DCT-Net: An effective method to diagnose retinal tears from B-scan ultrasound images.

Retinal tears (RTs) are usually detected by B-scan ultrasound images, particularly for individuals with complex eye conditions. However, traditional manual techniques for reading ultrasound images have the potential to overlook or inaccurately diagnose conditions. Thus, the development of rapid and accurate approaches for the diagnosis of an RT is highly important and urgent. The present study introduces a novel hybrid deep-learning model called DCT-Net to enable the automatic and precise diagnosis of RTs. The implemented model utilizes a vision transformer as the backbone and feature extractor. Additionally, in order to accommodate the edge characteristics of the lesion areas, a novel module called the residual deformable convolution has been incorporated. Furthermore, normalization is employed to mitigate the issue of overfitting and, a Softmax layer has been included to achieve the final classification following the acquisition of the global and local representations. The study was conducted by using both our proprietary dataset and a publicly available dataset. In addition, interpretability of the trained model was assessed by generating attention maps using the attention rollout approach. On the private dataset, the model demonstrated a high level of performance, with an accuracy of 97.78%, precision of 97.34%, recall rate of 97.13%, and an F1 score of 0.9682. On the other hand, the model developed by using the public funds image dataset demonstrated an accuracy of 83.82%, a sensitivity of 82.69% and a specificity of 82.40%. The findings, therefore present a novel framework for the diagnosis of RTs that is characterized by a high degree of efficiency, accuracy and interpretability. Accordingly, the technology exhibits considerable promise and has the potential to serve as a reliable tool for ophthalmologists.

Polar Heterobenzylic C(sp3)-H Chlorination Pathway Enabling Efficient Diversification of Aromatic Nitrogen Heterocycles.

Site-selective radical reactions of benzylic C-H bonds are now highly effective methods for C(sp3-H) functionalization and cross-coupling. The existing methods, however, are often ineffective with heterobenzylic C-H bonds in alkyl-substituted pyridines and related aromatic heterocycles that are prominently featured in pharmaceuticals and agrochemicals. Here, we report new synthetic methods that leverage polar, rather than radical, reaction pathways to enable the selective heterobenzylic C-H chlorination of 2- and 4-alkyl-substituted pyridines and other heterocycles. Catalytic activation of the substrate with trifluoromethanesulfonyl chloride promotes the formation of enamine tautomers that react readily with electrophilic chlorination reagents. The resulting heterobenzyl chlorides can be used without isolation or purification in nucleophilic coupling reactions. This chlorination-diversification sequence provides an efficient strategy to achieve heterobenzylic C-H cross-coupling with aliphatic amines and a diverse collection of azoles, among other coupling partners.

Genetic liability to multi-site chronic pain increases the risk of cardiovascular disease.

BACKGROUND: Observational studies have shown associations between multi-site chronic pain (MCP) and cardiovascular disease. However, it remains unclear whether these associations are causal. Therefore, this study aimed to assess the causal associations between MCP and cardiovascular disease and identify possible mediators between them. METHODS: A two-sample Mendelian randomisation analysis was applied in this study. The summary data for MCP were obtained from a genome-wide association study that included 387 649 individuals from the UK Biobank, whereas summary-level data for cardiovascular disease and its subtypes were obtained from relevant genome-wide association studies. Finally, summary-level data for common cardiovascular risk factors and inflammatory biomarkers were leveraged to identify possible mediators. RESULTS: Genetic liability to multi-site chronic pain is associated with higher risks for coronary artery disease (CAD), myocardial infarction (MI), heart failure (HF), and stroke, with a combined odds ratio (OR) of 1.537 (per site increment in MCP; 95% confidence interval [CI]: 1.271-1.858; P=0.0001) for CAD, 1.604 (95% CI: 1.277-2.014; P=0.0005) for MI, 1.722 (95% CI: 1.423-2.083; P<0.00001) for HF, and 1.332 (95% CI: 1.093-1.623; P=0.00001) for stroke. Genetic liability to MCP was found to be associated with mental disorders, smoking initiation, physical activity, BMI, and lipid metabolites. Multivariable Mendelian randomisation suggested a mediating role for mental disorders, smoking initiation, physical activity, and BMI in the relationship between multi-site chronic pain and cardiovascular disease. CONCLUSIONS: Our findings provide new insights into the role of multi-site chronic pain in cardiovascular disease. Additionally, we identified several modifiable risk factors for reducing cardiovascular disease.

