An Early Warning Tool for Predicting Mortality Risk of COVID-19 Patients Using Machine Learning.

COVID-19 pandemic has created an extreme pressure on the global healthcare services. Fast, reliable, and early clinical assessment of the severity of the disease can help in allocating and prioritizing resources to reduce mortality. In order to study the important blood biomarkers for predicting disease mortality, a retrospective study was conducted on a dataset made public by Yan et al. in [1] of 375 COVID-19 positive patients admitted to Tongji Hospital (China) from January 10 to February 18, 2020. Demographic and clinical characteristics and patient outcomes were investigated using machine learning tools to identify key biomarkers to predict the mortality of individual patient. A nomogram was developed for predicting the mortality risk among COVID-19 patients. Lactate dehydrogenase, neutrophils (%), lymphocyte (%), high-sensitivity C-reactive protein, and age (LNLCA)-acquired at hospital admission-were identified as key predictors of death by multi-tree XGBoost model. The area under curve (AUC) of the nomogram for the derivation and validation cohort were 0.961 and 0.991, respectively. An integrated score (LNLCA) was calculated with the corresponding death probability. COVID-19 patients were divided into three subgroups: low-, moderate-, and high-risk groups using LNLCA cutoff values of 10.4 and 12.65 with the death probability less than 5%, 5-50%, and above 50%, respectively. The prognostic model, nomogram, and LNLCA score can help in early detection of high mortality risk of COVID-19 patients, which will help doctors to improve the management of patient stratification.

2017 Bangladesh landslides: physical rehabilitation perspective.

PURPOSE: This report describes the general impact and direct health effects including death and traumatic injuries on populations impacted by the 2017 landslides in the affected hilly and coastal districts in southeastern Bangladesh. The medical response including emergency treatment and rehabilitation provided at pre-hospital and hospital care sites is also described. MATERIALS AND METHODS: An electronic literature search of appropriate databases was performed to identify relevant articles on landslides in Bangladesh, Southeast Asia, and other developing countries from 1990-2017. Summary landslide impact data was extracted from official government and non-government reports and injury data from selected district and tertiary level hospitals was reviewed. RESULTS AND CONCLUSIONS: Most fatalities in the 2017 Bangladesh landslides were due to suffocation and asphyxiation from burial. In Rangamati District, 6343 persons with minor injuries were treated in 22 emergency shelters. One hundred fifty-four injuries were treated at Rangamati General Hospital and 12 of the most severely injured persons were referred to regional tertiary Chittagong Medical College Hospital for specialized injury and rehabilitation management. Physical rehabilitation capacity and services in future landslides may be increased by providing rehabilitation technical skills training to responders and augmenting the emergency response with individual rehabilitation specialists and/or teams of rehabilitation professionals.Implications for rehabilitationLandslides may result in significant direct health effects including death and rehabilitation conditions such as severe traumatic physical injuries and less severe musculoskeletal conditions.Pre-hospital and hospital emergency medical response systems may lack capacity to adequately manage the surge of rehabilitation conditions in landslides.Physical rehabilitation treatment capacity in future landslides may be increased by providing rehabilitation technical skills training to responders and augmenting the emergency response structure with individual rehabilitation specialists and/or teams of rehabilitation professionals.Rehabilitation, disability, emergency management, and other stakeholders are advised to employ such training and workforce strategies to reduce rehabilitation-related health effects in Bangladesh and other South-East Asian countries which are heavily impacted by landslides due to seasonal monsoons.

Emergence, ecology and dispersal of the pandemic generating Vibrio cholerae lineage.

