In silico prediction of immune-escaping hot spots for future COVID-19 vaccine design.

The COVID-19 pandemic has had a widespread impact on a global scale, and the evolution of considerable dominants has already taken place. Some variants contained certain key mutations located on the receptor binding domain (RBD) of spike protein, such as E484K and N501Y. It is increasingly worrying that these variants could impair the efficacy of current vaccines or therapies. Therefore, analyzing and predicting the high-risk mutations of SARS-CoV-2 spike glycoprotein is crucial to design future vaccines against the different variants. In this work, we proposed an in silico approach, immune-escaping score (IES), to predict high-risk immune-escaping hot spots on the receptor-binding domain (RBD), implemented through integrated delta binding free energy measured by computational mutagenesis of spike-antibody complexes and mutation frequency calculated from viral genome sequencing data. We identified 23 potentially immune-escaping mutations on the RBD by using IES, nine of which occurred in omicron variants (R346K, K417N, N440K, L452Q, L452R, S477N, T478K, F490S, and N501Y), despite our dataset being curated before the omicron first appeared. The highest immune-escaping score (IES = 1) was found for E484K, which agrees with recent studies stating that the mutation significantly reduced the efficacy of neutralization antibodies. Furthermore, our predicted delta binding free energy and IES show a high correlation with high-throughput deep mutational scanning data (Pearson's r = 0.70) and experimentally measured neutralization titers data (mean Pearson's r = -0.80). In summary, our work presents a new method to identify the potentially immune-escaping mutations on the RBD and provides valuable insights into future COVID-19 vaccine design.

Schizotypy trait and striatal dopamine receptors in healthy volunteers.

Individuals with schizotypal features exhibit cognitive, perceptual and social deficits that are similar to but less prominent than those seen in patients with schizophrenia. Dopaminergic hyperactivity in the striatum has been related to the positive symptoms of schizophrenia, and brain-imaging studies of dopamine uptake in the striatum are thought to be linked to the pathophysiological mechanisms underlying schizophrenia. The aim of this study was to investigate whether the increased availability of striatal dopamine (DA) D(2/3) receptors is related to elevated levels of schizotypal features in healthy individuals. The Schizotypal Personality Questionnaire (SPQ) was administered to 55 healthy volunteers. The availability of their striatal DA D(2/3) receptors was analysed using [(123)I] iodobenzamide single photon emission computed tomography (SPECT). Although the SPQ total scores showed no correlation with the availability of total (left and right) striatal DA D(2) receptors, the SPQ disorganised subscale scores were positively correlated with the availability of right striatal DA D(2/3) receptors. Our findings demonstrated that the availability of striatal DA D(2/3) receptors may be associated with schizotypal features in healthy volunteers.

Globo H-KLH vaccine adagloxad simolenin (OBI-822)/OBI-821 in patients with metastatic breast cancer: phase II randomized, placebo-controlled study.

PURPOSE: This randomized, double-blind, placebo-controlled, parallel-group, phase II trial assessed the efficacy and safety of adagloxad simolenin (OBI-822; a Globo H epitope covalently linked to keyhole limpet hemocyanin (KLH)) with adjuvant OBI-821 in metastatic breast cancer (MBC). METHODS: At 40 sites in Taiwan, USA, Korea, India, and Hong Kong, patients with MBC of any molecular subtype and ≤2 prior progressive disease events with stable/responding disease after the last anticancer regimen were randomized (2:1) to adagloxad simolenin (AS/OBI-821) or placebo, subcutaneously for nine doses with low-dose cyclophosphamide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival, correlation of clinical outcome with humoral immune response and Globo H expression, and safety. RESULTS: Of 349 patients randomized, 348 received study drug. Patients with the following breast cancer subtypes were included: hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) (70.4%), triple negative (12.9%), and HER2+ (16.7%), similarly distributed between treatment arms. Median PFS was 7.6 months (95% CI: 6.5-10.9) with AS/OBI-821 (n=224) and 9.2 months (95% CI: 7.3-11.3) with placebo (n=124) (HR=0.96; 95% CI: 0.74-1.25; p=0.77), with no difference by breast cancer subtype. AS/OBI-821 recipients with anti-Globo H IgG titer ≥1:160 had significantly longer median PFS (11.1 months (95% CI: 9.3-17.6)) versus those with titers <1:160 (5.5 months (95% CI: 3.7-5.6); HR=0.52; p<0.0001) and placebo recipients (HR=0.71; p=0.03). Anti-KLH immune responses were similar at week 40 between AS/OBI-821 recipients with anti-Globo IgG titer ≥1:160 and those with anti-Globo IgG titer <1:160. The most common adverse events with AS/OBI-821 were grade 1 or 2 injection site reactions (56.7%; placebo, 8.9%) and fever (20.1%; placebo, 6.5%). CONCLUSION: AS/OBI-821 did not improve PFS in patients with previously treated MBC. However, humoral immune response to Globo H correlated with improved PFS in AS/OBI-821 recipients, leading the way to further marker-driven studies. Treatment was well tolerated.NCT01516307.