Accessing three-dimensional molecular diversity through benzylic C-H cross-coupling.

Pharmaceutical and agrochemical discovery efforts rely on robust methods for chemical synthesis that rapidly access diverse molecules1,2. Cross-coupling reactions are the most widely used synthetic methods3, but these methods typically form bonds to C(sp2)-hybridized carbon atoms (e.g., amide coupling, biaryl coupling) and lead to a prevalence of "flat" molecular structures with suboptimal physicochemical and topological properties4. Benzylic C(sp3)-H cross-coupling methods offer an appealing strategy to address this limitation by directly forming bonds to C(sp3)-hybridized carbon atoms, and emerging methods exhibit synthetic versatility that rivals conventional cross-coupling methods to access products with drug-like properties. Here, we use a virtual library of >350,000 benzylic ethers and ureas derived from benzylic C-H cross-coupling to test the widely held view that coupling at C(sp3)-hybridized carbon atoms affords products with improved three-dimensionality. The results show that the conformational rigidity of the benzylic scaffold strongly influences the product dimensionality. Products derived from flexible scaffolds often exhibit little or no improvement in three-dimensionality, unless they adopt higher energy conformations. This outcome introduces an important consideration when designing routes to topologically diverse molecular libraries. The concepts elaborated herein are validated experimentally through an informatics-guided synthesis of selected targets and the use of high-throughput experimentation to prepare a library of three-dimensional products that are broadly distributed across drug-like chemical space.

Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.

The leucine-rich repeat kinase 2 (LRRK2) protein has been genetically and functionally linked to Parkinson's disease (PD), a disabling and progressive neurodegenerative disorder whose current therapies are limited in scope and efficacy. In this report, we describe a rigorous hit-to-lead optimization campaign supported by structural enablement, which culminated in the discovery of brain-penetrant, candidate-quality molecules as represented by compounds 22 and 24. These compounds exhibit remarkable selectivity against the kinome and offer good oral bioavailability and low projected human doses. Furthermore, they showcase the implementation of stereochemical design elements that serve to enable a potency- and selectivity-enhancing increase in polarity and hydrogen bond donor (HBD) count while maintaining a central nervous system-friendly profile typified by low levels of transporter-mediated efflux and encouraging brain penetration in preclinical models.

Discovery of a new limestone karst-restricted odorous frog from northern Guangdong, China (Anura, Ranidae, Odorrana).

Karstic landscapes play an important role in biodiversity formation and often contain high levels of endemism. However, site-endemic taxa in karstic landscapes are being threatened by exploitation and weak legal protection. In this study, we describe Odorranaconcelata Wang, Zeng, & Lin, sp. nov., a limestone karst-restricted odorous frog from northern Guangdong, China. This new species shows distinctive genetic divergence and morphological differences from its congeners. Phylogenetic results suggest that the new species represents an independent lineage that is grouped with O.lipuensis and O.liboensis based on the mitochondrial 16S and 12S ribosomal RNA genes. We recommend the new species be listed as Vulnerable (VU) in the IUCN categorization as it is only known from the type locality with limited microhabitats and is threatened by habitat degradation.

Benzylic C-H isocyanation/amine coupling sequence enabling high-throughput synthesis of pharmaceutically relevant ureas.

