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Dynamic compression of iron to Earth-core conditions is one of the few ways to gather important elastic and transport properties needed to uncover key mechanisms surrounding the geodynamo effect. Herein, a machine-learned ab initio derived molecular-spin dynamics (MSD) methodology with explicit treatment for longitudinal spin-fluctuations is utilized to probe the dynamic phase-diagram of iron. This framework uniquely enables an accurate resolution of the phase-transition kinetics and Earth-core elastic properties, as highlighted by compressional wave velocity and adiabatic bulk moduli measurements. In addition, a unique coupling of MSD with time-dependent density functional theory enables gauging electronic transport properties, critically important for resolving geodynamo dynamics., Competing Interests: Competing interests statement:The authors declare no competing interest.

Generating high magnetic fields requires materials with not only high electric conductivity but also good strength properties in order to withstand the necessarily strong Lorentz forces. A number of bi-metal composites, most notably Cu/Nb, are considered to be good candidates for this purpose. Here, we generalize our previous work on Cu/Nb in order to predict, from theory, the dependence of electric conductivity on the microstructure and volume fraction of the less conductive component for a number of other bi-metal composites. Together with information on strength properties (taken from previous literature), the conductivity information we provide in this work can help to identify new promising candidate materials (such as Cu/Nb, Cu/Ag, Cu/W, …) for magnet applications with the highest achievable field strengths.

Cocrystallizing a given molecule with another can be useful for adjusting the physical properties of molecules in the solid state. However, most combinations of molecules do not readily cocrystallize but form either one-component crystals or amorphous solids. Computational methods of crystal structure prediction can, in principle, identify the thermodynamically stable cocrystal and thus predict if molecules will cocrystallize or not. However, the pronounced polymorphism and tendency of many organic molecules to form disordered solids suggest that kinetic factors can play an important role in cocrystallization. The question remains: if a binary system of molecules has a thermodynamically stable cocrystal, will it indeed cocrystallize? To address this question, we simulate the crystallization of more than 2600 distinct pairs of chiral model molecules of similar size in 2D and calculate accurate crystal energy landscapes for all of them. Our analysis shows that thermodynamic criteria alone are unreliable in the prediction of cocrystallization. While the vast majority of cocrystals that form in our simulations are thermodynamically favorable, most coformer systems that have a thermodynamically stable cocrystal do not cocrystallize. We furthermore show that cocrystallization rates increase 3-fold when coformers are used that do not form well-ordered single-component crystals. Our results suggest that kinetic factors of cocrystallization are decisive in many cases.

Before the colonial period, California harboured more language variation than all of Europe, and linguistic and archaeological analyses have led to many hypotheses to explain this diversity 1 . We report genome-wide data from 79 ancient individuals from California and 40 ancient individuals from Northern Mexico dating to 7,400-200 years before present (BP). Our analyses document long-term genetic continuity between people living on the Northern Channel Islands of California and the adjacent Santa Barbara mainland coast from 7,400 years BP to modern Chumash groups represented by individuals who lived around 200 years BP. The distinctive genetic lineages that characterize present-day and ancient people from Northwest Mexico increased in frequency in Southern and Central California by 5,200 years BP, providing evidence for northward migrations that are candidates for spreading Uto-Aztecan languages before the dispersal of maize agriculture from Mexico 2-4 . Individuals from Baja California share more alleles with the earliest individual from Central California in the dataset than with later individuals from Central California, potentially reflecting an earlier linguistic substrate, whose impact on local ancestry was diluted by later migrations from inland regions 1,5 . After 1,600 years BP, ancient individuals from the Channel Islands lived in communities with effective sizes similar to those in pre-agricultural Caribbean and Patagonia, and smaller than those on the California mainland and in sampled regions of Mexico., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The physical intravenous Y-site compatibility of 15 different medications with highly concentrated neonatal and pediatric parenteral nutrition (PN) compounds is described, using existing and novel methods., Methods: PN formulations were developed based on common prescribing practices in a 400+-bed freestanding children's hospital. Medications at commonly used pediatric concentrations were mixed in a 1:1 ratio with both pediatric and neonatal PN formulations and incubated at room temperature for 4 h to simulate Y-site administration. Samples were then analyzed using the light obscuration (LO) technique, as recommended by United States Pharmacopeia (USP) chapter 788, in addition to novel flow imaging (FI) microscopy and backgrounded membrane imaging (BMI). Physical compatibility was determined using USP 788 particle count limits for all techniques., Results: Most combinations were found to be compatible per USP 788 thresholds. Pediatric PN was incompatible by at least two methods with cisatracurium 2 mg/ml, sildenafil 0.8 mg/ml, furosemide 10 mg/ml, and ketamine 10 mg/ml. Neonatal PN was incompatible by at least two methods with cisatracurium 2 mg/ml and furosemide 10 mg/ml. Overall, results for 20 of the 30 combinations (66%) agreed across all three methods. FI and BMI results agreed for 22 of 30 combinations. LO agreed with FI in 25 of 30 combinations, and BMI and LO results agreed in 23 of 30 combinations., Conclusion: Most combinations tested were found to be compatible across all methods. Novel methods of FI and BMI seem useful to further evaluate LO findings and improve accuracy of particle counts when assessing PN-medication combinations., (© 2022 American Society for Parenteral and Enteral Nutrition.)

Objective: To evaluate the physical intravenous Y-site compatibility of 29 combinations of medications at commonly used pediatric concentrations using both existing and novel techniques., Methods: Medication combinations included were selected by a varied group of pediatric inpatient pharmacists, and then assessed by 3 independent reviewers for existing literature. For each combination, 2 different medications were mixed together in a 1:1 ratio and incubated at room temperature for 4 hours to simulate Y-site administration. Each sample was then analyzed using the US Pharmacopeia (USP) <788> recommended analytical technique of light obscuration (LO) in addition to novel flow imaging (FI) microscopy and backgrounded membrane imaging (BMI). Physical compatibility was determined using USP chapter <788> large volume particle count limits for all techniques., Results: A total of 29 different medication combinations were studied. Five combinations met criteria for compatibility by all 3 techniques. The remaining 24 combinations reached the threshold to be considered incompatible by at least 1 of the 3 techniques. Light obscuration, BMI, and FI identified 14%, 59%, and 76% of combinations as incompatible, respectively. All samples deemed incompatible by LO were also incompatible by at least 1 of the other 2 techniques. Flow imaging and BMI results agreed in 69% of samples tested., Conclusions: Most combinations tested were found to be incompatible by at least 1 of the 3 instruments used. Light obscuration appears to have reduced accuracy for identifying particulate resulting in physical medication incompatibility when compared with the novel techniques of FI and BMI., Competing Interests: Disclosures. The authors declare no conflicts. The authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis., (Copyright. Pediatric Pharmacy Association. All rights reserved. For permissions, email: membership@pediatricpharmacy.org 2023.)