Although cholera is an ancient disease that first arose at least half a millennium ago, it remains a major health threat globally. Its pandemic form is caused by strains from a single lineage of the bacterium Vibrio cholerae. The ancestor of this lineage harbored several distinctive characteristics, the most notable being the O1 antigen polysaccharide. This lineage generated two biotypes, first Classical, responsible for six pandemics, and later El Tor, responsible for the seventh and ongoing pandemic. Just as El Tor replaced Classical as the main cause of outbreaks in the last fifty years, several variants of El Tor have evolved and displaced their predecessors worldwide. Understanding the ecology, evolution and dispersal of pandemic V. cholerae is central to studying this complex disease with environmental reservoirs. Here, we present recent advancements of our knowledge on the emergence and spread of the pandemic generating lineage of V. cholerae in the light of established eco-evolutionary observations. Specific ecological interactions shape seasonal cholera, playing a role in the abundance and distribution of its causative agent. Both species-specific and lineage-specific genetic determinants play a role in the ability of V. cholerae strains to cause pandemics with seasonal outbreaks, having evolved gradually over centuries. On the basis of the current understanding, we outline future threats and changes in biogeographical and genomic-based investigation strategies to combat this global problem.

Rate of cesarean delivery at hospitals providing emergency obstetric care in Bangladesh.

OBJECTIVE: To assess the rate of cesarean delivery and its indications at public emergency obstetric care (EmOC) hospitals in a district in Bangladesh. METHODS: In a retrospective, cross-sectional study, data were extracted from the Safe Motherhood Promotion Project database and operation theater registers for cesarean deliveries at three district and three subdistrict EmOC hospitals in Narsingdi between January 1 and December 31, 2008. Information on cesarean deliveries and their indications, and maternal and neonatal outcomes were analyzed descriptively. RESULTS: Among 3329 deliveries, 1075 (32.3%) occurred by cesarean. The frequency of cesarean delivery ranged from 17.8% (147 of 824 deliveries) to 56.3% (174 of 309) among the six hospitals. Information on indications was available for 1043 cesarean deliveries. The main indications were previous cesarean delivery (251 deliveries, 24.1%), fetal distress (228, 21.9%), and prolonged or obstructed labor (214, 20.5%). There were no maternal deaths, but 10 (1.0%) cesarean deliveries resulted in stillbirth. CONCLUSION: The overall rate of cesarean delivery was high at EmOC hospitals. Interventions to improve decision making and limit possible unnecessary cesarean operations are needed.

Protannotator: a semiautomated pipeline for chromosome-wise functional annotation of the "missing" human proteome.

The chromosome-centric human proteome project (C-HPP) aims to define the complete set of proteins encoded in each human chromosome. The neXtProt database (September 2013) lists 20,128 proteins for the human proteome, of which 3831 human proteins (∼19%) are considered "missing" according to the standard metrics table (released September 27, 2013). In support of the C-HPP initiative, we have extended the annotation strategy developed for human chromosome 7 "missing" proteins into a semiautomated pipeline to functionally annotate the "missing" human proteome. This pipeline integrates a suite of bioinformatics analysis and annotation software tools to identify homologues and map putative functional signatures, gene ontology, and biochemical pathways. From sequential BLAST searches, we have primarily identified homologues from reviewed nonhuman mammalian proteins with protein evidence for 1271 (33.2%) "missing" proteins, followed by 703 (18.4%) homologues from reviewed nonhuman mammalian proteins and subsequently 564 (14.7%) homologues from reviewed human proteins. Functional annotations for 1945 (50.8%) "missing" proteins were also determined. To accelerate the identification of "missing" proteins from proteomics studies, we generated proteotypic peptides in silico. Matching these proteotypic peptides to ENCODE proteogenomic data resulted in proteomic evidence for 107 (2.8%) of the 3831 "missing proteins, while evidence from a recent membrane proteomic study supported the existence for another 15 "missing" proteins. The chromosome-wise functional annotation of all "missing" proteins is freely available to the scientific community through our web server (http://biolinfo.org/protannotator).

NMR measure of translational diffusion and fractal dimension. Application to molecular mass measurement.

Experimental NMR diffusion measure on polymers and on globular proteins are presented. These results, complemented with results found in the literature, enable a general description of effective fractal dimension for objects such as small organic molecules, sugars, polymers, DNA, and proteins. Results are compared to computational simulations as well as to theoretical values. A global picture of the diffusion phenomenon emerges from this description. A power law relating molecular mass with diffusion coefficients is described and found to be valid over 4 orders of magnitude. From this law, the fractal dimension of the molecular family can be measured, with experimental values ranging from 1.41 to 2.56 in full agreement with theoretical approaches. Finally, a method for evaluating the molecular mass of unknown solutes is described and implemented as a Web page.

