Review of COVID-19 Therapeutics by Mechanism: From Discovery to Approval.

The global research and pharmaceutical community rapidly mobilized to develop treatments for coronavirus disease 2019 (COVID-19). Existing treatments have been repurposed and new drugs have emerged. Here we summarize mechanisms and clinical trials of COVID-19 therapeutics approved or in development. Two reviewers, working independently, reviewed published data for approved COVID-19 vaccines and drugs, as well as developmental pipelines, using databases from the following organizations: United States Food and Drug Administration (US-FDA), European Medicines Agency (EMA), Japanese Pharmaceutical and Medical Devices Agency (PMDA), and ClinicalTrials.gov. In all, 387 drugs were found for initial review. After removing unrelated trials and drugs, 66 drugs were selected, including 17 approved drugs and 49 drugs under development. These drugs were classified into six categories: 1) drugs targeting the viral life cycle 2) Anti-severe acute respiratory syndrome coronavirus 2 Monoclonal Antibodies, 3) immunomodulators, 4) anti-coagulants, 5) COVID-19-induced neuropathy drugs, and 6) other therapeutics. Among the 49 drugs under development are the following: 6 drugs targeting the viral life cycle, 12 immunosuppression drugs, 2 immunostimulants, 2 HIF-PHD targeting drugs, 3 GM-CSF targeting drugs, 5 anti-coagulants, 2 COVID-19-induced neuropathy drugs, and 17 others. This review provides insight into mechanisms of action, properties, and indications for COVID-19 medications.

Dark Energy Survey Year 1 Results: Cosmological Constraints from Cluster Abundances, Weak Lensing, and Galaxy Correlations.

We present the first joint analysis of cluster abundances and auto or cross-correlations of three cosmic tracer fields: galaxy density, weak gravitational lensing shear, and cluster density split by optical richness. From a joint analysis (4×2pt+N) of cluster abundances, three cluster cross-correlations, and the auto correlations of the galaxy density measured from the first year data of the Dark Energy Survey, we obtain Ω_{m}=0.305_{-0.038}^{+0.055} and σ_{8}=0.783_{-0.054}^{+0.064}. This result is consistent with constraints from the DES-Y1 galaxy clustering and weak lensing two-point correlation functions for the flat νΛCDM model. Consequently, we combine cluster abundances and all two-point correlations from across all three cosmic tracer fields (6×2pt+N) and find improved constraints on cosmological parameters as well as on the cluster observable-mass scaling relation. This analysis is an important advance in both optical cluster cosmology and multiprobe analyses of upcoming wide imaging surveys.

Neurophysiological and Cognitive Correlates of Error Processing Deficits in Internet Gaming Disorder.

The ability to detect and correct errors is a critical aspect of human cognition. Neuronal dysfunction in error processing has been reported in addictive disorders. The aim of this study was to investigate neural systems underlying error processing using event-related potentials (ERPs) and current source localization as well as neurocognitive executive function tests in patients with Internet gaming disorder (IGD). A total of 68 individuals (34 patients with IGD and 34 healthy controls [HCs]) were included, and two ERP components, error-related negativity (ERN) and error positivity (Pe), were extracted during a GoNogo task. Patients with IGD exhibited significantly reduced ERN and Pe amplitudes compared with HCs. Standardized low-resolution brain electromagnetic tomography (sLORETA) in between-group comparisons revealed that patients with IGD had decreased source activations of the Pe component in the anterior cingulate cortex (ACC) under the Nogo condition. These ERP changes were associated with deficits in decision-making and response inhibition in IGD patients. The results suggest that IGD may be associated with functional abnormalities in the ACC and alterations in neural activity related to both the early unconscious and the later conscious stages of error processing, as well as deficits in area of decision-making.

Detection of Cross-Correlation between Gravitational Lensing and γ Rays.

In recent years, many γ-ray sources have been identified, yet the unresolved component hosts valuable information on the faintest emission. In order to extract it, a cross-correlation with gravitational tracers of matter in the Universe has been shown to be a promising tool. We report here the first identification of a cross-correlation signal between γ rays and the distribution of mass in the Universe probed by weak gravitational lensing. We use data from the Dark Energy Survey Y1 weak lensing data and the Fermi Large Area Telescope 9-yr γ-ray data, obtaining a signal-to-noise ratio of 5.3. The signal is mostly localized at small angular scales and high γ-ray energies, with a hint of correlation at extended separation. Blazar emission is likely the origin of the small-scale effect. We investigate implications of the large-scale component in terms of astrophysical sources and particle dark matter emission.