C(sp3)-H functionalization methods provide an ideal synthetic platform for medicinal chemistry; however, such methods are often constrained by practical limitations. The present study outlines a C(sp3)-H isocyanation protocol that enables the synthesis of diverse, pharmaceutically relevant benzylic ureas in high-throughput format. The operationally simple C-H isocyanation method shows high site selectivity and good functional group tolerance, and uses commercially available catalyst components and reagents [CuOAc, 2,2'-bis(oxazoline) ligand, (trimethylsilyl)isocyanate, and N-fluorobenzenesulfonimide]. The isocyanate products may be used without isolation or purification in a subsequent coupling step with primary and secondary amines to afford hundreds of diverse ureas. These results provide a template for implementation of C-H functionalization/cross-coupling in drug discovery.

Mapping the dark space of chemical reactions with extended nanomole synthesis and MALDI-TOF MS.

Understanding the practical limitations of chemical reactions is critically important for efficiently planning the synthesis of compounds in pharmaceutical, agrochemical, and specialty chemical research and development. However, literature reports of the scope of new reactions are often cursory and biased toward successful results, severely limiting the ability to predict reaction outcomes for untested substrates. We herein illustrate strategies for carrying out large-scale surveys of chemical reactivity by using a material-sparing nanomole-scale automated synthesis platform with greatly expanded synthetic scope combined with ultrahigh-throughput matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS).

Predicting reaction performance in C-N cross-coupling using machine learning.

Machine learning methods are becoming integral to scientific inquiry in numerous disciplines. We demonstrated that machine learning can be used to predict the performance of a synthetic reaction in multidimensional chemical space using data obtained via high-throughput experimentation. We created scripts to compute and extract atomic, molecular, and vibrational descriptors for the components of a palladium-catalyzed Buchwald-Hartwig cross-coupling of aryl halides with 4-methylaniline in the presence of various potentially inhibitory additives. Using these descriptors as inputs and reaction yield as output, we showed that a random forest algorithm provides significantly improved predictive performance over linear regression analysis. The random forest model was also successfully applied to sparse training sets and out-of-sample prediction, suggesting its value in facilitating adoption of synthetic methodology.

Radical Cation Cycloadditions Using Cleavable Redox Auxiliaries.

The incorporation of an easily oxidized arylsulfide moiety facilitates the photocatalytic generation of alkene radical cations that undergo a variety of cycloaddition reactions with electron-rich reaction partners. The sulfide moiety can subsequently be reductively cleaved in a traceless fashion, affording products that are not otherwise directly accessible using photoredox catalysis. This approach constitutes a novel oxidative "redox auxiliary" strategy that offers a practical means to circumvent a fundamental thermodynamic limitation facing photoredox reactions.

Aryl amination using ligand-free Ni(II) salts and photoredox catalysis.

Over the past two decades, there have been major developments in transition metal-catalyzed aminations of aryl halides to form anilines, a common structure found in drug agents, natural product isolates, and fine chemicals. Many of these approaches have enabled highly efficient and selective coupling through the design of specialized ligands, which facilitate reductive elimination from a destabilized metal center. We postulated that a general and complementary method for carbon-nitrogen bond formation could be developed through the destabilization of a metal amido complex via photoredox catalysis, thus providing an alternative approach to the use of structurally complex ligand systems. Here, we report the development of a distinct mechanistic paradigm for aryl amination using ligand-free nickel(II) salts, in which facile reductive elimination from the nickel metal center is induced via a photoredox-catalyzed electron-transfer event.

Corneal elevation in a large number of myopic Chinese patients.