Genome scan of Han Chinese schizophrenia families from Taiwan: confirmation of linkage to 10q22.3.

OBJECTIVE: Genome-wide linkage analyses of schizophrenia have identified several regions that may harbor schizophrenia susceptibility genes, but given the complex etiology of the disorder, it is unlikely that all susceptibility regions have been detected. To address this issue, the authors ascertained 606 Han Chinese families comprising 1,234 affected members. METHOD: Probands with schizophrenia were recruited from six data collection field research centers in Taiwan. Each proband underwent a diagnostic screen with supplemental medical records and a semistructured interview. Following this screen, the authors administered the Mandarin Chinese version of the Diagnostic Interview for Genetic Studies. Best-estimate final diagnoses were made by two board-certified psychiatrists. The genotyping was conducted by the Center for Inherited Disease Research, with 386 markers spaced at an average of 9-centimorgan (cM) intervals. Empirical simulations were generated to determine genome-wide significance. RESULTS: The authors found five regions with nonparametric linkage z scores 2.0 or greater. These were the following: 2.08 was reached for D1S551 (113.7) cM at 1p31.1 and 2.31 for D2S410 (125.2 cM) at 2q14.1; 2.00 was reached for D4S2361 (93.5 cM) at 4q21.23, and 2.07 for D15S1012 (36 cM) at 15q14, the largest nonparametric linkage z score was 2.88 for D10S2327 (100.92 cM) at 10q22.3. CONCLUSIONS: Our 10q22.3 finding at 100.9 cM is consistent with a previously reported nonparametric linkage score of 4.27 at 107.2 cM on chromosome 10, although it did not attain genome-wide significance in this study.

Cytokines and serotonin transporter in patients with major depression.

Altered cytokine secretion as a mechanism in the etiology of depression is still obscure. The serotonin transporter (5-HTT) may play an important role in the termination of serotonergic neurotransmission by serotonin (5-HT) uptaking into presynaptic neurons and representing as an initial action site for selective 5-HTT reuptake inhibitors (SSRI). In our study, we evaluated whether cytokines and 5-HTT acted as biological markers for depression. Blood samples were collected from 42 participants. The differences in cytokine and 5-HTT mRNA expressions of leukocytes were assessed between the patients with major depression (n=20) and the healthy controls (n=22), along with the measurements prior and after treatment with a SSRI, fluoxetine, for 3 months in the follow-up patient group (n=8). The results revealed that the mRNA expressions of IL-1beta, IL-6, IFNgamma, TNFalpha, and 5-HTT were higher in the depressed patients than those of the healthy controls. The higher level of mRNA expressions of IFNgamma and 5-HTT diminished after fluoxetine treatment. Furthermore, we found a positive correlation between 5-HTT and cytokines mRNA expressions in total participants, which suggested that pro-inflammatory cytokines and 5-HTT might play critical roles in the pathogenesis of major depression and that their levels were affected by chronic treatment with 5-HTT inhibitors.

A double-blind, randomized, group-comparative study of the tolerability and efficacy of 6 weeks' treatment with mirtazapine or fluoxetine in depressed Chinese patients.

