FLT3/CD99 Bispecific Antibody-Based Nanoparticles for Acute Myeloid Leukemia.

Cluster of differentiation 99 (CD99) is a receptor that is significantly upregulated in acute myeloid leukemia (AML). FMS-like tyrosine kinase 3 internal tandem duplication mutation in AML (FLT3-ITD AML) exhibits even higher levels of CD99 expression. Our group previously employed a novel peptide platform technology called elastin-like polypeptides and fused it with single-chain antibodies capable of binding to FLT3 (FLT3-A192) or CD99 (CD99-A192). Targeting either FLT3 or CD99 using FLT3-A192 or CD99-A192 led to AML cell death and reduced leukemia burden in AML mouse models. Here, we report on the development of a novel Co-Assembled construct that is capable of binding to both CD99 and FLT3 and the antileukemia activity of the bispecific construct in FLT3-ITD AML preclinical models. This dual-targeting Co-Assembled formulation exhibits cytotoxic effects on AML cells (AML cell lines and primary blasts) and reduced leukemia burden and prolonged survival in FLT3-ITD AML mouse models. Altogether, this study demonstrates the potential of an innovative therapeutic strategy that targets both FLT3 and CD99 in FLT3-ITD AML. SIGNIFICANCE: This study investigates a dual-targeting strategy in acute myeloid leukemia (AML), focusing on FLT3 and CD99. The approach demonstrates enhanced therapeutic potential, presenting a novel option for AML treatment.

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.

Biomechanical Considerations in the Orthodontic Treatment of a Patient with Stabilised Stage IV Grade C Generalised Periodontitis: A Case Report.

Orthodontic treatment of periodontally compromised patients presents unique challenges, including controlling periodontal inflammation, applying appropriate force, designing an effective dental anchorage, and maintaining treatment results. Deteriorated periodontal support leads to alterations in the biological responses of teeth to mechanical forces, and thus orthodontists must take greater care when treating patients with periodontal conditions than when treating those with a good periodontal status. In this article, we report the case of a 59-year-old woman with stabilised Stage IV grade C generalised periodontitis characterised by pathological tooth migration (PTM). The assessment, planning, and treatment of this patient with orthodontic fixed appliances is described. Moreover, the anchorage planning and biomechanical considerations are detailed. Specific orthodontic appliances were employed in this case to produce force systems for achieving precise tooth movement, which included a cantilever, mini-screws, and a box loop. Careful application of those appliances resulted in satisfactory aesthetic and functional orthodontic outcomes in the patient. This case highlights the importance of multidisciplinary collaboration in the treatment of patients with severe periodontitis and the potential for tailored biomechanical approaches in orthodontic treatment to furnish good outcomes.

The risk of stroke and post-stroke mortality in people with schizophrenia: A systematic review and meta-analysis study.

Sources of heterogeneity in risk of stroke and mortality risk following acute-stroke in schizophrenia are understudied. We systematically searched four electronic-databases until 1-November-2022, and conducted meta-analysis to synthesize estimates of stroke-risk and post-stroke mortality for schizophrenia patients relative to non-schizophrenia counterparts. Subgroup-analyses and meta-regression models stratified by sex, nature of sample (incident/prevalent), geographical region, study-period and time-frame following stroke were conducted when applicable. Fifteen and 5 studies were included for meta-analysis of stroke-risk (n=18,368,253; 129,095 schizophrenia patients) and all-cause post-stroke mortality (n=289,231; 4,477 schizophrenia patients), respectively. Schizophrenia patients exhibited elevated stroke-risk (relative-risk =1.55[95% CI:1.31-1.84]) relative to non-schizophrenia controls. Schizophrenia was associated with increased stroke-risk in both sexes, study-periods of 1990s and 2000s, and irrespective of nature of sample and geographical regions. Meta-regression revealed regional differences in relative-risk for stroke, but limited by small number of studies. After removal of an outlier study, meta-analysis demonstrated that schizophrenia was associated with increased overall (hazard-ratio=1.37[1.30-1.44]), short-term (≤90 days; 1.29[1.14-1.46]) and longer-term (≥1 year; 1.45[1.32-1.60]) post-stroke mortality rates. Raised post-stroke mortality rate for schizophrenia was observed irrespective of nature of sample, geographical regions and study-periods. Taken together, schizophrenia is associated with increased stroke-risk and post-stroke mortality. Multilevel-interventions are required to reduce these physical-health disparities.