Asymmetrical flow field-flow fractionation coupled with multi-angle light scattering and refractive index detections for characterization of ultra-high molar mass poly(acrylamide) flocculants.

The molar mass distributions of ultra-high molar mass polyacrylamide-based flocculants were measured using asymmetrical flow field-flow fractionation (AFFFF) coupled with multi-angle light scattering and refractive index detectors. The mass load onto the separation channel was found to be critical in obtaining a good size separation. The detailed investigation with ultra-high molar mass polyacrylamides found that the injected amount should be

Interaction of polycationic polymers with supported lipid bilayers and cells: nanoscale hole formation and enhanced membrane permeability.

Interactions of polycationic polymers with supported 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) lipid bilayers and live cell membranes (KB and Rat2) have been investigated using atomic force microscopy (AFM), cytosolic enzyme assays, confocal laser scanning microscopy (CLSM), and a fluorescence-activated cell sorter (FACS). Polycationic polymers poly-L-lysine (PLL), polyethylenimine (PEI), and diethylaminoethyl-dextran (DEAE-DEX) and sphere-like poly(amidoamine) (PAMAM) dendrimers are employed because of their importance for gene and drug delivery. AFM studies indicate that all the polycationic polymers cause the formation and/or expansion of preexisting defects in supported DMPC bilayers in the concentration range of 1-3 microg/mL. By way of contrast, hydroxyl-containing neutral linear poly(ethylene glycol) (PEG) and poly(vinyl alcohol) (PVA) do not induce hole formation or expand the size of preexisting defects in the same concentration range. All polymers tested are not toxic to KB or Rat2 cells up to a 12 microg/mL concentration (XTT assay). In the concentration range of 6-12 microg/mL, however, significant amounts of the cytosolic enzymes lactate dehydrogenase (LDH) and luciferase (LUC) are released. PEI, which possesses the greatest density of charged groups on its chain, shows the most dramatic increase in membrane permeability. In addition, treatment with polycationic polymers allows the small dye molecules propidium idodide (PI) and fluorescein (FITC) to diffuse in and out of the cells. CLSM images also show internalization of PLL labeled with FITC dye. In contrast, controls of membrane permeability using the neutral linear polymers PEG and PVA show dramatically less LDH and LUC leakage and no enhanced dye diffusion. Taken together, these data are consistent with the hypothesis that polycationic polymers induce the formation of transient, nanoscale holes in living cells and that these holes allow a greatly enhanced exchange of materials across the cell membrane.

Electrophoretic mobility and molecular distribution studies of poly(amidoamine) dendrimers of defined charges.

Generation 5 ethylenediamine (EDA)-cored poly(amidoamine) (PAMAM) dendrimers (E5, E denotes the EDA core and 5 the generation number) with different degrees of acetylation and carboxylation were synthesized and used as a model system to investigate the effect of charge and the influence of dendrimer surface modifications on electrophoretic mobility (EM) and molecular distribution. The surface-modified dendrimers were characterized by size-exclusion chromatography, 1H NMR, MALDI-TOF-MS, PAGE, and CE. The focus of our study was to determine how EM changes as a function of particle charge and molecular mass, and how the molecular distribution changes due to surface modifications. We demonstrate that partially modified dendrimers have much broader migration peaks than those of fully surface functionalized or unmodified E5 dendrimers due to variations in the substitution of individual dendrimer surfaces. EM decreased nonlinearly with increases in surface acetylation for both PAMAM acetamides and PAMAM succinamic acids, indicating a complex migration activity in CE separations that is not solely due to charge/mass ratio changes. These studies provide new insights into dendrimer properties under an electric field, as well as into the characterization of dendrimer-based materials being developed for medical applications.

