Receptor binding motif surrounding sites in the Spike 1 protein of infectious bronchitis virus have high susceptibility to mutation related to selective pressure

Background@#To date, various genotypes of infectious bronchitis virus (IBV) have cocirculated and in Korea, GI-15 and GI-19 lineages were prevailing. The spike protein, particularly S1 subunit, is responsible for receptor binding, contains hypervariable regions and is also responsible for the emerging of novel variants. @*Objective@#This study aims to investigate the putative major amino acid substitutions for the variants in GI-19. @*Methods@#The S1 sequence data of IBV isolated from 1986 to 2021 in Korea (n = 188) were analyzed. Sequence alignments were carried out using Multiple alignment using Fast Fourier Transform of Geneious prime. The phylogenetic tree was generated using MEGA-11 (ver.11.0.10) and Bayesian analysis was performed by BEAST v1.10.4. Selective pressure was analyzed via online server Datamonkey. Highlights and visualization of putative critical amino acid were conducted by using PyMol software (version 2.3). @*Results@#Most (93.5%) belonged to the GI-19 lineage in Korea, and the GI-19 lineage was further divided into seven subgroups: KM91-like (Clade A and B), K40/09-like, QX-like (I-IV).Positive selection was identified at nine and six residues in S1 for KM91-like and QX-like IBVs, respectively. In addition, several positive selection sites of S1-NTD were indicated to have mutations at common locations even when new clades were generated. They were all located on the lateral surface of the quaternary structure of the S1 subunits in close proximity to the receptor-binding motif (RBM), putative RBM motif and neutralizing antigenic sites in S1. @*Conclusions@#Our results suggest RBM surrounding sites in the S1 subunit of IBV are highly susceptible to mutation by selective pressure during evolution.

Structural and functional characteristics of SARS-CoV-2 Omicron subvariant BA.2 spike

The Omicron subvariant BA.2 has become the dominant circulating strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in many countries. We have characterized structural, functional and antigenic properties of the full-length BA.2 spike (S) protein and compared replication of the authentic virus in cell culture and animal model with previously prevalent variants. BA.2 S can fuse membranes more efficiently than Omicron BA.1, mainly due to lack of a BA.1-specific mutation that may retard the receptor engagement, but still less efficiently than other variants. Both BA.1 and BA.2 viruses replicated substantially faster in animal lungs than the early G614 (B.1) strain in the absence of pre-existing immunity, possibly explaining the increased transmissibility despite their functionally compromised spikes. As in BA.1, mutations in the BA.2 S remodel its antigenic surfaces leading to strong resistance to neutralizing antibodies. These results suggest that both immune evasion and replicative advantage may contribute to the heightened transmissibility for the Omicron subvariants.

Impact of Interpersonal Relationships and Acquired Capability for Suicide on Suicide Attempts: A Cross-Sectional Study

Objective@#This study examined the path model predicting suicide attempts (SA) by interpersonal need for suicide desire, acquired capability for suicide, the emotion dysregulation, and depression symptoms in people admitted to hospitals for medical treatment. @*Methods@#A total of 344 participants (200 depressed patients with attempted suicide, 144 depressed patients with suicidal ideation) were enrolled for this study. Depression, anxiety, emotion regulation, interpersonal needs, and acquired capability for suicide were evaluated. A model with pathways from emotion regulation difficulties and interpersonal needs to SA was proposed. Participants were divided into two groups according to the presence of SA or suicidal ideation. @*Results@#Acquired capability for suicide mediated the path from depression to SA. In the path model, difficulties in emotion regulation and interpersonal needs predicted depression significantly. Although depression itself was not significantly related to acquired capability for suicide, depression was significantly related to acquired capability for suicide in suicide attempter group. @*Conclusion@#Interventions with two factors affecting SA will clarify the suicide risk and contribute to finding risk factors.

