Iruplinalkib (WX­0593), a novel ALK/ROS1 inhibitor, overcomes crizotinib resistance in preclinical models for non-small cell lung cancer.

Despite remarkable initial responses of anaplastic lymphoma kinase (ALK) inhibitors in ALK-positive non-small cell lung cancer (NSCLC) patients, cancers eventually develop resistance within one to two years. This study aimed to compare the properties of iruplinalkib (WX­0593) with other ALK inhibitors and report the comprehensive characterization of iruplinalkib against the crizotinib resistance. The inhibitory effect of iruplinalkib on kinase activity was detected. A kinase screen was performed to evaluate the selectivity of iruplinalkib. The effect of iruplinalkib on related signal transduction pathways of ALK and c-ros oncogene 1 (ROS1) kinases was examined. The cellular and in vivo activities of ALK inhibitors were compared in engineered cancer-derived cell lines and in mice xenograft models, respectively. Human hepatocytes derived from three donors were used for evaluating hepatic enzyme inducing activity. HEK293 cell lines expressing transportors were used to invesigated the drug interaction potential mediated by several transporters. The results showed iruplinalkib potently inhibited the tyrosine autophosphorylation of wild-type ALK, ALKL1196M, ALKC1156Y and epidermal growth factor receptor (EGFR)L858R/T790M. The inhibitory effects of iruplinalkib in patient-derived xenograft and cell line-derived xenograft models were observed. Moreover, iruplinalkib showed robust antitumor effects in BALB/c nude mice xenograft models with ALK-/ROS1-positive tumors implanted subcutaneously, and the tumor suppressive effects in crizotinib-resistant model was significantly better than that of brigatinib. Iruplinalkib did not induce CYP1A2, CYP2B6 and CYP3A4 at therapeutic concentration, and was also a strong inhibitor of MATE1 and MATE2K transporters, as well as P-gp and BCRP. In conclusion, iruplinalkib, a highly active and selective ALK/ROS1 inhibitor, exhibited strong antitumor effects in vitro and in crizotinib-resistant models.

Can cognition help predict suicide risk in patients with major depressive disorder? A machine learning study.

BACKGROUND: Previous studies suggest that deficits in cognition may increase the risk of suicide. Our study aims to develop a machine learning (ML) algorithm-based suicide risk prediction model using cognition in patients with major depressive disorder (MDD). METHODS: Participants comprised 52 depressed suicide attempters (DSA) and 61 depressed non-suicide attempters (DNS), and 98 healthy controls (HC). All participants were required to complete a series of questionnaires, the Suicide Stroop Task (SST) and the Iowa Gambling Task (IGT). The performance in IGT was analyzed using repeated measures ANOVA. ML with extreme gradient boosting (XGBoost) classification algorithm and locally explanatory techniques assessed performance and relative importance of characteristics for predicting suicide attempts. Prediction performances were compared with the area under the curve (AUC), decision curve analysis (DCA), and net reclassification improvement (NRI). RESULTS: DSA and DNS preferred to select the card from disadvantageous decks (decks "A" + "B") under risky situation (p = 0.023) and showed a significantly poorer learning effect during the IGT (F = 2.331, p = 0.019) compared with HC. Performance of XGBoost model based on demographic and clinical characteristics was compared with that of the model created after adding cognition data (AUC, 0.779 vs. 0.819, p > 0.05). The net benefit of model was improved and cognition resulted in continuous reclassification improvement with NRI of 5.3%. Several clinical dimensions were significant predictors in the XGBoost classification algorithm. LIMITATIONS: A limited sample size and failure to include sufficient suicide risk factors in the predictive model. CONCLUSION: This study demonstrate that cognitive deficits may serve as an important risk factor to predict suicide attempts in patients with MDD. Combined with other demographic characteristics and attributes drawn from clinical questionnaires, cognitive function can improve the predictive effectiveness of the ML model. Additionally, explanatory ML models can help clinicians detect specific risk factors for each suicide attempter within MDD patients. These findings may be helpful for clinicians to detect those at high risk of suicide attempts quickly and accurately, and help them make proactive treatment decisions.

