IMPORTANCE: Sepsis is a heterogeneous syndrome. Identification of distinct clinical phenotypes may allow more precise therapy and improve care. OBJECTIVE: To derive sepsis phenotypes from clinical ...data, determine their reproducibility and correlation with host-response biomarkers and clinical outcomes, and assess the potential causal relationship with results from randomized clinical trials (RCTs). DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective analysis of data sets using statistical, machine learning, and simulation tools. Phenotypes were derived among 20 189 total patients (16 552 unique patients) who met Sepsis-3 criteria within 6 hours of hospital presentation at 12 Pennsylvania hospitals (2010-2012) using consensus k means clustering applied to 29 variables. Reproducibility and correlation with biological parameters and clinical outcomes were assessed in a second database (2013-2014; n = 43 086 total patients and n = 31 160 unique patients), in a prospective cohort study of sepsis due to pneumonia (n = 583), and in 3 sepsis RCTs (n = 4737). EXPOSURES: All clinical and laboratory variables in the electronic health record. MAIN OUTCOMES AND MEASURES: Derived phenotype (α, β, γ, and δ) frequency, host-response biomarkers, 28-day and 365-day mortality, and RCT simulation outputs. RESULTS: The derivation cohort included 20 189 patients with sepsis (mean age, 64 SD, 17 years; 10 022 50% male; mean maximum 24-hour Sequential Organ Failure Assessment SOFA score, 3.9 SD, 2.4). The validation cohort included 43 086 patients (mean age, 67 SD, 17 years; 21 993 51% male; mean maximum 24-hour SOFA score, 3.6 SD, 2.0). Of the 4 derived phenotypes, the α phenotype was the most common (n = 6625; 33%) and included patients with the lowest administration of a vasopressor; in the β phenotype (n = 5512; 27%), patients were older and had more chronic illness and renal dysfunction; in the γ phenotype (n = 5385; 27%), patients had more inflammation and pulmonary dysfunction; and in the δ phenotype (n = 2667; 13%), patients had more liver dysfunction and septic shock. Phenotype distributions were similar in the validation cohort. There were consistent differences in biomarker patterns by phenotype. In the derivation cohort, cumulative 28-day mortality was 287 deaths of 5691 unique patients (5%) for the α phenotype; 561 of 4420 (13%) for the β phenotype; 1031 of 4318 (24%) for the γ phenotype; and 897 of 2223 (40%) for the δ phenotype. Across all cohorts and trials, 28-day and 365-day mortality were highest among the δ phenotype vs the other 3 phenotypes (P < .001). In simulation models, the proportion of RCTs reporting benefit, harm, or no effect changed considerably (eg, varying the phenotype frequencies within an RCT of early goal-directed therapy changed the results from >33% chance of benefit to >60% chance of harm). CONCLUSIONS AND RELEVANCE: In this retrospective analysis of data sets from patients with sepsis, 4 clinical phenotypes were identified that correlated with host-response patterns and clinical outcomes, and simulations suggested these phenotypes may help in understanding heterogeneity of treatment effects. Further research is needed to determine the utility of these phenotypes in clinical care and for informing trial design and interpretation.
Non-aqueous redox flow batteries (NAqRFBs) employing redox-active organic molecules show promise to meet requirements for grid energy storage. Here, we combine the rational design of organic ...molecules with flow cell engineering to boost NAqRFB performance. We synthesize two highly soluble phenothiazine derivatives, N-(2-methoxyethyl)phenothiazine (MEPT) and N-2-(2-methoxyethoxy)ethylphenothiazine (MEEPT), via a one-step synthesis from inexpensive precursors. Synthesis and isolation of the radical-cation salts permit UV-vis decay studies that illustrate the high stability of these open-shell species. Cyclic voltammetry and bulk electrolysis experiments reveal the promising electrochemical properties of MEPT and MEEPT under dilute conditions. A high performance non-aqueous flow cell, employing interdigitated flow fields and carbon paper electrodes, is engineered and demonstrated; polarization and impedance studies quantify the cell's low area-specific resistance (3.2-3.3 Omega cm2). We combine the most soluble derivative, MEEPT, and its tetrafluoroborate radical-cation salt in the flow cell for symmetric cycling, evincing a current density of 100 mA cm-2 with undetectable capacity fade over 100 cycles. This coincident high current density and capacity retention is unprecedented in NAqRFB literature.
Abstract
Motivation
Metagenomic read classification is a critical step in the identification and quantification of microbial species sampled by high-throughput sequencing. Although many algorithms ...have been developed to date, they suffer significant memory and/or computational costs. Due to the growing popularity of metagenomic data in both basic science and clinical applications, as well as the increasing volume of data being generated, efficient and accurate algorithms are in high demand.
Results
We introduce MetaOthello, a probabilistic hashing classifier for metagenomic sequencing reads. The algorithm employs a novel data structure, called l-Othello, to support efficient querying of a taxon using its k-mer signatures. MetaOthello is an order-of-magnitude faster than the current state-of-the-art algorithms Kraken and Clark, and requires only one-third of the RAM. In comparison to Kaiju, a metagenomic classification tool using protein sequences instead of genomic sequences, MetaOthello is three times faster and exhibits 20-30% higher classification sensitivity. We report comparative analyses of both scalability and accuracy using a number of simulated and empirical datasets.
Availability and implementation
MetaOthello is a stand-alone program implemented in C ++. The current version (1.0) is accessible via https://doi.org/10.5281/zenodo.808941.
Supplementary information
Supplementary data are available at Bioinformatics online.
