Prevalence and correlates of depression, anxiety and trauma-like symptoms in Chinese psychiatric patients during the fifth wave of COVID-19 pandemic: a cross-sectional study in Hong Kong.

BACKGROUND: Psychiatric patients are susceptible to adverse mental health outcome during COVID-19 pandemic, but its associated factors are understudied. This observational cross-sectional study aimed to comprehensively examine prevalence and correlates of psychological distress, in terms of depression, anxiety and post-traumatic-stress-disorder (PTSD)-like symptoms, among Chinese adult psychiatric outpatients amidst the peak of fifth COVID-19 wave in Hong-Kong. METHODS: A total of 415 patients (comprising 246 patients with common-mental-disorders [CMD] and 169 with severe-mental-disorders [SMD]) and 399 demographically-matched controls without mental disorders were assessed with self-rated questionnaires between 28-March and 8-April-2022, encompassing illness profile, mental health symptoms, psychosocial measures (loneliness, resilience, coping styles) and COVID-19 related factors. Univariate and multivariable logistic regression analyses were conducted to determine variables associated with moderate-to-severe depressive, anxiety and PTSD-like symptoms among psychiatric patients. RESULTS: Our results showed that CMD patients had the greatest psychological distress relative to SMD patients and controls. Approximately 40-55% CMD patients and 25% SMD patients exhibited moderate-to-severe depression, anxiety and PTSD-like symptoms. Multivariable regression analyses revealed that female gender, lower educational attainment, single marital status, being housewife, more severe insomnia, psychotic-like symptoms and cognitive complaints, self-harm behavior, lower resilience, avoidance coping, never contracting COVID-19 infection, greater fear of contagion, and longer exposure to pandemic-related information were independently associated with depression, anxiety and/or PTSD-like symptoms in psychiatric patients. CONCLUSIONS: Our results affirm increased vulnerability of psychiatric patients toward psychological distress during pandemic. An array of identified correlates facilitates early detection of high-risk psychiatric patients for targeted strategies to minimize pandemic-related negative psychological impact.

Network analysis on psychopathological symptoms, psychological measures, quality of life and COVID-19 related factors in Chinese psychiatric patients in Hong Kong.

BACKGROUND: Psychiatric patients are susceptible to adverse mental health impacts during COVID-19, but complex interplays between psychopathology and pandemic-related variables remain elusive. This study aimed to investigate concomitant associations between psychopathological symptoms, psychological measures and COVID-19 related variables in Chinese psychiatric patients during the peak of fifth pandemic wave in Hong Kong. METHODS: We employed network analysis to investigate inter-relationships among psychopathological symptoms (including depression, anxiety, post-traumatic stress disorder-like [PTSD-like] symptoms, insomnia, psychotic symptoms), cognitive complaints, health-related quality of life, loneliness, resilience and selected pandemic-related factors in 415 psychiatric outpatients between 28 March and 8 April, 2022. Network comparisons between genders, diagnosis (common mental disorders [CMD] vs. severe mental disorders [SMD]), and history of contracting COVID-19 at fifth wave were performed as exploratory analyses. RESULTS: Our results showed that anxiety represented the most central node in the network, as indicated by its highest node strength and expected influence, followed by depression and quality of life. Three comparatively strong connections between COVID-19 and psychopathological variables were observed including: fear of contagion and PTSD-like symptoms, COVID-19 stressor burden and PTSD-like symptoms, and COVID-19 stressor burden and insomnia. Network comparison tests revealed significant network structural difference between participants with history of contracting COVID-19 and those without, but showed no significant difference between genders as well as between CMD and SMD patients. CONCLUSIONS: Our findings suggest the pivotal role of anxiety in psychopathology network of psychiatric patients amidst COVID-19. Pandemic-related variables are critically associated with trauma/stress and insomnia symptoms. Future research is required to elucidate potential network structural changes between pandemic and post-COVID periods.

Short Report: CAR Tregs mediate linked suppression and infectious tolerance in islet transplantation.

