Automatic measurements of left ventricular volumes and ejection fraction by artificial intelligence: clinical validation in real time and large databases.

AIMS: Echocardiography is a cornerstone in cardiac imaging, and left ventricular (LV) ejection fraction (EF) is a key parameter for patient management. Recent advances in artificial intelligence (AI) have enabled fully automatic measurements of LV volumes and EF both during scanning and in stored recordings. The aim of this study was to evaluate the impact of implementing AI measurements on acquisition and processing time and test-retest reproducibility compared with standard clinical workflow, as well as to study the agreement with reference in large internal and external databases. METHODS AND RESULTS: Fully automatic measurements of LV volumes and EF by a novel AI software were compared with manual measurements in the following clinical scenarios: (i) in real time use during scanning of 50 consecutive patients, (ii) in 40 subjects with repeated echocardiographic examinations and manual measurements by 4 readers, and (iii) in large internal and external research databases of 1881 and 849 subjects, respectively. Real-time AI measurements significantly reduced the total acquisition and processing time by 77% (median 5.3 min, P < 0.001) compared with standard clinical workflow. Test-retest reproducibility of AI measurements was superior in inter-observer scenarios and non-inferior in intra-observer scenarios. AI measurements showed good agreement with reference measurements both in real time and in large research databases. CONCLUSION: The software reduced the time taken to perform and volumetrically analyse routine echocardiograms without a decrease in accuracy compared with experts.

Automated 2-D and 3-D Left Atrial Volume Measurements Using Deep Learning.

OBJECTIVE: Echocardiography, a critical tool for assessing left atrial (LA) volume, often relies on manual or semi-automated measurements. This study introduces a fully automated, real-time method for measuring LA volume in both 2-D and 3-D imaging, in the aim of offering accuracy comparable to that of expert assessments while saving time and reducing operator variability. METHODS: We developed an automated pipeline comprising a network to identify the end-systole (ES) time point and robust 2-D and 3-D U-Nets for segmentation. We employed data sets of 789 2-D images and 286 3-D recordings and explored various training regimes, including recurrent networks and pseudo-labeling, to estimate volume curves. RESULTS: Our baseline results revealed an average volume difference of 2.9 mL for 2-D and 7.8 mL for 3-D, respectively, compared with manual methods. The application of pseudo-labeling to all frames in the cine loop generally led to more robust volume curves and notably improved ES measurement in cases with limited data. CONCLUSION: Our results highlight the potential of automated LA volume estimation in clinical practice. The proposed prototype application, capable of processing real-time data from a clinical ultrasound scanner, provides valuable temporal volume curve information in the echo lab.

Regulated synthesis of an Au NB-DT@Ag bimetallic core-molecule-shell nanostructure for reliable SERS detection.

In recent research, anisotropic plasmonic core-shell nanomaterials have gained a lot of attention in surface-enhanced Raman scattering (SERS) due to their brilliant uniformity and optical properties. Herein, a bimetallic core-molecule-shell (CMS) composite nanorod SERS substrate nanomaterial (Au NB-DT@Ag NRs) was designed and synthesized under precise regulation. The inner core is gold nanobipyramids (Au NBs), which possess superior plasmonic properties. Uniform Au NBs of five different sizes were fabricated via a penta-twinned gold seed mediated growth method. The length varied from 160 to 62 nm and the corresponding diameter varied from 60 to 23 nm while the longitudinal surface plasmonic resonance (SPR) changed from 908 to 715 nm. The SERS activity of five Au NBs were compared and the optimally sized one with a length of 78 nm and width of 28 nm was set as the inner core. After modification with the Raman reporter (DT), different amounts of silver were deposited on the surface of Au NB-DTs to form an Au NB-DT@Ag nanocomposite. The shape of the nanostructure gradually became a rod and lengthened while the longitudinal SPR wavelength varied from 733 nm to 664 nm with an increase in the amount of silver nitrate added. The Au NB-DT@Ag NRs with the best SERS activity (b-3) could realize the quantitative detection of the toxic dyes malachite green (MG) and crystal violet (CV) of concentrations as low as 5 × 10-9 M, showing good reproducibility and stability. This work offers a new design strategy for a SERS substrate for reliable quantitative SERS detection applications.

Construction of an enzyme-free biosensor utilizing CuO nanoparticles enriched in DNA polymer to catalyze a click chemistry reaction for SERS detection of the p53 gene.