Electrophysiological Changes Related to Childhood Trauma in Patients with Major Depressive Disorder: An Event-related Potential Study

Objective@#Childhood trauma is the most important environmental factor for several psychiatric disorders. Depressed patients with childhood trauma appear to have severe symptoms that frequently recur. This study investigated whether depressed patients with childhood trauma showed attenuated Nogo event-related potentials (ERPs) and source activity during response-inhibition tasks. @*Methods@#Forty-four patients patients with major depressive disorder (MDD) were instructed to perform a Go/Nogo task during electroencephalography. Sensors and source activities of N2 and P3 of the Nogo ERPs were analyzed. The participants’ clinical symptoms were assessed using the Childhood Trauma Questionnaire (CTQ), Beck Depression Inventory, State-Trait Anxiety Inventory, Barratt Impulsivity Scale, and Affective Lability Scale. The participants were divided into two groups (low and high), based on their total CTQ scores. @*Results@#MDD subjects with high CTQ scores showed significantly decreased Nogo P3 amplitudes at the frontal, frontocentral, central, and parietal electrodes than those with low CTQ scores (all p ＜ 0.01). In Nogo P3, the source activities of the right cuneus, right posterior cingulate cortex, right precuneus, left supramarginal gyrus, and left lingual gyrus were significantly lower in the high CTQ group than in the low one (all p ＜ 0.01). There were significant negative correlations between the total CTQ scores and the Nogo P3 amplitudes in the frontocentral (p = 0.03) and parietal regions (p = 0.02), which showed lower source activity in the Nogo P3 condition. @*Conclusion@#Depressed patients with severe childhood trauma showed different Nogo-ERP characteristics, which might reflect inhibitory failure and dysfunction in related brain regions.

Camel nanobodies broadly neutralize SARS-CoV-2 variants

With the emergence of SARS-CoV-2 variants, there is urgent need to develop broadly neutralizing antibodies. Here, we isolate two VHH nanobodies (7A3 and 8A2) from dromedary camels by phage display, which have high affinity for the receptor-binding domain (RBD) and broad neutralization activities against SARS-CoV-2 and its emerging variants. Cryo-EM complex structures reveal that 8A2 binds the RBD in its up mode and 7A3 inhibits receptor binding by uniquely targeting a highly conserved and deeply buried site in the spike regardless of the RBD conformational state. 7A3 at a dose of [≥]5 mg/kg efficiently protects K18-hACE2 transgenic mice from the lethal challenge of B.1.351 or B.1.617.2, suggesting that the nanobody has promising therapeutic potentials to curb the COVID-19 surge with emerging SARS-CoV-2 variants. One-Sentence SummaryDromedary camel (Camelus dromedarius) VHH phage libraries were built for isolation of the nanobodies that broadly neutralize SARS-CoV-2 variants.

B.1.1.7 and B.1.351 variants are highly virulent in K18-ACE2 transgenic mice and show different pathogenic patterns from early SARS-CoV-2 strains

SARS-CoV-2 continues to circulate globally resulting in emergence of several variants of concern (VOC), including B.1.1.7 and B.1.351 that show increased transmissibility and enhanced resistance to antibody neutralization. In a K18-hACE2 transgenic mouse model, we demonstrate that Both B.1.1.7 and B.1.351 are 100 times more lethal than the original SARS-CoV-2 bearing 614D. Mice infected with B.1.1.7 and B.1.351 exhibited more severe lesions in internal organs than those infected with early SARS-CoV-2 strains bearing 614D or 614G. Infection of B.1.1.7 and B.1.351 also results in distinct tissue-specific cytokine signatures, significant D-dimer depositions in vital organs and less pulmonary hypoxia signaling before death as compared to the mice infected with early SARS-CoV-2 strains. However, K18-hACE2 mice with the pre-existing immunity from prior infection or immunization were resistant to the lethal reinfection of B.1.1.7 or B.1.351, despite having reduced neutralization titers against these VOC. Our study reveals distinguishing pathogenic patterns of B.1.1.7 and B.1.351 variants from those early SARS-CoV-2 strains in K18-hACE2 mice, which will help to inform potential medical interventions for combatting COVID-19.