The application of surfactants in liquid protein formulation is a common practice to protect proteins from liquid-air interface-induced protein aggregation. Typically, Polysorbate 20 or 80 are used, but degradation of these surfactants can result in particle formation and/or protein degradation. The purpose of the current study was to directly compare three alternative protein stabilizing molecules - Poloxamer 188, hydroxypropyl-cyclodextrin and a trehalose-based surfactant - to Polysorbate 80 for their capacities to reduce agitation-induced protein aggregation and particle formation; and furthermore, investigate their underlying protein stabilizing mechanisms. To this end, a small-volume, rapid agitation stress approach was used to quantify the molecules' abilities to stabilize two model proteins. This assay was presented to be a powerful tool to screen the protein stabilizing capability of surfactants using minimum of material and time. SEC, turbidity measurements and particle analysis showed an efficient protein stabilization of all tested surfactants as well as cyclodextrin. STD-NMR and dynamic surface tension measurements indicated the competitive surface adsorption to be the main protein stabilizing mechanism of the three surfactants tested. It might also play a role to some extent in the protein stabilization by HPβCD. However, additional mechanisms might also contribute to protein stabilization leaving room for further investigations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

Purpose: Since particles are released in syringes during intravitreal injections, we assessed them quantitatively after agitating syringes commonly used for intravitreal injections., Methods: With and without agitation, the SR 1-ml insulin, Becton-Dickinson Ultra-Fine 0.3-ml Short Needle with a half-unit scale, HSW Norm-Ject Tuberculin, and Becton-Di-ckinson 1-ml Luer Lok Tip were examined with buffer and bevacizumab, aflibercept, and ziv-aflibercept. Flow imaging microscopy was performed to assess the particle numbers, concentrations, morphology, and size distribution., Results: Using the Becton-Dickinson Ultra-Fine syringe, the average particle count after agitation was higher than in the no-agitation group. For particles greater than 10 and 25 µm, differences were observed using the SR syringe between the two studied conditions. There were no significant differences in the means for the other syringes. Without agitation, the SR syringe had the highest number of particles (2,417,361.7 ± 3,421,575.5) followed by the Becton-Dickinson Ultra-Fine with 812.530,9 ± 996.187,2. The Becton-Dickinson Luer Lok Tip and HSW Norm-Ject performed equally with 398,396.8 ± 484,239.2 and 416,016.4 ± 242,650.1 particles, respectively., Conclusions: Flicking syringes to eliminate air bubbles results in increased numbers of particles released during intravitreal injections into the human vitreous.

Biological systems employ multimetallic assemblies to achieve a range of functions. Here we demonstrate the preparation of metal-organic cages that contain either homobimetallic or heterobimetallic vertices. These vertices are constructed using 2-formyl-6-diphenylphosphinopyridine, which forms ligands that readily bridge between a pair of metal centers, thus enforcing the formation of bimetallic coordination motifs. Two pseudo-octahedral homometallic M I 12 L 4 cages (M I = Cu I or Ag I ) were prepared, with a head-to-head configuration of their vertices confirmed by X-ray crystallography and multinuclear NMR for Ag I . The phosphino-pyridine subcomponent also enabled the formation of a class of octanuclear Cd II 4 Cu I 4 L 4 tetrahedral cages, representing an initial example of self-assembled cages containing well-defined heterobimetallic vertices.

In hospitals, often drug products in intravenous (IV) bags are transported via pneumatic tube systems (PTS). The goal of this study was to evaluate the effects of such transportation of protein products on particle formation in polyvinyl chloride (PVC) and polyolefin (PO) IV bags, containing either IV saline or dextrose. We studied intravenous immunoglobulin (IVIG) and a monoclonal antibody (mAb). Particles were quantified with flow imaging, light obscuration and nanoparticle tracking analysis. PTS transportation of IVIG caused large increases in protein particle concentrations, with much greater increases observed in saline than in dextrose. The increases were greater in IV solutions in PO than those in PVC bags. With the mAb, PTS transportation in saline caused increases in protein particle levels in PO bags, but not in PVC bags. Transportation in dextrose did not result in significant increases in mAb particle concentrations in IV bags made of either material. Overall, the results document that the PTS transportation can result in large increases in protein particles and that magnitude of these increases depends the protein itself, the bag material and the IV solution. The main conclusion is that protein products in IV solutions should not be transported in hospital PTS., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

SignificanceTirzepatide is a dual agonist of the glucose-dependent insulinotropic polypeptide receptor (GIPR) and the glucagon-like peptide-1 receptor (GLP-1R), which are incretin receptors that regulate carbohydrate metabolism. This investigational agent has proven superior to selective GLP-1R agonists in clinical trials in subjects with type 2 diabetes mellitus. Intriguingly, although tirzepatide closely resembles native GIP in how it activates the GIPR, it differs markedly from GLP-1 in its activation of the GLP-1R, resulting in less agonist-induced receptor desensitization. We report how cryogenic electron microscopy and molecular dynamics simulations inform the structural basis for the unique pharmacology of tirzepatide. These studies reveal the extent to which fatty acid modification, combined with amino acid sequence, determines the mode of action of a multireceptor agonist.

To reduce the risk of infection during intravitreal injections, the external surface of prefilled syringes (PFSs) must be sterilized. Usually, ethylene oxide (EO) gas or vaporized hydrogen peroxide (VHP) is used for sterilization. More recently, nitrogen dioxide (NO 2 ) gas sterilization has been developed. It is known that gas permeability is approximately zero into glass-PFSs. However, polymer-PFSs (P-PFSs) have relatively high gas permeability. Therefore, there are concerns about the potential impact of external surface sterilization on drug solutions in P-PFSs. In this study, P-PFSs [filled with water for injection (WFI) or human serum albumin (HSA) solution] were externally sterilized using EO, VHP, and NO 2 gases. For the WFI-filled syringes, the concentration of each gas that ingressed into the WFI was measured. For the HSA solution-filled syringes, the physical and chemical degradation of HSA molecules by each sterilant gas was quantified. For the EO- or VHP-sterilized syringes, the ingressed EO or hydrogen peroxide (H 2 O 2 ) molecules were detected in the filled WFI. Additionally, EO-adducted or oxidized HSA molecules were observed in the HSA-filled syringes. In contrast, the NO 2 -sterilized WFI-filled syringes exhibited essentially immeasurable ingressed NO 2 , and protein degradation was not detected in HSA-filled syringes., (Copyright © 2021. Published by Elsevier Inc.)