Molecular heterogeneity analysis of poly(amidoamine) dendrimer-based mono- and multifunctional nanodevices by capillary electrophoresis.

Poly(amidoamine) (PAMAM) dendrimer-based nanodevices are of recent interest in targeted cancer therapy. Characterization of mono- and multifunctional PAMAM-based nanodevices remains a great challenge because of their molecular complexity. In this work, various mono- and multifunctional nanodevices based on PAMAM G5 (generation 5) dendrimer were characterized by UV-Vis spectrometry, (1)H NMR, size exclusion chromatography (SEC), and capillary electrophoresis (CE). CE was extensively utilized to measure the molecular heterogeneity of these PAMAM-based nanodevices. G5-FA (FA denotes folic acid) conjugates (synthesized from amine-terminated G5.NH(2) dendrimer, approach 1) with acetamide and amine termini exhibit bimodal or multi-modal distributions. In contrast, G5-FA and bifunctional G5-FA-MTX (MTX denotes methotrexate) conjugates with hydroxyl termini display a single modal distribution. Multifunctional G5.Ac(n)-FI-FA, G5.Ac(n)-FA-OH-MTX, and G5.Ac(n)-FI-FA-OH-MTX (Ac denotes acetamide; FI denotes fluorescein) nanodevices (synthesized from partially acetylated G5 dendrimer, approach 2) exhibit a monodisperse distribution. It indicates that the molecular distribution of PAMAM conjugates largely depends on the homogeneity of starting materials, the synthetic approaches, and the final functionalization steps. Hydroxylation functionalization of dendrimers masks the dispersity of the final PAMAM nanodevices in both synthetic approaches. The applied CE analysis of mono- and multifunctional PAMAM-based nanodevices provides a powerful tool to evaluate the molecular heterogeneity of complex dendrimer conjugate nanodevices for targeted cancer therapeutics.

Analysis of poly(amidoamine)-succinamic acid dendrimers by slab-gel electrophoresis and capillary zone electrophoresis.

Ethylenediamine (EDA)-core poly(amidoamine) (PAMAM) succinamic acid dendrimers (Ex.SAH, where x refers to the generation) were synthesized and analyzed by polyacrylamide gel electrophoresis (PAGE), size-exclusion chromatography (SEC), potentiometric acid-base titration, and capillary zone electrophoresis (CZE). Various generations (E1.SAH-E7.SAH) PAMAMs and a succinamic acid terminated core-shell tecto(dendrimer) (E5(E3.SAH)(n)) were first analyzed by PAGE. PAGE results show that the relative mobilities of generation 2 to generation 7 dendrimers decreased with the increasing number of generations. The molecular mass of a generation 5 core generation 3 shell tecto(dendrimer) (denoted as E5(E3.SAH)(n)) was determined to be between the Mw of E6.SAH and E7.SAH. CZE analysis allowed the evaluation of electrophoretic properties of given-generation dendrimers. The electrophoretic mobilities of individual generations PAMAM polyanions are similar, indicating that the separation mainly depends on their approximately identical charge/mass ratio. The E5(E3.SAH)(n) tectodendrimer had a lower electrophoretic mobility, which was consistent with its lower charge/mass ratio. The combination of PAGE and CZE analysis provides an alternative and effective way to characterize this group of PAMAM-succinamic acid dendrimers.

Capillary electrophoresis of polycationic poly(amidoamine) dendrimers.

Generation 2 to generation 5 poly(amidoamine) (PAMAM) dendrimers having different terminal functionalities were analyzed by capillary electrophoresis (CE). Polyacrylamide gel electrophoresis was also used to assess the composition of the individual generations for comparison with the CE results. Separation of PAMAMs can be accomplished by either using uncoated silica or silanized silica capillaries, although reproducibility is poor using the uncoated silica capillary. To improve run-to-run reproducibility, silanized capillary was used and various internal standards were also tested. Relative and normalized migration times of primary amine terminated PAMAM dendrimers were then determined using 2,3-diaminopyridine (2,3-DAP) as an internal standard. Using silanized capillaries and internal standards, the relative and normalized migration times are fully reproducible and comparable between runs. Apparent dimensionless electrophoretic mobilities were determined and the results were compared to theoretical calculations. It is concluded that for PAMAMs a complex separation mechanism has to be considered in CE, where the movement of the ions is due to the electric field, but the separation is rather the consequence of the adsorption/desorption equilibria on the capillary wall ("electrokinetic capillary chromatography"). The described method may be used for quality control and may serve as an effective technique to analyze polycationic PAMAM dendrimers and their derivatives with different surface modifications.