Synthetic chemists customarily tune the redox characteristics of π-conjugated molecules by introducing electron-donating or electron-withdrawing substituents onto the molecular core, or by modifying ...the length of the π-conjugated pathway. Any steric effects of such efforts on molecular geometry typically affect both the neutral and charged (oxidized or reduced) states indiscriminately. However, in electroactive systems that undergo significant conformational changes upon oxidation or reduction, we can leverage the steric and inductive effects of substitution to attain considerable control over individual redox potentials. Here, we make use of density functional theory to elucidate the interplay between electronic and geometric effects of peripheral substitution on the model system of phenothiazine. For instance, we introduce substituents at positions ortho to the nitrogen atom (positions 1 and 9) to induce steric strain in the radical-cation state without significant effect on the neutral molecule, thereby augmenting the overall ionization potential. Notably, this steric effect persists for electron-donating substituents; the resulting ionization potentials therefore deviate from outcomes foretold by Hammett constants. Moreover, the same procedure has limited effect on electron affinities because of differences in phenothiazines' relaxation process upon reduction compared to oxidation. Our results promote molecular design guidelines for manipulating redox potentials in classes of electroactive compounds that experience dramatic changes in geometry upon ionization.
Phenothiazine and five N‐substituted derivatives were evaluated as electrolyte additives for overcharge protection in LiFePO4/synthetic graphite lithium‐ion batteries. We report on the stability and ...reactivity of both the neutral and radical‐cation forms of these six compounds. While three of the compounds show extensive overcharge protection, the remaining three last for only one to a few cycles. UV/Vis studies of redox shuttle stability in the radical cation form are consistent with the overcharge performance: redox shuttles with spectra that show little change over time exhibit extensive overcharge performance, whereas those with changing spectra have limited overcharge protection. In one case, we determined that a CN bond cleaves upon oxidation, forming the phenothiazine radical cation and leading to premature overcharge protection failure; in another case, poor solubility appears to limit protection.
Redox shuttles are electrolyte additives that can prevent overcharge in batteries. They travel between the anode and cathode in their neutral and oxidized forms, mitigating excess current and stabilizing cell voltage. However, if the neutral or radical cation form of the shuttle decomposes, products can form that no longer protect the battery from overcharge, as is observed in the case of N‐tert‐butylphenothiazine.
A phenothiazine derivative with high solubility in carbonate solvents containing lithium salts showed extensive overcharge protection and, as a result, has been evaluated as a catholyte for ...non‐aqueous redox flow batteries. We report the testing of 3,7‐bis(trifluoromethyl)‐N‐ethylphenothiazine as a catholyte and 2,3,6‐trimethylquinoxaline as the anolyte in redox flow batteries containing 0.05, 0.15, and 0.35 M active material and found the longest capacity retention over about 60 cycles at 0.15 M. To our knowledge, this is the most soluble catholyte candidate with a robust radical cation.
Electro‐active materials are evaluated in stationary models of non‐aqueous redox flow batteries. On the left side, a phenothiazine derivative is oxidized to form its radical cation, and on the right, quinoxaline is reduced to form its radical anion, both part of the charging process. The cells survive for approximately 60 cycles at a concentration of 0.15 M electro‐active species.
Stable electron-donating organic compounds are of interest for numerous applications that require reversible electron-transfer reactions. Although many organic compounds are stable one-electron ...donors, removing a second electron from a small molecule to form its dication usually leads to rapid decomposition. For cost-effective electrochemical energy storage utilizing organic charge-storage species, the creation of high-capacity materials requires stabilizing more charge whilst keeping molecular weights low. Here we report the simple modification of N -ethylphenothiazine, which is only stable as a radical cation (not as a dication), and demonstrate that introducing electron-donating methoxy groups para to nitrogen leads to dramatically improved stability of the doubly oxidized (dication) state. Our results reveal that this derivative is more stable than an analogous compound with substituents that do not allow for further charge delocalization, rendering it a promising scaffold for developing atom-efficient, two-electron donors.
Herein we present the R package
rFSA
, which implements an algorithm for improved variable selection. The algorithm searches a data space for models of a user-specified form that are statistically ...optimal under a measure of model quality. Many iterations afford a set of
feasible solutions
(or candidate models) that the researcher can evaluate for relevance to his or her questions of interest. The algorithm can be used to formulate new or to improve upon existing models in bioinformatics, health care, and myriad other fields in which the volume of available data has outstripped researchers’ practical and computational ability to explore larger subsets or higher-order interaction terms. The package accommodates linear and generalized linear models, as well as a variety of criterion functions such as Allen’s PRESS and AIC. New modeling strategies and criterion functions can be adapted easily to work with
rFSA
.
The stability and reactivity of the multiple oxidation states of aromatic compounds are critical to the performance of these species as additives and electrolytes in energy-storage applications. Both ...for the overcharge mitigation in ion-intercalation batteries and as electroactive species in redox flow batteries, neutral, radical-cation, and radical-anion species may be present during charging and discharging processes. Despite the wide range of compounds evaluated for both applications, the progress identifying stable materials has been slow, limited perhaps by the overall lack of analysis of the failure mechanism when a material is utilized in an energy-storage device. In this study, we examined the reactivity of phenothiazine derivatives, which have found interest as redox shuttles in lithium-ion battery applications. We explored the products of the reactions of neutral compounds in battery electrolytes and the products of radical cation formation using bulk electrolysis and coin cell cycling. Following the failure of each cell, the electrolytes were characterized to identify redox shuttle decomposition products. Based on these results, a set of decomposition mechanisms is proposed and further explored using experimental and theoretical approaches. The results highlight the necessity to fully characterize and understand the chemical degradation mechanisms of the redox species in order to develop new generations of electroactive materials.
3,7-Disubstituted N-ethylphenothiazine derivatives were synthesized as redox shuttle candidates for lithium-ion batteries. Battery cycling results show that three derivatives prevent overcharge.
PDF