Relationship between suicide rate and antidepressant prescription: An ecological study in the People's Republic of China.

OBJECTIVES: The objective of this study was to estimate the features of suicide rate and its association with antidepressant prescriptions during the past decade in China. METHODS: Official data on suicides were obtained and stratified by four age groups, gender, urban/rural areas, and regions (East, Central, and West). The annual antidepressant prescriptions were expressed in pills per 100 persons calculated as the volume of prescriptions divided by the total population. Negative binomial regression was carried out to examine the association between suicide and other variables. RESULTS: Suicide rates in each stratum typically decreased from 2008 to 2015, while annual antidepressant prescriptions were generally increased by the year. The suicide rate increased with age and was greater in adult males than in females; higher in the central area and greater in rural than in urban areas. Suicide rates are negatively associated with antidepressant prescriptions including selective serotonin reuptake inhibitors (Incidence rate ratio [IRR] 0.983, 95% confidence interval [CI] 0.983-0.983), serotonin-norepinephrine reuptake inhibitors (IRR 0.951, 95% CI 0.951-0.951), tricyclic antidepressant (IRR 0.925, 95% CI 0.925-0.925) and total antidepressants (IRR 0.990, 95% CI 0.990-0.990) during 2008-2012. CONCLUSION: Suicide varied among different studied stratum. Suicide rates are negatively associated with antidepressant prescriptions.

Neutralizing Antibody Responses to Severe Acute Respiratory Syndrome Coronavirus 2 in Coronavirus Disease 2019 Inpatients and Convalescent Patients.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a pandemic with no specific antiviral treatments or vaccines. There is an urgent need for exploring the neutralizing antibodies from patients with different clinical characteristics. METHODS: A total of 117 blood samples were collected from 70 COVID-19 inpatients and convalescent patients. Antibodies were determined with a modified cytopathogenic neutralization assay (NA) based on live severe acute respiratory syndrome coronavirus 2 and enzyme-linked immunosorbent assay (ELISA). The dynamics of neutralizing antibody levels at different time points with different clinical characteristics were analyzed. RESULTS: The seropositivity rate reached up to 100.0% within 20 days since onset, and remained 100.0% till days 41-53. The total geometric mean titer was 1:163.7 (95% confidence interval [CI], 128.5-208.6) by NA and 1:12 441.7 (95% CI, 9754.5-15 869.2) by ELISA. The antibody level by NA and ELISA peaked on days 31-40 since onset, and then decreased slightly. In multivariate generalized estimating equation analysis, patients aged 31-45, 46-60, and 61-84 years had a higher neutralizing antibody level than those aged 16-30 years (ß = 1.0470, P = .0125; ß = 1.0613, P = .0307; ß = 1.3713, P = .0020). Patients with a worse clinical classification had a higher neutralizing antibody titer (ß = 0.4639, P = .0227). CONCLUSIONS: The neutralizing antibodies were detected even at the early stage of disease, and a significant response was shown in convalescent patients.

Effect of immunonutrition on colorectal cancer patients undergoing surgery: a meta-analysis.

