BIRS Course: RNA Vaccine Manufacture and Assessment of Regulatory Documents for RNA Vaccines

This paper is in three segments: (A) Segment on Vaccine Manufacture; (B) Segment on Ready to Use (RTU) Fluid Path for Compounded Sterile Preparations, mRNA Vaccines, and Phage Therapy, (C) Segment on Competency Framework for Addressing Regulatory Review These segments can be used separately or in combination. Additionally, they can be presented in any order. The time devoted to each segment depends on the depth of the course coverage. These segments are interrelated and describe how to make vaccines, how to manufacture vaccines with a point-of-care system built from ready-to-use parts; and how to regulate vaccines. This is a timely review because of the importance of vaccines for the treatment of diseases. It is hoped that it will lead to new approaches to vaccine manufacture and regulation

Stable carbon and nitrogen isotope enrichment in primate tissues

Isotopic studies of wild primates have used a wide range of tissues to infer diet and model the foraging ecologies of extinct species. The use of mismatched tissues for such comparisons can be problematic because differences in amino acid compositions can lead to small isotopic differences between tissues. Additionally, physiological and dietary differences among primate species could lead to variable offsets between apatite carbonate and collagen. To improve our understanding of the isotopic chemistry of primates, we explored the apparent enrichment (ε*) between bone collagen and muscle, collagen and fur or hair keratin, muscle and keratin, and collagen and bone carbonate across the primate order. We found that the mean ε* values of proteinaceous tissues were small (≤1‰), and uncorrelated with body size or phylogenetic relatedness. Additionally, ε* values did not vary by habitat, sex, age, or manner of death. The mean ε* value between bone carbonate and collagen (5.6 ± 1.2‰) was consistent with values reported for omnivorous mammals consuming monoisotopic diets. These primate-specific apparent enrichment values will be a valuable tool for cross-species comparisons. Additionally, they will facilitate dietary comparisons between living and fossil primates

Clinical characteristics and outcomes of patients with heart failure with reduced ejection fraction and chronic obstructive pulmonary disease: insights from PARADIGM-HF

Background: Chronic obstructive pulmonary disease (COPD) is a common comorbidity in heart failure with reduced ejection fraction, associated with undertreatment and worse outcomes. New treatments for heart failure with reduced ejection fraction may be particularly important in patients with concomitant COPD. Methods and Results: We examined outcomes in 8399 patients with heart failure with reduced ejection fraction, according to COPD status, in the PARADIGM‐HF (Prospective Comparison of Angiotensin Receptor Blocker–Neprilysin Inhibitor With Angiotensin‐Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure) trial. Cox regression models were used to compare COPD versus non‐COPD subgroups and the effects of sacubitril/valsartan versus enalapril. Patients with COPD (n=1080, 12.9%) were older than patients without COPD (mean 67 versus 63 years; P<0.001), with similar left ventricular ejection fraction (29.9% versus 29.4%), but higher NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide; median, 1741 pg/mL versus 1591 pg/mL; P=0.01), worse functional class (New York Heart Association III/IV 37% versus 23%; P<0.001) and Kansas City Cardiomyopathy Questionnaire–Clinical Summary Score (73 versus 81; P<0.001), and more congestion and comorbidity. Medical therapy was similar in patients with and without COPD except for beta‐blockade (87% versus 94%; P<0.001) and diuretics (85% versus 80%; P<0.001). After multivariable adjustment, COPD was associated with higher risks of heart failure hospitalization (hazard ratio [HR], 1.32; 95% CI, 1.13–1.54), and the composite of cardiovascular death or heart failure hospitalization (HR, 1.18; 95% CI, 1.05–1.34), but not cardiovascular death (HR, 1.10; 95% CI, 0.94–1.30), or all‐cause mortality (HR, 1.14; 95% CI, 0.99–1.31). COPD was also associated with higher risk of all cardiovascular hospitalization (HR, 1.17; 95% CI, 1.05–1.31) and noncardiovascular hospitalization (HR, 1.45; 95% CI, 1.29–1.64). The benefit of sacubitril/valsartan over enalapril was consistent in patients with and without COPD for all end points. Conclusions: In PARADIGM‐HF, COPD was associated with lower use of beta‐blockers and worse health status and was an independent predictor of cardiovascular and noncardiovascular hospitalization. Sacubitril/valsartan was beneficial in this high‐risk subgroup. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01035255

Proceedings of the 3rd Biennial Conference of the Society for Implementation Research Collaboration (SIRC) 2015: advancing efficient methodologies through community partnerships and team science