SARS-CoV-2 show no infectivity at later stages in a prolonged COVID-19 patient despite positivity in RNA testing

Inpatient COVID-19 cases present enormous costs to patients and health systems. Many hospitalized patients may still test COVID-19 positive, even after resolution of symptoms. Thus, a pressing concern for clinicians is the safety of discharging these asymptomatic patients if they have any remaining infectivity. This case report explores the viral viability in a patient with persistent COVID-19 over the course of a two-month hospitalization. Positive nasopharyngeal swab samples, analyzed by quantitative reverse transcription polymerase chain reactions (qRT-PCR), were collected and isolated in the laboratory, and infectious doses were analyzed throughout the hospitalization period. The patient experienced waning symptoms by hospital day 40 and had no viable virus growth in the laboratory by hospital day 41, suggesting no risk of infectivity, despite positive RT-PCR results, which prolonged his hospital stay. Notably, this case showed infectivity for at least 24 days from disease onset, which is longer than the discontinuation of transmission-based precautions recommendation by CDC. Thus, our findings suggest that the timeline for discontinuing transmission-based precautions may need to be extended for patients with prolonged illness. Additional large-scale studies are needed to draw definitive conclusions on the appropriate clinical management for these patients.

Dexamethasone reduces infectious bursal disease mortality in chickens

Very virulent infectious bursal disease virus (vvIBDV) causes high mortality in chickens but measures to reduce the mortality have not been explored. Chickens (8–9 weeks) were treated with 3 agents before and during vvIBDV inoculation. Dexamethasone treatment reduced the mortality of infected chickens (40.7% vs. 3.7%; p < 0.001), but treatment with aspirin or vitamin E plus selenium did not affect the mortality. The bursa of Fabricius appeared to have shrunk in both dead and surviving chickens (p < 0.01). The results indicate that dexamethasone can reduce mortality in vvIBDV-infected chickens and may provide therapeutic clues for saving individual birds infected by the virus.

Dexamethasone reduces infectious bursal disease mortality in chickens

Very virulent infectious bursal disease virus (vvIBDV) causes high mortality in chickens but measures to reduce the mortality have not been explored. Chickens (8–9 weeks) were treated with 3 agents before and during vvIBDV inoculation. Dexamethasone treatment reduced the mortality of infected chickens (40.7% vs. 3.7%; p < 0.001), but treatment with aspirin or vitamin E plus selenium did not affect the mortality. The bursa of Fabricius appeared to have shrunk in both dead and surviving chickens (p < 0.01). The results indicate that dexamethasone can reduce mortality in vvIBDV-infected chickens and may provide therapeutic clues for saving individual birds infected by the virus.

Federated Learning of Electronic Health Records Improves Mortality Prediction in Patients Hospitalized with COVID-19

Machine learning (ML) models require large datasets which may be siloed across different healthcare institutions. Using federated learning, a ML technique that avoids locally aggregating raw clinical data across multiple institutions, we predict mortality within seven days in hospitalized COVID-19 patients. Patient data was collected from Electronic Health Records (EHRs) from five hospitals within the Mount Sinai Health System (MSHS). Logistic Regression with L1 regularization (LASSO) and Multilayer Perceptron (MLP) models were trained using local data at each site, a pooled model with combined data from all five sites, and a federated model that only shared parameters with a central aggregator. Both the federated LASSO and federated MLP models performed better than their local model counterparts at four hospitals. The federated MLP model also outperformed the federated LASSO model at all hospitals. Federated learning shows promise in COVID-19 EHR data to develop robust predictive models without compromising patient privacy.

The Relationship Between Response-Inhibitory Event-Related Potentials and Symptoms of Attention-Deficit/Hyperactivity Disorder in Adult Patients with Major Depressive Disorder

Objective@#Attention-deficit and poor impulse control have frequently been observed in major depressive disorder (MDD) and attention-deficit and hyperactivity disorder (ADHD). Altered event-related potential (ERP) performance, such as GoNogo tasks, has been regarded as a neurocognitive process associated with attention and behavioral inhibition. The aim of this study was to investigate the association between Nogo ERP and adult ADHD in MDD. @*Methods@#A total of 64 participants with MDD (32 comorbid with ADHD) and 32 healthy controls aged 19–45 years were recruited; they performed GoNogo paradigms during electroencephalogram measurement. Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), and the Adult ADHD Self-Report Scale (ASRS) were evaluated. Clinical measures and GoNogo ERP were compared between three groups: depression with ADHD, depression without ADHD, and healthy controls. @*Results@#MDD subjects with ADHD showed significantly decreased Nogo P3 amplitude at frontal electrode, compared with those without ADHD and healthy controls. MDD subjects with ADHD showed significantly longer Nogo N2 latency at frontal and frontocentral electrodes, compared with those without ADHD and healthy controls. In MDD subjects with ADHD, the Nogo P3 amplitude at the frontal electrode was negatively correlated with the ASRS score and inattention. The Nogo N2 latency at the frontal electrode was positively correlated with false alarm rate. @*Conclusion@#The decreased Nogo P3 amplitude in the frontal area might be a potential biological marker for inattention in depressed patients with ADHD.