PURPOSE: Immunonutrition has been used to prevent the complications after colorectal elective surgery. This systematic review aimed to analyze and assess the effect of immunonutrition on colorectal cancer patients who received elective surgery. METHODS: Three electronic databases (Medline, Embase, Cochrane) were used to search the latent studies which investigated the effects of enteral immunonutrition (EIN) compared with standard enteral nutrition (EN) or parenteral immunonutrition (PIN) compared with standard parenteral nutrition (PN) on colorectal cancer patients who are undergoing surgery until 21st of April, 2017. Meta-analysis was conducted to calculate odd risk (OR), mean difference (MD), or standard mean difference (SMD) with 95% confidence interval (CI), and heterogeneity was tested by Q test. RESULTS: Nine publications were included. The meta-analysis results presented that EIN improved the length of hospital stay (pooled MD, 2.53; 95% CI, 1.29-3.41), infectious complications (pooled OR, 0.33; 95% CI, 0.21-0.53) which contains the Surgical Site Infections (pooled OR, 0.25; 95% CI, 0.22-0.58) and Superficial/Deep incisional infections (pooled OR, 0.27; 95% CI, 0.12-0.64); meanwhile, PIN improved the length of hospital stay (pooled MD, 2.66; 95% CI, 0.62-4.76), IL-6 (pooled MD, - 6.09; 95% CI, - 10.11 to - 2.07), CD3 (pooled MD, 7.50; 95% CI, 3.57-11.43), CD4 (pooled MD, 5.47; 95% CI, 2.54-8.40), and CD4/CD8 (pooled MD, 0.50; 95% CI, 0.22-0.78); the level of CD8 was lower (pooled MD, - 4.32; 95% CI, - 7.09 to - 1.55) in PIN. CONCLUSION: Immunonutrition could be an effective approach to enhance the immune function of colorectal cancer patients undergoing elective surgery and to improve the clinical and laboratory outcomes.

Prevalence of Anemia and its Risk Factors among Children under 36 Months Old in China.

This study aims to evaluate the prevalence and sociodemographic factors of anemia in children <36 months old in China. In this study, data of 24 235 children were investigated from 32 primary health care (PHC) facilities in 11 province-level regions. Pearson χ2-test and logistic regression model were used to estimate potential risk factors associated with anemia. The overall prevalence of anemia was 24.4%, and 32.8% children from rural areas were anemic, but no statistically significant difference was observed between male and female. Predictors of anemia are different regions of China, cesarean delivery, premature birth and neonatal asphyxia. We also found that education level and income of children's parents are important determinants of childhood anemia. In additional, feeding practice would affect anemia among children aged 6-12 months. Our results could provide some insights for prevention and control of childhood anemia in PHC facilities.

An economic-research-based approach to calculate community health-staffing requirements in Xicheng District, Beijing.

BACKGROUND: A shortage of community health professionals has been a crucial issue hindering the development of CHS. Various methods have been established to calculate health workforce requirements. This study aimed to use an economic-research-based approach to calculate the number of community health professionals required to provide community health services in the Xicheng District of Beijing and then assess current staffing levels against this ideal. METHODS: Using questionnaires, we collected relevant data from 14 community health centers in the Xicheng District, including resident population, number of different health services provided, and service volumes. Through 36 interviews with family doctors, nurses, and public health workers, and six focus groups, we were able to calculate the person-time (equivalent value) required for each community health service. Field observations were conducted to verify the duration. RESULTS: In the 14 community health centers in Xicheng District, 1752 health workers were found in our four categories, serving a population of 1.278 million. Total demand for the community health service outstripped supply for doctors, nurses, and public health workers, but not other professionals. The method suggested that to properly serve the study population an additional 64 family doctors, 40 nurses, and 753 public health workers would be required. CONCLUSIONS: Our calculations indicate that significant numbers of new health professionals are required to deliver community health services. We established time standards in minutes (equivalent value) for each community health service activity, which could be applied elsewhere in China by government planners and civil society advocates.

A model to estimate the cost of the National Essential Public Health Services Package in Beijing, China.

