Development of Stabilizing Formulations of a Trivalent Inactivated Poliovirus Vaccine in a Dried State for Delivery in the Nanopatch™ Microprojection Array

The worldwide switch to inactivated polio vaccines (IPVs) is a key component of the overall strategy to achieve and maintain global polio eradication. To this end, new IPV vaccine delivery systems may enhance patient convenience and compliance. In this work, we examine Nanopatch? (a solid, polymer microprojection array) which offers potential advantages over standard needle/syringe administration including intradermal delivery and reduced antigen doses. Using trivalent IPV (tIPV) and a purpose-built evaporative dry-down system, candidate tIPV formulations were developed to stabilize tIPV during the drying process and on storage. Identifying conditions to minimize tIPV potency losses during rehydration and potency testing was a critical first step. Various classes and types of pharmaceutical excipients (～50 total) were then evaluated to mitigate potency losses (measured through D-antigen ELISAs for IPV1, IPV2, and IPV3) during drying and storage. Various concentrations and combinations of stabilizing additives were optimized in terms of tIPV potency retention, and 2 candidate tIPV formulations containing cyclodextrin and a reducing agent (e.g., glutathione), maintained ≥80% D-antigen potency during drying and subsequent storage for 4 weeks at 4°C, and ≥60% potency for 3 weeks at room temperature with the majority of losses occurring within the first day of storage.     

Coformulation of Broadly Neutralizing Antibodies 3BNC117 and PGT121: Analytical Challenges During Preformulation Characterization and Storage Stability Studies

In this study, we investigated analytical challenges associated with the formulation of 2 anti-HIV broadly neutralizing antibodies (bnAbs), 3BNC117 and PGT121, both separately at 100 mg/mL and together at 50 mg/mL each. The bnAb formulations were characterized for relative solubility and conformational stability followed by accelerated and real-time stability studies. Although the bnAbs were stable during 4°C storage, incubation at 40°C differentiated their stability profiles. Specific concentration-dependent aggregation rates at 30°C and 40°C were measured by size exclusion chromatography for the individual bnAbs with the mixture showing intermediate behavior. Interestingly, although the relative ratio of the 2 bnAbs remained constant at 4°C, the ratio of 3BNC117 to PGT121 increased in the dimer that formed during storage at 40°C. A mass spectrometry-based multiattribute method, identified and quantified differences in modifications of the Fab regions for each bnAb within the mixture including clipping, oxidation, deamidation, and isomerization sites. Each bnAb showed slight differences in the levels and sites of lysine residue glycations. Together, these data demonstrate the ability to differentiate degradation products from individual antibodies within the bnAb mixture, and that degradation rates are influenced not only by the individual bnAb concentrations but also by the mixture concentration.     

UniProt genomic mapping for deciphering functional effects of missense variants

Understanding the association of genetic variation with its functional consequences in proteins is essential for the interpretation of genomic data and identifying causal variants in diseases. Integration of protein function knowledge with genome annotation can assist in rapidly comprehending genetic variation within complex biological processes. Here, we describe mapping UniProtKB human sequences and positional annotations, such as active sites, binding sites, and variants to the human genome (GRCh38) and the release of a public genome track hub for genome browsers. To demonstrate the power of combining protein annotations with genome annotations for functional interpretation of variants, we present specific biological examples in disease‐related genes and proteins. Computational comparisons of UniProtKB annotations and protein variants with ClinVar clinically annotated single nucleotide polymorphism (SNP) data show that 32% of UniProtKB variants colocate with 8% of ClinVar SNPs. The majority of colocated UniProtKB disease‐associated variants (86%) map to 'pathogenic' ClinVar SNPs. UniProt and ClinVar are collaborating to provide a unified clinical variant annotation for genomic, protein, and clinical researchers. The genome track hubs, and related UniProtKB files, are downloadable from the UniProt FTP site and discoverable as public track hubs at the UCSC and Ensembl genome browsers.     