Regulatory T cells (Tregs) have potential as a cell-based therapy to prevent or treat transplant rejection and autoimmunity. Using an HLA-A2-specific chimeric antigen receptor (A2-CAR), we previously showed that adoptive transfer of A2-CAR Tregs limited anti-HLA-A2 alloimmunity. However, it was unknown if A2-CAR Tregs could also limit immunity to autoantigens. Using a model of HLA-A2+ islet transplantation into immunodeficient non-obese diabetic mice, we investigated if A2-CAR Tregs could control diabetes induced by islet-autoreactive (BDC2.5) T cells. In mice transplanted with HLA-A2+ islets, A2-CAR Tregs reduced BDC2.5 T cell engraftment, proliferation and cytokine production, and protected mice from diabetes. Tolerance to islets was systemic, including protection of the HLA-A2negative endogenous pancreas. In tolerant mice, a significant proportion of BDC2.5 T cells gained FOXP3 expression suggesting that long-term tolerance is maintained by de novo Treg generation. Thus, A2-CAR Tregs mediate linked suppression and infectious tolerance and have potential therapeutic use to simultaneously control both allo- and autoimmunity in islet transplantation.

Life expectancy and years of potential life lost in people with mental disorders: a systematic review and meta-analysis.

Background: Mental disorders are associated with premature mortality. There is increasing research examining life expectancy and years-of-potential-life-lost (YPLL) to quantify the disease impact on survival in people with mental disorders. We aimed to systematically synthesize studies to estimate life expectancy and YPLL in people with any and specific mental disorders across a broad spectrum of diagnoses. Methods: In this systematic review and meta-analysis, we searched Embase, MEDLINE, PsychINFO, WOS from inception to July 31, 2023, for published studies reporting life expectancy and/or YPLL for mental disorders. Criteria for study inclusion were: patients of all ages with any mental disorders; reported data on life expectancy and/or YPLL of a mental-disorder cohort relative to the general population or a comparison group without mental disorders; and cohort studies. We excluded non-cohort studies, publications containing non-peer-reviewed data or those restricted to population subgroups. Survival estimates, i.e., life expectancy and YPLL, were pooled (based on summary data extracted from the included studies) using random-effects models. Subgroup analyses and random-effects meta-regression analyses were performed to explore sources of heterogeneity. Risk-of-bias assessment was evaluated using the Newcastle-Ottawa Scale. This study is registered with PROSPERO (CRD42022321190). Findings: Of 35,865 studies identified in our research, 109 studies from 24 countries or regions including 12,171,909 patients with mental disorders were eligible for analysis (54 for life expectancy and 109 for YPLL). Pooled life expectancy for mental disorders was 63.85 years (95% CI 62.63-65.06; I2 = 100.0%), and pooled YPLL was 14.66 years (95% CI 13.88-15.98; I2 = 100.0%). Disorder-stratified analyses revealed that substance-use disorders had the shortest life expectancy (57.07 years [95% CI 54.47-59.67]), while neurotic disorders had the longest lifespan (69.51 years [95% CI 67.26-71.76]). Substance-use disorders exhibited the greatest YPLL (20.38 years [95% CI 18.65-22.11]), followed by eating disorders (16.64 years [95% CI 7.45-25.82]), schizophrenia-spectrum disorders (15.37 years [95% CI 14.18-16.55]), and personality disorders (15.35 years [95% CI 12.80-17.89]). YPLLs attributable to natural and unnatural deaths in mental disorders were 4.38 years (95% CI 3.15-5.61) and 8.11 years (95% CI 6.10-10.13; suicide: 8.31 years [95% CI 6.43-10.19]), respectively. Stratified analyses by study period suggested that the longevity gap persisted over time. Significant cross-study heterogeneity was observed. Interpretation: Mental disorders are associated with substantially reduced life expectancy, which is transdiagnostic in nature, encompassing a wide range of diagnoses. Implementation of comprehensive and multilevel intervention approaches is urgently needed to rectify lifespan inequalities for people with mental disorders. Funding: None.

Prevalence and correlates of subjective cognitive impairment in Chinese psychiatric patients during the fifth wave of COVID-19 in Hong Kong.