BACKGROUND: In order to address several health challenges, the Chinese government issued the National Essential Public Health Services Package (NEPHSP) in 2009. In China's large cities, the lack of funding for community health centers and consequent lack of comprehensive services and high quality care has become a major challenge. However, no study has been carried out to estimate the cost of delivering the services in the package. This project was to develop a cost estimation approach appropriate to the context and use it to calculate the cost of the NEPHSP in Beijing in 2011. METHODS: By adjusting models of cost analysis of primary health care and workload indicators of staffing need developed by the World Health Organization, a model was developed to estimate the cost of the services in the package through an intensive interactive process. A total of 17 community health centers from eight administrative districts in Beijing were selected. Their service volume and expenditure data in 2010 were used to evaluate the costs of providing the NEPHSP in Beijing based on the applied model. RESULTS: The total workload of all types of primary health care in 17 sample centers was equivalent to the workload requirement for 14,056,402 standard clinic visits. The total expenditure of the 17 sample centers was 26,329,357.62 USD in 2010. The cost of the workload requirement of one standard clinic visit was 1.87 USD. The workload of the NEPHSP was equivalent to 5,514,777 standard clinic visits (39.23 % of the total workload). The model suggests that the cost of the package in Beijing was 7.95 USD per capita in 2010. The cost of the NEPHSP in urban areas was lower than suburban areas: 7.31 and 8.65 USD respectively. CONCLUSIONS: The average investment of 3.97 USD per capita in NEPHSP was lower than the amount needed to meet its running costs. NEPHSP in Beijing is therefore underfunded. Additional investment is needed, and a dynamic cost estimate mechanism should be introduced to ensure services remain adequately funded.

Immune responses during COVID-19 breakthrough cases in vaccinated children and adolescents.

Background: Vaccine effectiveness against SARS-CoV-2 infection has been somewhat limited due to the widespread dissemination of the Omicron variant, its subvariants, and the immune response dynamics of the naturally infected with the virus. Methods: Twelve subjects between 3-17 years old (yo), vaccinated with two doses of CoronaVac®, were followed and diagnosed as breakthrough cases starting 14 days after receiving the second dose. Total IgGs against different SARS-CoV-2 proteins and the neutralizing capacity of these antibodies after infection were measured in plasma. The activation of CD4+ and CD8+ T cells was evaluated in peripheral blood mononuclear cells stimulated with peptides derived from the proteins from the wild-type (WT) virus and Omicron subvariants by flow cytometry, as well as different cytokines secretion by a Multiplex assay. Results: 2 to 8 weeks post-infection, compared to 4 weeks after 2nd dose of vaccine, there was a 146.5-fold increase in neutralizing antibody titers against Omicron and a 38.7-fold increase against WT SARS-CoV-2. Subjects showed an increase in total IgG levels against the S1, N, M, and NSP8 proteins of the WT virus. Activated CD4+ T cells showed a significant increase in response to the BA.2 subvariant (p<0.001). Finally, the secretion of IL-2 and IFN-γ cytokines showed a discreet decrease trend after infection in some subjects. Conclusion: SARS-CoV-2 infection in the pediatric population vaccinated with an inactivated SARS-CoV-2 vaccine produced an increase in neutralizing antibodies against Omicron and increased specific IgG antibodies for different SARS-CoV-2 proteins. CD4+ T cell activation was also increased, suggesting a conserved cellular response against the Omicron subvariants, whereas Th1-type cytokine secretion tended to decrease. Clinical Trial Registration: clinicaltrials.gov #NCT04992260.

[Gender and its impact on condom use among HIV male serodiscordant couples].

OBJECTIVE: To study the gender-based factors which influence the condom use among the HIV serodiscordant couples in selected regions of China. METHODS: Based on the analysis of the existing case reporting database and convenient sampling in the cross-sectional study, a total of 481 female HIV-negative spouses completed an interviewer-administered questionnaire regarding demographic characters, the knowledge, behaviors and the gender-based factors in five sites of four provinces Sichuan (Zhaojue), Yunnan (Dali), Henan (Weishi) and Guangxi (Lingshan and Luzhai), during June-September 2011. χ(2) analysis and logistic regression were used to study the gender-based factors influencing condom use among the participants. RESULTS: Among the 481 female HIV-negative spouses, the average age was (35.1 ± 6.7) years, and the proportion of Han and Yi nationality were high, 43.5% (209/481) and 41.8% (201/481), respectively. The awareness of knowledge related to HIV spousal transmission was high (≥ 79.6%). A total of 86.9% (418/481) used condom more frequently after informed the status of HIV infection of their spouses, and the condom use consistency was 56.6% (272/481). A total of 57.6% (277/481) reported low sexual relationship power; 34.5% (166/481) experienced forced sex in the past 1 year. And the proportion of condom use self-efficacy from 0 to 3 scores were 12.7% (61/481), 23.9% (115/481), 8.7% (42/481) and 54.7% (263/481), respectively (median = 3). Han and other nationality were significantly more likely to use condom consistently than Yi, with odds ratio (95%CI) of 0.01 (0.00 - 0.03) and 0.01 (0.00 - 0.04), and the female spouses with higher condom use self-efficacy used condom more consistently than the lower ones, with odds ratio (95%CI) of 0.20(0.11 - 0.34). CONCLUSION: The female spouses with higher condom use self-efficacy were more likely to use condom consistently after excluding the confounding effect of nationality.

