Discovery of Clinical Manifestations in Spontaneous Glaucoma Suspect Nonhuman Primates.

INTRODUCTION: The primary aim of this study was to assess the longitudinal changes in retinal nerve fiber layer (RNFL) thickness and relative ONH parameters using spectral-domain optical coherence tomography (SD-OCT) in the living eyes of nonhuman primates with spontaneous glaucoma. METHODS: Totally 9 macaque subjects underwent a standard fundus photo and OCT examination, including 3 adult monkeys with stable elevated intraocular pressure (IOP) as the glaucoma suspect group and 6 normal IOP monkeys as the control group. Each eye of primates with IOP measurement was repeated three times. OCT measurements recorded RNFL, Bruch's membrane opening (BMO) minimum rim width (MRW). The follow-up scan of glaucomatous subjects was undergone in 10 months. RESULTS: The mean ages of glaucoma and healthy subjects are 19.33 ± 0.33 and 20.5 ± 1.46 years. Elevated IOP was achieved in three nonhuman primate eyes with an average increase of 10 mm Hg over the study period. Elevated IOP was associated with decreased RNFL thickness in all the regions and decreased RNFL phase retardation in the superior and inferior regions. When averaged over the entire retinal area, only the whole RNFL and temporal regions showed a significant decrease. The mean IPL thicknesses are 87.17 ± 2.15 µm in glaucomatous and 93.33 ± 1.51 µm in healthy eyes (p = 0.03). Lamina cribrosa parameters are measured from the OCT images and showed significant differences between glaucoma primates and normal primates. CONCLUSIONS: Of the measured parameters, decreased RNFL and MRW were correlated with glaucomatous damage. Natural glaucoma primate can be a natural glaucoma model which is closer to glaucoma in humans.

Regio- and Enantioselective Synthesis of Dihydropyrido[1,2-a]indoles via Catalytic Asymmetric Annulative Allylic Alkylation.

A palladium-catalyzed asymmetric annulative allylic alkylation reaction of 2-[(1H-indol-2-yl)methyl]malonates with (E)-but-2-ene-1,4-diyl dicarbonates is described, leading to the regio- and enantioselective synthesis of dihydropyrido[1,2-a]indoles with a chiral cyclic allyl stereocenter adjacent to the ring-junction nitrogen atom in moderate to good yields. The salient features of this protocol include mild conditions, a broad substrate scope, and good compatibility with substituents as well as high regio- and stereoselectivities, providing a catalytic asymmetric entry for fabricating chiral pyridoindole scaffolds.

Wavelet-Domain Information-Hiding Technology with High-Quality Audio Signals on MEMS Sensors.

Due to the rapid development of sensor technology and the popularity of the Internet, not only has the amount of digital information transmission skyrocketed, but also its acquisition and dissemination has become easier. The study mainly investigates audio security issues with data compression for private data transmission on the Internet or MEMS (micro-electro-mechanical systems) audio sensor digital microphones. Imperceptibility, embedding capacity, and robustness are three main requirements for audio information-hiding techniques. To achieve the three main requirements, this study proposes a high-quality audio information-hiding technology in the wavelet domain. Due to the fact that wavelet domain provides a useful and robust platform for audio information hiding, this study applies multi-coefficients of discrete wavelet transform (DWT) to hide information. By considering a good, imperceptible concealment, we combine signal-to-noise ratio (SNR) with quantization embedding for these coefficients in a mathematical model. Moreover, amplitude-thresholding compression technology is combined in this model. Finally, the matrix-type Lagrange principle plays an essential role in solving the model so as to reduce the carrying capacity of network transmission while protecting personal copyright or private information. Based on the experimental results, we nearly maintained the original quality of the embedded audio by optimization of signal-to-noise ratio (SNR). Moreover, the proposed method has good robustness against common attacks.

Intelligent Healthcare System Using Mathematical Model and Simulated Annealing to Hide Patients Data in the Low-Frequency Amplitude of ECG Signals.