Introduction: The extent of cognitive impairment and its association with psychological distress among people with pre-existing mental illness during COVID-19 is understudied. This study aimed to investigate prevalence and correlates of subjective cognitive impairment (SCI) in Chinese psychiatric patients during fifth-wave of COVID-19 in Hong Kong (HK). Methods: Four-hundred-eight psychiatric outpatients aged 18-64 years were assessed with questionnaires between 28 March and 8 April 2022, encompassing illness profile, psychopathological symptoms, coping-styles, resilience, and COVID-19 related factors. Participants were categorized into moderate-to-severe and intact/mild cognitive impairment (CI+ vs. CI-) groups based on severity of self-reported cognitive complaints. Univariate and multivariate regression analyses were conducted to determine variables associated with CI+ status. Results: One-hundred-ninety-nine participants (48.8%) experienced CI+. A multivariate model on psychopathological symptoms found that depressive and post-traumatic-stress-disorder (PTSD)-like symptoms were related to CI+, while a multivariate model on coping, resilience and COVID-19 related factors revealed that avoidant coping, low resilience and more stressors were associated with CI+. Final combined model demonstrated the best model performance and showed that more severe depressive and PTSD-like symptoms, and adoption of avoidant coping were significantly associated with CI+. Conclusion: Almost half of the sample of psychiatric patients reported cognitive complaints during fifth-wave of COVID-19 in HK. Greater depressive and PTSD-like symptom severity, and maladaptive (avoidant) coping were found as correlates of SCI. COVID-19 related factors were not independently associated with SCI in psychiatric patients. Early detection with targeted psychological interventions may therefore reduce psychological distress, and hence self-perceived cognitive difficulties in this vulnerable population.

Tregs integrate native and CAR-mediated costimulatory signals for control of allograft rejection.

Tregs expressing chimeric antigen receptors (CAR-Tregs) are a promising tool to promote transplant tolerance. The relationship between CAR structure and Treg function was studied in xenogeneic, immunodeficient mice, revealing advantages of CD28-encoding CARs. However, these models could underrepresent interactions between CAR-Tregs, antigen-presenting cells (APCs), and donor-specific Abs. We generated Tregs expressing HLA-A2-specific CARs with different costimulatory domains and compared their function in vitro and in vivo using an immunocompetent model of transplantation. In vitro, the CD28-encoding CAR had superior antigen-specific suppression, proliferation, and cytokine production. In contrast, in vivo, Tregs expressing CARs encoding CD28, ICOS, programmed cell death 1, and GITR, but not 4-1BB or OX40, all extended skin allograft survival. To reconcile in vitro and in vivo data, we analyzed effects of a CAR encoding CD3ζ but no costimulatory domain. These data revealed that exogenous costimulation from APCs can compensate for the lack of a CAR-encoded CD28 domain. Thus, Tregs expressing a CAR with or without CD28 are functionally equivalent in vivo, mediating similar extension of skin allograft survival and controlling the generation of anti-HLA-A2 alloantibodies. This study reveals a dimension of CAR-Treg biology and has important implications for the design of CARs for clinical use in Tregs.

The prevalence and correlates of suicidal ideation in Chinese psychiatric patients during the fifth wave of COVID-19 in Hong Kong.