The Impact of Emotional Exhaustion on Psychological Factors in Workers with Secondary Traumatic Experiences: A Multi-Group Path Analysis

Objective@#The objective of the present study was to explore causal pathways to understand how second traumatic experiences could affect the development of emotional exhaustion and psychiatric problems. @*Methods@#A total of 582 workers who had jobs vulnerable to secondary traumatic experiences were enrolled for this study. Emotional exhaustion, secondary trauma, resilience, perceived stress, depression, anxiety, and sleep problems were evaluated. A model with pathways from secondary traumatic experience score to depression and anxiety was proposed. The participants were divided into three groups according to the resilience: the low, middle and high resilience group. @*Results@#Resilience was a meaningful moderator between secondary traumatic experiences and psychiatric problems. In the path model, the secondary trauma and perceived stress directly and indirectly predicted perceived stress, emotional exhaustion, depression, anxiety, and sleep problems in all three groups. Direct effects of perceived stress on depression and anxiety were the largest in the low resilience group. However, direct effects of secondary trauma on perceived stress and emotional exhaustion were the largest in the high resilience group. @*Conclusion@#Understanding the needs of focusing for distinct psychological factors offers a valuable direction for the development of intervention programs to prevent emotional exhaustion among workers with secondary traumatic experiences.

Mismatch Negativity Indices as a Prognostic Factor for Remission in Schizophrenia

Objective@#Mismatch negativity (MMN) is known to be associated with neuro-cognition and functional outcomes. Remission and recovery rates are related to the neuro-cognition of patients with schizophrenia. The present study explored the relationship of MMN with remission in patients with schizophrenia. @*Methods@#Forty patients with schizophrenia were recruited and divided into two groups, with or without remission, according to the Remission in Schizophrenia Working Group criteria (RSWGcr). Symptom severity (Positive and Negative Syndrome Scale, PANSS), cognitive function, functional outcome, and MMN of the patients were evaluated. A regression analysis was used to identify the factors that significantly predicted symptom improvement and remission including MMN at frontal site assessed at baseline, and anticipated clinical variables as predictive factors. @*Results@#MMN amplitudes in frontal sites were further decreased in the groups without remission compared to the groups with remission. MMN amplitude was significantly correlated with measures of symptom change and functional outcome measurements in patients with schizophrenia. Regression analysis revealed that symptom severity and MMN significantly predicted remission in patients with schizophrenia. Symptom improvement significantly predicted PANSS at baseline, illness duration, and antipsychotic dose, as did MMN amplitude at frontal site. @*Conclusion@#Our results suggest that MMN reflected symptom improvement and remission in patients with schizophrenia. MMN indices appear to be promising candidates as predictive factors for schizophrenia remission.

Inattention in Bipolar and Unipolar Depression: Event-Related Potentials Associated with Performing a GoNogo Task / 우울ㆍ조울병

Background@#This study aimed to examine the changes in Nogo N2 and P3 amplitudes in patients with bipolar affective disorder (BD) or major depressive disorder (MDD) and in healthy controls (HCs). The association between attention and Nogo N2 and P3 changes was also investigated. @*Methods@#The study included 30 participants with BD, 30 participants with MDD, and 30 HCs aged 19-60 years. They performed a GoNogo task while their electroencephalograms were recorded. Beck Depression Inventory and StateTrait Anxiety Inventory were used for evaluation. Furthermore, behavioral measures and GoNogo N2 and P3 amplitudes were compared between the three groups. @*Results@#Patients with BD or MDD exhibited a significantly poorer performance in Nogo accuracy than the HCs. Patients with BD or MDD showed significantly lower Nogo N2 amplitudes at the frontal, fronto-central, and central electrodes than the HCs. In patients with BD or MDD, the Nogo N2 amplitudes at the frontal or fronto-central electrode were positively correlated with state of anxiety scores and inattention. @*Conclusion@#These findings suggest that decreased Nogo N2 amplitudes in the frontal or fronto-central areas could be a biological marker for inattention during depressive episodes associated with BD or MDD.

