fNIRS is capable of distinguishing laterality of lower body contractions.

The use of functional near-infrared spectroscopy (fNIRS) for brain imaging during human movement continues to increase. This technology measures brain activity non-invasively using near-infrared light, is highly portable, and robust to motion artifact. However, the spatial resolution of fNIRS is lower than that of other imaging modalities. It is unclear whether fNIRS has sufficient spatial resolution to differentiate nearby areas of the cortex, such as the leg areas of the motor cortex. Therefore, the purpose of this study was to determine fNIRS' ability to discern laterality of lower body contractions. Activity in the primary motor cortex was recorded in forty participants (mean = 23.4 years, SD = 4.5, female = 23, male = 17) while performing unilateral lower body contractions. Contractions were performed at 30% of maximal force against a handheld dynamometer. These contractions included knee extension, knee flexion, dorsiflexion, and plantar flexion of the left and right legs. fNIRS signals were recorded and stored for offline processing and analysis. Channels of fNIRS data were grouped into regions of interest, with five tolerance conditions ranging from strict to lenient. Four of five tolerance conditions resulted in significant differences in cortical activation between hemispheres. During right leg contractions, the left hemisphere was more active than the right hemisphere. Similarly, during left leg contractions, the right hemisphere was more active than the left hemisphere. These results suggest that fNIRS has sufficient spatial resolution to distinguish laterality of lower body contractions. This makes fNIRS an attractive technology in research and clinical applications in which laterality of brain activity is required during lower body activity.

Digestion of lipid micelles leads to increased membrane permeability.

Lipid-based drug carriers are an attractive option to solubilise poorly water soluble therapeutics. Previously, we reported that the digestion of a short tail PC lipid (2C6PC) by the PLA2 enzyme has a significant effect on the structure and stability of the micelles it forms. Here, we studied the interactions of micelles of varying composition representing various degrees of digestion with a model ordered (70 mol% DPPC & 30 mol% cholesterol) and disordered (100% DOPC) lipid membrane. Micelles of all compositions disassociated when interacting with the two different membranes. As the percentage of digestion products (C6FA and C6LYSO) in the micelle increased, the disassociation occurred more rapidly. The C6FA inserts preferentially into both membranes. We find that all micelle components increase the area per lipid, increase the disorder and decrease the thickness of the membranes, and the 2C6PC lipid molecules have the most significant impact. Additionally, there is an increase in permeation of water into the membrane that accompanies the insertion of C6FA into the DOPC membranes. We show that the natural digestion of lipid micelles result in molecular species that can enhance the permeability of lipid membranes that in turn result in an enhanced delivery of drugs.

Clinical Trial Site Perspectives and Practices on Study Participant Diversity and Inclusion.

Clinical trial participant populations fail to adequately represent target populations that drugs are intended to serve. Improving racial and ethnic diversity of clinical trial participants is essential for generalizable, quality clinical research results and ensuring social and medical equity. Site-level clinical research professionals (CRPs) have unique insights on diversity improvement strategies for clinical trial enrollment. A survey was distributed to current CRPs working at clinical research sites in the United States to describe current practices and perceptions of the impact these practices have on participant diversity. Subsequently, descriptive quantitative analysis and inductive content analysis were performed. For the practices surveyed, there are discrepancies between frequency of use and perceived impact on diversity enrollment. Common current practices include phone-based or telemedicine study visits, electronic/digital data collection, and participant compensation. However, we report travel reimbursement and services, translated documents and translator services, and adequate participant compensation as most impactful on diverse enrollment. A multistakeholder approach is necessary to enhance diversity and inclusion (D&I) of study participants. Besides large-scale solutions such as countering community distrust, actionable steps are needed by sponsors and study sites to improve D&I of trial participants. Study leadership at the sponsor, contract research organization (CRO), and site-level should create diversity plans prior to study start, and CRO and sponsor budgets should consider D&I strategies during study planning. Planning should incorporate strategies to improve D&I including adequate participant compensation, translated documents and translator services, and travel reimbursements.

An Ultrasound-based Prediction Model to Predict Ureterolysis during Laparoscopic Endometriosis Surgery.