People with mental disorders have increased risk of psychological distress during COVID-19. However, there is limited research comprehensively examining factors associated with suicidal ideation, the strongest predictor of suicidal behavior, among psychiatric patients amidst pandemic. We investigated prevalence and correlates of suicidal ideation in 407 Chinese psychiatric outpatients (diagnosed with mood, anxiety or schizophrenia-spectrum disorders) aged 18-64 years during the peak of fifth COVID-19 wave in Hong Kong between 28 March and 8 April, 2022, based on a comprehensive array of variables encompassing socio-demographics, illness profile, psychopathological symptoms, psychological measures and pandemic-related factors. Univariate and multivariate logistic regression analyses were conducted to determine correlates of suicidal ideation. Results showed that 128 (31.4%) participants exhibited suicidal ideation. Univariate analyses revealed that being unemployed or full-time student, more severe depressive, anxiety, PTSD-like, insomnia and psychotic symptoms, higher levels of loneliness, avoidant-coping, greater pandemic-related stress burden and distress by social-distancing measures were related to suicidal ideation. Conversely, participants with higher monthly household-income, better quality-of-life, and greater resilience were less likely to have suicidal ideation. Notably, only depressive symptom severity was retained in final multivariate model as a factor significantly associated with suicidal ideation. Hence, we observed that approximately one-third of Chinese psychiatric patients experienced suicidal ideation during fifth pandemic wave. Our findings underscore the influence of depressive symptoms being above and beyond that of other psychopathological symptoms, psychological and pandemic-related variables on suicidal ideation. Longitudinal research is required to clarify suicidal ideation trajectories and predictors of persistent suicidal ideation across pandemic and post-pandemic periods.

Human A2-CAR T Cells Reject HLA-A2 + Human Islets Transplanted Into Mice Without Inducing Graft-versus-host Disease.

BACKGROUND: Type 1 diabetes is an autoimmune disease characterized by T-cell-mediated destruction of pancreatic beta-cells. Islet transplantation is an effective therapy, but its success is limited by islet quality and availability along with the need for immunosuppression. New approaches include the use of stem cell-derived insulin-producing cells and immunomodulatory therapies, but a limitation is the paucity of reproducible animal models in which interactions between human immune cells and insulin-producing cells can be studied without the complication of xenogeneic graft-versus-host disease (xGVHD). METHODS: We expressed an HLA-A2-specific chimeric antigen receptor (A2-CAR) in human CD4 + and CD8 + T cells and tested their ability to reject HLA-A2 + islets transplanted under the kidney capsule or anterior chamber of the eye of immunodeficient mice. T-cell engraftment, islet function, and xGVHD were assessed longitudinally. RESULTS: The speed and consistency of A2-CAR T-cell-mediated islet rejection varied depending on the number of A2-CAR T cells and the absence/presence of coinjected peripheral blood mononuclear cells (PBMCs). When <3 million A2-CAR T cells were injected, coinjection of PBMCs accelerated islet rejection but also induced xGVHD. In the absence of PBMCs, injection of 3 million A2-CAR T cells caused synchronous rejection of A2 + human islets within 1 wk and without xGVHD for 12 wk. CONCLUSIONS: Injection of A2-CAR T cells can be used to study rejection of human insulin-producing cells without the complication of xGVHD. The rapidity and synchrony of rejection will facilitate in vivo screening of new therapies designed to improve the success of islet-replacement therapies.

Cognitive subgroups and the relationships with symptoms, psychosocial functioning and quality of life in first-episode non-affective psychosis: a cluster-analysis approach.

Introduction: Prior research examining cognitive heterogeneity in psychotic disorders primarily focused on chronic schizophrenia, with limited data on first-episode psychosis (FEP). We aimed to identify distinct cognitive subgroups in adult FEP patients using data-driven cluster-analytic approach, and examine relationships between cognitive subgroups and a comprehensive array of illness-related variables. Methods: Two-hundred-eighty-nine Chinese patients aged 26-55 years presenting with FEP to an early intervention program in Hong Kong were recruited. Assessments encompassing premorbid adjustment, illness-onset profile, symptom severity, psychosocial functioning, subjective quality-of-life, and a battery of cognitive tests were conducted. Hierarchical cluster-analysis was employed, optimized with k-means clustering and internally-validated by discriminant-functional analysis. Cognitive subgroup comparisons in illness-related variables, followed by multivariable multinominal-regression analyzes were performed to identify factors independently predictive of cluster membership. Results: Three clusters were identified including patients with globally-impaired (n = 101, 34.9%), intermediately-impaired (n = 112, 38.8%) and relatively-intact (n = 76, 26.3%) cognition (GIC, IIC and RIC subgroups) compared to demographically-matched healthy-controls' performance (n = 50). GIC-subgroup was older, had lower educational attainment, greater positive, negative and disorganization symptom severity, poorer insight and quality-of-life than IIC- and RIC-subgroups, and higher antipsychotic-dose than RIC-subgroup. IIC-subgroup had lower education levels and more severe negative symptoms than RIC-subgroup, which had better psychosocial functioning than two cognitively-impaired subgroups. Educational attainment and disorganization symptoms were found to independently predict cluster membership. Discussion: Our results affirmed cognitive heterogeneity in FEP and identified three subgroups, which were differentially associated with demographic and illness-related variables. Further research should clarify longitudinal relationships of cognitive subgroups with clinical and functional outcomes in FEP.