Kinetics can play an important role in the crystallization of molecules and can give rise to polymorphism, the tendency of molecules to form more than one crystal structure. Current computational methods of crystal structure prediction, however, focus almost exclusively on identifying the thermodynamically stable polymorph. Kinetic factors of nucleation and growth are often neglected because the underlying microscopic processes can be complex and accurate rate calculations are numerically cumbersome. In this work, we use molecular dynamics computer simulations to study simple molecular models that reproduce the crystallization behavior of real chiral molecules, including the formation of enantiopure and racemic crystals, as well as polymorphism. A significant fraction of these molecules forms crystals that do not have the lowest free energy. We demonstrate that at high supersaturation crystal formation can be accurately predicted by considering the similarities between oligomeric species in solution and molecular motifs in the crystal structure. For the case of racemic mixtures, we even find that knowledge of crystal free energies is not necessary and kinetic considerations are sufficient to determine if the system will undergo spontaneous chiral separation. Our results suggest conceptually simple ways of improving current crystal structure prediction methods.

Purpose: This study aimed to quantify the amount of silicone oil (SO) released across a variety of syringe and needle models routinely used for intravitreal injection., Methods: The release of SO was assessed in eight models of syringes, two of which were reported to be 'SO-free', and eleven models of needles with unknown SO content. To evaluate SO release within the context of anti-VEGF therapeutics, syringes were evaluated using aflibercept, bevacizumab, buffer, ziv-aflibercept and formulation buffer. All syringe tests were performed with or without agitation by flicking for syringes. Needles were evaluated without agitation only. Samples were fluorescently labelled to identify SO, and triplicate measurements were collected using imaging flow cytometry., Results: Seven out of 8 syringe models showed a statistically significant increase in the SO particle count after agitation. The two SO-free syringe models (HSW Norm-Ject, Daikyo Crystal Zenith) released the least SO particles, with or without agitation, whereas the BD Ultra-Fine and Saldanha-Rodrigues syringes released the most. More SO was released when the syringes were prefilled with formulation buffer than with ziv-aflibercept. Syringes filled with aflibercept and bevacizumab had intermediate levels. Agitation increased the release of SO into each of the drug solutions. Silicone oil (SO) was detected in all needles., Conclusions: Agitation of the syringe by flicking leads to a substantial increase in the number of SO particles. Silicone oil (SO)-free syringes had the best performance, but physicians must also be aware that needles are siliconized and also contribute to the injection of SO into the vitreous., (© 2021 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.)

Varicella vaccine meningitis is an uncommon delayed adverse event of vaccination. Varicella vaccine meningitis has been diagnosed in 12 children, of whom 3 were immunocompromised. We now report two additional cases of vaccine meningitis in twice-immunized immunocompetent children and we perform further testing on a prior third case. We used three methods to diagnose or investigate cases of varicella vaccine meningitis, none of which have been used previously on this disease. These include metagenomic next-generation sequencing and cytokine multiplex profiling of cerebrospinal fluid and immunology exome analysis of white blood cells. In one new case, the diagnosis was confirmed by metagenomic next-generation sequencing of cerebrospinal fluid. Both varicella vaccine virus and human herpesvirus 7 DNA were detected. We performed cytokine multiplex profiling on the cerebrospinal fluid of two cases and found ten elevated biomarkers: interferon gamma, interleukins IL-1RA, IL-6, IL-8, IL-10, IL-17F, chemokines CXCL-9, CXCL-10, CCL-2, and G-CSF. In a second new case, we performed immunology exome sequencing on a panel of 356 genes, but no errors were found. After a review of all 14 cases, we concluded that (i) there is no common explanation for this adverse event, but (ii) ingestion of an oral corticosteroid burst 3-4 weeks before onset of vaccine meningitis may be a risk factor in some cases.

This paper explores the potential contribution of timebanking, an innovative volunteering scheme, to the co-production of preventive social care with adults in England. Interest in volunteering in social care has increased as one proposed solution to the international crisis of a rising demand for services in juxtaposition with decreased resources. Volunteering has been particularly promoted in preventive services that prevent or delay care needs arising. Despite sustained interest in volunteering and co-production in social care, little is known about how theory translates into practice. Reporting implementation data from a Realistic Evaluation of six case studies in England, this paper explores one volunteering scheme, timebanking. The research explores how timebanks were working, what contribution they can make to adult social care, and whether they are an example of co-production. Data collected included interviews, focus groups or open question responses on surveys from 84 timebank members, and semi-structured interviews with 13 timebank staff. Each timebank was visited at least twice, and all timebank activity was analysed for a period of 12 months. Data were triangulated to improve reliability. The research found that in practice, timebanks were not working as described in theory, there were small numbers of person-to-person exchanges and some timebanks had abandoned this exchange model. Timebanks faced significant implementation challenges including managing risk and safeguarding and the associated bureaucracy, a paternalistic professional culture and the complexity of the timebank mechanism which required adequate resources. Lessons for timebanks are identified, as well as transferable lessons about co-production and volunteering in social care if such schemes are to be successful in the future., (© 2020 The Authors. Health and Social Care in the Community published by John Wiley & Sons Ltd.)

Low pH virus inactivation (VI) step is routinely used in antibody production manufacturing. In this work, a mimic of the VI step was developed to focus on evaluating adverse effects on product quality. A commercially available lab-scale glass reactor system was utilized to assess impacts of process and solution conditions on process-induced monoclonal antibody particle formation. Flow imaging was found to be more sensitive than light obscuration in detecting microparticles. NaOH as a base titrant increased protein microparticles more than Tris. Both stirring and NaCl accelerated particle formation, indicating that interfacial stress and protein colloidal stability were important factors. Polysorbate 80 was effective at suppressing particle formation induced by stirring. In contrast, trehalose led to higher microparticle levels suggesting a conformational stabilizer may have other adverse effects during titration with stirring. Additionally, conformational and colloidal stability of antibodies were characterized to investigate the potential roles of antibody physicochemical properties in microparticle formation during VI. The stability data were supportive in rationalizing particle formation behaviors, but they were not predictive of particle formation during the mimicked viral inactivation steps. Overall, the results demonstrate the value of testing various solution and processing conditions in a scaled-down system prior to larger-scale VI bioprocesses., (Copyright © 2021. Published by Elsevier Inc.)

