Patient-reported outcomes and subsequent management in atrial fibrillation clinical practice: Results from the Utah mEVAL AF program.

BACKGROUND: Atrial fibrillation (AF) significantly reduces health-related quality of life (HRQoL), previously measured in clinical trials using patient-reported outcomes (PROs). We examined AF PROs in clinical practice and their association with subsequent clinical management. METHODS: The Utah My Evaluation (mEVAL) program collects the Toronto AF Symptom Severity Scale (AFSS) in AF outpatients at the University of Utah. Baseline factors associated with worse AF symptom score (range 0-35, higher is worse) were identified in univariate and multivariable analyses. Secondary outcomes included AF burden and AF healthcare utilization. We also compared subsequent clinical management at 6 months between patients with better versus worse AF HRQoL. RESULTS: Overall, 1338 patients completed the AFSS symptom score, which varied by sex (mean 7.26 for males vs. 10.27 for females; p < .001), age (<65, 9.73; 65-74, 7.66; ≥75, 7.58; p < .001), heart failure (9.39 with HF vs. 7.67 without; p < .001), and prior ablation (7.28 with prior ablation vs. 8.84; p < .001). In multivariable analysis, younger age (mean difference 2.92 for <65 vs. ≥75; p < .001), female sex (mean difference 2.57; p < .001), pulmonary disease (mean difference 1.88; p < .001), and depression (mean difference 2.46; p < .001) were associated with higher scores. At 6-months, worse baseline symptom score was associated with the use of rhythm control (37.1% vs. 24.5%; p < .001). Similar cofactors and results were associated with increased AF burden and health care utilization scores. CONCLUSIONS: AF PROs in clinical practice identify highly-symptomatic patients, corroborating findings in more controlled, clinical trials. Increased AFSS score correlates with more aggressive clinical management, supporting the utility of disease-specific PROs guiding clinical practice.

IDPQuantify: combining precursor intensity with spectral counts for protein and peptide quantification.

Differentiating and quantifying protein differences in complex samples produces significant challenges in sensitivity and specificity. Label-free quantification can draw from two different information sources: precursor intensities and spectral counts. Intensities are accurate for calculating protein relative abundance, but values are often missing due to peptides that are identified sporadically. Spectral counting can reliably reproduce difference lists, but differentiating peptides or quantifying all but the most concentrated protein changes is usually beyond its abilities. Here we developed new software, IDPQuantify, to align multiple replicates using principal component analysis, extract accurate precursor intensities from MS data, and combine intensities with spectral counts for significant gains in differentiation and quantification. We have applied IDPQuantify to three comparative proteomic data sets featuring gold standard protein differences spiked in complicated backgrounds. The software is able to associate peptides with peaks that are otherwise left unidentified to increase the efficiency of protein quantification, especially for low-abundance proteins. By combing intensities with spectral counts from IDPicker, it gains an average of 30% more true positive differences among top differential proteins. IDPQuantify quantifies protein relative abundance accurately in these test data sets to produce good correlations between known and measured concentrations.

Social Media Influence Does Not Reflect Scholarly or Clinical Activity in Real Life.

BACKGROUND: Social media has become a major source of communication in medicine. We aimed to understand the relationship between physicians' social media influence and their scholarly and clinical activity. METHODS: We identified attending US electrophysiologists on Twitter. We compared physician Twitter activity to (1) scholarly publication record (h-index) and (2) clinical volume according to Centers for Medicare and Medicaid Services. The ratio of observed versus expected (obs/exp) Twitter followers was calculated based on each scholarly (K-index) and clinical activity. RESULTS: We identified 284 physicians, with mean Twitter age of 5.0 (SD, 3.1) years and median 568 followers (25th, 75th: 195, 1146). They had a median 34.5 peer-reviewed articles (25th, 75th: 14, 105), 401 citations (25th, 75th: 102, 1677), and h-index 9 (25th, 75th: 4, 19.8). The median K-index was 0.4 (25th, 75th: 0.15, 1.0), ranging from 0.0008 to 29.2. The median number of electrophysiology procedures was 77 (25th, 75th: 0, 160) and evaluation and management visits 264 (25th, 75th: 59, 516) in 2017. The top 1% electrophysiologists for followers accounted for 20% of all followers, 17% of status updates, had a mean h-index of 6 (versus 15 for others, P=0.3), and accounted for 1% of procedural and evaluation and management volumes. They had a mean K-index of 21 (versus 0.77 for others, P<0.0001) and clinical obs/exp follower ratio of 17.9 and 18.1 for procedures and evaluation and management (P<0.001 each, versus others [0.81 for each]). CONCLUSIONS: Electrophysiologists are active on Twitter, with modest influence often representative of scholarly and clinical activity. However, the most influential physicians appear to have relatively modest scholarly and clinical activity.