Validation of the Korean Version of the Depression in Old Age Scale and Comparison with Other Depression Screening Questionnaires Used in Elderly Patients in Medical Settings

OBJECTIVE: The Depression in Old Age Scale (DIA-S) is a new screening tool for assessing depression in the elderly. The primary aims of this study were to describe the validation of the Korean version of the DIA-S (K-DIA-S) and to compare its validity with that of other depression screening questionnaires used in elderly outpatients in medical settings. METHODS: A total of 385 elderly outpatients completed the K-DIA-S and underwent the Mini International Neuropsychiatric Interview to diagnose depressive disorders. Other measures included the 15-item short form of the Geriatric Depression Scale (SGDS), the 9-item depression module of the Patient Health Questionnaire (PHQ-9), and the Montgomery–Asberg Depression Rating Scale (MADRS). Reliability and validity tests, an optimal cutoff point estimate, and receiver operating characteristic curve analysis were performed to investigate the diagnostic validity of the K-DIA-S. Areas under the curves (AUCs) for the K-DIA-S, SGDS, and PHQ-9 were compared statistically. RESULTS: The K-DIA-S showed good internal consistency and strong correlations with the SGDS (r = 0.853), PHQ-9 (r = 0.739), and MADRS (r = 0.772). The cut-off point of the K-DIA-S that can be recommended for screening depressive symptoms was a score of 4. For “any depressive disorder”, the AUC (standard error) for the K-DIA-S was 0.896 (0.015), which was significantly larger than that for the PHQ-9 (p = 0.033). CONCLUSION: The present findings suggest that the K-DIA-S has good psychometric properties and is a valid and reliable tool for assessing depressive symptoms in elderly populations and medically ill patients.

Molecular identification of coagulase-negative staphylococci by rpoB sequence typing

Bovine mastitis (BM) has resulted in enormous economic loss in the dairy industry and coagulase-negative staphylococci (CNS) have caused subclinical BM. Although VITEK 2 GP ID card (VITEK 2) has been used for CNS identification, the probability of identification varies. The rpoB sequence typing (RSTing) method has been used for molecular diagnosis and epidemiology of bacterial infections. In this study, we undertook RSTing of CNS and compared the results with those of VITEK2 and 16S rRNA gene sequencing. As compared VITEK2, the molecular-based methods were more reliable for species identification; moreover, RSTing provided more molecular epidemiological information than that from 16S rRNA gene sequencing.

Molecular prophage typing of Staphylococcus aureus isolates from bovine mastitis

Staphylococcus aureus is one of the major pathogens causing bovine mastitis and foodborne diseases associated with dairy products. To determine the genetic relationships between human and bovine or bovine isolates of S. aureus, various molecular methods have been used. Previously we developed an rpoB sequence typing (RSTing) method for molecular differentiation of S. aureus isolates and identification of RpoB-related antibiotic resistance. In this study, we performed spa typing and RSTing with 84 isolates from mastitic cows (22 farms, 72 cows, and 84 udders) and developed a molecular prophage typing (mPPTing) method for molecular epidemiological analysis of bovine mastitis. To compare the results, human isolates from patients (n = 14) and GenBank (n = 166) were used for real and in silico RSTing and mPPTing, respectively. Based on the results, RST10-2 and RST4-1 were the most common rpoB sequence types (RSTs) in cows and humans, respectively, and most isolates from cows and humans clearly differed. Antibiotic resistance-related RSTs were not detected in the cow isolates. A single dominant prophage type and gradual evolution through prophage acquisition were apparent in most of the tested farms. Thus, RSTing and mPPTing are informative, simple, and economic methods for molecular epidemiological analysis of S. aureus infections.