Among patients that receive Remicade® therapy, more than 20% have adverse infusion related reactions and approximately 50% have immunogenic responses. 1-3 Upon characterization of initial Remicade®-IV solution we observed a high concentration of subvisible particles that could inadvertently be delivered to patients. This solution was processed through the IV infusion system, mimicking the typical clinical administration setup - either with or without an in-line filter connected to the IV line. The samples generated thereafter were tested using various in vitro assays for activation of the innate immune system via cytokine release in whole blood and in peripheral blood mononuclear cell (PBMC) cultures, and activation of the Toll like receptors (TLRs). Activation of the adaptive immune system was evaluated by monitoring upregulation of surface receptors on dendritic cells (DCs) and CD4+ T cell proliferation in response to IV solution of Remicade®. Our results indicate that subvisible particles in Remicade®-saline solution have a significant role in activation of the immune system but there are extrinsic factors potentially contributed by the in-line filters or other process parameters that also contribute to immune system activation., (Copyright © 2021 American Pharmacists Association. Published by Elsevier Inc. All rights reserved.)

In clinical decision making, myocardial viability is defined as myocardium in acute or chronic coronary artery disease and other conditions with contractile dysfunction but maintained metabolic and electrical function, having the potential to improve dysfunction upon revascularization or other therapy. Several pathophysiological conditions may coexist to explain this phenomenon. Cardiac imaging may allow identification of myocardial viability through different principles, with the purpose of prediction of therapeutic response and selection for treatment. This expert consensus document reviews current insight into the underlying pathophysiology and available methods for assessing viability. In particular the document reviews contemporary viability imaging techniques, including stress echocardiography, single photon emission computed tomography, positron emission tomography, cardiovascular magnetic resonance, and computed tomography and provides clinical recommendations for how to standardize these methods in terms of acquisition and interpretation. Finally, it presents clinical scenarios where viability assessment is clinically useful., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Dr. Serge N. Timasheff, our mentor and friend, passed away in 2019. This article is a collection of tributes from his postdoctoral fellows, friends, and daughter, who all have been associated with or influenced by him or his research. Dr. Timasheff is a pioneer of research on thermodynamic linkage between ligand interaction and macromolecular reaction. We all learned a great deal from Dr. Timasheff, not only about science but also about life., (© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2021.)

Background: The ambulatory arterial stiffness index (AASI) obtained during ambulatory blood pressure monitoring (ABPM) has been cited as an independent predictor of major adverse cardiovascular events (MACEs) including cardiovascular death, stroke and worsening chronic kidney disease (CKD) among mixed-sex adult populations. This study aimed to determine the relationship between AASI and MACE and its predictive precision in women., Methods: This work follows the guidelines of the STROBE initiative for cohort studies. This was a retrospective single-center observational study of adult women (aged 18 - 75 years), who underwent 24-h ABPM for the diagnosis of hypertension or its control. The primary endpoint was a composite MACE of cardiovascular death, acute limb ischemia, stroke, acute coronary syndrome (ACS), or progression to stage V CKD., Results: A total of 219 women aged 57.4 ± 13.3 years were followed up for a median (interquartile range (IQR)) of 25.5 (18.3 - 31.3) months. Overall, 16 (7.3%) patients suffered one or more MACE events. AASI was significantly higher in patients with known coronary artery disease (CAD), diabetes mellitus, peripheral vascular disease (PVD), heart failure, previous stroke, or transient ischemic attack (TIA). AASI was a significant predictor of MACE (area under the curve: 0.78; P < 0.001) with an optimal cut-off of ≥ 0.56. On Kaplan-Meier analysis AASI ≥ 0.56 was significantly associated with MACE (log-rank test, P < 0.001). The only independent predictors of MACE on Cox proportional hazard analysis were diabetes mellitus, low high-density lipoprotein (HDL) levels, cumulative AASI values, or AASI ≥ 0.56., Conclusions: An AASI of ≥ 0.56 is an independent predictor of MACE in women. A further validation study in a larger cohort of women is recommended., Competing Interests: We have no conflict of interest to declare., (Copyright 2021, Boos et al.)

Purpose: To assess the variability of silicone oil (SO) particles released across syringes from the same lot and the role of different needle gauges., Materials and Methods: Four syringe models and six needle models were assessed for SO release. About 50 microliters of a buffer solution were loaded into the syringe, needle or syringe/needle setup. The data were analyzed by imaging flow cytometry with fluorescently labeling for SO., Results: All syringe models had a high coefficient of variation in SO release across syringes from the same lot. The amount of SO was significantly greater in the syringe when the needle was attached. SO particles with the BD 30G needle attached to the syringe were statistically greater than the 27G counterpart ( p  = 0.005). None of the other comparisons was statistically different. Finally, the number of SO particles was higher in the syringe/needle setup than in needles only ( p  = 0.0024)., Conclusion: We found a high variability in SO content across syringes from the same lot. Additionally, there was no clear association between needle gauge and the number of SO particles, as well as their coefficient of variation. Finally, the needles accounted for a small number of SO particles in comparison to the combined syringe-needle setup.

Previous studies have reported silicone oil (SO) applied to needles and syringes in the vitreous of patients after intravitreal injections. We evaluated four syringes (SR 1-mL insulin, Saldanha-Rodrigues; BD 1-mL Tuberculin Slip Tip, Becton-Dickinson; BD Ultra-Fine 0.3 mL, HSW Norm-Ject Tuberculin, Henke Sass Wolf) and 10 needles (BD PrecisionGlide 27- and 30-gauge (G); BD Eclipse and JBP Nanoneedle 27-, 30-, 33- and 34-G; TSK Invisible Needle and 27 and 30-G Steriject Control Hub). The protein-free buffer samples injected into the syringes and needles under study were collected in an Eppendorf tube and taken to Flow imaging microscopy, that characterized the concentration and morphology of the microsized particles. The number of particles was analyzed. The coefficients of variation (CV) were the primary outcome. The Feltz and Miller test compared the CVs. The significance level was 5%. Numerous particles and high CVs were associated with both devices, needles and syringes; the comparisons among them did not reach significance. The BD Ultrafine 0.3 mL syringe (149.7%) had the highest CV and the SO-free HSW Norm-Ject (66.4%) syringe the lowest, and the TSK Invisible needle (149.5%) had the highest and the BD Precision Glide 30G needle (35.9%) needle the lowest. In conclusion, particle release, including those with SO morphology, varied greatly among instruments, even from the same lots, which is relevant considering that fewer particles are injected into some eyes compared with others.