HPLC analysis of PAMAM dendrimer based multifunctional devices.

Comprehensive high-performance liquid chromatography (HPLC) analyses were performed on poly(amidoamine) (PAMAM) dendrimer based multifunctional devices. The nanometer-size devices were synthesized by conjugating partially acetylated (Ac) poly(amidoamine) dendrimers of generation 5 (G5) with fluorescein isothiocyanate (FITC), folic acid (FA) and methotrexate (MTX). The devices are intended for targeted intracellular drug delivery to tumor cells through the folate receptor. Methods were developed for detection and separation of various surface functionalized dendrimer conjugates and small molecules (FITC, FA, MTX) using a common gradient. Results indicate that the HPLC technique can be used as a quality control tool for determining purity of the G5 carrier, its acetylated form, and mono-, bi- and tri-functional nanodevices. More importantly, the chromatograms of these novel nanodevices, reported for the first time, provide information on critical properties such as polydispersity, surface heterogeneity and solubility. The benchmark data can be used to optimize the physicochemical properties of the conjugates to improve drug delivery to cancer cells.

HPLC separation of different generations of poly(amidoamine) dendrimers modified with various terminal groups.

Polyamidoamine (PAMAM) dendrimers of different generations with various terminal groups were analyzed, for the first time, using a combination of high-performance liquid chromatography (HPLC), size exclusion chromatography (SEC), and matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) techniques. Separation of amine-terminated dendrimers from generation 1 through generation 9 (G1NH(2)-G9NH(2)) was achieved using reversed-phase HPLC with elution time increasing gradually as the density of terminal amine groups increases as a function of generation. Furthermore, separation of dendrimers with terminal amino, acetamide, hydroxyl, and carboxylate groups was obtained. It has also been shown that HPLC can be used to separate dendrimers based on some structural defects inherent during the syntheses of PAMAM dendrimers. MALDI-TOF mass spectra of G1NH(2) identify the major imperfections present during typical synthesis processes. The absolute molar masses (M(n)) and molar mass distributions of the dendrimers were measured using the SEC system equipped with multiangle laser light scattering and refractive-index detectors. Findings from this study suggest HPLC can be a vital tool for characterization and preparative separation of PAMAM dendrimers.

Synthesis and functional evaluation of DNA-assembled polyamidoamine dendrimer clusters for cancer cell-specific targeting.

We sought to produce dendrimers conjugated to different biofunctional moieties (fluorescein [FITC] and folic acid [FA]), and then link them together using complementary DNA oligonucleotides to produce clustered molecules that target cancer cells that overexpress the high-affinity folate receptor. Amine-terminated, generation 5 polyamidoamine (G5 PAMAM) dendrimers are first partially acetylated and then conjugated with FITC or FA, followed by the covalent attachment of complementary, 5'-phosphate-modified 34-base-long oligonucleotides. Hybridization of these oligonucleotide conjugates led to the self-assembly of the FITC- and FA-conjugated dendrimers. In vitro studies of the DNA-linked dendrimer clusters indicated specific binding to KB cells expressing the folate receptor. Confocal microscopy also showed the internalization of the dendrimer cluster. These results demonstrate the ability to design and produce supramolecular arrays of dendrimers using oligonucleotide bridges. This will also allow for further development of DNA-linked dendrimer clusters as imaging agents and therapeutics.

The potential of Raman spectroscopy as a process analytical technique during formulations of topical gels and emulsions.