STUDY OBJECTIVE: To develop a model, including clinical features and ultrasound findings, to predict the need for ureterolysis (i.e., dissection of the ureter) during laparoscopy for endometriosis. DESIGN: A retrospective observational study of patients who had undergone transvaginal ultrasound (TVS) according to the International Deep Endometriosis Analysis consensus and subsequent laparoscopy ± excision of endometriosis between January 2017 and February 2021 was conducted. SETTING: Sydney Medical School Nepean, University of Sydney, Nepean Hospital, and Blue Mountains Hospital, New South Wales, Australia. PATIENTS/PARTICIPANT: 177 patients. INTERVENTION: The demographic, clinical, TVS, and intraoperative data were extracted through electronic clinical records. MEASUREMENTS AND MAIN RESULTS: Multicategorical decision-tree and baseline models were built to choose the variables most correlated to the outcome under study. Receiver operating characteristic analysis was performed on the binary classification. Based on our results, we selected the variables performing with significant statistical differences (p <.05). During the study period, 177 consecutive patients were recruited and divided into 2 subgroups, ureterolysis (51.4%) and nonureterolysis (48.6%). Ureterolysis was noted in 87.5% of patients in which the left ovary was immobile (p <.001) and in 82.5% in which the right ovary was fixed (p <.001). For patients with right uterosacral ligament (USL) deep endometriosis (DE), ureterolysis was performed in 96.2% patients (p <.001) and 64.6% (p = .043) for left USL DE. Among patients with bowel DE, the proportion of patients undergoing ureterolysis was 95.5% (p <.001). The prognostic variables used in the final model to predict ureterolysis included dyschezia, absence of ovarian mobility, presence of right or left USL DE, and presence of bowel DE on TVS. According to the developed model, the baseline risk for performing ureterolysis is 20% in our sample. The overall model performance demonstrated an area under the receiver operating characteristic curve 0.82. CONCLUSION: Our study demonstrates that it is possible to predict the need for ureterolysis with clinical and sonographic data. Furthermore, patients presenting with a combination of the variables of our model (dyschezia, ovarian immobility, USL, and bowel DE lesions) have a high risk of ureterolysis. In contrast, patients without these features have a low risk (approximately 20%) of needing ureterolysis.

Clonality assessment and detection of clonal diversity in classic Hodgkin lymphoma by next-generation sequencing of immunoglobulin gene rearrangements.

Clonality analysis in classic Hodgkin lymphoma (cHL) is of added value for correctly diagnosing patients with atypical presentation or histology reminiscent of T cell lymphoma, and for establishing the clonal relationship in patients with recurrent disease. However, such analysis has been hampered by the sparsity of malignant Hodgkin and Reed-Sternberg (HRS) cells in a background of reactive immune cells. Recently, the EuroClonality-NGS Working Group developed a novel next-generation sequencing (NGS)-based assay and bioinformatics platform (ARResT/Interrogate) to detect immunoglobulin (IG) gene rearrangements for clonality testing in B-cell lymphoproliferations. Here, we demonstrate the improved performance of IG-NGS compared to conventional BIOMED-2/EuroClonality analysis to detect clonal gene rearrangements in 16 well-characterized primary cHL cases within the IG heavy chain (IGH) and kappa light chain (IGK) loci. This was most obvious in formalin-fixed paraffin-embedded (FFPE) tissue specimens, where three times more clonal cases were detected with IG-NGS (9 cases) compared to BIOMED-2 (3 cases). In total, almost four times more clonal rearrangements were detected in FFPE with IG-NGS (N = 23) as compared to BIOMED-2/EuroClonality (N = 6) as judged on identical IGH and IGK targets. The same clonal rearrangements were also identified in paired fresh frozen cHL samples. To validate the neoplastic origin of the detected clonotypes, IG-NGS clonality analysis was performed on isolated HRS cells, demonstrating identical clonotypes as detected in cHL whole-tissue specimens. Interestingly, IG-NGS and HRS single-cell analysis after DEPArray™ digital sorting revealed rearrangement patterns and copy number variation profiles indicating clonal diversity and intratumoral heterogeneity in cHL. Our data demonstrate improved performance of NGS-based detection of IG gene rearrangements in cHL whole-tissue specimens, providing a sensitive molecular diagnostic assay for clonality assessment in Hodgkin lymphoma.

Interplay of lipid and surfactant: Impact on nanoparticle structure.

Liquid lipid nanoparticles (LLN) are oil-in-water nanoemulsions of great interest in the delivery of hydrophobic drug molecules. They consist of a surfactant shell and a liquid lipid core. The small size of LLNs makes them difficult to study, yet a detailed understanding of their internal structure is vital in developing stable drug delivery vehicles (DDVs). Here, we implement machine learning techniques alongside small angle neutron scattering experiments and molecular dynamics simulations to provide critical insight into the conformations and distributions of the lipid and surfactant throughout the LLN. We simulate the assembly of a single LLN composed of the lipid, triolein (GTO), and the surfactant, Brij O10. Our work shows that the addition of surfactant is pivotal in the formation of a disordered lipid core; the even coverage of Brij O10 across the LLN shields the GTO from water and so the lipids adopt conformations that reduce crystallisation. We demonstrate the superior ability of unsupervised artificial neural networks in characterising the internal structure of DDVs, when compared to more conventional geometric methods. We have identified, clustered, classified and averaged the dominant conformations of lipid and surfactant molecules within the LLN, providing a multi-scale picture of the internal structure of LLNs.