64Cu-labeled folate-conjugated shell cross-linked nanoparticles for tumor imaging and radiotherapy: synthesis, radiolabeling, and biologic evaluation.

UNLABELLED: Long-circulating nanoparticles functionalized with ligands for receptors overexpressed by tumor cells have promising applications for active and passive tumor targeting. The purpose of this study was to evaluate 64Cu-radiolabeled folate-conjugated shell cross-linked nanoparticles (SCKs) as candidate agents to shuttle radionuclides and drugs into tumors overexpressing the folate receptor (FR). METHODS: SCKs were obtained by cross-linking the shell of micelles obtained from amphiphilic diblock copolymers. SCKs were then functionalized with folate, fluorescein thiosemicarbazide (FTSC), and 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (TETA). The specific interaction of SCK-folate with the FR was investigated on KB cells. The biodistributions of 64Cu-TETA-SCK and 64Cu-TETA-SCK-folate were evaluated in athymic mice bearing small-size KB cell xenografts (10-100 mg), whereas the intratumor distributions were investigated by autoradiography in 0.3- to 0.6-g KB cell xenografts. RESULTS: A global solution-state functionalization strategy has been introduced for attaching optimum numbers of targeting and imaging agents onto the SCKs for increasing the efficiency of interaction with cell-surface receptors. Epifluorescence microscopy confirmed the specific interaction of FTSC-SCK-folate with the FR in vitro. 64Cu labeling of TETA-SCKs led to the radiolabeled compounds with 15%-20% yield and >95% radiochemical purity. The biodistribution results demonstrated high accumulation of 64Cu-labeled SCKs in organs of the reticuloendothelial system (RES) (56.0 +/- 7.1 %ID/g and 45.7 +/- 3.5 %ID/g [percentage injected dose per gram] in liver at 10 min after injection for folated and nonfolated SCKs, respectively) and a prolonged blood circulation. No increase of SCK tumor uptake deriving from folate conjugation was observed (5.9 +/- 2.8 %ID/g and 6.0 +/- 1.9 %ID/g at 4 h after injection for folated and nonfolated SCKs, respectively). However, tumor accumulation was higher in small-size tumors, where competitive block of SCK-folate uptake with excess folate was observed. Autoradiography results confirmed the extravasation of radiolabeled SCKs in vascularized areas of the tumor, whereas no diffusion was observed in necrotic regions. CONCLUSION: Despite high RES uptake, the evaluated 64Cu-labeled SCKs exhibited long circulation in blood and were able to passively accumulate in tumors. Furthermore, SCK-folate uptake was competitively blocked by excess folate in small-size solid tumors, suggesting interaction with the FR. For these reasons, functionalized SCKs are promising drug-delivery agents for imaging and therapy of early-stage solid tumors.

Regiochemical functionalization of a nanoscale cage-like structure: robust core-shell nanostructures crafted as vessels for selective uptake and release of small and large guests.

As synthetic methods evolve toward the preparation of increasingly complex nanostructured materials inspired from biological nano-objects, the ability to tailor the three-dimensional architecture and the placement of functional groups at well-defined positions within those frameworks is advancing. In this report, we demonstrate the ability to functionalize selectively internal and external sites (regiochemically) within polymer nanocages, to advance their development as synthetic analogs of viral capsids. Nanocages, possessing carbonyl groups on their internal surfaces and acrylic acid residues throughout their structure were prepared and functionalized, through either Schiff-base chemistry, to attach covalently phosphatidylethanolamine-based lipids within the nanocage, or carbodiimide-mediated coupling, to attach covalently the lipids throughout the shell. The resulting nanostructures were altered by the insertion of molecules within and on the structure, including, for the Schiff base functionalized nanostructure, an enhanced response to pH and increased uptake of hydrophobic guests. Additionally, the use of phosphatidylethanolamine lipids labeled with 7-nitrobenz-2-oxa-1,3-diazole (NBD) allowed for determination of the environmental polarities of the lipid domains within the lipid-nanocage constructs.