[Cost-effectiveness analysis of HIV testing strategy in hospitals from 2006 to 2010 in Guangzhou].

OBJECTIVE: To evaluate the cost effectiveness of HIV testing strategy in hospitals from 2006 to 2010 in Guangzhou. METHODS: According to the HIV test strategy costs and the number of HIV patients found in Guangzhou, following aspects were calculated as the total cost of HIV testing strategy in hospitals from 2006 to 2010 of Guangzhou, the cost of finding each HIV patient, and the cost of obtaining one quality adjusted life year (QALY) using Markov model. RESULTS: The total HIV test strategy costs increased from 11 106.98 thousand Yuan to 25 105.58 thousand Yuan, and 4599 HIV positive patients were found due to this strategy. The cost-effectiveness of HIV testing were different in hospitals from 2006 to 2010 in Guangzhou. The lowest cost-effectiveness ratio of HIV testing strategy was 11 810 Yuan per HIV positive patient, the highest was 23 510 Yuan, and the average was 16 070 Yuan. According to the Markov model result, 7.2855 QALYs could be gained per HIV patient on average via HIV testing strategy in 113 hospitals in Guangzhou, and the cost of obtaining one QALY was 2210 Yuan. CONCLUSION: The cost effectiveness ratio of HIV testing strategy in hospitals in Guangzhou was significantly lower than the standard of WHO recommended, and it was cost-effective to carry out the HIV testing strategy in Guangzhou.

[Acceptability status of early antiretroviral therapy among HIV-positive men who have sex with men].

OBJECTIVE: To assess the acceptability and influence factors of early antiretroviral therapy (ART) among HIV-positive men who have sex with men (MSM) . METHODS: From June to August 2012, through convenience sampling, HIV-positive MSM who were willing to cooperate with the survey were selected from the Hangzhou and Ningbo AIDS prevention and control database. A total of 280 HIV-positive MSM who did not receive ART participated in the study.Using self-designed questionnaire, general demographic information, awareness of AIDS knowledge, sexual behavior, use of condom, current physical condition, awareness and attitude towards early ART were investigated.Excluding 60 HIV-infected MSM whose CD4(+)T count didn't meet the inclusion criteria, a total of 220 subjects were included in the analysis. Chi-square was used to compare the difference of early ART acceptance among subjects with different characteristics.Non-conditional logistic regression was used to analyze the influence factors of the acceptability of early ART. RESULTS: The acceptance rate of early ART among HIV-infected MSM was 62.7% (138/220). Delaying the disease development, preventing partners from infection, not worrying others to suspect them of having HIV, and partners unknowing the HIV-infected status were the factors which had a relatively higher acceptance rate of early ART. Correspondingly, the acceptance rate was 68.8% (130/189), 68.7% (103/150), 78.4% (69/88) and 72.5% (74/102) respectively and the acceptance rate among subjects with opposite opinions or characteristics was 24.1% (7/29) , 50.0% (30/60), 52.7% (68/129) and 45.8% (58/107) respectively (chi-square values were 21.46, 6.43, 14.84 7.55, all P values <0.05).Logistic regression analysis showed that delaying the disease development (OR = 11.50, 95%CI:3.29-40.22) and preventing partners from infection (OR = 3.72, 95%CI:1.53-9.03) were inclined to the acceptance of early ATR.While concerning others' suspection of them having HIV (OR = 0.19, 95%CI:0.08-0.48) and partners knowing the HIV-infected status were inclined to unacceptance of ART(OR = 0.31, 95%CI:0.13-0.70). CONCLUSION: The acceptability of early ART among HIV-positive MSM is high. The recognition of early ART and concern of privacy leak are the major influence factors which can stimulate the acceptance of early ART.