AIM: To compare the efficacy and tolerability of mirtazapine and fluoxetine treatment in a sample population consisting of Chinese patients suffering moderate-to-severe depression. METHOD: 133 patients with a diagnosis of major depressive episode (DSM-IV) and scoring 15 or more on the 17-item Hamilton Rating Scale for Depression (HAM-D) were randomly assigned to receive 6 weeks of treatment with either mirtazapine (15-45 mg/day) or fluoxetine (20-40 mg/day). Efficacy was assessed using the HAM-D and Clinical Global Impressions scale, with analyses performed on the intent-to-treat sample using the last-observation-carried-forward method. Safety analysis was based on the all-subjects-treated group. RESULTS: Mean daily doses were 34.1 mg for mirtazapine (N = 66) and 30.7 mg for fluoxetine (N = 66). Thirty patients in the mirtazapine group and 22 in the fluoxetine group dropped out. Both drugs proved equally effective for reduction of the overall symptoms of depression throughout the treatment period. At day 42, the mean reductions in HAM-D total score (compared with baseline) were 11.8 and 10.6 for the mirtazapine and fluoxetine groups, respectively; however, the changes were not statistically significant. Both treatments were well tolerated, with more nausea and influenza-like symptoms observed for the fluoxetine group, and greater weight increase and somnolence for the mirtazapine analog. CONCLUSION: Both mirtazapine and fluoxetine were indistinguishable in effectiveness for treatment of depressive symptoms, and both were well tolerated by our population of depressed Chinese patients. In line with analogous Western reports, the safety of mirtazapine and fluoxetine was comparable for our depressed Chinese patients; however, slightly different side effect profiles were noted for the 2 drugs in our study.

Psychiatric morbidity and posttraumatic symptoms among earthquake victims in primary care clinics.

Three months after the devastating Chi-Chi earthquake (magnitude of 7.3 on the Richter scale) struck the central area of Taiwan, 663 victims were screened for psychiatric morbidity at a local general hospital in a community mental health program. The rate of psychiatric morbidity as defined by the 12-item Chinese Health Questionnaire as greater than 4, was 24.5%. Posttraumatic symptoms were still prevalent. The rate of posttraumatic stress disorder was 11.3%, and the rate of partial PTSD was 32.0%. Variables associated with the presence of psychiatric morbidity and posttraumatic symptoms included female gender, old age, financial loss, obsessive trait, and nervous trait. A disproportionate use of mental health services (18%) was found, suggesting an urgent need to deliver mental health care to disaster victims at local medical settings. In addition, health care professionals who work with the earthquake victims need to be promptly and efficiently trained in mental health crisis intervention.

Association between regional cerebral blood flow and eye-tracking performance and the Wisconsin Card Sorting Test in schizophrenics: a single photon emission computed tomography study.

The objectives of this study were (1). to examine the changes in regional cerebral blood flow (rCBF) during Wisconsin Card Sorting Test (WCST) performance in two different eye-tracking groups; (2). to explore the relationship between eye-tracking movement and rCBF at rest; and (3). to estimate the association between WCST performance and rCBF in patients with schizophrenia. A total of 17 patients with schizophrenia were recruited. SPECT with Tc-99m HMPAO (Tc-99m hexamethylpropyleneamine oxime) was carried out while patients were performing the WCST and resting. Brodmann area 9 of the prefrontal cortex, a part of the dorsal lateral prefrontal cortex (DLPFC), was less activated during performance of the WCST in poor trackers (relative to good trackers). The eye pursuit tracking error measure in schizophrenic patients was negatively associated with decreases in rCBF in the middle temporal area, superior parietal lobule, thalami, and caudate nuclei. The rCBF increased significantly in the superior temporal gyri, inferior parietal lobe, and some frontal regions during WCST performance; however, this was not the case in the DLPFC. Additionally, significant correlations were found between WCST scores and rCBF during WCST performance in the prefrontal lobes, and in thalamic and cerebellar regions. Our findings suggest that the rCBF changes during WCST performance may be distinctive in different eye-tracking groups. Our results confirm the hypothesis that the middle temporal area, superior parietal lobule, thalami, and caudate nuclei-mainly parts of the oculomotor circuit-are involved in eye pursuit tracking. Surprisingly, no significant association was found in the frontal eye field. Although the frontal lobe plays a significant role in WCST performance, our findings demonstrate that WCST performance is widely involved with other regions in patients with schizophrenia.

Correlation between fine motor activity and striatal dopamine D2 receptor density in patients with schizophrenia and healthy controls.