A bis-urea-functionalized ditopic subcomponent assembled with 2-formylpyridine and Fe II , resulting in a dynamic library of metal-organic assemblies: an irregular Fe II 4 L 6 structure and three Fe II 2 L 3 stereoisomers: left- and right-handed helicates and a meso-structure. This library reconfigured in response to the addition of monosaccharide derivatives, which served as guests for specific library members, and the rate of saccharide mutarotation was also enhanced by the library. The (P) enantiomer of the Fe II 2 L 3 helical structure bound β-D-glucose selectively over α-D-glucose. As a consequence, the library collapsed into the (P)-Fe II 2 L 3 helicate following glucose addition. The α-D-glucose was likewise transformed into the β-D-anomer during equilibration and binding. Thus, β-D-glucose and (P)-3 amplified each other in the product mixture, as metal-organic and saccharide libraries geared together into a single equilibrating system., (© 2020 Wiley-VCH GmbH.)

Intravitreal injections have become the most commonly performed intraocular treatments worldwide. Because intravitreal injections may induce severe adverse events, such as infectious and noninfectious endophthalmitis, cataract, ocular hypertension, vitreous hemorrhage, or retinal detachment, appropriate awareness of the materials and techniques used are essential to reduce these sight-threatening complications. This review provides insights into the needles, syringes, silicone oil coating, sterilization methods, devices to assist intravitreal injections, scleral piercing techniques using needles, syringe handling, anesthesia, and safety issues related to materials and techniques. It is paramount that physicians be aware of every step involved in intravitreal injections and consider the roles and implications of all materials and techniques used. The ability to understand the theoretical and practical circumstances may definitely lead to state-of-the-art treatments delivered to patients. The most important practical recommendations are: choosing syringes with as little silicone oil as possible, or, preferably, none; avoiding agitation of syringes; awareness that most biologics (e.g., antiangiogenic proteins) are susceptible to changes in molecular properties under some conditions, such as agitation and temperature variation; understanding that improper materials and techniques may lead to complications after intravitreal injections, e.g., inflammation; and recognizing that some devices may contribute to an enhanced, safer, and faster intravitreal injection technique., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To determine the physical intravenous Y-site compatibility of 19 commonly used medications at pediatric concentrations with 3 different types of lipid emulsion., Methods: Medications at commonly used pediatric concentrations were mixed in a 1:1 ratio with lipid emulsions (Intralipid, Nutrilipid, and Smoflipid) and incubated at room temperature for 4 hours to simulate Y-site administration. Each sample was then diluted with particle-free water and analyzed using the analytical technique of light obscuration recommended in United States Pharmacopeia (USP) general information chapter 729 (USP <729>). Physical compatibility was determined by measuring the percentage of fat residing in globules larger than 5 µm (PFAT5) per USP <729> recommendations., Results: Most combinations tested were physically compatible based on USP <729> regulations. Incompatibilities differed for the different brands of lipid emulsion. The two combinations that met USP <729> criteria for physical incompatibility were cisatracurium 2 mg/mL with Intralipid and gentamicin 2 mg/mL with Smoflipid., Conclusion: Three different lipid emulsions were physically compatible at the Y site with the majority of medications tested. Data regarding Y-site compatibility for one lipid emulsion product cannot be safely extrapolated to another without additional testing., (© American Society of Health-System Pharmacists 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Objectives: Preoperative chemotherapy produces tumor shrinkage in most patients with locally advanced breast cancer, including some pathological complete responses (pCRs). We attempted this using a much less toxic sequential regimen, given with concurrent bevacizumab., Methods: Patients with locally advanced breast cancer received 3 intravenous doses each of preoperative sequential liposome encapsulated doxorubicin 25 mg/m 2 , paclitaxel 175 mg/m 2 , and cyclophosphamide 600 mg/m 2 , with concurrent bevacizumab every 2 weeks without growth factor support., Results: Between March 2008 and December 2009, 32 patients received treatment. There was no cardiotoxicity, and other toxicity was mild (no grade 4 or 5 toxicity). No long-term toxicity, including cardiotoxicity, has been observed. Every patient had ≥30% reduction in tumor size; 9 of 31 patients who completed chemotherapy had pCR at operation. Seven years later, 22 of 32 patients remain free of recurrence and 27 of 32 are alive., Conclusions: The preoperative chemotherapy used appears to be comparably effective, but much less toxic than that used in most conventional regimens and should be studied further. Concurrent treatment with bevacizumab (reported separately) did not provide any additional benefit.

The long-term stability of therapeutic protein products can be extended by freeze-drying. However, the freeze-drying process itself has several harmful stresses. A rationalized formulation design can significantly mitigate protein damage caused by freezing, dehydration and interfacial stresses of lyophilization and reconstitution. Recently, a continuous spin-freeze-drying concept was proposed as a more economical, controllable, flexible and qualitative alternative to batch freeze-drying. The purpose of this work is to compare spin-freeze-drying to traditional batch freeze-drying with regard to protein physical stability. The impacts of spinning, freezing and drying were investigated for both processing methods. Herewith, the interaction between these process phases and two common rational formulation strategies, (i.e. adding a disaccharide and a surfactant) was examined. Protein aggregates formed due to the process phase stresses were characterized with particle counting techniques and size exclusion chromatography. It was found that spin-freeze-drying exhibited essentially identical stresses causing comparable aggregation in all the process phases as compared to batch freeze-drying. Moreover, there were also analogous impacts of the formulation excipients. These observations led to the conclusion that similar freeze-drying formulation excipients and strategies tested for decades in batch freeze-drying of proteins can be utilized for spin-freeze-drying; in order to maintain protein stability during processing., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Varicella-zoster virus vaccination is recommended for virtually all young children in the United States, Canada, and several other countries. Varicella vaccine is a live attenuated virus that retains some of its neurotropic properties. Herpes zoster caused by vaccine virus still occurs in immunized children, although the rate is much lower than in children who had wild-type varicella. It was commonly thought that 2 varicella vaccinations would protect children against the most serious complication of meningitis following herpes zoster; however, 2 meningitis cases have already been published. We now report a third case of varicella vaccine meningitis and define risk factors shared by all 3 immunized adolescents. The diagnosis in cerebrospinal fluid in this third case was verified by amplifying and sequencing portions of the viral genome, to document fixed alleles found only in the vaccine strain. Viral antibody was also detected in the cerebrospinal fluid by confocal microscopy. When compared with the other 2 cases, remarkably all 3 were 14 years old when meningitis occurred. All 3 were treated with intravenous acyclovir, with complete recovery. The adolescent in our case report also had recurrent asthma, which was treated with both prednisone tablets and beclomethasone inhaler before onset of meningitis. When the 3 cases were considered together, they suggested that immunity to varicella-zoster virus may be waning sufficiently in some twice-immunized adolescents to make them vulnerable to varicella vaccine virus reactivation and subsequent meningitis. This complication rarely happens in children after wild-type varicella.

