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.

Neuromodulatory Effect of Transcranial Direct Current Stimulation on Resting-State EEG Activity in Internet Gaming Disorder: A Randomized, Double-Blind, Sham-Controlled Parallel Group Trial.

Transcranial direct current stimulation (tDCS) has been used as an adjunct therapy for psychiatric disorders; however, little is known about the underlying neurophysiological effects of tDCS in Internet gaming disorder (IGD). We investigated the effects of tDCS on cortical activity using resting-state electroencephalography (EEG) in patients with IGD. This randomized, double-blind, sham-controlled parallel group study of tDCS (ClinicalTrials.gov NCT03347643) included 31 IGD patients. Participants received 10 sessions (2 sessions per day for 5 consecutive days) of active repetitive tDCS (2 mA for 20 min per session) or sham stimulation. Anode/cathode electrodes were placed over the left and right dorsolateral prefrontal cortex, respectively. In total, 26 participants (active group n = 14; sham group n = 12) completed the trial. Resting-state EEG spectral activity (absolute power) and functional connectivity (coherence) were used to assess the effects of tDCS on cortical activity before stimulation and 1 month after the intervention. Active stimulation of tDCS suppressed increase of intra-hemispheric beta coherence after 1 month, which was observed in the sham group. The 1-month follow-up assessment revealed that absolute gamma power in the left parietal region was decreased in the active group relative to the sham group. Our findings suggest that repetitive tDCS stabilizes fast-wave activity in IGD.

Event-related brain response to visual cues in individuals with Internet gaming disorder: relevance to attentional bias and decision-making.

This study investigated attentional bias toward game-related cues in Internet gaming disorder (IGD) using electrophysiological markers of late positive potential (LPP) and identifying the sources of LPP. In addition, the association between LPP and decision-making ability was investigated. The IGD (n = 40) and healthy control (HC; n = 39) participants viewed a series of game-related and neutral pictures, while their event-related potentials (ERPs) were recorded. LPPs were calculated as the mean amplitudes between 400 and 700 ms at the centro-parietal (CP3, CP1, Cpz, CP2, and CP4) and parietal (P3, P1, Pz, P2, and P4) electrode sites. The source activations of LPP were estimated using standardized low-resolution brain electromagnetic tomography (sLORETA). In addition, decision-making ability was evaluated by the Cambridge Gambling Task. Higher LPP amplitudes were found for game-related cues in the IGD group than in the HC group. sLORETA showed that the IGD group was more active in the superior and middle temporal gyri, which are involved in social perception, than in the HC group, whereas it was less active in the frontal area. Individuals with IGD have deficits in decision-making ability. In addition, in the HC group, the lower the LPP when looking at the game-related stimuli, the better the quality of decision-making, but not in the IGD group. Enhanced LPP amplitudes are associated with emotional arousal to gaming cues and decision-making deficits in IGD. In addition, source activities suggest that patients with IGD perceive game-related cues as social stimuli. LPP can be used as a neurophysiological marker of IGD.

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.

Point-of-care detection of lactate in cerebrospinal fluid.

PURPOSE: Measurements of cerebrospinal fluid (CSF) lactate can aid in detecting infections of the central nervous system and surrounding structures. Neurosurgical patients with temporary lumbar or ventricular CSF drainage harbor an increased risk for developing infections of the central nervous system, which require immediate therapeutic responses. Since blood gas analyzers enable rapid blood-lactate measurements, we were interested in finding out if we can reliably measure CSF-lactate by this point-of-care technique. METHODS: Neurosurgical patients on our intensive care unit (ICU) with either lumbar or external ventricular drainage due to a variety of reasons were included in this prospective observational study. Standard of care included measurements of leucocyte counts, total protein and lactate measurements in CSF by the neurochemical laboratory of our University Medical Center twice a week. With respect to this study, we additionally performed nearly daily measurements of cerebrospinal fluid by blood gas analyzers to determine the reliability of CSF-lactate measured by blood gas analyzers as compared to the standard measurements with a certified device. RESULTS: 62 patients were included in this study. We performed 514 CSF-lactate measurements with blood gas analyzers and compared 180 of these to the in-house standard CSF-lactate measurements. Both techniques correlated highly significantly (Pearson correlation index 0.94) even though lacking full concordance in a Bland-Altman plotting. Of particular importance, regular measurements enabled immediate detection of central infection in three patients who had developed meningitis during the course of their treatment. CONCLUSION: Blood gas analyzers measure CSF-lactate with sufficient reliability and can help in the timely detection of a developing meningitis. In addition to and triggering established CSF diagnostics, CSF-lactate measurements by blood gas analyzers may improve surveillance of patients with CSF drainage. This study was retrospectively registered on April 20th 2020 in the German trial register. The trial registration number is DRKS00021466.

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.

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.

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.

Ultrasound Feature-Based Diagnostic Model Focusing on the "Submarine Sign" for Epidermal Cysts among Superficial Soft Tissue Lesions.