The p53 gene is a known cancer marker. We report a novel protocol for the SERS tandem strategy to detect the p53 gene with high sensitivity. Herein, the click reaction between azide and alkyne was catalyzed by utilizing copper oxide nanoparticles (CuONPs), which were enriched by a T-DNA-triggered hybridization chain reaction (HCR). The T-DNA signal was amplified by establishing the correlation between the T-DNA signal and the concentration of CuONPs in a nonenzymatic isothermal environment. In contrast to other Raman reporters, we used alkynyl compounds as Raman reporters, which showed excellent characteristics in the Raman-silent region (1800-2800 cm-1). Therefore, the highly sensitive and highly selective SERS signals could be obtained in complex biological matrices. Due to utilizing multistep amplification strategies, including the nanoparticle-modified HCR polymer and "click" reaction, the limit of detection (LOD) and the limit of quantification (LOQ) of this sensor could be as low as 0.0174 pM and 0.0583 pM, respectively. The accuracy of the strategy expressed as the RSD was in the range of 3.14%-6.21%. The results indicated that the constructed sensor has excellent performance for the detection of the p53 gene in serum samples in a low concentration range, which suggests that the proposed enzyme-free SERS analytical sensor has good clinical application prospects.

A colorimetric and SERS dual-readout sensor for sensitive detection of tyrosinase activity based on 4-mercaptophenyl boronic acid modified AuNPs.

Tyrosinase (TYR) is as a well-known polyphenol oxidase and important biomarker of melanocytic lesions. Thus, developing powerful methods to determine TYR activity is of great value in the early diagnosis of skin disease. Direct surface-enhanced Raman scattering (SERS) detection of biomolecules is usually affected by non-specific interference and complicate structure of the analytes. It is a challenge to develop Raman-active molecules with specific recognition to analytes in complex media. Here, we report a novel colorimetric and surface-enhanced Raman scattering (SERS) dual-readout assay for the determination of TYR using commercially available and economical 4-mercaptophenyl boronic acid (4-MPBA) as a Raman-active and recognition molecule. 4-MPBA provides a unique interactive boronic acid group to the diol group of TYR substrate and exhibits good SERS signal. Also, the introduction of magnetic beads could promptly improve the anti-interference ability of dual-mode sensor. The TYR-incubated tyramine-modified magnetic beads could obviously change the concentration of 4-MPBA-AuNPs in the presence of O2 and ascorbic acid, where the ultraviolet visible (UV-vis) absorption and SERS intensity were directly related to the concentration of TYR added. The dual-mode sensor had a rapid response to TYR within 1 min under optimized conditions and had high selectivity for TYR with a limit of detection at 0.001 U/mL. In addition, the dual-mode strategy showed promising prospects in the determination of TYR activity in serum samples and could be used to screen TYR inhibitors.

Association of vitamin D status of septic patients in intensive care units with altered procalcitonin levels and mortality.

OBJECTIVE: The purpose of this study was to determine whether vitamin D levels correlate with procalcitonin (PCT) levels and mortality in septic patients. METHODS: The following data were collected from 236 patients upon admission to intensive care units (ICUs): demographics; Acute Physiology and Chronic Health Evaluation (APACHE) II score; Sequential Organ Failure Assessment (SOFA) score; 25-hydroxyvitamin D (25OHD), PCT, intact PTH, albumin, creatinine, and ionized calcium (iCa) levels; 25OHD sampling seasonality; fluid load (colloid and crystalloid before 25OHD sampling); mechanical ventilation duration; and length of stay (LOS) in the ICU. The primary endpoint was all-cause mortality 28 days after ICU admission. RESULTS: Patients with 25OHD deficiency had significantly higher APACHE II and SOFA scores, positive blood culture rates, PCT levels, intact PTH levels, and 28-day mortality rates. These patients also had lower iCa levels, longer LOS in the ICU, and longer ventilator durations than patients with 25OHD insufficiency or sufficiency. Age, sex, 25OHD sampling seasonality, serum albumin and creatinine levels, and fluid load did not vary among the 3 groups. Serum 25OHD levels at admission were significantly negatively correlated with PCT levels. PTH responders had significantly higher 28-day mortality rates than did PTH nonresponders. Cox regression showed that a 25OHD level of <20 ng/mL was an independent risk factor for 28-day mortality. CONCLUSIONS: Lower serum 25OHD levels at ICU admission were associated with 28-day mortality in septic patients. Serum 25OHD levels were inversely correlated with PCT levels. Hypovitaminosis D was associated with higher mortality rates in PTH responders than in nonresponders.

A concise [C+NC+CC] coupling-enabled synthesis of kaitocephalin.

A 15-step synthesis of the iGluR antagonist kaitocephalin from aspartic acid is reported. The linchpin pyrrolidine ring of the target molecule is efficiently assembled with in a single operation via an asymmetric [C+NC+CC] reaction.

Changes in the calcium-parathyroid hormone-vitamin d axis and prognosis for critically ill patients: a prospective observational study.

