Multivariate hyperspectral data analytics across length scales to probe compositional, phase, and strain heterogeneities in electrode materials.

The origins of performance degradation in batteries can be traced to atomistic phenomena, accumulated at mesoscale dimensions, and compounded up to the level of electrode architectures. Hyperspectral X-ray spectromicroscopy techniques allow for the mapping of compositional variations, and phase separation across length scales with high spatial and energy resolution. We demonstrate the design of workflows combining singular value decomposition, principal-component analysis, k-means clustering, and linear combination fitting, in conjunction with a curated spectral database, to develop high-accuracy quantitative compositional maps of the effective depth of discharge across individual positive electrode particles and ensembles of particles. Using curated reference spectra, accurate and quantitative mapping of inter- and intraparticle compositional heterogeneities, phase separation, and stress gradients is achieved for a canonical phase-transforming positive electrode material, α-V2O5. Phase maps from single-particle measurements are used to reconstruct directional stress profiles showcasing the distinctive insights accessible from a standards-informed application of high-dimensional chemical imaging.

Association of Back Pain with Mortality: a Systematic Review and Meta-analysis of Cohort Studies.

BACKGROUND: Back pain is the most common cause of disability worldwide. While disability generally is associated with greater mortality, the association between back pain and mortality is unclear. Our objective was to examine whether back pain is associated with increased mortality risk and whether this association varies by age, sex, and back pain severity. METHODS: A systematic search of published literature was conducted using PubMed, Web of Science, and Embase databases from inception through March 2019. We included English-language prospective cohort studies evaluating the association of back pain with all-cause mortality with follow-up periods >5 years. Three reviewers independently screened studies, abstracted data, and appraised risk of bias using the Quality in Prognosis Studies (QUIPS) tool. A random-effects meta-analysis estimated combined odds ratios (OR) and 95% confidence intervals (CI), using the most adjusted model from each study. Potential effect modification by a priori hypothesized factors (age, sex, and back pain severity) was evaluated with meta-regression and stratified estimates. RESULTS: We identified eleven studies with 81,337 participants. Follow-up periods ranged from 5 to 23 years. The presence of any back pain, compared to none, was not associated with an increase in mortality (OR, 1.06; 95% CI, 0.97 to 1.16). However, back pain was associated with mortality in studies of women (OR, 1.22; 95% CI, 1.02 to 1.46) and among adults with more severe back pain (OR, 1.26; 95% CI, 1.14 to 1.40). CONCLUSION: Back pain was associated with a modest increase in all-cause mortality among women and those with more severe back pain.

The Integrated Review: FDA Modernizes the Review of New Drug Marketing Applications.

New Drug Applications and Biologics Licensing Applications submitted to the US Food and Drug Administration (FDA) are reviewed by an interdisciplinary team of regulatory scientists that includes medical officers, clinical pharmacologists, toxicologists, statisticians, and drug labeling experts. Upon review of an applicant's submitted evidence from nonclinical studies, clinical trials, and manufacturing capabilities, the review team evaluates the benefits and risks of the drug and makes a scientifically-informed decision. As part of a multi-year, multi-phase New Drugs Regulatory Program Modernization effort, the FDA has recently redesigned how it reviews and documents its decisions with regard to marketing applications. This article describes the origins and rationale of the new Integrated Assessment process and Integrated Review document, summarizes how these differ from the FDA's traditional review of marketing applications, and discusses what industry can expect from a modernized drug review.

New Drugs Regulatory Program Modernization: Vision, Strategic Objectives, and Impact.

In response to a rapid increase in drug development activity during the past two decades, the Food and Drug Administration's Center for Drug Evaluation and Research launched a multi-year effort in 2017 to modernize the program by which new drug products are regulated, known as the New Drugs Regulatory Program. Following a detailed analysis of FDA activities in new drug development, premarket review, and postmarket monitoring, the Office of New Drugs was restructured to therapeutically align its clinical offices and to add new cross-functional offices for regulatory support. An interdisciplinary review process for new drug and biologics applications was rolled out to reduce redundancy and produce review documents that effectively communicate the scientific basis for the regulatory decision. The investigational new drug (IND) review process was also streamlined. During the next 2 years, the modernization initiative will seek to attract and retain new scientific and regulatory staff, improve postmarket safety monitoring, increase efficiency of drug review via technology-enabled workflows, and standardize the capture and use of scientific data to inform future regulatory decisions. The modernization effort will position the New Drugs Regulatory Program to continually improve and adapt to innovations in science, technology, and drug development.