Tregs with an MHC class II peptide-specific chimeric antigen receptor prevent autoimmune diabetes in mice.

Adoptive immunotherapy with Tregs is a promising approach for preventing or treating type 1 diabetes. Islet antigen-specific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity for the insulin B chain 10-23 peptide presented in the context of the IAg7 MHC class II allele present in NOD mice. Peptide specificity of the resulting InsB-g7 CAR was confirmed by tetramer staining and T cell proliferation in response to recombinant or islet-derived peptide. The InsB-g7 CAR redirected NOD Treg specificity such that insulin B 10-23-peptide stimulation enhanced suppressive function, measured via reduction of proliferation and IL-2 production by BDC2.5 T cells and CD80 and CD86 expression on dendritic cells. Cotransfer of InsB-g7 CAR Tregs prevented adoptive transfer diabetes by BDC2.5 T cells in immunodeficient NOD mice. In WT NOD mice, InsB-g7 CAR Tregs prevented spontaneous diabetes. These results show that engineering Treg specificity for islet antigens using a T cell receptor-like CAR is a promising therapeutic approach for the prevention of autoimmune diabetes.

Investigation of momentary negative symptoms in patients with early psychosis in daily life: An experience sampling study.

Negative symptoms are a key therapeutic target in promoting functional recovery in early psychosis intervention, but momentary negative symptom manifestations remain understudied in the early stage of illness. We employed an experience-sampling methodology (ESM) to evaluate momentary affective experiences, hedonic capacity for an event recalled, current activities and social interactions, and associated appraisals for 6 consecutive days in 33 clinically-stable early psychosis patients (within 3 years of treatment for first-episode psychosis) and 35 demographically-matched healthy controls. Adjusted multilevel linear-mixed models revealed higher intensity and variability of negative affect in patients than controls, but no group difference in affect instability as well as positive affect intensity and variability. Patients demonstrated no significantly greater anhedonia for event, activity or social interactions relative to controls. Higher preference for company (when alone) and to be alone (when in company) was observed in patients than controls. No significant group difference in pleasantness to be alone or proportion of time being alone. Our results indicate no evidence for blunting of affective experiences, anhedonia (social and non-social) and asociality in early psychosis. Future research complementing ESM with multiple digital phenotyping measures will facilitate more refined negative symptom assessment in the daily life of patients with early psychosis.

COVID-19 perseverative cognition and depressive symptoms in Hong Kong: The moderating role of resilience, loneliness and coping strategies.

BACKGROUND: The COVID-19 pandemic significantly increased depression prevalence in general population. However, the relationship between persistent dysfunctional thinking associated with COVID-19 (perseverative-cognition) and depression, and its potential moderators are understudied. We aimed to examine the association between COVID-19 perseverative-cognition and depression, and the moderating effect of potential risk and protective factors on this association in general public during the peak of fifth COVID-19 wave in Hong Kong. METHODS: This survey recruited 14,269 community-dwelling adults between March 15-April 3, 2022 to investigate association between COVID-19 perseverative-cognition and depression, and the moderating effect of resilience, loneliness and three coping strategies (including emotion-focused, problem-focused and avoidant coping) on this association, using hierarchical regression models and simple slope analyses. COVID-19 perseverative cognition was assessed by the Obsession with COVID-19 Scale (OCS) and depressive symptoms were measured by the Patient Health Questionnaire-9 (PHQ-9). RESULTS: Perseverative-cognition was positively associated with depression severity. Resilience, loneliness and three coping strategies moderated the association between perseverative-cognition and depression. Specifically, greater resilience and emotion-focused coping ameliorated the association between perseverative-cognition and depression, while higher levels of loneliness, avoidant and problem-focused coping accentuated such association. LIMITATIONS: Cross-sectional design precluded establishing causality among variables. CONCLUSION: This study affirms that COVID-19 perseverative-cognition is significantly related to depression. Our findings indicate the potential critical role of enhanced personal resilience and social support, and adoption of emotion-focused coping in mitigating negative effect of COVID-19 related maladaptive thinking on depression severity, thereby facilitating development of targeted strategies to reduce psychological distress amidst the prolonged pandemic.