Healthcare is an important medical topic in recent years. In this study, the novelty we propose is the intelligent healthcare system using an inequality-type optimization mathematical model with signal-to-noise ratio (SNR) and wavelet-domain low-frequency amplitude adjustment techniques to hide patients' confidential data in their electrocardiogram (ECG) signals. The extraction of the hidden patient information also utilizes the low-frequency amplitude adjustment. The detailed steps of establishing the system are as follows. To integrate confidential patient data into ECG signals, we first propose a nonlinear model to optimize the quality of ECG signals with the embedded patients' confidential data including patient name, patient birthdate, date of medical treatment, and medical history. Then, we apply Simulated Annealing (SA) to solve the nonlinear model such that the ECG signals with embedded patients' confidential data have good SNR, good root mean square error (RMSE), and high similarity. In other words, the distortion of the PQRST complexes and the ECG shape caused by the embedded patients' confidential data is very small, and thus the quality of the embedded ECG signals meets the requirements of physiological diagnostics. In the terminals, one can receive the ECG signals with the embedded patients' confidential data. In addition, the embedded patients' confidential data can be received and extracted without the original ECG signals. The experimental results confirm the efficiency that our method maintains a high quality of each ECG signal with the embedded patient confidential data. Moreover, the embedded confidential data shows a good robustness against common attacks.

Uncertainty measurement of radiomics features against inherent quantum noise in computed tomography imaging.

OBJECTIVES: Quantum noise is a random process in X-ray-based imaging systems. We addressed and measured the uncertainty of radiomics features against this quantum noise in computed tomography (CT) images. METHODS: A clinical multi-detector CT scanner, two homogeneous phantom sets, and four heterogeneous samples were used. A solid tumor tissue removed from a male BALB/c mouse was included. We the placed phantom sets on the CT scanning table and repeated 20 acquisitions with identical imaging settings. Regions of interest were delineated for feature extraction. Statistical quantities-average, standard deviation, and percentage uncertainty-were calculated from these 20 repeated scans. Percentage uncertainty was used to measure and quantify feature stability against quantum noise. Twelve radiomics features were measured. Random noise was added to study the robustness of machine learning classifiers against feature uncertainty. RESULTS: We found the ranges of percentage uncertainties from homogeneous soft tissue phantoms, homogeneous bone phantoms, and solid tumor tissue to be 0.01-2138%, 0.02-15%, and 0.18-16%, respectively. Overall, it was found that the CT features ShortRunHighGrayLevelEmpha (SRHGE) (0.01-0.18%), ShortRunLowGrayLevelEmpha (SRLGE) (0.01-0.41%), LowGrayLevelRunEmpha (LGRE) (0.01-0.39%), and LongRunLowGrayLevelEmpha (LRLGE) (0.02-0.66%) were the most stable features against the inherent quantum noise. The most unstable features were cluster shade (1-2138%) and max probability (1-16%). The impact of random noise to the prediction accuracy by different machine learning classifiers was found to be between 0 and 12%. CONCLUSIONS: Twelve features were used for uncertainty measurements. The upper and lower bounds of percentage uncertainties were determined. The quantum noise effect on machine learning classifiers is model dependent. KEY POINTS: • Quantum noise is a random process and is intrinsic to X-ray-based imaging systems. This inherent quantum noise creates unpredictable fluctuations in the gray-level intensities of image pixels. Extra cautions and further validations are strongly recommended when unstable radiomics features are selected by a predictive model for disease classification or treatment outcome prognosis. • We addressed and used the statistical quantity of percentage uncertainty to measure the uncertainty of radiomics features against the inherent quantum noise in computed tomography (CT) images. • A clinical multi-detector CT scanner, two homogeneous phantom sets, and four heterogeneous samples were used in the stability measurement. A solid tumor tissue removed from a male BALB/c mouse was included in the heterogeneous sample.

Tunable Electrocatalytic Annulations of o-Arylalkynylanilines: Green and Switchable Syntheses of Skeletally Diverse Indoles.

Tunable electrocatalytic annulation reactions of o-arylalkynylanilines have been established, leading to green and divergent syntheses of skeletally diverse indoles by adjusting the electrolytes and the solvents. The presence of ammonium halides as the electrolytes enabled the halogenation of o-arylalkynylanilines to give C3-halogenated indoles whereas naphtho[1',2':4,5]furo[3,2-b]indoles could be obtained by changing the electrolyte from ammonium halides to KI. Interestingly, by combining acetone as the solvent and both NH4I and NH4Cl as the electrolytes, the reaction worked through an intramolecular annulation and [5 + 1] cyclization cascade to form naphtho[1',2':5,6][1,3]oxazino[3,4-a]indoles.

Cyclic Oxime Esters as Deconstructive Bifunctional Reagents for Cyanoalkyl Esterification of 1,6-Enynes.

A concise copper catalysis strategy for the addition-cyclization of cyclic oxime esters across 1,6-enynes with high stereoselectivity to generate 1-indanones bearing an all-carbon quaternary center is reported. In this process, single-electron reduction of cyclic oxime esters enables deconstructive carbon-carbon cleavage to provide a key cyanopropyl radical poised for the addition-cyclization. This reaction is redox-neutral, exhibits good functional group compatibility, and features 100% atomic utilization. This process driven by copper catalyst makes readily available cyclic oxime esters as bifunctional reagents to demonstrate convergent synthesis.