Maladaptive neurovisceral interactions in patients with Internet gaming disorder: A study of heart rate variability and functional neural connectivity using the graph theory approach.

Heart rate variability (HRV) can be used to represent the regulatory adaptive system and is a proxy for neurovisceral integration. Consistent with the view that, like other addictions, Internet gaming disorder (IGD) involves disrupted regulatory function, the present study hypothesized that IGD patients would show (a) decreased HRV, (b) ineffective functional neural connectivity, and (c) differential patterns of association between HRV and functional neural connectivity relative to healthy controls (HCs). The present study included 111 young adults (53 IGD patients and 58 age- and sex-matched HCs) who underwent simultaneous recordings with an electrocardiogram and electroencephalogram during a resting state. Heart rate (HR), HRV, and functional neural connectivity were calculated using the graph theory approach. Compared with the HCs, the IGD patients exhibited elevated HR and decreased HRV based on the high frequency (HF), which reflects suppression of parasympathetic and/or vagal tone. The IGD patients also exhibited a heightened theta band characteristic path length (CPL) compared with HCs, indicating decreased efficacy of the functional network. Furthermore, IGD patients exhibited negative correlations between the standard deviation of the normal-to-normal interval index (SDNNi) and theta and delta CPL values, which were not observed in HCs. In conclusion, the present findings suggest that IGD patients might have maladaptive brain-body integration features involving disruptions of the autonomic nervous system and brain function.

Resection of the irradiated esophagus: the impact of lymph node yield on survival.

There is debate surrounding the appropriate threshold for lymph node harvest during esophagectomy in patients with esophageal cancer, specifically for those receiving preoperative radiation. The purpose of this study was to determine the impact of lymph node yield on survival in patients receiving preoperative chemoradiation for esophageal cancer. The National Cancer Database (NCDB) was utilized to identify patients with esophageal cancer that received preoperative radiation. The cohort was divided into patients undergoing minimal (<9) or extensive (≥9) lymph node yield. Demographic, operative, and postoperative outcomes were compared between the groups. Kaplan-Meier analysis with the log rank test was used to compare survival between the yield groups. Cox proportional hazards model was used to determine the association between lymph node yield and survival. In total, 886 cases were included: 349 (39%) belonging to the minimal node group and 537 (61%) to the extensive group. Unadjusted 5-year survival was similar between the minimal and extensive groups, respectively (37.3% vs. 38.8%; P > 0.05). After adjustment using Cox regression, extensive lymph node yield was associated with survival (hazard ratio 0.80, confidence interval 0.66-0.98, P = 0.03). This study suggests that extensive lymph node yield is advantageous for patients with esophageal cancer undergoing esophagectomy following induction therapy. This most likely reflects improved diagnosis and staging with extensive yield.

Drug repositioning of herbal compounds via a machine-learning approach.

BACKGROUND: Drug repositioning, also known as drug repurposing, defines new indications for existing drugs and can be used as an alternative to drug development. In recent years, the accumulation of large volumes of information related to drugs and diseases has led to the development of various computational approaches for drug repositioning. Although herbal medicines have had a great impact on current drug discovery, there are still a large number of herbal compounds that have no definite indications. RESULTS: In the present study, we constructed a computational model to predict the unknown pharmacological effects of herbal compounds using machine learning techniques. Based on the assumption that similar diseases can be treated with similar drugs, we used four categories of drug-drug similarity (e.g., chemical structure, side-effects, gene ontology, and targets) and three categories of disease-disease similarity (e.g., phenotypes, human phenotype ontology, and gene ontology). Then, associations between drug and disease were predicted using the employed similarity features. The prediction models were constructed using classification algorithms, including logistic regression, random forest and support vector machine algorithms. Upon cross-validation, the random forest approach showed the best performance (AUC = 0.948) and also performed well in an external validation assessment using an unseen independent dataset (AUC = 0.828). Finally, the constructed model was applied to predict potential indications for existing drugs and herbal compounds. As a result, new indications for 20 existing drugs and 31 herbal compounds were predicted and validated using clinical trial data. CONCLUSIONS: The predicted results were validated manually confirming the performance and underlying mechanisms - for example, irinotecan as a treatment for neuroblastoma. From the prediction, herbal compounds were considered to be drug candidates for related diseases which is important to be further developed. The proposed prediction model can contribute to drug discovery by suggesting drug candidates from herbal compounds which have potentials but few were studied.