PNA-directed solution- and surface-assembly of shell crosslinked (SCK) nanoparticle conjugates.

The conjugation of complementary peptide nucleic acid (PNA) sequences to well defined shell crosslinked (SCK) nanoparticles is reported as a mechanism by which to direct their self assembly into higher order structures selective and tunable binding interactions. Base-pairing-driven aggregation of the SCK's occurred for mixtures of SCK's that presented complementary sequences in aqueous sodium chloride solutions and upon mica substrates. The assembly processes were monitored by dynamic light scattering and atomic force microscopy as a function of salt concentration, and by UV-vis spectroscopy as a function of salt concentration and temperature. Moreover, the stoichiometries of the PNA sequences conjugated per SCK nanoparticle and the stoichiometric ratios in the production of mixtures of SCK's bearing complementary PNA sequences were each altered to tune the hierarchical assemblies.

Folic acid-conjugated nanostructured materials designed for cancer cell targeting.

Shell cross-linked nanoparticles (SCKs) constitute a unique class of materials with amphiphilic core-shell morphology; SCKs are characterised by their structural integrity and available functionality to attach receptor-recognising or receptor-specific ligands on the shell surface and, therefore, hold great potential in drug delivery applications; in an attempt to develop novel, cancer cell specific delivery vehicles, folate receptor targeted SCKs have been prepared.

Fabrication of hybrid nanocapsules by calcium phosphate mineralization of shell cross-linked polymer micelles and nanocages.

Self-assembled shell cross-linked poly(acrylic acid-b-isoprene) (PAA78-b-PI97) micelles or cross-linked PAA nanocages in aqueous solution were used as templates for the preparation of novel polymer-inorganic nanocapsules. The hybrid nanostructures were typically 50-70 nm in diameter and consisted of spherical polymer nanoparticles or nanocages enclosed within a continuous 10-20 nm thick surface layer of amorphous calcium phosphate. Nucleation of calcium phosphate specifically in association with the polymer nanoparticles was facilitated by low supersaturation levels and by sequestration of Ca2+ ions within the carboxylate-rich PAA domains prior to addition of HPO4(2-). Modifications in ionic concentrations were used to control the calcium phosphate surface layer thickness and prepare mineralized cross-linked PAA-b-PI micelles with variable shell permeability. The permeability of beta-carotene into the hydrophobic PI core of mineralized shell cross-linked PAA-b-PI micelles was reduced by approximately 50 or 100% respectively for hybrid nanostructures enclosed within 10 or 20 nm thick calcium phosphate layers. Our results suggest that calcium phosphate-polymer cross-linked nanocapsules could have potential applications as pH-responsive biocompatible hybrid nanostructures for use in applications such as drug delivery, bioimaging, and therapeutics.

An assessment of the effects of shell cross-linked nanoparticle size, core composition, and surface PEGylation on in vivo biodistribution.

Amphiphilic core-shell nanoparticles have drawn considerable interest in biomedical applications. The precise control over their physicochemical parameters and the ability to attach various ligands within specific domains suggest shell cross-linked (SCK) nanoparticles may be used as multi-/polyvalent scaffolds for drug delivery. In this study, the biodistribution of four SCKs, differing in size, core composition, and surface PEGylation, was evaluated. To facilitate in-vivo tracking of the SCKs, the positron-emitting radionuclide copper-64 was used. By using biodistribution and microPET imaging approaches, we found that small diameter (18 nm) SCKs possessing a polystyrene core showed the most favorable biological behavior in terms of prolonged blood retention and low liver accumulation. The data demonstrated that both core composition, which influenced the SCK flexibility and shape adaptability, and hydrodynamic diameter of the nanoparticle play important roles in the respective biodistributions. Surface modification with poly(ethylene glycol) (PEG) had no noticeable effects on SCK behavior.