Advance care planning preferences in Chinese nursing home residents: results from two cross-sectional studies in Hong Kong and Taiwan.

BACKGROUND: The proportion of hospital deaths has declined in the past few decades, while the proportions of nursing home deaths have increased. This trend of increasing deaths in long-term care facilities underlines the importance of improving end-of-life care provisions in these settings to meet individual preferences and needs. Under these circumstances, a comprehensive understanding of end-of-life care preferences in local nursing home residents can help healthcare professionals and policymakers develop strategies to increase the advance directive completion rate and quality of care. This study aimed to explore and compare advance directive and end-of-life care preferences of nursing home residents in Hong Kong and Taiwan. METHODS: A structured questionnaire was developed by the research team to investigate advance directive and end-of-life care preferences in older Chinese nursing home residents. Nursing home residents with frail or pre-frail status and over the age of 64 were invited to participate in the study, and information on demographics, functional status, advance directive experiences, and end-of-life care expectations was collected through questionnaire interviews. RESULTS: A total of 325 eligible participants from 32 facilities completed the survey, including 238 older residents in Hong Kong and 87 in Taiwan. A significantly lower proportion of the Hong Kong residents had completed an advance directive compared with the Taiwanese (3 vs. 13%, p = 0.001). Among participants who did not have an advance directive, 46% of the Taiwanese participants said they would consider completing one in the future, compared with 20% of the Hong Kong participants (p < 0.001). A total of 79% of the Hong Kong participants and 80% of the Taiwanese participants responded that prolonging life in the given hypothetical dying scenario was "not important" (p = 0.76). Only 14% of participants in Hong Kong and 18% of participants in Taiwan reported prior occurrence of end-of-life care discussions with family members or health professionals (p = 0.37). CONCLUSIONS: This paper adds evidence in support of improving end-of-life communication and the advance directive completion rate in nursing homes in Hong Kong and Taiwan. Further research is necessary to explore cross-cultural differences in end-of-life preferences and its applications in predicting decision-making and the quality of end-of-life care.

Molecular Pathways Modulating Sensory Hair Cell Regeneration in Adult Mammalian Cochleae: Progress and Perspectives.

Noise-induced, drug-related, and age-related disabling hearing loss is a major public health problem and affect approximately 466 million people worldwide. In non-mammalian vertebrates, the death of sensory hair cells (HCs) induces the proliferation and transdifferentiation of adjacent supporting cells into new HCs; however, this capacity is lost in juvenile and adult mammalian cochleae leading to permanent hearing loss. At present, cochlear implants and hearing devices are the only available treatments and can help patients to a certain extent; however, no biological approach or FDA-approved drug is effective to treat disabling hearing loss and restore hearing. Recently, regeneration of mammalian cochlear HCs by modulating molecular pathways or transcription factors has offered some promising results, although the immaturity of the regenerated HCs remains the biggest concern. Furthermore, most of the research done is in neonates and not in adults. This review focuses on critically summarizing the studies done in adult mammalian cochleae and discusses various strategies to elucidate novel transcription factors for better therapeutics.

Palladium/N,N'-Disulfonyl Bisimidazoline-Catalyzed Enantioselective Addition of Arylboronic Acids to Cyclic N-Sulfonyl Ketimines.

The combination of Pd(TFA)2 and an N,N'-disulfonyl bisimidazoline ligand shows high catalytic activity and excellent asymmetric induction in the addition of arylboronic acids to cyclic N-sulfonyl ketimines including benzo[d]isothiazole-1,1-dioxides, benzo[e][1,2,3]oxathiazine-2,2-dioxides, and 1,2,5-thiadiazole-1,1-dioxides, by which three types of chiral quaternary carbon-containing sultams with substantial substitution diversity were synthesized with high yields and excellent enantioselectivities (up to >99% ee). The current catalysis demonstrated a remarkable tolerance to oxygen and thus provided an operationally simple approach for constructing enantioenriched cyclic quaternary stereocenters.

Ligand-Free Pd-Catalyzed Synthesis of 3-Allylbenzofurans by Merging Decarboxylative Allylation and Nucleophilic Cyclization.

A new single Pd-catalyzed decarboxylative allylation-nucleophilic cyclization relay is reported by using α-alkynyl arylols and vinylethylene carbonates (or vinyl carbamates), and a wide range of 3-allyl benzofurans with generally good yields were stereoselectively synthesized under mild conditions, among which the complete stereoselectivity of some cases was also observed. Notably, the present catalysts can tolerate air conditions without any ligand, additive, or base, opening new avenues to build up oxa-heterocycle frameworks through catalytic difunctionalization of internal alkynes.