Human A2-CAR T cells reject HLA-A2+ human islets transplanted into mice without inducing graft versus host disease.

Background: Type 1 diabetes (T1D) is an autoimmune disease characterised by T cell mediated destruction of pancreatic beta-cells. Islet transplantation is an effective therapy, but its success is limited by islet quality and availability along with the need for immunosuppression. New approaches include use of stem cell-derived insulin-producing cells and immunomodulatory therapies, but a limitation is the paucity of reproducible animal models in which interactions between human immune cells and insulin-producing cells can be studied without the complication of xenogeneic graft- versus -host disease (xGVHD). Methods: We expressed an HLA-A2-specific chimeric antigen receptor (A2-CAR) in human CD4+ and CD8+ T cells and tested their ability to reject HLA-A2+ islets transplanted under the kidney capsule or anterior chamber of the eye of immunodeficient mice. T cell engraftment, islet function and xGVHD were assessed longitudinally. Results: The speed and consistency of A2-CAR T cells-mediated islet rejection varied depending on the number of A2-CAR T cells and the absence/presence of co-injected peripheral blood mononuclear cells (PBMCs). When <3 million A2-CAR T cells were injected, co-injection of PBMCs accelerated islet rejection but also induced xGVHD. In the absence of PBMCs, injection of 3 million A2-CAR T cells caused synchronous rejection of A2+ human islets within 1 week and without xGVHD for 12 weeks. Conclusions: Injection of A2-CAR T cells can be used to study rejection of human insulin-producing cells without the complication of xGVHD. The rapidity and synchrony of rejection will facilitate in vivo screening of new therapies designed to improve the success of isletreplacement therapies.

Insulin B peptide-MHC class II-specific chimeric antigen receptor-Tregs prevent autoimmune diabetes.

Adoptive immunotherapy with Tregs is a promising approach for prevention or treatment of type 1 diabetes. Islet antigen-specific Tregs have more potent therapeutic effects than polyclonal cells, but their low frequency is a barrier for clinical application. To generate Tregs that recognize islet antigens, we engineered a chimeric antigen receptor (CAR) derived from a monoclonal antibody with specificity for the insulin B-chain 10-23 peptide presented in the context of the IA g7 MHC class II allele present in NOD mice. Peptide specificity of the resulting InsB-g7 CAR was confirmed by tetramer staining and T cell proliferation in response to recombinant or islet-derived peptide. The InsB-g7 CAR re-directed NOD Treg specificity such that insulin B 10-23-peptide stimulation enhanced suppressive function, measured via reduction of proliferation and IL-2 production by BDC2.5 T cells and CD80 and CD86 expression on dendritic cells. Co-transfer of InsB-g7 CAR Tregs prevented adoptive transfer diabetes by BDC2.5 T cells in immunodeficient NOD mice. In wild type NOD mice, InsB-g7 CAR Tregs stably expressed Foxp3 and prevented spontaneous diabetes. These results show that engineering Treg specificity for islet antigens using a T cell receptor-like CAR is a promising new therapeutic approach for the prevention of autoimmune diabetes. Brief Summary: Chimeric antigen receptor Tregs specific for an insulin B-chain peptide presented by MHC class II prevent autoimmune diabetes.

Antidepressant utilization patterns and predictors of treatment continuation in pregnant women: A 16-year population-based cohort.