Striatal dopamine D2 receptor density is an important indicator of many neuropsychiatric disorders and also of motor activity. This study examined the relationship between a fine motor task (finger tapping test, FTT) and striatal D2 dopamine receptor density by examining 20 healthy volunteers and 20 schizophrenic patients. Striatal D2 receptor density was determined with single photon emission computed tomography using [123I]IBZM (iodo-benzamide). The correlation between the FTT score and striatal D2 receptor density was statistically significant not only in the patient group but also in healthy controls. The FTT scores and striatal D2 receptor density were lower in medicated patients than that in healthy controls. Compared with the Simpson-Angus Scale scores, the FTT scores were more strongly associated with striatal D2 receptor density. The use of neuroleptic medication seemed to influence the associations between FTT scores and striatal D2 receptor density in the patient group. The FTT scores and striatal D2 receptor density were age-sensitive in healthy controls. FTT may be a more sensitive tool for detecting neuroleptic-induced motor impairment in patients with schizophrenia. The sensitivity of the FTT to age and neuroleptic effects may be explained in part by a decline in dopamine D2 density.

The association between psychological distress and musculoskeletal symptoms experienced by Chinese high school students.

STUDY DESIGN: A cross-sectional nonexperimental study. OBJECTIVES: To determine the prevalence of musculoskeletal symptoms during a 6-month period and explore the contributing factors associated with these symptoms in Chinese senior class high school students. We also explored the relationship between psychological distress and musculoskeletal symptoms in this population. BACKGROUND: Musculoskeletal symptoms with no underlying identifiable pathology are a management puzzle to medical professionals. Finding the prevalence of musculoskeletal symptoms is the first step in the prevention of further chronic pain syndromes in young adults. No study, however, has directly measured the prevalence of musculoskeletal symptoms in this population. Investigations of the contributing factors to these symptoms, though rare, can provide information to assist in the prevention of further injuries. METHODS: The Musculoskeletal Symptom Questionnaire (MSQ) and the 12-question version of the Chinese Health Questionnaire (CHQ-12) were randomly distributed to students (n = 550) in 4 different high schools in the Tainan area of Taiwan. Of these, 471 students returned the questionnaires for analysis. Descriptive statistics were computed for means, standard deviations, and frequencies. Chi-square statistics were used for analysis of the association between psychological distress and musculoskeletal symptoms. RESULTS: The most frequent complaints of musculoskeletal symptoms among the adolescent Chinese student population were reported as being located in the following anatomical areas: neck (56%), shoulder (45%), and back (37%). Based on the results from the CHQ-12, all of the participants were divided into 2 groups: a high psychological (CHQ-12 score > or = 5) and a low psychological (CHQ-12 score < 5) distress group. There were significant differences of prevalence of musculoskeletal symptoms between these 2 groups (P < .05), especially for the neck region (P = .003). CONCLUSION: The results showed that the prevalence of musculoskeletal symptoms was high in this adolescent population and demonstrated a certain association with psychological distress. We suggest that surveys of this type may serve as preclinical detectors of future musculoskeletal disorders and may permit early interventions. Developing an intervention that addresses both physical and psychological problems may be beneficial for this population.

Pregabalin reduces sleep disturbance in patientswith generalized anxiety disorder via bothdirect and indirect mechanisms

Background and Objectives: To characterize the impact of pregabalin onsleep in patients with generalized anxiety disorder (GAD) and to determine whether the impactis a direct or an indirect effect, mediated through the reduction of anxiety symptoms.Methods: A post-hoc analysis of data from a randomized, double-blind, placebo- and active-controlled study in patients with GAD was conducted. Patients received pregabalin 300mg/day, venlafaxine XR 75 mg/day or placebo for a week, followed by pregabalin 300–600mg/day, venlafaxine XR 75–225 mg/day, or placebo for 7 weeks. Treatment effect on sleepwas evaluated using the Medical Outcomes Study Sleep Scale. Anxiety symptoms were assessedwith the Hamilton Anxiety Rating Scale. A mediation model was used to estimate separatelyfor both treatment arms the direct and indirect treatment effects on sleep disturbance.Results: Compared with placebo (n = 128), treatment with pregabalin (n = 121) significantlyreduced scores on the sleep disturbance subscale and Sleep Problems Index II atboth week 4 and week 8, and the sleep adequacy subscale at week 8. Venlafaxine XR (n =125) had no significant effect on these measures. The mediation model indicated that 53%of the total pregabalin effect on sleep disturbance was direct (p < 0.01) and 47% indirect,mediated through anxiety symptoms (p < 0.05).Conclusions: Pregabalin decreased sleep disturbance in patients with GAD both directly,and indirectly by reducing anxiety symptoms. Given the drug specificity of the results,this study provides evidence of an additional important pathway of action for pregabalinand its efficacy in GAD (AU)

Taiwan schizophrenia linkage study: the field study.