Association of adenosine triphosphate-related genes to major depression and suicidal behavior: Cognition as a potential mediator.

BACKGROUND: Soluble epoxide hydrolase (sEH, encoded by EPHX2) and P2X2 (a subtype of ATP receptors) may mediate the antidepressant-like effects of ATP. We sought to determine whether polymorphisms and mRNA expression of EPHX2 and P2X2 are associated with depression and suicidal behavior and how cognition may mediate such associations. METHOD: We examined 83 single nucleotide polymorphisms (SNPs) of EPHX2 and P2X2. Subjects were MDD suicide attempters (N = 143), MDD non-suicide attempters (N = 248), and healthy volunteers (HV, N = 110). Data on demographics, depression severity, and suicide attempts were collected. Participants completed a set of cognitive tasks. Polymorphisms were genotyped using MALDI-TOF MS within the MassARRAY system. The expression of mRNA was measured using real-time polymerase chain reaction (RT-PCR). RESULTS: Cognitive function was a significant mediator (p = 0.006) of the genetic effect on depression. Allele C of rs202059124 was associated with depression risk (OR = 11.57, 95%CI: 2.33-209.87, p = 0.0181). A significant relationship was found between P2X2 mRNA expression and depression (OR = 0.68, 95%CI: 0.49-0.94, p = 0.0199). One haploblock (rs9331942 and rs2279590) was associated with suicide attempts: subjects with haplotype GC (frequency = 19.8 %, p = 0.017) and AT (frequency = 35.2 %, p < 0.001) had a lower rate of suicide attempts. CONCLUSIONS: Our results confirmed that cognitive impairment plays a role in the effect of rs9331949 on depression. Moreover, we confirmed a relationship between P2X2, EPHX2, and MDD in humans and presented preliminary haplotype-based evidence that implicates EPHX2 in suicide. LIMITATIONS: The main limitation of this study is the limited sample size. More comprehensive and multi-domain cognition tasks and different assessment measures are required in further study.

Different Safety Pattern of an Inactivated SARS-CoV-2 Vaccine (CoronaVac®) According to Age Group in a Pediatric Population from 3 to 17 Years Old, in an Open-Label Study in Chile.

During the COVID-19 pandemic, the importance of vaccinating children against SARS-CoV-2 was rapidly established. This study describes the safety of CoronaVac® in children and adolescents between 3- and 17-years-old in a multicenter study in Chile with two vaccine doses in a 4-week interval. For all participants, immediate adverse events (AEs), serious AEs (SAEs), and AEs of special interest (AESIs) were registered throughout the study. In the safety subgroup, AEs were recorded 28 days after each dose. COVID-19 surveillance was performed throughout the study. A total of 1139 individuals received the first and 1102 the second dose of CoronaVac®; 835 were in the safety subgroup. The first dose showed the highest number of AEs: up to 22.2% of participants reported any local and 17.1% systemic AE. AEs were more frequent in adolescents after the first dose, were transient, and mainly mild. Pain at the inoculation site was the most frequent AE for all ages. Fever was the most frequent systemic AE for 3-5 years old and headache in 6-17 years old. No SAEs or AESIs related to vaccination occurred. Most of the COVID-19 cases were mild and managed as outpatients. CoronaVac® was safe and well tolerated in children and adolescents, with different safety patterns according to age.

HIV testing among men who have sex with men in China: a systematic review and meta-analysis.