OBJECTIVE: To develop a diagnostic model for superficial soft tissue lesions to differentiate epidermal cyst (EC) from other lesions based on ultrasound (US) features. MATERIALS AND METHODS: This retrospective study included 205 patients who had undergone US examinations for superficial soft tissue lesions and subsequent surgical excision. The study population was divided into the derivation set (n = 112) and validation set (n = 93) according to the imaging date. The following US features were analyzed to determine those that could discriminate EC from other lesions: more-than-half-depth involvement of the dermal layer, "submarine sign" (focal projection of the hypoechoic portion to the epidermis), posterior acoustic enhancement, posterior wall enhancement, morphology, shape, echogenicity, vascularity, and perilesional fat change. Using multivariable logistic regression, a diagnostic model was constructed and visualized as a nomogram. The performance of the diagnostic model was assessed by calculating the area under the curve (AUC) of the receiver operating characteristic curve and calibration plot in both the derivation and validation sets. RESULTS: More-than-half-depth involvement of the dermal layer (odds ratio [OR] = 3.35; p = 0.051), "submarine sign" (OR = 12.2; p < 0.001), and morphology (OR = 5.44; p = 0.002) were features that outweighed the others when diagnosing EC. The diagnostic model based on these features showed good discrimination ability in both the derivation set (AUC = 0.888, 95% confidence interval [95% CI] = 0.825-0.950) and validation set (AUC = 0.902, 95% CI = 0.832-0.972). CONCLUSION: More-than-half-depth of involvement of the dermal layer, "submarine sign," and morphology are relatively better US features than the others for diagnosing EC.

Hypometabolism and altered metabolic connectivity in patients with internet gaming disorder and alcohol use disorder.

Internet gaming disorder (IGD) has become the subject of growing concern as an addictive behavior and has been compared with substance/non-substance-related addiction. Although IGD show clinical impairments and social dysfunction, neurobiological alterations in IGD have not been clearly elucidated. We used 18F-fluorodeoxyglucose PET to investigate differences in glucose metabolism and metabolic connectivity in young men [thirty-six patients with IGD, twenty-six patients with alcohol use disorder (AUD) and thirty-nine healthy controls (HC)]. Compared with the HC, IGD showed hypometabolism in the anterior cingulate cortex (ACC), temporal, frontal, parietal and striatum and AUD exhibited hypometabolism in the occipital, temporal and parietal lobule. Furthermore, IGD showed negative correlations between the ACC and game duration and between the orbitofrontal cortex and impulsivity. Also, IGD had lower metabolic connectivity between temporal and limbic regions and between the motor area and occipital region. And AUD showed greater metabolic connectivity between the orbitofrontal and parietal regions, and between the somatosensory or parietal and temporal regions, but lower metabolic connectivity in the fronto-striatal or fronto-limbic regions. Our results provide evidences that hypometabolism and altered metabolic connectivity in IGD might be related to the abnormal sensory function by longtime gaming and dysfunction of impulsive/motivational states.

The Mediating Effects of Affect on Associations between Impulsivity or Resilience and Internet Gaming Disorder.

Internet gaming disorder (IGD) is a new disease proposed by the Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5), and has been studied extensively in relation to depression and impulsivity. The relationship between resilience and disease has been found in a variety of addictive disorders, but studies on IGD are lacking. In this study, 71 IGD patients and 78 healthy controls (HCs) were recruited. Impulsivity, resilience, affects, and the degree of internet game addiction were measured using formal tools. The measured values were analyzed by mediation analysis to evaluate the mediating role of affects on resilience and impulsivity related to IGD symptoms. The IGD group showed higher impulsivity, lower resilience, lower positive affect, and higher negative affect than the HC group. The mediation analysis showed that a positive affect was a mediator between impulsivity and the severity of addiction in both groups. Negative affect mediated impulsivity/resilience and the severity of addiction only in the IGD group. Although the results of this study are based on a narrow category of subjects, who are young male adults around 25 years of age, the results suggest that positive affect can be strengthened to prevent the IGD illness, and that illness symptoms may be alleviated by reducing negative affect.

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.

Application of Diagnostic Interview for Internet Addiction (DIA) in Clinical Practice for Korean Adolescents.

The increased prevalence of Internet Gaming Disorder (IGD) and the inclusion of IGD in DSM-5 and ICD-11 emphasizes the importance of measuring and describing the IGD symptoms. We examined the psychometric properties of the Diagnostic Interview for Internet Addiction (DIA), a semi-structured diagnostic interview tool for IGD, and verified the application of DIA in clinical practice for Korean adolescents. The DIA is conducted in a manner that interviews both adolescents and their caregivers, and each item has a standardized representative question and various examples. It consists of 10 items based on the DSM-5 IGD diagnostic criteria, which is cognitive salience, withdrawal, tolerance, difficulty in regulating use, loss of interest in other activities, persistent use despite negative results, deception regarding Internet/games/SNS use, use of Internet/games/SNS to avoid negative feelings, interference with role performance, and craving. The study included 103 adolescents divided into three subgroups (mild risk, moderate risk, and addicted group) based on the total score of DIA. Demographic and clinical characteristics were compared among the DIA subgroups using the chi-square test and analysis of variance (ANOVA), and correlation analysis was used to examine the associations of IGD symptoms with clinical variables (e.g., impulsivity, aggression, depression, anxiety, self-esteem). The DIA total score was significantly correlated with Internet and smartphone addiction, depression, state anxiety, self-esteem, impulsivity, aggression, and stress. Furthermore, the moderate risk and addicted group showed significantly higher levels of Internet and smartphone addiction, anxiety, depression, impulsivity, aggression, stress, and lower self-esteem compared with the mild risk group. The Junior Temperament and Character Inventory (JTCI), which measures temperament and character traits, revealed that the mild risk group had higher levels of persistence and self-directedness than did the addicted group. Our findings confirmed the psychometric properties of DIA and the application of the DIA classifications in Korean adolescents.

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.