OBJECTIVE: Existing data on prenatal antidepressant prescribing patterns are mostly derived from Western countries, with limited research assessing antidepressant continuation and reinitiation during pregnancy. This study aimed to examine antidepressant prescribing practice among Chinese pregnant women in Hong Kong. METHODS: This population-based study identified women aged 15-50 years who delivered their first and singleton child, and had redeemed at least one antidepressant prescription within 3 months pre-pregnancy and/or during pregnancy between 2003 and 2018, using data from the health-record database of Hong Kong public healthcare services. Antidepressant utilization patterns before and during pregnancy, and factors associated with antidepressant continuation and reinitiation following medication discontinuation were evaluated. RESULTS: Of 466,358 pregnancies, 3019 (0.67%) received antidepressants within 3 months of pre-pregnancy and/or during pregnancy, and 2700 (0.58%) had prenatal antidepressant use. There was a significant rising trend of prenatal antidepressant use over time (0.6% in 2003 to 1.3% in 2018; odds ratio: 1.09, 95% confidence interval = [1.08, 1.10], p < 0.001). A consistent pattern of decreasing overall antidepressant use from 3 months pre-pregnancy to the second trimester was observed, followed by a slight increase in the third trimester. Almost half (n = 949, 49.5%) of 1918 women on antidepressants in 3 months pre-pregnancy continued treatment beyond the first trimester. A total of 8.2% that discontinued antidepressants in 3 months pre-pregnancy or in the first trimester reinitiated treatment in the later stage of pregnancy. Older age at conception (⩾35 years), recent calendar year of delivery (2015-2018), pre-existing depression/anxiety disorders, longer-term pre-pregnancy antidepressant treatment and pre-pregnancy prescription of other psychotropics were significantly associated with antidepressant continuation. Antidepressant reinitiation was predicted by pre-existing depression/anxiety disorders. CONCLUSIONS: Our results that prenatal antidepressant use is increasingly prevalent and half of pregnant women discontinued antidepressants 3 months before or after conception underscore the need for future research to clarify the risk and benefit of antidepressant continuation versus discontinuation to facilitate development of evidence-based guidelines, so as to optimize maternal and fetal outcomes.

Prevalence and correlates of suicidal ideation in the general public during the fifth wave of COVID-19 pandemic in Hong Kong.

Introduction: Literature reveals increased suicidal ideation in the general population during pandemic. However, few COVID-19 studies comprehensively assessed factors associated with suicidal ideation, and mixed findings were observed. We aimed to examine prevalence and correlates of suicidal ideation in general public during the peak of fifth COVID-19 wave in Hong Kong based on a broad array of relevant measures. Methods: This survey assessed 14,709 community-dwelling adults during March 15-April 3, 2022. Comprehensive assessment was administered including socio-demographics, pre-existing mental/physical morbidity, mental-health symptoms, resilience, loneliness, coping strategies, and pandemic-related factors. Presence of suicidal ideation was evaluated by ratings of item 9 on Patient-Health-Questionnaire-9. Results: A total of 2,249 (15.3%) participants exhibited suicidal ideation. Multivariable-regression analysis found that being single and unemployed, pre-existing mental disorder, more severe depressive and anxiety symptoms, higher levels of loneliness and engagement in avoidant coping were significantly associated with suicidal ideation. Conversely, attaining tertiary educational level or above, greater resilience and adopting problem-focused coping were associated with lower likelihood of suicidal ideation. Although univariate-analyses revealed that a number of pandemic-related factors were linked to suicidal ideation, none remained significant in the multivariable model. Conclusion: A significant proportion of people experienced suicidal ideation during the peak of fifth COVID-19 wave. Risk and protective factors identified would facilitate early identification of high-risk individuals and provision of targeted interventions to minimize suicidal ideation and risk of self-harm. Caution should be exercised due to study limitations of a cross-sectional design which precluded establishing causality among variables, and reliance on self-reported data.

Modelling Graft-Versus-Host Disease in Mice Using Human Peripheral Blood Mononuclear Cells.