PURPOSE: To establish a normative database for corneal elevation in Chinese myopic patients who underwent refractive surgery, and analyze the association of corneal elevation with sex, age, and ocular parameters. METHODS: A total of 3000 eyes in 1500 patients were evaluated with the Pentacam. Anterior and posterior elevations were measured at the apex and thinnest point. Normative thresholds were defined according to the Tukey method. Univariate and multivariate analyses were performed to assess the association of corneal elevation with sex, age, and ocular parameters. RESULTS: Normal upper limits for corneal elevation in adult Chinese were 4.95µm, 5.25µm, 6.2µm, and 11.0µm at the anterior apex, anterior thinnest point, posterior apex, and posterior thinnest point, respectively. Thinner corneal pachymetry at the apex and greater anterior corneal astigmatism tended to show greater anterior corneal elevation values. Younger age, greater anterior corneal astigmatism, lower anterior and posterior keratometry, and shallower anterior chamber depth resulted in greater posterior corneal elevation values. CONCLUSIONS: Locally derived thresholds may offer higher sensitivity and specificity when screening eyes for myopic refractive surgery, and keratoconic and post-orthokeratology eyes. Anterior and posterior corneal elevation at the apex and thinnest point were associated significantly with anterior corneal astigmatism, showing a positive correlation.

Corneal Power Measurement Obtained by Fourier-Domain Optical Coherence Tomography: Repeatability, Reproducibility, and Comparison With Scheimpflug and Automated Keratometry Measurements.

PURPOSE: To assess the repeatability and reproducibility of corneal power values obtained by a Fourier-domain optical coherence tomography (FD-OCT) system (RTVue) and to compare them with the values obtained by a Scheimpflug camera system (Pentacam HR) and by automated keratometry (IOL Master). METHODS: Thirty-two eyes from 32 healthy subjects were included in this prospective study. Two experienced observers measured each eye 3 consecutive times with the Pentacam, IOLMaster, and RTVue centered on either the pupil or corneal vertex. The conventional keratometry equivalent (CKE) and anterior (Ka), posterior (Kp), and net (Kn) corneal power values were determined. RESULTS: The corneal power values obtained by the RTVue showed high repeatability (all intraclass correlation coefficient >0.96) and reproducibility (coefficient of variation <1.0%). Pupil-centered FD-OCT performed slightly better than corneal vertex-centered FD-OCT. Mean corneal values had higher reproducibly than any of the individual values. CKE, Ka, Kp, and Kn obtained by FD-OCT were 0.62 to 0.68 diopters (D), 0.70 to 0.76 D, 0.11 to 0.13 D, and 0.93 to 0.94 D higher than those obtained by the Pentacam HR, respectively. CKE and Ka obtained with the RTVue were also 0.60 to 0.74 D higher than those obtained with the IOLMaster, respectively. CONCLUSIONS: The corneal power measurements obtained by the RTVue FD-OCT system showed high repeatability and reproducibility. Measurements obtained by FD-OCT with pupil centration were more reproducible than those obtained by FD-OCT with corneal vertex centration. We recommend that pupil-centered FD-OCT be used in clinical applications. Neither RTVue versus Pentacam HR nor RTVue versus IOLMaster can be used interchangeably.

Axial Length Measurement Failure Rates with the IOLMaster and Lenstar LS 900 in Eyes with Cataract.

PURPOSE: To evaluate axial length (AL) measurement failure rate with the IOLMaster (Carl Zeiss AG, Germany) and Lenstar LS 900 (Haag-Streit AG, Switzerland) in eyes with cataract. METHODS: Two hundred and ninety-six eyes of 170 patients with cataract were enrolled. Cataract type and severity were graded using the Lens Opacities Classification System III (LOCS III) and AL measurements were attempted with IOLMaster (version 5.4) and Lenstar LS 900 (version 1.1). Chi-squared analysis was used to assess if the difference in AL measurement acquisition rate was statistically significant between the two devices. The association of the different cataract types and severity with the AL measurement acquisition rate was evaluated with logistic regression analysis. RESULTS: AL measurements were obtained in 184 eyes (62.16%) using the IOLMaster and 191 eyes (64.53%) using the Lenstar, which corresponds to a failure rate of 37.84% and 35.47% respectively. Chi-square analysis indicated no significant difference between the Lenstar and IOLMaster for AL measurement failure rate (x2 = 0.356, P = 0.550). Logistic regression analysis indicated no association between acquisition rates and cortical or nuclear cataracts with either device. There was a statistically significant association between acquisition rates and increasing severity of posterior subcapsular cataracts with the IOLMaster (ß = -1.491, P<0.001) and Lenstar LS 900 (ß = -1.507, P<0.001). CONCLUSION: The IOLMaster and Lenstar LS 900 have similar AL measurement failure rates (35-38%) for Chinese public hospital cataract patients. Increasing severity of posterior subcapsular cataracts was problematic for both devices.