Liquid Nitrogen Spray Cryotherapy is Associated With Less Postprocedural Pain Than Radiofrequency Ablation in Barrett's Esophagus: A Multicenter Prospective Study.

GOALS AND BACKGROUND: Two common endoscopic therapies for eradication of dysplastic Barrett's esophagus are radiofrequency ablation (RFA) and liquid nitrogen spray cryotherapy (LNC). There is no data comparing postprocedural pain. This study aimed to compare the incidence of postprocedural pain between the 2 ablation modalities. METHODS: This is a multicenter prospective study in which pain intensity scores and the presence of dysphagia were assessed immediately before and after treatment, 48 hours posttreatment and at 3 weeks posttreatment using validated instruments. RESULTS: Of 94 patients, 35 underwent LNC and 59 underwent RFA [36 with focal radiofrequency ablation (RFA-F) and 23 with circumferential radiofrequency ablation (RFA-C)]. Immediately posttreatment, patients in the LNC group reported an average Numeric Pain Scale score that was lower than in the RFA groups [LNC 0.41 vs. RFA-F 1.18 (P=0.026), LNC 0.41 vs. RFA-C 1.38 (P=0.010)]. These differences persisted at 48 hours posttreatment [LNC 0.76 vs. RFA-F 1.77 (P=0.013), LNC 0.76 vs. RFA-C 1.73 (P=0.018)]. The odds of pain after RFA were at least 5 times greater than after LNC [immediately posttreatment odds ratio, 5.26 (95% confidence interval, 1.85-14.29) and 48 h posttreatment odds ratio, 5.56 (95% confidence interval, 2.27-14.29)]. There was no difference in dysphagia after treatment in either group, at any time point (P=0.429). CONCLUSION: LNC was associated with less postprocedural pain when compared with RFA. These results help inform patients and physicians about the expected symptoms after ablative endotherapy.

Considerations for Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease.

Advances in our understanding of the molecular underpinnings of disease have spurred the development of targeted therapies and the use of precision medicine approaches in patient care. While targeted therapies have improved our capability to provide effective treatments to patients, they also present additional challenges to drug development and benefit-risk assessment such as identifying the subset(s) of patients likely to respond to the drug, assessing heterogeneity in response across molecular subsets of a disease, and developing diagnostic tests to identify patients for treatment. These challenges are particularly difficult to address when targeted therapies are developed to treat diseases with multiple molecular subtypes that occur at low frequencies. To help address these challenges, the US Food and Drug Administration recently published a draft guidance entitled "Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease." Here we provide additional information on specific aspects of targeted therapy development in diseases with low-frequency molecular subsets.

Thermal Properties of SiOC Glasses and Glass Ceramics at Elevated Temperatures.

In the present study, the effect of the chemical and phase composition on the thermal properties of silicon oxide carbides (SiOC) has been investigated. Dense monolithic SiOC materials with various carbon contents were prepared and characterized with respect to their thermal expansion, as well as thermal conductivity. SiOC glass has been shown to exhibit low thermal expansion (e.g., ca. 3.2 × 10-6 K-1 for a SiOC sample free of segregated carbon) and thermal conductivity (ca. 1.5 W/(m∙K)). Furthermore, it has been observed that the phase separation, which typically occurs in SiOC exposed to temperatures beyond 1000-1200 °C, leads to a decrease of the thermal expansion (i.e., to 1.83 × 10-6 K-1 for the sample above); whereas the thermal conductivity increases upon phase separation (i.e., to ca. 1.7 W/(m∙K) for the sample mentioned above). Upon adjusting the amount of segregated carbon content in SiOC, its thermal expansion can be tuned; thus, SiOC glass ceramics with carbon contents larger than 10-15 vol % exhibit similar coefficients of thermal expansion to that of the SiOC glass. Increasing the carbon and SiC content in the studied SiOC glass ceramics leads to an increase in their thermal conductivity: SiOC with relatively large carbon and silicon carbides (SiC) volume fractions (i.e., 12-15 and 20-30 vol %, respectively) were shown to possess thermal conductivities in the range from 1.8 to 2.7 W/(m∙K).