The literature on the egress of different herpesviruses after secondary envelopment is contradictory. In this report, we investigated varicella-zoster virus (VZV) egress in a cell line from a child with Pompe disease, a glycogen storage disease caused by a defect in the enzyme required for glycogen digestion. In Pompe cells, both the late autophagy pathway and the mannose-6-phosphate receptor (M6PR) pathway are interrupted. We have postulated that intact autophagic flux is required for higher recoveries of VZV infectivity. To test that hypothesis, we infected Pompe cells and then assessed the VZV infectious cycle. We discovered that the infectious cycle in Pompe cells was remarkably different from that of either fibroblasts or melanoma cells. No large late endosomes filled with VZV particles were observed in Pompe cells; only individual viral particles in small vacuoles were seen. The distribution of the M6PR pathway ( trans -Golgi network to late endosomes) was constrained in infected Pompe cells. When cells were analyzed with two different anti-M6PR antibodies, extensive colocalization of the major VZV glycoprotein gE (known to contain M6P residues) and the M6P receptor (M6PR) was documented in the viral highways at the surfaces of non-Pompe cells after maximum-intensity projection of confocal z-stacks, but neither gE nor the M6PR was seen in abundance at the surfaces of infected Pompe cells. Taken together, our results suggested that (i) Pompe cells lack a VZV trafficking pathway within M6PR-positive large endosomes and (ii) most infectious VZV particles in conventional cell substrates are transported via large M6PR-positive vacuoles without degradative xenophagy to the plasma membrane. IMPORTANCE The long-term goal of this research has been to determine why VZV, when grown in cultured cells, invariably is more cell associated and has a lower titer than other alphaherpesviruses, such as herpes simplex virus 1 (HSV1) or pseudorabies virus (PRV). Data from both HSV1 and PRV laboratories have identified a Rab6 secretory pathway for the transport of single enveloped viral particles from the trans -Golgi network within small vacuoles to the plasma membrane. In contrast, after secondary envelopment in fibroblasts or melanoma cells, multiple infectious VZV particles accumulated within large M6PR-positive late endosomes that were not degraded en route to the plasma membrane. We propose that this M6PR pathway is most utilized in VZV infection and least utilized in HSV1 infection, with PRV's usage being closer to HSV1's usage. Supportive data from other VZV, PRV, and HSV1 laboratories about evidence for two egress pathways are included., (Copyright © 2020 Girsch et al.)

This pilot study was conducted to analyze the quality of the antimicrobials sold in the street markets in Port-au-Prince, Haiti. A total of 258 packs containing antimicrobials were bought in 28 street markets in Port-au-Prince (Haiti). Tablets and contents of capsules included in 196 packs were analyzed using a Raman handheld spectrometer (NanoRAM of BWTEK, Model: BWS456-785) during the first quarter of 2019. Three out of 11 antimicrobials (Amoxicillin, Metronidazole, and Cotrimoxazole) had a high spectral match with an HQI ≥ 90 to the respective authentic medicine for more than 95% of their tablets/capsules. For six antimicrobials (Tetracycline, Erythromycin, Cloxacillin, Azithromycin, Clarithromycin, and the combination Amoxicillin + Clavulanic Acid) none of their tablets/capsules showed a sufficient spectral match with the authentic medicine. This finding indicates that these products sold in the markets did not contain the labeled drug and/or contained a degraded drug. In addition to the fact that prescription antimicrobials can be purchased in street markets, the present field study found that for most of them (including "Watch" antimicrobials according to the AWaRe classification) were substandard, which contributes to the present antimicrobials resistance epidemic.

Predicting the crystallization of chiral molecules from solution is a major challenge in the chemical sciences. In this paper, we use molecular dynamics computer simulations to study the crystallization of a family of coarse-grained models of chiral molecules with a broad range of molecular shapes and interactions. Our simulations reproduce the experimental crystallization behavior of real chiral molecules, including racemic and enantiopure crystals, as well as amorphous solids. Using efficient algorithms for the packing of shapes, we enumerate millions of low-energy crystal structures for each model and analyze the thermodynamic landscape of polymorphs. In agreement with recent conjectures, our analysis shows that the ease of crystallization is largely determined by the number of competing polymorphs with low free energy. We find that this number and, hence, crystallization outcomes depend on molecular interactions in a simple way: Strongly heterogeneous interactions across molecules promote crystallization and favor the spontaneous resolution of racemic mixtures. Our results help rationalize a number of experimental observations and can provide guidance for the design of molecules and experimental conditions for desired crystallization outcomes.

Filling pump operation is an important cause of particle formation in therapeutic protein formulations. The goals of the present study were to investigate the impacts of peristaltic filling pump tubing type, pump operating parameters (acceleration and velocity), and formulation on both nanoparticle and microparticle formation in water, placebo, and a 120 mg/mL mAb drug formulation. Microparticles were quantified using flow imaging microscopy and light obscuration, and nanoparticles were counted with nanoparticle tracking analysis. Pumping of all solutions through Pharmed® tubing resulted in much higher particle levels than processing with Accusil™ or Masterflex® tubing. Pump acceleration did not measurably affect particle levels in pumped solutions, but in some cases, a relatively high pumping velocity of 400 rpm enhanced nanoparticle formation. The presence of surfactants reduced pumping-induced particle formation in the mAb solution, and the effects of 4 different surfactants tested were similar. Biophysical properties (secondary and tertiary structure, and thermal stability) of the protein in solution were not altered by pumping. Overall, this study demonstrates that investigations of pumping parameters and formulations using both nanoparticle and microparticle measurement methods are important for understanding pumping-induced particle formation and developing effective control strategies., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Competing interests: None declared.

