitive test battery for pediatric mild traumatic brain injury.

OBJECTIVE: This study assessed classification accuracy of paper-and-pencil and computerized cognitive batteries at subacute (SA; 1-11 days) and early chronic (EC; ∼4 months) phases of pediatric mild traumatic brain injury (pmTBI). Two statistical approaches focused on single-subject performance (individual task scores, total impairments) were used to maximize clinical utility. METHOD: Two hundred thirty-five pmTBI and 169 healthy controls (HC) participants aged 8-18 were enrolled, with a subset (190 pmTBI; 160 HC) returning for the EC visit. The paper-and-pencil battery included several neuropsychological tests selected from recommended common data elements, whereas computerized testing was performed with the Cogstate Brief Battery. Hierarchical logistic regressions (base model: Parental education and premorbid reading abilities; full model: Base model and cognitive testing variables) were used to examine sensitivity/specificity, with diagnosis as the dependent variable. RESULTS: Number Sequencing and Cogstate One-Card Learning accuracy significantly predicted SA diagnosis (full model accuracy = 71.6%-71.7%, sensitivity = 80.6%-80.8%, specificity = 59.1%-59.6%), while only immediate recall was significant at EC visit (accuracy = 68.5%, sensitivity = 74.6%, specificity = 61.5%). Other measures (Letter Fluency, Cogstate Detection, and One-Card Learning accuracy) demonstrated higher proportions of impairment for pmTBI subacutely (pmTBI: 11.5%-19.8%; HC: 3.7%-6.1%) but did not improve classification accuracy. Evidence of multiple impairments across the entire testing battery significantly predicted diagnosis at both visits (full model accuracy = 66.2%-68.6%, sensitivity = 71.2%-78.9%, specificity = 54.3%-61.5%). CONCLUSIONS: Current results suggest similar modest diagnostic accuracy for computerized and paper-and-pencil batteries across multiple pmTBI phases. Moreover, findings suggest the total number of impairments may be more clinically useful than any single test or cognitive domain in terms of diagnostic accuracy at both assessment points. (PsycInfo Database Record (c) 2022 APA, all rights reserved).