HIV testing among men who have sex with men (MSM) in China has not been well studied. We systematically reviewed studies addressing HIV testing among MSM in China and conducted a meta-analysis on testing indicators before and after the adoption of China's National Plan for HIV/AIDS Prevention and Control among MSM in 2007. Rate of lifetime HIV testing (24 % [period 1-before adoption] vs. 47 % [period 2-after adoption]) and testing in the past 12 months (21 vs. 38 %) were both significantly higher in period 2. Rate of lifetime pre-test counseling showed a significant increase from period 1 to period 2 (72 vs. 90 %), while the figure for the past 12 months pre-test counseling did not change (51 vs. 50 %). More efforts are needed to promote frequent HIV testing among MSM.

Thematic trends and knowledge structure on cognitive behavior therapy for insomnia: A bibliometric and visualization analysis.

Objective: To find publications trend about cognitive behavior therapy for insomnia (CBTI) using bibliometric and visualization analysis. In this study, the authors sought to identify the publication trends of peer-reviewed articles about CBTI. Materials and methods: Analyses were focused on the past 18 years from 2004 to 2021. All searches were performed on the Web of Science Core Collection database. The search was repeated to include structural cognitive behavior therapy for insomnia. Quantitative analysis was assessed using the bibliometric tool. Visualization analysis was carried out using VOSviewer. Results: In the 736 articles reviewed, the number of publications has been increasing every year for the past 18 years. Behavioral sleep medicine and sleep were the most active journals published on CBTI. The United States and Canada had the highest scientific publications in the field. Morin CM and Espie CA were the most active authors. The study type mostly observed were randomized controlled trials, meta-analyses, and epidemiological. Publications on digital-based cognitive behavior therapy and accessibility to primary care settings represent the future trends of research on CBTI. Conclusion: Possible explanations for CBTI publication trends were discussed, including the emergence of the evidence-based therapy, feasibility, and scalability. Potential CBTI publications trends in the future and clinical implications were also discussed.

Six-month follow-up of a booster dose of CoronaVac in two single-centre phase 2 clinical trials.

Determining the duration of immunity induced by booster doses of CoronaVac is crucial for informing recommendations for booster regimens and adjusting immunization strategies. In two single-centre, double-blind, randomised, placebo-controlled phase 2 clinical trials, immunogenicity and safety of four immunization regimens are assessed in adults aged 18 to 59 years and one immunization regimen in adults aged 60 years and older, respectively. Serious adverse events occurring within 6 months after booster doses are recorded as pre-specified secondary endpoints, geometric mean titres (GMTs) of neutralising antibodies one year after the 3-dose schedule immunization and 6 months after the booster doses are assessed as pre-specified exploratory endpoints, GMT fold-decreases in neutralization titres are assessed as post-hoc analyses. Neutralising antibody titres decline approximately 4-fold and 2.5-fold from day 28 to day 180 after third doses in adults aged 18-59 years of age and in adults aged 60 years and older, respectively. No safety concerns are identified during the follow-up period. There are increases in the magnitude and duration of humoral response with homologous booster doses of CoronaVac given 8 months after a primary two-dose immunization series, which could prolong protection and contribute to building our wall of population immunity. Trial number: NCT04352608 and NCT04383574.

Brain-wide projection reconstruction of single functionally defined neurons.

Reconstructing axonal projections of single neurons at the whole-brain level is currently a converging goal of the neuroscience community that is fundamental for understanding the logic of information flow in the brain. Thousands of single neurons from different brain regions have recently been morphologically reconstructed, but the corresponding physiological functional features of these reconstructed neurons are unclear. By combining two-photon Ca2+ imaging with targeted single-cell plasmid electroporation, we reconstruct the brain-wide morphologies of single neurons that are defined by a sound-evoked response map in the auditory cortices (AUDs) of awake mice. Long-range interhemispheric projections can be reliably labelled via co-injection with an adeno-associated virus, which enables enhanced expression of indicator protein in the targeted neurons. Here we show that this method avoids the randomness and ambiguity of conventional methods of neuronal morphological reconstruction, offering an avenue for developing a precise one-to-one map of neuronal projection patterns and physiological functional features.

Inactivated Vaccine-Induced SARS-CoV-2 Variant-Specific Immunity in Children.