Graft-versus-host disease (GvHD) is a significant complication of allogeneic hematopoietic stem cell transplantation. In order to develop new therapeutic approaches, there is a need to recapitulate GvHD effects in pre-clinical, in vivo systems, such as mouse and humanized mouse models. In humanized mouse models of GvHD, mice are reconstituted with human immune cells, which become activated by xenogeneic (xeno) stimuli, causing a multi-system disorder known as xenoGvHD. Testing the ability of new therapies to prevent or delay the development of xenoGvHD is often used as pre-clinical, proof-of-concept data, creating the need for standardized methodology to induce, monitor, and report xenoGvHD. Here, we describe detailed methods for how to induce xenoGvHD by injecting human peripheral blood mononuclear cells into immunodeficient NOD SCID gamma mice. We provide comprehensive details on methods for human T cell preparation and injection, mouse monitoring, data collection, interpretation, and reporting. Additionally, we provide an example of the potential utility of the xenoGvHD model to assess the biological activity of a regulatory T-cell therapy. Use of this protocol will allow better standardization of this model and comparison of datasets across different studies. Graft-versus-host disease (GvHD) is a significant complication of allogeneic hematopoietic stem cell transplantation. In order to develop new therapeutic approaches, there is a need to recapitulate GvHD effects in pre-clinical, in vivo systems, such as mouse and humanized mouse models. In humanized mouse models of GvHD, mice are reconstituted with human immune cells, which become activated by xenogeneic (xeno) stimuli, causing a multi-system disorder known as xenoGvHD. Testing the ability of new therapies to prevent or delay the development of xenoGvHD is often used as pre-clinical, proof-of-concept data, creating the need for standardized methodology to induce, monitor, and report xenoGvHD. Here, we describe detailed methods for how to induce xenoGvHD by injecting human peripheral blood mononuclear cells into immunodeficient NOD SCID gamma mice. We provide comprehensive details on methods for human T cell preparation and injection, mouse monitoring, data collection, interpretation, and reporting. Additionally, we provide an example of the potential utility of the xenoGvHD model to assess the biological activity of a regulatory T-cell therapy. Use of this protocol will allow better standardization of this model and comparison of datasets across different studies. This protocol was validated in: Sci Transl Med (2020), DOI: 10.1126/scitranslmed.aaz3866 Graphical abstract.

Transduction of Human T Cell Subsets with Lentivirus.

Lentivirus-mediated gene transfer is an efficient method to introduce a variety of transgenes to human T cells. Here we describe a protocol to transduce human CD4+, CD8+, or CD4+ regulatory T cells. To illustrate the method, we use transduction with lentivirus encoding an HLA-A2-specific chimeric antigen receptor (CAR) and a transduction marker as an example. Methods to isolate, transduce, purify, and expand CD4+ and CD8+ T cells as well as regulatory T cells are provided. We also describe how to carry out cytotoxicity or suppression assays to assess the function of the resulting CAR T cell or CAR regulatory T cells, respectively.

Functional effects of chimeric antigen receptor co-receptor signaling domains in human regulatory T cells.

Antigen-specific regulatory T cells (Tregs) engineered with chimeric antigen receptors (CARs) are a potent immunosuppressive cellular therapy in multiple disease models and could overcome shortcomings of polyclonal Treg therapy. CAR therapy was initially developed with conventional T cells, which have different signaling requirements than do Tregs To date, most of the CAR Treg studies used second-generation CARs, encoding a CD28 or 4-1BB co-receptor signaling domain and CD3ζ, but it was not known if this CAR design was optimal for Tregs Using a human leukocyte antigen-A2-specific CAR platform and human Tregs, we compared 10 CARs with different co-receptor signaling domains and systematically tested their function and CAR-stimulated gene expression profile. Tregs expressing a CAR encoding CD28wt were markedly superior to all other CARs tested in an in vivo model of graft-versus-host disease. In vitro assays revealed stable expression of Helios and an ability to suppress CD80 expression on dendritic cells as key in vitro predictors of in vivo function. This comprehensive study of CAR signaling domain variants in Tregs can be leveraged to optimize CAR design for use in antigen-specific Treg therapy.