Quality Improvement Initiative to Reduce Nighttime Noise in a Transplantation and Cellular Therapy Unit

Sleep is an essential biologic function vital for physiologic rest, healing, and emotional well-being. Sleep disruption is commonly seen in patients and caregivers with lengthy hospital stays such as patients undergoing hematopoietic stem cell transplantation and cellular therapy (TCT). Sleep disruption can lead to increased stress and fatigue, affecting caregivers’ ability to support their loved one. The global aim of our quality improvement initiative was to improve sleep quality in TCT patients and caregivers. The smart aim of our project was to decrease nighttime hallway noise from 47 dB to 43 dB and decrease the number of overnight noise peaks greater than 60 dB from 865 to 432 in 6 months. Through a cross-sectional quantitative and qualitative evaluation of sleep we had previously identified poor sleep quality, and with a cross-sectional focus group analysis of patients, caregivers, and medical staff we identified the factors associated with poor sleep. Hallway noise was a major factor. A simplified failure mode analysis identified 4 main key drivers; unobtrusive nighttime cleaning process, nighttime awareness maintenance system, quiet nighttime nursing system, and reliable nighttime awareness system. Several plan-do-study-act interventions took place and were adopted. From January to June 2018 the overnight mean decibel level decreased from 47 dB to 44 dB (6% reduction). Overnight noise spikes above 60 dB decreased from a mean of 865 spikes to a mean of 463 spikes (46% reduction). With a quality improvement initiative, we identified the causes of hallway nighttime hospital unit noise that negatively impact sleep and through a team-based approach performed interventions that successfully mitigated these factors.     

A study of CdS nanoparticle surface states by potential-modulated sub-bandgap spectroscopy

The potential modulation spectrum of CdS Q-dots deposited on an optically transparent electrode has been investigated. A peak at 580 nm, that corresponded to bleaching of a sub-bandgap absorption, was observed. It was established that the peak was related to electron injection into the conduction band of the CdS Q-dots. The mechanism by which the absorption of surface states may be monitored using potential-modulated absorption spectroscopy is outlined.     

Perceived Cognitive Impairment among African American elders: health and functional impairments in daily life

Objectives: The Center for Disease Control began to assess Perceived Cognitive Impairment in 2009, yet there has been no in-depth study of how perceived decline in thinking or memory skills may be associated to the health and lifestyle of an independent community-dwelling older person. Among urban-dwelling older African Americans who are at elevated risk for cognitive impairment and dementia, we know even less regarding the interaction of these risk factors.Method: Five hundred and one African American elders (n = 501) between the ages of 55 and 95 with an average age of 70.73 years (SD = 8.6 years) participated in telephone interviews.Results: Approximately one-third of the elders reported that their memory, thinking skills, or ability to reason was worse than a year ago (n = 150; 29.9%) and 25% of this group (n = 38) reported that this Perceived Cognitive Impairment impacted their daily activities and/or warranted a consultation with their doctor. Bivariate analyses indicated that Perceived Cognitive Impairment was associated with increased health problems, mobility limitations, depressed mood, and lower social functioning.Conclusion: Elders who reported that cognitive problems impacted their daily functioning reported the greatest health and mental health problems. Perceived Cognitive Impairment is an important health variable with implications for an older adult's overall health, mobility, and mental health.     

Early experience of MAGEC magnetic growing rods in the treatment of early onset scoliosis

Purpose

Magnetically controlled growing rod systems have been introduced over recent years as an alternative to traditional growing rods for management of early onset scoliosis. The purpose of this paper is to report our early experience of a magnetically controlled growing rod system (MAGEC, Ellipse).

Methods

Review of pre-operative, postoperative and follow-up Cobb angles and spinal growth in case series of eight patients with a minimum 23 months’ follow-up (23–36 months).

Results

A total of six patients had dual rod constructs implanted and two patients received single-rod constructs. Four patients had MAGEC rods as a primary procedure. Four were revisions from other systems. Mean age at surgery in the primary group was 4.5 years (range 3.9–6.9). In patients who had MAGEC as a primary procedure, mean pre-operative Cobb angle was 74° (63–94), with postoperative Cobb angle of 42° (32–56) p ≤ 0.001 (43 % correction). Mean Cobb angle at follow-up was 42° (35–50). Spinal growth rate was 6 mm/year. One sustained proximal screw pull out. A final patient sustained a rod fracture. Mean age at surgery in the revision group was 10.9 years (range 9–12.6). Mean pre-operative Cobb angle was 45° (34–69). Postoperative Cobb angle was 42° (33–63) (2 % correction). Mean Cobb angle at follow-up was 44° (28–67). Mean spinal growth rate was 12 mm/year. Two patients developed loss of distraction.

Conclusion

MAGEC growing rod system effectively controls early onset scoliosis when used as either a primary or revision procedure. Although implant-related complications are not uncommon, the avoidance of multiple surgeries following implantation is beneficial compared with traditional growing rod systems.