Biallelic Mutations in Citron Kinase Link Mitotic Cytokinesis to Human Primary Microcephaly.

Cell division terminates with cytokinesis and cellular separation. Autosomal-recessive primary microcephaly (MCPH) is a neurodevelopmental disorder characterized by a reduction in brain and head size at birth in addition to non-progressive intellectual disability. MCPH is genetically heterogeneous, and 16 loci are known to be associated with loss-of-function mutations predominantly affecting centrosomal-associated proteins, but the multiple roles of centrosomes in cellular function has left questions about etiology. Here, we identified three families affected by homozygous missense mutations in CIT, encoding citron rho-interacting kinase (CIT), which has established roles in cytokinesis. All mutations caused substitution of conserved amino acid residues in the kinase domain and impaired kinase activity. Neural progenitors that were differentiated from induced pluripotent stem cells (iPSCs) derived from individuals with these mutations exhibited abnormal cytokinesis with delayed mitosis, multipolar spindles, and increased apoptosis, rescued by CRISPR/Cas9 genome editing. Our results highlight the importance of cytokinesis in the pathology of primary microcephaly.

TonoVet versus Tonopen in a high intraocular pressure monkey model.

Purpose: The purpose of this study is to evaluate the consistency of and deviation in intraocular pressure (IOP) measurements obtained by the TonoVet rebound tonometer and the Tonopen applanation tonometer in a primate model. Methods: Twenty-four-hour IOPs (nine time points) were recorded in ten monkeys with normal IOP and eight monkeys with chronic high IOP (one eye was randomly selected for measurement in each animal) using a Tonopen and TonoVet device. Measurements obtained using both handheld devices were first compared in the healthy control group (90 readings). The monkeys with chronic ocular hypertension (COHT, 72 IOP readings) were divided into three subgroups according to the level of IOP. The consistency of and deviations in the measurements were analyzed using Bland-Altman plots, linear regression, and two-tailed Student t tests. Results: In monkeys with normal IOP, the two devices produced similar IOP readings (mean IOP deviation, 0.06 ± 2.08 mmHg, p = 0.761), with 56.67% of the deviation between -1 mmHg and 1 mmHg and 91.12% between -3 mmHg and 3 mmHg. However, in the animal model group (23-60 mmHg), the readings obtained by the TonoVet tonometer were higher than those obtained by the Tonopen tonometer (mean deviation, 13.76 ± 9.19 mmHg); furthermore, 75.68% of the TonoVet measurements deviated by ± 5 mmHg from the Tonopen measurements. Conclusions: In animals with normal IOP, the TonoVet and Tonopen tonometers produced consistent measurements. However, in a monkey model of chronic high IOP, the measurements obtained by these tonometers were inconsistent, with higher IOPs associated with larger measurement errors. Therefore, it is necessary to be aware that among different tonometers, there may be systemic errors and deviations in IOP measurements. These findings should facilitate efforts to obtain more accurate individualized diagnoses and prevent the utilization of misleading IOP values.

Generation of 1,3-Dimethylene-Substituted Isobenzofurans via Pd(II)-Catalyzed Selective Oxo-cyclization/SO2 Insertion Cascade of ß-Alkynyl Ketones.

A new palladium(II)-catalyzed cyclization-radical addition cascade enables the direct construction of 1,3-dimethylene-substituted isobenzofuran derivatives containing a vinyl aryl sulfone unit in good yields by treating with ß-alkynyl ketones, aryl diazonium salts, and DABCO·(SO2)2. The oxidant-free multicomponent reaction features good substrate scope and functional group tolerance, which proceeds through a sequence of Heck coupling, oxo-cyclization, and SO2 insertion.

Synthesis of Diastereoenriched 1-Indanones via Double-Base Cooperatively Promoted 1,4-Oxo-Migration/Cyclization of ß-Alkynyl Ketones.

A double-base copromoted 1,4-oxo-migration/cyclization cascade of ß-alkynyl ketones was reported, enabling to form a range of functionalized 1-indanones with moderate to good yields and high diastereoselectivity in the presence of t-BuOK as a Brønsted base and N,N'-dimethylethanediamine (DMEDA) as a Lewis base. Some of these 1-indanones were successfully transformed into 2-haloethyl benzoates with one all-carbon quaternary stereocenter by 1,2-dichloroethane (DCE) or 1,2-dibromoethane (DBE) as both a reactant and a reaction media. This method also features high atomic utilization (100%), high diastereoselectivity, and mild reaction conditions.