One possible reason of the inconsistent results of linkage analyses of schizophrenia, a complex disorder, was mainly due to the small sample size of studies. This Taiwan Schizophrenia Linkage Study (TSLS) was designed to collect a large family sample with at least two affected siblings of a single ethnicity. The 17.6 millions of Taiwanese Chinese, age over 15, was the sample population, and 78 psychiatric hospitals or health centers participated in this TSLS program. Before data collection started, every study subject signed the informed consent. The ascertainment protocol for data collection included blood sample, structured Diagnostic Interview for Genetic Studies (DIGS), Structured Interview for Schizotypy (SIS), scales for assessment of positive and negative symptoms (SAPS, SANS), and continuous performance test (CPT), Wisconsin card sort test (WCST) of neuropsychological functions. We have contacted 831 families for this study and 607 families, comprised 2,490 subjects, were successfully recruited. The recruitment rate was 38.4% from the estimated total of 1,582 families with at least two affected siblings. These collected family samples were fairly evenly distributed all over Taiwan. Those 2,490 study subjects (1,283 male, 1,117 female) comprised 1,568 siblings (mean age 35.7 years old) and 922 parents (mean age 63.6 years old). Of these 1,568 siblings, 1,258 (80.2%) were affected (male 795, female 463), and the mean age of onset was 22.6 years old. Among 922 parents, 65 were affected (male 14, female 51) and the age of onset was 33.1 years old. This TSLS demonstrated a successful establishment of an efficient research infrastructure to collect a large nation-wise sample of schizophrenic family for genetic linkage study.

The psychological well-being and associated factors of caregivers of outpatients with schizophrenia in Taiwan.

The purpose of this study attempted to understand the psychological well-being of caregivers of individuals with schizophrenia and factors affecting the caregivers' psychological well-being. More specifically, quality of life and psychiatric morbidity were used to represent the psychological well-being. Personal interviews using questionnaires were administrated to 57 caregivers. Data regarding knowledge of schizophrenia, perceived causes of schizophrenia, quality of life and psychiatric morbidity was collected. Psychiatrists assessed the symptoms severity of the schizophrenic patients. Compared with the controls, the psychological well-being of caregivers of patients with schizophrenia was poorer. There was a significant association between the positive symptoms score and the psychological well-being of caregivers. Life quality and psychiatric morbidity were affected by caregivers' knowledge of schizophrenia and beliefs about the cause of schizophrenia. Health care providers should consider the patients and their caregivers as a whole and provide psychoeducaiton to reduce the negative psychological impact of caregivers.

Cloninger's Tridimensional Personality Questionnaire: psychometric properties and construct validity in Taiwanese adults.

Despite the wide use of the Tridimensional Personality Questionnaire (TPQ) in Western populations as a useful tool integrating both genetic and environmental influences on personality, some of its constructs remain questionable. In this study, we examined the psychometric properties of the TPQ and its relationship with aggression in Taiwanese adults. The subjects were 201 Taiwanese adults of wide ranges in age and educational level. Subjects were assessed using a Chinese version of the TPQ and the Brown-Goodwin Aggression Inventory. The internal consistency of the Chinese version of the TPQ scales is found to be mostly in the acceptable range except for the reward dependence (RD) scale and its subscales. The results of factor analysis of the 12 TPQ subscales partially support the four-factor model rather than the original three-factor model. The construct validity of the novelty seeking (NS) and harm avoidance (HA) dimensions is supported by the findings that the NS is negatively correlated with age, the NS1 subscale is slightly negatively correlated with all the HA subscales, and the NS is positively correlated with aggression. We conclude that both the HA and NS scales of the TPQ are cross-culturally robust, while the RD scale needs to be refined.