The Impact of Lipid Digestion on the Dynamic and Structural Properties of Micelles.

Self-assembled, lipid-based micelles, such as those formed by the short-chain phosphocholine, dihexanoylphosphatidylcholine (2C6PC), are degraded by the pancreatic enzyme, phospholipase A2 (PLA2). Degradation yields 1-hexanoyl-lysophosphocholine (C6LYSO) and hexanoic acid (C6FA) products. However, little is known about the behavior of these products during and after the degradation of 2C6PC. In this work, a combination of static and time-resolved small angle neutron scattering, as well as all-atom molecular dynamics simulations, is used to characterize the structure of 2C6PC micelles. In doing so a detailed understanding of the substrate and product aggregation behavior before, during and after degradation is gained. Consequently, the formation of mixed micelles containing 2C6PC, C6LYSO and C6FA is shown at every stage of the degradation process, as well as the formation of mixed C6LYSO/C6FA micelles after degradation is complete. The use of atomistic molecular dynamics has allowed us to characterize the structure of 2C6PC, 2C6PC/C6LYSO/C6FA, and C6LYSO/C6FA micelles throughout the degradation process, showing the localization of the different molecular species within the aggregates. In addition, the hydration of the 2C6PC, C6LYSO, and C6FA species both during micellization and as monomers in aqueous solution is documented to reveal the processes driving their micellization.

How to perform lung ultrasound in pregnant women with suspected COVID-19.

Under certain circumstances, such as during the current COVID-19 outbreak, pregnant women can be a target for respiratory infection, and lung examination may be required as part of their clinical evaluation, ideally while avoiding exposure to radiation. We propose a practical approach for obstetricians/gynecologists to perform lung ultrasound examination, discussing potential applications, semiology and practical aspects, which could be of particular importance in emergency situations, such as the current pandemic infection of COVID-19. Copyright © 2020 ISUOG. Published by John Wiley & Sons Ltd.

Immunogenicity, Safety, and Efficacy of a Standalone Universal Influenza Vaccine, FLU-v, in Healthy Adults: A Randomized Clinical Trial.

Background: FLU-v is a broad-spectrum influenza vaccine that induces antibodies and cell-mediated immunity. Objective: To compare the safety, immunogenicity, and exploratory efficacy of different formulations and dosing regimens of FLU-v versus placebo. Design: Randomized, double-blind, placebo-controlled, single-center phase 2b clinical trial. (ClinicalTrials.gov: NCT02962908; EudraCT: 2015-001932-38). Setting: The Netherlands. Participants: 175 healthy adults aged 18 to 60 years. Intervention: 0.5-mL subcutaneous injection of 500 µg of adjuvanted (1 dose) or nonadjuvanted (2 doses) FLU-v (A-FLU-v or NA-FLU-v) or adjuvanted or nonadjuvanted placebo (A-placebo or NA-placebo) (2:2:1:1 ratio). Measurements: Vaccine-specific cellular responses at days 0, 42, and 180 were assessed via flow cytometry and enzyme-linked immunosorbent assay. Solicited information on adverse events (AEs) was collected for 21 days after vaccination. Unsolicited information on AEs was collected throughout the study. Results: The AEs with the highest incidence were mild to moderate injection site reactions. The difference between A-FLU-v and A-placebo in the median fold increase in secreted interferon-γ (IFN-γ) was 38.2-fold (95% CI, 4.7- to 69.7-fold; P = 0.001) at day 42 and 25.0-fold (CI, 5.7- to 50.9-fold; P < 0.001) at day 180. The differences between A-FLU-v and A-placebo in median fold increase at day 42 were 4.5-fold (CI, 2.3- to 9.8-fold; P < 0.001) for IFN-γ-producing CD4+ T cells, 4.9-fold (CI, 1.3- to 40.0-fold; P < 0.001) for tumor necrosis factor-α (TNF-α), 7.0-fold (CI, 3.5- to 18.0-fold; P < 0.001) for interleukin-2 (IL-2), and 1.7-fold (CI, 0.1- to 4.0-fold; P = 0.004) for CD107a. At day 180, differences were 2.1-fold (CI, 0.0- to 6.0-fold; P = 0.030) for IFN-γ and 5.7-fold (CI, 2.0- to 15.0-fold; P < 0.001) for IL-2, with no difference for TNF-α or CD107a. No differences were seen between NA-FLU-v and NA-placebo. Limitation: The study was not powered to evaluate vaccine efficacy against influenza infection. Conclusion: Adjuvanted FLU-v is immunogenic and merits phase 3 development to explore efficacy. Primary Funding Source: SEEK and the European Commission Directorate-General for Research and Innovation, European Member States within the UNISEC (Universal Influenza Vaccines Secured) project.