Correction to: Licochalcone A induces apoptosis through endoplasmic reticulum stress via a phospholipase Cγ1-, Ca2+-, and reactive oxygen species-dependent pathway in HepG2 human hepatocellular carcinoma cells.

The original version of this article contained mistakes in figures. The western blot data for pro-caspase-3 and cleaved caspase-3 (Fig. 1d), ß-actin (Fig. 1d), PLCγ1 (Fig. 5d), and eIF2α (Fig. 7d) are incorrect. The corrected Figs. 1d, 5d, and 7d are shown below. The corrections do not influence either the validity of the published data or the conclusion described in the article.

Correction to: Apicidin induces endoplasmic reticulum stress- and mitochondrial dysfunction-associated apoptosis via phospholipase Cγ1- and Ca2+-dependent pathway in mouse Neuro-2a neuroblastoma cells.

The original version of this article contained a mistake in the figure. The Ca2 + confocal image for the 2-APB/Apicidin-120 min in Fig. 5d is incorrect. The correction does not influence either the validity of the published data or the conclusion described in the article. The corrected Fig. 5d is given below.

Diversity of activity participation determines bone mineral content in the lower limbs of pre-pubertal children with developmental coordination disorder.

This study examined the relationships between activity participation and bone mineralization in children with developmental coordination disorder. Limited participation in physical, recreational, social, and skill-based and self-improvement activities contributed to lower bone mineral content. For improved bone health, these children should participate in a variety of activities, not only physical activities. INTRODUCTION: Limited activity participation in children with developmental coordination disorder (DCD) may have a negative impact on bone mineral accrual. The objectives of this study were to compare bone mineralization and activity participation patterns of pre-pubertal children with DCD and those with typical development, and to determine the association between activity participation patterns and bone mineralization in children with DCD. METHODS: Fifty-two children with DCD (mean age = 7.51 years) and 61 children with typical development (mean age = 7.22 years) participated in the study. Appendicular and total body (less head) bone mineral content (BMC) and bone mineral density (BMD) were evaluated by a whole-body dual-energy X-ray absorptiometry scan. Activity participation patterns were assessed using the Children's Assessment of Participation and Enjoyment (CAPE) questionnaire. RESULTS: Children with DCD had lower appendicular and total body BMCs and BMDs than children with typical development overall (p < 0.05). They also had lower CAPE total activity and physical activity diversity scores (p < 0.05). After accounting for the effects of age, sex, height, lean mass, and fat mass, the total activity diversity score remained independently associated with leg BMC in children with DCD, explaining 5.1% of the variance (p = 0.030). However, the physical activity diversity score was no longer associated with leg BMC (p = 0.090). CONCLUSIONS: Diversity of activity participation and bone mineralization were lower in pre-pubertal children with DCD. Decreased total activity participation diversity was a contributing factor to lower BMC in the legs of children with DCD.

Effectiveness of an oral health education seminar for paediatric and family medicine residents.

AIM: To assess the immediate effect of a 60-minute oral health educational seminar for paediatric and family medicine residents in improving their knowledge, attitude, likelihoodtowards incorporating oral health preventive practice in their current practices to well-child visits, and confidence in identifying and referring patients with dental trauma. MATERIALS AND METHODS: Baseline pre- and post-test design was used to evaluate the immediate effect of a 60-minute PowerPoint oral health educational seminar given to the paediatric and family medicine residents. STATISTICS: Multiple-choice items were used and the pre- and post-test data were analysed with McNemar and Wilcoxon signed-rank tests. A p-value <0.05 was considered statistically significant. RESULTS: Sixty-eight residents participated in the oral health educational seminar and completed the questionnaire. The mean age of participants was 29.9 years old (SD ±4.8 yrs.). Immediately following a 60-minute oral health educational seminar, there was an overall significant increase in participants' knowledge, attitudes and likelihood towards incorporating oral health preventive practice in their current practices to well-child visits (p<0.05). More confidence in identifying and referring patients with dental trauma was reported by 100% of participants. CONCLUSIONS: A 60-minute oral health educational seminar was effective in improving paediatric and family medicine residents' immediate knowledge, attitude, and likelihood towards incorporating oral health preventive practice in their current practices to well-child visits. Significantly more residents felt more confident in identifying and referring patients with dental trauma. Key messages: an oral health educational seminar can be effective in improving paediatric and family medicine residents' immediate knowledge, attitude, and likelihood towards incorporating oral health preventive practice in their current practices to well-child visits.

Temporal expression of CD184(CXCR4) and CD171(L1CAM) identifies distinct early developmental stages of human retinal ganglion cells in embryonic stem cell derived retina.