It is well documented that the majority of adults, children and families in need of evidence-based behavioral health interventionsi do not receive them [1, 2] and that few robust empirically supported methods for implementing evidence-based practices (EBPs) exist. The Society for Implementation Research Collaboration (SIRC) represents a burgeoning effort to advance the innovation and rigor of implementation research and is uniquely focused on bringing together researchers and stakeholders committed to evaluating the implementation of complex evidence-based behavioral health interventions. Through its diverse activities and membership, SIRC aims to foster the promise of implementation research to better serve the behavioral health needs of the population by identifying rigorous, relevant, and efficient strategies that successfully transfer scientific evidence to clinical knowledge for use in real world settings [3]. SIRC began as a National Institute of Mental Health (NIMH)-funded conference series in 2010 (previously titled the “Seattle Implementation Research Conference”; $150,000 USD for 3 conferences in 2011, 2013, and 2015) with the recognition that there were multiple researchers and stakeholdersi working in parallel on innovative implementation science projects in behavioral health, but that formal channels for communicating and collaborating with one another were relatively unavailable. There was a significant need for a forum within which implementation researchers and stakeholders could learn from one another, refine approaches to science and practice, and develop an implementation research agenda using common measures, methods, and research principles to improve both the frequency and quality with which behavioral health treatment implementation is evaluated. SIRC’s membership growth is a testament to this identified need with more than 1000 members from 2011 to the present.ii SIRC’s primary objectives are to: (1) foster communication and collaboration across diverse groups, including implementation researchers, intermediariesi, as well as community stakeholders (SIRC uses the term “EBP champions” for these groups) – and to do so across multiple career levels (e.g., students, early career faculty, established investigators); and (2) enhance and disseminate rigorous measures and methodologies for implementing EBPs and evaluating EBP implementation efforts. These objectives are well aligned with Glasgow and colleagues’ [4] five core tenets deemed critical for advancing implementation science: collaboration, efficiency and speed, rigor and relevance, improved capacity, and cumulative knowledge. SIRC advances these objectives and tenets through in-person conferences, which bring together multidisciplinary implementation researchers and those implementing evidence-based behavioral health interventions in the community to share their work and create professional connections and collaborations

The physical state of solutes in frozen and freeze dried systems

The phase behavior of glycine during freezing and freeze drying was studied as a function of the glycine salt form, pH, and ionic strength. Glycine hydrochloride and sodium glycinate solutions adjusted to pH 7 crystallized slowly from frozen solution, forming a mixture of the $\beta$ and $\gamma$-polymorphs of neutral glycine. Neutral glycine and sodium chloride mixtures crystallized slowly from frozen solutions forming a mixture of the $\beta$ and $\gamma$ polymorphs. The data suggest that adding sodium chloride to a neutral glycine solution slows the rate of crystallization which favors the formation of the $\gamma$-polymorph over the $\beta$-polymorph. Glycine hydrochloride was used as a model compound to study the kinetics of solute crystallization from \u27frozen\u27 solution. Glycine hydrochloride undergoes crystallization from the \u27frozen\u27 solution relatively slowly when annealed. The crystallization of glycine hydrochloride proceeds via a Prout-Tompkin\u27s model, indicating crystal growth from nuclei formed during the freezing process. The temperature dependence of the crystallization rate in the temperature range between -37\sp\circC to -70\sp\circC follows Arrhenius kinetics, as opposed to William-Landel-Ferry kinetics. The state behavior of lyotropic liquid crystals was studied using nafcillin sodium and methylprednisolone sodium succinate as model solutes. Concentrated solutions of both solutes showed birefringent textures when observed through crossed-polarized light, indicating the formation of lyotropic liquid crystals. Differential scanning calorimetry (DSC) thermograms of nafcillin sodium and methylprednisolone sodium succinate solutions contained endotherms at -5.5\sp\circC and -3.5\sp\circC, respectively, corresponding to melting of the liquid crystalline structure. X-ray powder diffractograms (XRD) of freeze-dried nafcillin sodium and methylprednisolone sodium succinate were indicative of smectic type A liquid crystals. The data suggest solutes which form lyotropic liquid crystals in solution may form \u27dried\u27 lyotropic liquid crystalline powders when freeze dried. Finally, manometric temperature measurement was evaluated as a non-invasive method of monitoring product temperature during the primary drying phase of lyophilization. The experimental transient pressure response data were fitted to a mathematical equation which described the transient pressure response and the calculated manometric temperature compared to thermocouple measurements. Manometrically measured temperatures were consistently lower than the thermocouple measurements, as would be expected from the temperature gradient across the cake

President's address and tenth anniversary reports of Milton Historical Society : a record of the Society's first ten years.

President: Nathaniel T. Kidder.Cover title.Mode of access: Internet