Multiple vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been evaluated in clinical trials. However, trials addressing the immune response in the pediatric population are scarce. The inactivated vaccine CoronaVac has been shown to be safe and immunogenic in a phase 1/2 clinical trial in a pediatric cohort in China. Here, we report interim safety and immunogenicity results of a phase 3 clinical trial for CoronaVac in healthy children and adolescents in Chile. Participants 3 to 17 years old received two doses of CoronaVac in a 4-week interval until 31 December 2021. Local and systemic adverse reactions were registered for volunteers who received one or two doses of CoronaVac. Whole-blood samples were collected from a subgroup of 148 participants for humoral and cellular immunity analyses. The main adverse reaction reported after the first and second doses was pain at the injection site. Four weeks after the second dose, an increase in neutralizing antibody titer was observed in subjects relative to their baseline visit. Similar results were found for activation of specific CD4+ T cells. Neutralizing antibodies were identified against the Delta and Omicron variants. However, these titers were lower than those for the D614G strain. Importantly, comparable CD4+ T cell responses were detected against these variants of concern. Therefore, CoronaVac is safe and immunogenic in subjects 3 to 17 years old, inducing neutralizing antibody secretion and activating CD4+ T cells against SARS-CoV-2 and its variants. (This study has been registered at ClinicalTrials.gov under no. NCT04992260.) IMPORTANCE This work evaluated the immune response induced by two doses of CoronaVac separated by 4 weeks in healthy children and adolescents in Chile. To date, few studies have described the effects of CoronaVac in the pediatric population. Therefore, it is essential to generate knowledge regarding the protection of vaccines in this population. Along these lines, we reported the anti-S humoral response and cellular immune response to several SARS-CoV-2 proteins that have been published and recently studied. Here, we show that a vaccination schedule consisting of two doses separated by 4 weeks induces the secretion of neutralizing antibodies against SARS-CoV-2. Furthermore, CoronaVac induces the activation of CD4+ T cells upon stimulation with peptides from the proteome of SARS-CoV-2. These results indicate that, even though the neutralizing antibody response induced by vaccination decreases against the Delta and Omicron variants, the cellular response against these variants is comparable to the response against the ancestral strain D614G, even being significantly higher against Omicron.

Influence of the GABA Receptor Subunit Gene Polymorphism and Childhood Sexual Abuse on Processing Speed in Major Depression and Suicide Attempt.

Background: Suicide is moderately heritable and also more common in those who report childhood abuse. Previously, it was found that allele A of GABRG2 (GABA A receptor subunit gamma2) polymorphism rs211034 was protective in a suicide attempt (SA). Hence, it was proposed that rs211034 may interact with childhood trauma to influence cognitive deficits related to SA or depression risk. Genetic variants may predict the benefits of certain cognitive treatments. Methods: A total of 52 individuals who had attempted suicide, 59 individuals with major depressive disorder (MDD) or bipolar depression who had not previously attempted suicide, and 90 healthy volunteers were subjected to the modified Suicide Stroop task and were clinically assessed using the Childhood Trauma Questionnaire (CTQ) and Hamilton Depression Scale-24 items (HAMD-24). rs211034 was genotyped using Sanger sequencing. Results: After correcting for covariates, depressed participants displayed longer reaction times for all emotional conditions, including suicide-related words, compared with healthy controls. Depressed suicide attempters displayed longer reaction times for negative words than depressed non-attempters. Depressed non-attempters displayed higher interference scores for negative words compared with healthy controls. There was an interaction between rs211034 risk allele and the effects of reported childhood sexual abuse (CSA) on reaction time for all emotional words and suicide-related words. Carriers of the rs211034 risk allele A exhibited shorter reaction times, but the protective effects of this allele were eliminated in those exposed to reported CSA. Conclusion: Only limited results were found regarding effects of a past suicide attempt on response times to emotional and suicide-related words, but there was an overall effect of major depression on slower response time. Protective genetic effects of the rs211034 A allele on this slowing were eliminated in those with a history of sexual abuse during childhood. Further research is needed to better characterize the mechanisms underlying the effects of childhood trauma on these genetic effects.