OBJECTIVE: Vitamin D deficiency is prevalent in critically ill patients and may contribute to suboptimal clinical outcomes, but little is known about alterations of the calcium-parathyroid hormone (PTH)-vitamin D axis and prognosis in these individuals. METHODS: A prospective observational study was conducted on 216 patients admitted to a university-affiliated, tertiary-care medical intensive care unit(MICU) between June 2011 and December 2012. Serum levels of 25-hydroxyvitamin D, ionised calcium and intact PTH were determined within 24 h of MICU admission. The primary end point was all-cause hospital mortality within 90-days of admission. RESULTS: 95 patients (44%) showed 25-hydroxyvitamin D deficiency. Patients deficient in vitamin D showed significantly higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, rate of positive blood culture, incidence of multiple organ dysfunction syndrome, and 90-day mortality rate than did patients with vitamin D insufficiency or sufficiency (P<0.05), as well as lower levels of serum IgG. 25-Hydroxyvitamin D deficiency was identified as an independent risk factor for mortality (OR = 3.018, 95%CI 1.329-6.854, P = 0.008). Hypovitaminosis D in PTH-responders was associated with higher mortality than was the same condition in non-responders (P<0.05). CONCLUSIONS: These results suggest that vitamin D deficiency is prevalent among MICU patients, suggesting a significant derangement of the calcium-PTH-vitamin D axis in critically ill patients. Vitamin D deficiency is an independent risk factor for 90-day mortality, and hypovitaminosis D in PTH-responders is associated with higher mortality than is the same condition in non-responders.

Thieno[3,2-b]thiophene-2-carboxylic acid derivatives as GPR35 agonists.

The optimization of a series of thieno[3,2-b]thiophene-2-carboxylic acid derivatives for agonist activity against the GPR35 is reported. Compounds were optimized to achieve ß-arrestin-biased agonism for developing probe molecules that may be useful for elucidating the biology and physiology of GPR35. Compound 13 was identified to the most potent GPR35 agonist, and compounds 30 and 36 exhibited the highest efficacy to cause ß-arrestin translocation.

Discovery of 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives as G protein-coupled receptor 35 (GPR35) agonists.

Screening with dynamic mass redistribution (DMR) assays in a native cell line HT-29 led to identification of two novel series of chemical compounds, 2-(4-methylfuran-2(5H)-ylidene)malononitrile and thieno[3,2-b]thiophene-2-carboxylic acid derivatives, as GPR35 agonists. Of these, 2-(3-cyano-5-(3,4-dichlorophenyl)-4,5-dimethylfuran-2(5H)-ylidene)malononitrile (YE120) and 6-bromo-3-methylthieno[3,2-b]thiophene-2-carboxylic acid (YE210) were found to be the two most potent GPR35 agonists with an EC(50) of 32.5 ± 1.7 nM and 63.7 ± 4.1 nM, respectively. Both agonists exhibited better potency than that of zaprinast, a known GPR35 agonist. DMR antagonist assays, knockdown of GPR35 with interference RNA, receptor internalization assays, and Tango ß-arrestin translocation assays confirmed that the agonist activity of these ligands is specific to GPR35. The present study provides novel chemical series as a starting point for further investigations of GPR35 biology and pharmacology.

Asymmetric multicomponent [C+NC+CC] synthesis of highly functionalized pyrrolidines catalyzed by silver(I).

[reaction: see text] Highly functionalized pyrrolidines are obtained in a single chemical step via a mild, efficient, and selective Ag(I)-catalyzed asymmetric [C+NC+CC] coupling process. Oppolzer's camphorsultam enables the desired reaction cascade and provides a reliable means to control the developing stereochemistry and purify the products. This three-component reaction provides unprecedented access to structurally diverse pyrrolidines for both target- and diversity-oriented syntheses.

3,3'-Br2-BINOL-Zn complex: a highly efficient catalyst for the enantioselective hetero-Diels-Alder reaction.

[reaction: see text] A BINOLate-zinc complex prepared in situ from Et(2)Zn and 3,3'-dibromo-1,1'-bi-2-naphthol (3,3'-Br(2)-BINOL) was found to be a highly efficient catalyst for the enantioselective hetero-Diels-Alder reaction of Danishefsky's diene and aldehydes to give 2-substituted 2,3-dihydro-4H-pyran-4-one in up to quantitative yield and 98% ee.

Discovery of exceptionally efficient catalysts for solvent-free enantioselective hetero-Diels-Alder reaction.

Combinatorial coordination chemistry strategy combined with high-throughput screening techniques has been successfully applied to engineering practical enantioselective catalysts for asymmetric hetero-Diels-Alder reaction. The reaction of Danishefsky's diene with a variety of aldehydes can be carried out with 0.1-0.005 mol % of H4-BINOL/Ti/H4-BINOL or H4-BINOL/Ti/H8-BINOL catalysts at room temperature under solvent- and MS-free conditions to afford dihydropyrone derivatives with up to quantitative yield and 99.8% ee.