Physical Mechanisms Providing Clinical Information From Ultrasound Lung Images: Hypotheses and Early Confirmations.

In standard B mode imaging, a set of ultrasound pulses is used to reconstruct a 2-D image even though some of the assumptions needed to do this are not fully satisfied. For this reason, ultrasound medical images show numerous artifacts which physicians recognize and evaluate as part of their diagnosis since even one artifact can provide clinical information. Understanding the physical mechanisms at the basis of the formation of an artifact is important to identify the physiopathological state of the biological medium which generated the artifact. Ultrasound lung images are a significant example of this challenge since everything that is represented beyond the thickness of the chest wall ( ≈ 2 cm) is artifactual information. A convincing physical explanation of the genesis of important ultrasound lung artifacts does not exist yet. Physicians simply base their diagnosis on a correlation observed over the years between the manifestation of some artifacts and the occurrence of particular lung pathologies. In this article, a plausible genesis of some important lung artifacts is suggested.

On the Structure of Solid Lipid Nanoparticles.

Solid lipid nanoparticles (SLNs) have a crystalline lipid core which is stabilized by interfacial surfactants. SLNs are considered favorable candidates for drug delivery vehicles since their ability to store and release organic molecules can be tailored through the identity of the lipids and surfactants used. When stored, polymorphic transitions in the core of drug-loaded SLNs lead to the premature release of drug molecules. Significant experimental studies have been conducted with the aim of investigating the physicochemical properties of SLNs, however, no molecular scale investigations have been reported on the behaviors that drive SLN formation and their polymorphic transitions. A combination of small angle neutron scattering and all-atom molecular dynamics simulations is therefore used to yield a detailed atomistic description of the internal structure of an SLN comprising triglyceride, tripalmitin, and the nonionic surfactant, Brij O10 (C18:1 E10 ). The molecular scale mechanisms by which the surfactants stabilize the crystalline structure of the SLN lipid core are uncovered. By comparing these results to simulated liquid and solid aggregates of tripalmitin lipids, how the morphology of the lipids vary between these systems is demonstrated providing further insight into the mechanisms that control drug encapsulation and release from SLNs.

Magnetic high throughput screening system for the development of nano-sized molecularly imprinted polymers for controlled delivery of curcumin.

Curcumin is a versatile anti-inflammatory and anti-cancer agent known for its low bioavailability, which could be improved by developing materials capable of binding and releasing drug in a controlled fashion. The present study describes the preparation of magnetic nano-sized Molecularly Imprinted Polymers (nanoMIPs) for the controlled delivery of curcumin and their high throughput characterisation using microtitre plates modified with magnetic inserts. NanoMIPs were synthesised using functional monomers chosen with the aid of molecular modelling. The rate of release of curcumin from five polymers was studied under aqueous conditions and was found to correlate well with the binding energies obtained computationally. The presence of specific monomers was shown to be significant in ensuring effective binding of curcumin and to the rate of release obtained. Characterisation of the polymer particles was carried out using dynamic light scattering (DLS) technique and scanning electron microscopy (SEM) in order to establish the relationship between irradiation time and particle size. The protocols optimised during this study could be used as a blueprint for the development of nanoMIPs capable of the controlled release of potentially any compound of interest.

A contrast source method for nonlinear acoustic wave fields in media with spatially inhomogeneous attenuation.

Experimental data reveals that attenuation is an important phenomenon in medical ultrasound. Attenuation is particularly important for medical applications based on nonlinear acoustics, since higher harmonics experience higher attenuation than the fundamental. Here, a method is presented to accurately solve the wave equation for nonlinear acoustic media with spatially inhomogeneous attenuation. Losses are modeled by a spatially dependent compliance relaxation function, which is included in the Westervelt equation. Introduction of absorption in the form of a causal relaxation function automatically results in the appearance of dispersion. The appearance of inhomogeneities implies the presence of a spatially inhomogeneous contrast source in the presented full-wave method leading to inclusion of forward and backward scattering. The contrast source problem is solved iteratively using a Neumann scheme, similar to the iterative nonlinear contrast source (INCS) method. The presented method is directionally independent and capable of dealing with weakly to moderately nonlinear, large scale, three-dimensional wave fields occurring in diagnostic ultrasound. Convergence of the method has been investigated and results for homogeneous, lossy, linear media show full agreement with the exact results. Moreover, the performance of the method is demonstrated through simulations involving steered and unsteered beams in nonlinear media with spatially homogeneous and inhomogeneous attenuation.