Comparison of keratometry and white-to-white measurements obtained by Lenstar with those obtained by autokeratometry and corneal topography.

PURPOSE: To compare anterior eye segment measurements obtained using low optical coherence reflectometry (LENSTAR LS900, Haag-Streit), autokeratometry (RC-5000, Tomey) and corneal topography (Topolyzer, Wavelight). METHODS: In 46 healthy subjects, flat keratometry (Kf), steep keratometry (Ks), mean keratometry (Km) and white-to-white (WTW) distance were measured by Lenstar, Tomey RC-5000 and Topolyzer. RESULTS: Kf and Km measurements of Lenstar were significantly steeper than Tomey RC-5000 (both p<0.001), but the 95% LoA of them were narrow (-0.22 to 0.46D, -0.16 to 0.36D, respectively). There were no significant differences between the Kf and Km measurements of Lenstar and Topolyzer, with a narrow 95% LoA. There were no significant differences between the Ks measurements of Lenstar and Tomey RC-5000, and Lenstar and Topolyzer. A good agreement was found between them with 95% LoA of -0.40 to 0.56D, and -0.56 to 0.64D, respectively. WTW measurements with Lenstar were greater than those with Tomey RC-5000 and Topolyzer (p=0.042, p<0.01, respectively). A good agreement existed between the WTW obtained by Lenstar and Topolyzer, Tomey RC-5000, with 95% LoA ranging from -0.13 to 0.74mm and -0.33 to 0.51mm. CONCLUSIONS: Generally good agreement was found between the Lenstar and Tomey RC-5000, Topolyzer for K and WTW measurements. In clinical practice, K and WTW measurements obtained by Lenstar and Tomey RC-5000, Topolyzer can be used interchangeably.

Visible light photocatalysis of intramolecular radical cation Diels-Alder cycloadditions.

Intramolecular radical cation Diels-Alder reactions can be conducted under photocatalytic conditions using visible light irradiation. The photocatalyst system involves the use of a Ru(bpy)(3) (2+) chromophore and methyl viologen as a co-oxidant. These reactions enable the cycloaddition of substrates whose thermal Diels-Alder cycloadditions are electronically mismatched and thus require forcing conditions. Nevertheless, the radical cation cycloadditions can be conducted on gram scale using ambient sunlight as the only source of irradiation.

Radical cation Diels-Alder cycloadditions by visible light photocatalysis.

Ruthenium(II) polypyridyl complexes promote the efficient radical cation Diels-Alder cycloaddition of electron-rich dienophiles upon irradiation with visible light. These reactions enable facile [4 + 2] cycloadditions that would be electronically mismatched under thermal conditions. Key to the success of this methodology is the availability of ligand-modified ruthenium complexes that enable rational tuning of the electrochemical properties of the catalyst without significantly perturbing the overall photophysical properties of the system.

Enantioselective protonation of itaconimides with thiols and the rotational kinetics of the axially chiral C-N bond.

Bicyclic guanidines are able to catalyze the protonation reactions of 2-phthalimidoacrylates with thiols in excellent yields and enantioselectivities. The protonation reaction of itaconimides with secondary phosphine oxides is also known. Herein, the tandem conjugate addition-enantioselective protonation of N-substituted itaconimides with thiols catalyzed by chiral bicyclic guanidine is investigated. The rotational barrier of the C-N axis of N-2-tert-butyl phenylitaconimide is also studied, both experimentally and computationally.