Completely Stereoselective Synthesis of Sulfonated 1,3-Dihydroisobenzofurans via Radical Multicomponent Reactions.

Two types of new oxidant-free radical multicomponent reactions of ß-alkynyl ketones, aryldiazonium salts, and DABCO·(SO2)2 (DABSO) were established, leading to the tunable generation of two class of sulfonated 1,3-dihydroisobenzofurans with moderate to good yields and complete stereoselectivity under the mild conditions. The radical-induced scission/recombination of the C(sp3)-C(sp3) bond enabled direct 1,8-halosulfonylation of ß-alkynyl ketones, giving 1,3-dimethylene-substituted (1Z,3Z)-1,3-dihydroisobenzofurans with substituent diversity by p-nitrobenzyl bromide (PNBB) or p-nitrobenzyl chloride (PNBC) as the halo source. Fine-tuning substituents to strong electron-withdrawing ones, such as nitro, cyano, and trifluoromethyl, linked to aryldiazonium tetrafluoroborates allowed a different annulation/1,5-azosulfonylation process to access sulfonated (Z)-1,3-dihydroisobenzofurans with one quaternary carbon-amino functionality.

Pd(II)-Catalyzed Carbonyl-Directing Activation of Alkenes: Selective Fluorosulfonylation and Aminosulfonylation of 1,7-Enynes.

A new Pd(II)-catalyzed carbonyl-directing activation of alkenes has been established, enabling radical-induced selective fluorosulfonylation and aminosulfonylation of carbonyl-tethered 1,7-enynes with sulfinic acids and N-fluorobenzenesulfonimide (NFSI) under mild and redox neutral conditions to access densely functionalized ( E)-3,4-dihydronaphthalen-1(2 H)-ones with generally good yields and high stereoselectivity. The selectivity of these bifunctionalizations relies on the electronic nature of substituents on both aryl rings of 1,7-enynes.

Substrate-Controlled Generation of 3-Sulfonylated 1-Indenones and 3-Arylated ( Z)-Indenes via Cu-Catalyzed Radical Cyclization Cascades of o-Alkynylbenzonitriles.

Substrate-controlled generation of 3-sulfonylated 1-indenones and 3-arylated ( Z)-indenes through radical cyclization cascades of o-alkynylbenzonitriles with sulfonyl hydrazides was established by combining copper(II) with tert-butyl hydroperoxide (TBHP) as a catalytic oxidative system. With the installation of the aryl group (R1) into the alkynyl unit, sulfonyl radicals triggered addition-cyclization cascades to access 3-sulfonylated 1-indenones with good yields by using a Cu/TBHP system, whereas a series of new functionalized 3-arylated ( Z)-indenes were obtained in good yields when o-alkynylbenzonitriles bearing the alkyl group in the alkynyl unit were subjected with arylsulfonyl hydrazides with an electron-rich nature under the above conditions.

I2-Mediated Iodobenzannulation of Yne-Allenones toward 1-Naphthols and Their Synthetic Application.

A new I2-mediated iodobenzannulation of yne-allenones has been established, enabling breaking/rearranging of C≡C bonds to selectively access 4-iodonaphthalen-1-ols with generally good yields. The resulting 4-iodonaphthalen-1-ols could serve as a new and reliable coupling reagent, which further reacted with H2O under the oxygen conditions to generate unexpected 1,2-carbonyls with good yields through Pd-catalyzed deiodinated carbonylation, whereas employment of benzene-1,2-diamine as the nucleophile rendered 3-(quinoxalin-2-yl)naphthalen-1-ols through Pd-catalyzed [4 + 2] heterocyclization. On the basis of the controlled experiments, the mechanism for forming 1,2-carbonyls was proposed, including an oxidative addition, 1,3-palladium migration, reductive elimination, and oxidative dehydrogenation sequence.

Atom-economic synthesis of cyclobuta[a]naphthalen-4-ols via a base-promoted [2 + 2] cycloaddition/1,6-nucleophilic addition cascade.

A first atom-economic [2 + 2] cycloaddition/1,6-conjugate addition cascade of yne-allenones with C-nucleophiles including 1,3-dicarbonyls and α,α-dicyanoolefins under base-promoted conditions has been established, enabling the direct construction of C(sp3)-C(sp3) bonds to generate cyclobuta[a]naphthalen-1-ols with generally good yields. These resulting products have a cyclobutene unit that contains both an aryl and alkyl group.