The Association between Suicide Attempts and Toxoplasma gondii Infection

OBJECTIVE: Chronic ‘latent’ infection by Toxoplasma gondii is common and most of the hosts have minimal symptoms or they are even asymptomatic. However, there are possible mechanisms by which T. gondii may affect human behavior and it may also cause humans to attempt suicide. This article aimed to investigate the potential pathophysiological relationship between suicide attempts and T. gondii infection in Korea. METHODS: One hundred fifty-five psychiatric patients with a history of suicide attempt and 135 healthy control individuals were examined with enzyme-linked immunoassays and fluorescent antibody technique for T. gondii seropositivity and antibody titers. The group of suicide attempters was interviewed regarding the history of suicide attempt during lifetime and evaluated using 17-item Korean version of Hamilton Depression Scale (HAMD), Columbia Suicide Severity Rating Scale (C-SSRS), State-Trait Anxiety Inventory (STAI) and Korean-Barratt Impulsiveness Scale (BIS). RESULTS: Immunoglobulin G antibodies were found in 21 of the 155 suicide attempters and in 8 of the 135 controls (p=0.011). The Toxoplasma-seropositive suicide attempters had a higher HAMD score on the depressed mood and feeling of guilt subscales and a higher total score than the seronegative suicide attempters. T. gondii seropositive status was associated with higher C-SSRS in the severity and lethality subscales. T. gondii IgG seropositivity was significantly associated with higher STAI-X1 scores in the suicide attempters group. CONCLUSION: Suicide attempters showed higher seroprevalence of T. gondii than healthy controls. Among the suicide attempters, the T. gondii seropositive and seronegative groups showed several differences in the aspects of suicide. These results suggested a significant association between T. gondii infection and psychiatric problems in suicidality.

Differences in Psychopathology between Offspring of Parents with Bipolar I Disorder and Those with Bipolar II Disorder: A Cross-Sectional Study

OBJECTIVE: The aim of this study was to evaluate differences in psychopathology between offspring of parents with bipolar I disorder (BP-I) and those with bipolar II disorder (BP-II). METHODS: The sample included 201 offspring between 6 and 17 years of age who had at least one parent with BP-I or BP-II. The offspring were diagnostically evaluated using the Korean Kiddie-Schedule for Affective Disorders and Schizophrenia-Present and Lifetime Version. Psychopathology and Clinical characteristics were evaluated, including lifetime DSM-5 diagnoses, depression, and childhood trauma. Lifetime DSM-5 diagnoses were also compared between schoolchildren aged 6 to 11 years and adolescents aged 12 to 17 years. RESULTS: In lifetime DSM-5 diagnoses, offspring of parents with BP-I had significantly increased risk of developing MDD and BP-I than those with BP-II. Regarding clinical characteristics, ADHD rating scale and childhood trauma scale were significantly higher in offspring of parents with BP-I than that in those with BP-II. CONCLUSION: The present study supports that BP-I may be etiologically distinct from BP-II by a possible genetic liability. Our findings indicate that additional research related to bipolar offspring is needed to enhance understanding of differences between BP-I and BP-II.

The Prognostic Significance of Compliance with Postoperative Adjuvant Chemotherapy in Patients with Stage III Gastric Cancer: an Observational Study

PURPOSE: Postoperative adjuvant chemotherapy is usually prescribed to improve the survival of patients with advanced gastric cancer who undergo curative surgery. This study was designed to determine the impact that the degree of compliance with chemotherapy has on the prognosis of patients with gastric cancer. MATERIALS AND METHODS: Among 252 patients with stage III gastric cancer who underwent curative surgery between July 2004 and December 2014, 85 patients were postoperatively treated with S-1, the oral fluoropyrimidine derivative, 23 received no chemotherapy, and 144 received other regimens. Overall survival was compared between the complete compliance group (who received 8 cycles of S-1 chemotherapy, n=44) and the incomplete compliance group (who received less than 8 cycles of S-1 chemotherapy, n=41). Factors that influenced patient compliance with chemotherapy were also analyzed. RESULTS: The overall 5-year survival rate was significantly different between the complete chemotherapy and incomplete chemotherapy groups (80.0% vs. 42.7%, P<0.001). Based on univariate and multivariate survival analyses of patients who received S-1 chemotherapy, the independent prognostic factors were tumor, node, and metastasis (TNM) stage (IIIa vs. IIIb vs. IIIc) and compliance with chemotherapy. TNM stage and age are significant factors that influence compliance with chemotherapy. CONCLUSIONS: TNM stage and compliance with chemotherapy are independent prognostic factors in patients with stage III gastric cancer who received postoperative chemotherapy. TNM stage and age are significant factors that influence patient compliance with chemotherapy.