Protein-based medications are expensive and susceptible to damage from mechanical shock, which may occur during shipping to patients from pharmacies. Our objectives were to evaluate the performance of 2 packaging systems and to describe the mechanical shock that occurs during shipments. The packaging systems evaluated were boxes containing expanded polystyrene (EPS) or soft lint-like foam, prepared with and without polymer cooling packs. In laboratory-based studies, accelerometers measured g forces in boxes dropped from varying heights. Transportation studies evaluated the EPS cooler when sent to locations via 2 vendors. The relationship between drop height and maximum force vector was approximately linear for drop heights of 7.5″ through 30″, with lower magnitude forces at 45″ and 60″. Soft foam reduced force by 9.8 g on average compared to EPS (p < 0.009). The presence of polymer packs mitigated forces; frozen packs reduced forces by 28 g versus thawed packs (p < 0.001). Transportation experiments demonstrated most impacts were in the low (10-24 g) and low-medium (25-49 g) range (95% of all impacts). There was no difference between impacts during shipments with the vendors, and there was no correlation between distance traveled and number of impacts. Overall, mechanical shock during shipping is both prevalent and contingent upon the packing materials used., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Concerns regarding the impact of subvisible particulate impurities on the safety and efficacy of therapeutic protein products have led manufacturers to implement strategies to minimize protein aggregation and particle formation during manufacturing, storage, and shipping. However, once these products are released, manufacturers have limited control over product handling. In this work, we investigated the effect of di(2-ethylhexyl) phthalate (DEHP) nanodroplets generated in polyvinyl chloride (PVC) bags of intravenous (IV) saline on the stability and immunogenicity of IV immunoglobulin (IVIG) formulations. We showed that PVC IV bags containing saline can release DEHP droplets into the solution when agitated or transported using a pneumatic tube transportation system in a clinical setting. We next investigated the effects of emulsified DEHP nanodroplets on IVIG stability and immunogenicity. IVIG adsorbed strongly to DEHP nanodroplets, forming a monolayer. In addition, DEHP nanodroplets accelerated IVIG aggregation in agitated samples. The immunogenicity of DEHP nanodroplets and IVIG aggregates generated in these formulations were evaluated using an in vitro assay of complement activation in human serum. The results suggested DEHP nanodroplets shed from PVC IV bags could reduce protein stability and induce activation of the complement system, potentially contributing to adverse immune responses during the administration of therapeutic proteins., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The main goal of this study was to use state-of-the-art instruments for nanoparticle (nanoparticle tracking analysis and resonant mass measurement) and microparticle counting (flow imaging) to assess the effects of peristaltic filling pump operation on particle formation in formulations of intravenous immunoglobulin. Microparticle levels were also measured with light obscuration. Postpumping agitation was studied as an accelerated degradation method, 3 different commercial peristaltic tubing types were tested, and the effects of formulation pH and inclusion of polysorbate 80 were determined. Overall, the results documented that nanoparticle measurements, as well as microparticle determinations with flow imaging, were essential to gain rigorous insights into impacts of processing and formulation parameters on pumping- and agitation-induced particle formation. In addition, light obscuration was a relatively insensitive method and failed to detect large increases in protein particles caused by pumping and postpumping agitation. Formulation studies showed that the presence of polysorbate 80 or increasing protein colloidal stability with appropriate choice of buffer generally reduced particle formation. The results highlight the need for filling pump assessments in formulation development studies. Combining such assessments with appropriate analytical methods should help assure that particle levels are controlled during filling pump operation and that the highest quality products are manufactured., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The phase-appropriate application of analytical methods to characterize, monitor, and control particles is an important aspect of the development of safe and efficacious biotherapeutics. The AAPS Product Attribute and Biological Consequences (PABC) focus group (which has since transformed into an AAPS community) conducted a survey where participating labs rated their method of choice to analyze protein aggregation/particle formation during the different stages of the product life cycle. The survey confirmed that pharmacopeial methods and SEC are the primary methods currently applied in earlier phases of the development to ensure that a product entering clinical trials is safe and efficacious. In later phases, additional techniques are added including those for non-GMP extended characterization for product and process characterization. Finally, only robust, globally-accepted, and stability-indicating methods are used for GMP quality control purposes. This was also consistent with the feedback during a webinar hosted by the group to discuss the survey results. In this white paper, the team shares the results of the survey and provides guidance on selecting phase-appropriate analytical methods and developing a robust particle control strategy.

Protein fibrils are of great interest due to their involvement in several pathologies and their roles in the degradation of many therapeutic protein products. Fibrils share highly similar secondary structural motifs across different proteins and applied stress conditions. However, fibril morphology differs according to the surrounding conditions, with aromatic and hydrophobic amino acids playing important roles in mature fibril formation. In this study, we use Raman microscopy, by means of the aromatic amino acids in insulin molecules as markers, to probe for tertiary structure differences within fibrils. We compared 2 different fibril types, linear fibril bundles and spherulites. Generation of linear fibril bundles was undertaken in an acetic acid-containing formulation, whereas spherulites were generated in a hydrochloric acid-containing formulation. The Raman intensities of tyrosine and phenylalanine side chains suggest that there are significant differences between the fibril bundles. The findings suggest that the insulin components of the fibril strands are not arranged identically in the 2 fibril types and that this gives rise to differences in their tertiary structures. Overall, the work indicates that the physicochemical properties of fibril structures can be altered by changing the formulation and that these alterations can be monitored by Raman spectroscopy., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Here we describe the formation of a trigonal prismatic cage, utilizing 2-formyl-1,8-naphthyridine subcomponents to bind pairs of silver(I) ions in close proximity. This cage is the first example of a new class of subcomponent self-assembled polyhedral structures having bimetallic vertices, as opposed to the single metal centers that typically serve as structural elements within such cages. Our new cage self-assembles around a pair of anionic templates, which are shown by crystallographic and solution-phase data to bind within the central cavity of the structure. Many different anions serve as competent templates and guests. Elongated dianions, such as the strong oxidizing agent peroxysulfate, also serve to template and bind within the cavity of the prism. The principle of using subcomponents that have more than one spatially close, but nonchelating, binding site may thus allow access to other higher-order structures with multimetallic vertices.

The cavities of artificial receptors are defined by how their components fit together. The encapsulation of specific molecules can thus be engineered by considering geometric principles; however, intermolecular interactions and steric fit scale with receptor size, such that the ability to bind multiple guests from a specific class of compounds remains a current challenge. By employing metal-organic self-assembly, we have prepared a triangular prism from two different ligands that is capable of binding more than 20 different natural products, drugs, and steroid derivatives within its prolate cavity. Encapsulation inflates the host, enhancing its ability to bind other guests in peripheral pockets and thus enabling our system to bind combinations of different drug and natural product cargoes in different locations simultaneously. This new mode of entropically favorable self-assembly thus enables central encapsulation to amplify guest-binding events around the periphery of an artificial receptor.