PURPOSE: The primary objective of this study is to investigate the possibility of using Raman spectroscopy as a process analytical technique (PAT) for quality control during manufacturing of topical dosage forms. METHODS: A fiber-optic Raman probe was used to monitor the formulation of pharmaceutical gel and emulsion in laboratory scale. Raman shifts of typical commercial raw materials used in topical dosage forms were measured to ascertain the potential of this technique for monitoring and analyzing topical products. Spectra of some well-characterized topical gels manufactured in our laboratory were also measured. RESULTS: Commercial raw materials were found to be Raman sensitive. Due to the difference in chemical composition, raw materials exhibit characteristic peaks that can be exploited to monitor formulation processes. Spectra taken during formulation of an emulsion using Carbopol Ultrez as thickener and Tefose as emulsifying agent show changes in Raman shifts immediately after major formulation steps. CONCLUSIONS: The findings from this work suggest that Raman spectroscopy can be a valuable process analytical technique for quality control of topical gel and cream formulations.

Rheological characterization of topical carbomer gels neutralized to different pH.

PURPOSE: The primary objective of this study is to perform detailed and extensive rheological characterization of rheology of carbomer (Carbopol) microgels formulated using a solvent system typically used in topical gel formulations. Solvents like glycerin and propylene glycol can alter rheology and drug delivery characteristics of topical gels owing to their different viscosities and due to the change in solvent-polymer and solvent-solvent interactions. METHODS: Aqueous gels with different pH were prepared by dissolving cross-linked Carbopol polymers in a co-solvent system comprising water, propylene glycol, and glycerol and subsequently neutralizing the carboxylic groups of the polymers with triethanolamine (TEA). Oscillatory, steady, and transient shear measurements were performed to measure viscoelastic properties, temperature dependency, yield strength, and thixotropy of carbomer pharmaceutical gels. RESULTS: The topical pharmaceutical gels exhibit remarkable temperature stability. Flow curves obtained at different temperatures indicate Carbopol microgels show much more pseudoplastic behavior (lower power law index) compared to Carbopol gels dissolved only in water. Substantial yield strength is required to break the microgel network of the topical gels. The gel samples exhibit modest thixotropy at higher deformation rates. CONCLUSIONS: The theological behavior of the Carbopol microgels do not change appreciably in the pH range 5.0-8.0, and the gels can be used as effective dermatological base for topical applications.

Fourier transform infrared spectroscopy for the analysis of neutralizer-Carbomer and surfactant-Carbomer interactions in aqueous, hydroalcoholic, and anhydrous gel formulations.

The objective of the present study is to evaluate the polymer-surfactant and polymer-neutralizer interactions in topical aqueous, anhydrous, and hydroalcoholic gel formulations using Fourier transform infrared (FTIR) spectroscopy. The gels were prepared by dispersing Carbomer (Carbopol 980) in water and ethanol for aqueous and anhydrous systems, respectively. Glycerol and propylene glycol were also added to ensure that the compositions of gels closely resembled those used in typical topical gel formulations. Comparisons of the spectra of Carbopol dispersions in aqueous, anhydrous, and hydroalcoholic systems, performed for the first time, show Carbopol-neutralizer and Carbopol-surfactant interactions vary depending on the nature of the solvents used for gel formation. Analysis of the spectra of aqueous gel formulations indicates significant presence of ionized carboxyl groups only at higher pH (approximately 8.0). Drying of the aqueous gels causes a shift in the carbonyl stretch band toward higher energy, suggesting changes in polymer-neutralizer interaction. Anhydrous gels exhibit 2 different carbonyl stretch bands: the one at approximately 1653 cm(-1) is related to the carboxyl group that is hydrogen bonded and is akin to hydrous gels; the second one at approximately 1717 cm(-1) is indicative of free carbonyl groups. The carbonyl bands of dried gels appear at different energy levels than the solvated gels. This shift resulting from solvent evaporation, reported for the first time, indicates changes in hydrogen bond characteristics. The results show that FTIR can be a good technique compared with other more time-consuming means of analysis for topical formulations.