Human retinal ganglion cells (RGCs) derived from pluripotent stem cells (PSCs) have anticipated value for human disease study, drug screening, and therapeutic applications; however, their full potential remains underdeveloped. To characterize RGCs in human embryonic stem cell (hESC) derived retinal organoids we examined RGC markers and surface antigen expression and made comparisons to human fetal retina. RGCs in both tissues exhibited CD184 and CD171 expression and distinct expression patterns of the RGC markers BRN3 and RBPMS. The retinal progenitor cells (RPCs) of retinal organoids expressed CD184, consistent with its expression in the neuroblastic layer in fetal retina. In retinal organoids CD184 expression was enhanced in RGC competent RPCs and high CD184 expression was retained on post-mitotic RGC precursors; CD171 was detected on maturing RGCs. The differential expression timing of CD184 and CD171 permits identification and enrichment of RGCs from retinal organoids at differing maturation states from committed progenitors to differentiating neurons. These observations will facilitate molecular characterization of PSC-derived RGCs during differentiation, critical knowledge for establishing the veracity of these in vitro produced cells. Furthermore, observations made in the retinal organoid model closely parallel those in human fetal retina further validating use of retinal organoid to model early retinal development.

Integrative analysis of genes and miRNA alterations in human embryonic stem cells-derived neural cells after exposure to silver nanoparticles.

Given the rapid growth of engineered and customer products made of silver nanoparticles (Ag NPs), understanding their biological and toxicological effects on humans is critically important. The molecular developmental neurotoxic effects associated with exposure to Ag NPs were analyzed at the physiological and molecular levels, using an alternative cell model: human embryonic stem cell (hESC)-derived neural stem/progenitor cells (NPCs). In this study, the cytotoxic effects of Ag NPs (10-200µg/ml) were examined in these hESC-derived NPCs, which have a capacity for neurogenesis in vitro, at 6 and 24h. The results showed that Ag NPs evoked significant toxicity in hESC-derived NPCs at 24h in a dose-dependent manner. In addition, Ag NPs induced cell cycle arrest and apoptosis following a significant increase in oxidative stress in these cells. To further clarify the molecular mechanisms of the toxicological effects of Ag NPs at the transcriptional and post-transcriptional levels, the global expression profiles of genes and miRNAs were analyzed in hESC-derived NPCs after Ag NP exposure. The results showed that Ag NPs induced oxidative stress and dysfunctional neurogenesis at the molecular level in hESC-derived NPCs. Based on this hESC-derived neural cell model, these findings have increased our understanding of the molecular events underlying developmental neurotoxicity induced by Ag NPs in humans.

Total Colonic Decompression After Colonoscopy Decreases Postcolonoscopy Abdominal Pain: A Randomized Double-Blind Controlled Trial.

GOALS: The purpose of this study was to determine whether total colonic decompression after colonoscopy decreased postcolonoscopy abdominal pain. BACKGROUND: Abdominal pain that occurs after a colonoscopy may cause significant discomfort in some patients, and residual bowel gas is thought to be a key contributor to this abdominal pain. STUDY: Asymptomatic 300 patients who underwent colonoscopy under sedation were randomized to either the decompression group or the control group. Initial colonoscopic procedure was performed uniformly in both the groups. After the colonoscopy examination was completed, the colonoscope was reinserted into the cecum, and the intraluminal air was aspirated during withdrawal in the decompression group. Abdominal pain was assessed before discharge and 24 to 48 hours after colonoscopy using a 10-point visual analogue scale (VAS). RESULTS: The 2 groups were similar with regard to clinical, demographic, and procedural factors. Among 288 patients, the incidence of abdominal pain (VAS≥1) after colonoscopy was 38 (26.6%) of 143 patients in the decompression group and 95 (65.5%) of 145 patients in the control group (VAS 0.68±1.35 vs. 2.14±2.15, P<0.001). There was an 86.1% reduction rate of abdominal pain by colonic decompression, based on multivariate analysis (odds ratio 0.139 [95% confidence interval, 0.077-0.250], P<0.001). Furthermore, independent factors for abdominal pain included female gender and total duration of procedure >800 seconds. There were no reinsertion-related complications in the decompression group. CONCLUSION: Total colonic decompression after colonoscopy has a beneficial effect and can reduce postcolonoscopy abdominal pain without additional complications.

Twelve-point scale grading system of scanning electron microscopic examination to investigate subtle changes in damaged hair surface.