The impact of drug conjugation on intra- and intermolecular interactions of trastuzumab (TmAb) was determined by comparing the conformational and colloidal stabilities of TmAb and trastuzumab emtansine (T-DM1). In low ionic strength formulations, drug conjugation to native lysine residues of TmAb significantly reduced the repulsive electrostatic interactions between T-DM1 molecules. When these electrostatic interactions were screened in solutions with high ionic strength, intermolecular interactions between T-DM1 molecules were found to be more attractive than those between TmAb molecules. Drug conjugation lowered the colloidal stability of T-DM1 compared to TmAb, making T-DM1 more susceptible to agitation-induced aggregation. The presence of polysorbate-20 in the formulations inhibited aggregation of TmAb and T-DM1 induced by the hydrophobic air-water interface. Furthermore, the effect of increased hydrophobic interactions between T-DM1 molecules was studied by monitoring aggregation in TmAb and T-DM1 solutions that were incubated at 4°C, 25°C, and 50°C. Conjugating DM1 to TmAb increased the hydrophobicity of the molecule, and faster aggregation of T-DM1 at 50°C could be attributed to a temperature-dependent increase in hydrophobic interactions between T-DM1 molecules., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Characterizing and quantifying subvisible particles in protein drug products is critical to ensuring product quality. A variety of analytical methods are used to detect and make meaningful measurements of subvisible particles. Resonant mass measurement (RMM) is a novel technology that characterizes the subvisible particle content of samples on a particle-by-particle basis. The technology presents great promise in the study of therapeutic protein products. As an emerging tool in the biopharmaceutical field, the best practices and limitations of RMM for protein products have not been well established. One key challenge of particle analysis is producing robust and reliable data, with high precision and accuracy, for particle characterization. In this study, we develop a set of possible best practices for RMM using a model protein system. We test the effects of these practices on the repeatability and reproducibility of particle measurements. Additionally, we present the data collected under a rigorously controlled set of operating conditions at 3 collaborating sites as well as a summary of the resulting optimal practices. In employing these practices, we successfully obtained improved relative standard deviation values and achieved high reproducibility and repeatability in both sizing and concentration measurement results over a broad range of sample volumes., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

The analysis of subvisible particles is currently challenging but pivotal to the understanding and control of the quality of protein therapeutics. While a range of characterization methods is available for subvisible particles, information on the protein conformation in a particle-considered a possible parameter in eliciting unwanted immunogenicity of protein therapeutics-is especially challenging in the lower micrometer range using existing analytical technologies. Using 6 different protein particle populations, we show that transmission Fourier transform infrared (FTIR) microscopy can determine protein secondary structure in single particles down to 10 μm. The analytical setup presented here is able to immobilize protein particles and obtain transmission FTIR spectra on individual protein particles in their intact aqueous environment. Spectra of dried particles, on the other hand, were found to occasionally differ from spectra of particles in aqueous environment. In summary, using the analytical setup described in this study, transmission FTIR microscopy uniquely provides information on single protein particles in particle populations in their aqueous environment without interference from the background protein solution., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Background: Systematic reviews of quantitative research on the effects of childhood epilepsy have established its association with higher levels of psychiatric diagnosis, externalizing and internalizing problems, lower health-related quality of life, social competence, and poorer academic achievements, compared with their peers. However, much less is known about young people's experiences of living with epilepsy and its impact on their development from their own perspectives., Methods: Semistructured interviews were conducted with 15 young people aged between 13 and 16 years. Participants were recruited as part of a larger mixed methods study examining individual and family influences on outcomes for young people with epilepsy. These young people attended an epilepsy clinic in KK Women's and Children's Hospital, Singapore. The framework approach to data management and analyses involved both inductive and deductive generation of themes., Results: Findings from young people's interviews provided in-depth descriptions of stressful circumstances encountered. Interconnectedness between severity of the impairment and its impact on key developmental tasks, such as independence, autonomy, and social development, were emphasized. Seizures and illness-related demands disrupted their day-to-day functioning and challenged their abilities to meet these tasks. In addition to these impairment effects, young people's experiences of social exclusion were also affected by social and environmental factors, which act as systemic barriers to participation. In turn, this has an effect on their self-esteem. Nevertheless, young people reported positive experiences, such as support from both family and friends, which served as protective factors against the stress of living with a chronic medical condition., Conclusion: The demands of epilepsy affect various domains of young people's lives. In order to obtain a holistic understanding of young people's inclusion or exclusion to participation, it is necessary to consider impairment effects, barriers to doing, and barriers to being., (© 2019 John Wiley & Sons Ltd.)

We report the preparation and characterization of charged nanoporous membranes by self-assembly of "hairy" silica nanoparticles (HNPs) functionalized with polyelectrolyte copolymer brushes. We show that HNP membranes possess high water flux, have well-defined pore sizes, and rejection up to 80% of charged species in solution. The properties of these membranes can be tuned by controlling the length and composition of polymer brushes and the electrolyte concentration in solution. We demonstrate that membrane pore sizes undergo changes of up to 40% in response to changes in the ionic strength of the salt solution. Using MD computer simulations of a coarse-grained model, we link these tunable properties to the conformations of polymer chains in the spaces between randomly packed HNPs. As polymer length increases, the polymers fill the interparticle gaps, and the pore size decreases markedly. On the basis of their straightforward fabrication and tunable properties, HNP membranes may find applications in size- and charge-selective separations, water desalination, and responsive devices.

To reduce the risk of immunogenicity that may be caused by therapeutic protein products, it is important to properly characterize subvisible particles and to develop strategies to reduce the levels of particles delivered to patients. In the present study, by using state-of-the-art methods to quantify particle levels, we found that the factor VIII product, Kogenate FS, contained relatively high levels of protein particles and silicone oil droplets, the vast majority of which were submicron in size. In a test of effects of product mishandling, the Kogenate FS vial was shaken instead of swirled during reconstitution. Levels of silicone oil droplets and protein particles were increased. In contrast, these levels were greatly reduced by 2 mitigation strategies tested, using a nonsiliconized syringe for the diluent container or using submicron pore size syringe filters during simulated infusion. Thus, to avoid potential adverse effects due to mishandling-induced increases in particle levels, it is important to educate end-users about proper product handling. Furthermore, effective particle mitigation and reduction strategies should be developed for factor VIII, and other therapeutic protein products. Such efforts could lead to clinically useful approaches to reduce the levels of particles delivered to patients and to an associated reduction in adverse immunogenicity., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)