BACKGROUND: To assess the hair surface condition, scanning electron microscope (SEM) is commonly used and it remains an indispensable hair morphology characterization technique. Yet, the technique is criticized for having subjective viewpoints and limitations in distinguishing the appearance of cuticle layers. OBJECTIVES: The aim of this study is to establish an objective classification system and also to subdivide by detailed description of damaged cuticle layers. METHODS: Hair samples were collected from female subjects (n = 500) who participated in hair efficacy study and Asian hair bunches (n = 180) that were previously collected. Damage to hair was initiated by chemical, heat stress and ultraviolet irradiation. We suggested the grading criterion on a 12-point scale and compared with a wide range grading system on a 5-point scale. We evaluated other hair surface-related parameters such as hair luster-ring and combing load to verify the validity and efficacy of our new grading system. RESULTS: The grading criterion on our 12-point scale revealed an improved discrimination compared to the wide range grading system. Hair surface-related parameters were significantly improved after hair care product, and these tendencies were likely to be determined to be similarly improved using the 12-point scale grading system. CONCLUSION: The 12-point scale classification system was demonstrated to be a more precise standardization and appropriate evaluation method to investigate the subtle distinction of the hair shaft after hair care product application.

Facial skin physiology recovery kinetics during 180 min post-washing with a cleanser.

BACKGROUND/PURPOSE: Facial cleansing is important to clean and exfoliate the skin while maintaining optimal physiologic function. However, there is insufficient data on the very early stage of skin change after applying soap or cleansing foam. We investigated the recovery kinetics of facial skin physiology during 180 min after exposure to the cleanser. METHODS: For the study, 22 Korean female subjects with normal and dry to oily skin type were recruited in this study. Study subjects were required to have face washing done within the 12 hours prior to visiting the research center, with only toner, lotion, or cream applied. The next day, the subjects visited the research center without face washing. We evaluated the skin hydration (Corneometer(®) CM 825), sebum (Sebumeter(®) SM 815), transepidermal water loss (Tewameter(®) TM 300), and pH (Skin-pH-Meter(®) PH 905) to define recovery kinetics of facial skin physiology during 180 min exposure post-cleansing. RESULTS: Skin hydration, sebum, and TEWL were significantly decreased at 20 min after washing, as compared to the baseline (P < 0.05). And skin hydration returned at 40 min, and skin sebum and TEWL returned at 120 min after washing. However, skin pH did not show significant differences at all times points. CONCLUSIONS: This study indicated that each of the skin parameters was restored at defined time points post-cleansing. Our result could be a useful reference to set the resting time in the estimation of skin bioengineering parameters.

Licochalcone A induces apoptosis through endoplasmic reticulum stress via a phospholipase Cγ1-, Ca(2+)-, and reactive oxygen species-dependent pathway in HepG2 human hepatocellular carcinoma cells.

Licochalcone A (LicA), an estrogenic flavonoid, induces apoptosis in multiple types of cancer cells. In this study, the molecular mechanisms underlying the anti-cancer effects of LicA were investigated in HepG2 human hepatocellular carcinoma cells. LicA induced apoptotic cell death, activation of caspase-4, -9, and -3, and expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by CHOP knockdown or treatment with the ER stress inhibitors, salubrinal and 4-phenylbutyric acid, reduced LicA-induced cell death. LicA also induced reactive oxygen species (ROS) accumulation and the anti-oxidant N-acetylcysteine reduced LicA-induced cell death and CHOP expression. In addition, LicA increased the levels of cytosolic Ca(2+), which was blocked by 2-aminoethoxydiphenyl borate (an antagonist of inositol 1,4,5-trisphosphate receptor) and BAPTA-AM (an intracellular Ca(2+) chelator). 2-Aminoethoxydiphenyl borate and BAPTA-AM inhibited LicA-induced cell death. Interestingly, LicA induced phosphorylation of phospholipase Cγ1 (PLCγ1) and inhibition of PLCγ1 reduced cell death and ER stress. Moreover, the multi-targeted receptor tyrosine kinase inhibitors, sorafenib and sunitinib, reduced LicA-induced cell death, ER stress, and cytosolic Ca(2+) and ROS accumulation. Finally, LicA induced phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and c-Met receptor and inhibition of both receptors by co-transfection with VEGFR2 and c-Met siRNAs reversed LicA-induced cell death, Ca(2+) increase, and CHOP expression. Taken together, these findings suggest that induction of ER stress via a PLCγ1-, Ca(2+)-, and ROS-dependent pathway may be an important mechanism by which LicA induces apoptosis in HepG2 hepatocellular carcinoma cells.