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.

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.

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.

Rate and correlates of self-stigma in adult patients with early psychosis.

Introduction: Self-stigma impedes recovery process and is associated with poorer clinical and functional outcomes in people with psychotic disorders. However, there is limited research specifically examining self-stigma in the early stage of illness, and mixed findings were observed regarding factors associated with increased self-stigma. We aimed to investigate the rate and correlates of self-stigma in a cohort of adult patients with early psychosis using a comprehensive array of clinical, treatment and other illness-related variables. Methods: A total of 101 Chinese adult early psychosis patients aged 26-55 years who had received three-year psychiatric treatment for first psychotic episode in Hong Kong and completed self-stigma assessment were included for the current investigation. A broad range of assessments encompassing socio-demographics, premorbid adjustment, onset and illness profiles, symptom severity, psychosocial functioning, treatment characteristics and medication side-effects were conducted. Results: Twenty-eight (27.7%) patients had moderate-to-high levels of self-stigma. Univariate linear regression analyses showed that age at study entry, sex, educational level, age at psychosis onset, duration of untreated psychosis (DUP), insight level, global psychosocial functioning, and the use of second-generation antipsychotic were related to self-stigma levels. Final multivariable regression model revealed that female sex, younger age at entry, longer DUP and better insight were independently associated with higher levels of self-stigma. Conclusion: More than one-fourth of early psychosis patients experienced significant self-stigma, highlighting an unmet need for early detection and intervention of self-stigma in the initial years of illness. Further investigation is warranted to clarify trajectories and predictors of self-stigma in the early illness course.

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.

Effort-based decision making in schizotypy and its relationship with amotivation and psychosocial functioning.

Introduction: Suboptimal effort-based decision-making with reduced willingness to expend effort for high-probability/high-value reward is observed in schizophrenia patients and is related to diminished motivation, but is understudied in schizotypy. This study aimed to examine effort-allocation in schizotypy individuals and its association with amotivation and psychosocial functioning. Methods: We recruited 40 schizotypy individuals and 40 demographically-matched healthy controls, based on Schizotypal Personality Questionnaire-Brief (SPQ-B) score (top and bottom 10% SPQ-B scores, respectively), from 2400 young people aged 15-24 years participating a population-based mental health survey in Hong Kong and examined effort-allocation using the Effort Expenditure for Reward Task (EEfRT). Negative / amotivation symptoms and psychosocial functioning were assessed by the Brief Negative Symptom Scale (BNSS) and the Social Functioning and Occupational Assessment Scale (SOFAS), respectively. Schizotypy individuals were categorized into high-amotivation and low-amotivation groups based on a median-split of BNSS amotivation domain score. Results: Our results showed no main group effect (in either two or three-group comparison) on effort task performance. Three-group comparison analyses on selected EEfRT performance indices revealed that high-amotivation schizotypy individuals displayed significantly less increase in effortful options from low-value to high-value reward (reward-difference score) and from low-probability/low-value to high-probability/high-value reward (probability/reward-difference score) than low-amotivation individuals and controls. Correlation analyses demonstrated trend-wise significance between BNSS amotivation domain score and several EEfRT performance indices in schizotypy group. Schizotypy individuals with poorer psychosocial functioning tended to exhibit smaller probability/reward-difference score relative to other two groups. Discussion: Our findings indicate subtle effort-allocation abnormalities in schizotypy individuals with high levels of diminished motivation, and suggest the link between laboratory-based effort-cost measures and real-world functional outcome.

Cost-Effectiveness of First-Line Pembrolizumab Monotherapy Versus Chemotherapy in High Programmed Death-Ligand 1 Advanced Non-Small Cell Lung Cancer in the Irish Healthcare Setting.

OBJECTIVES: This study aimed to assess the cost-effectiveness of pembrolizumab monotherapy in the first-line treatment of advanced non-small cell lung cancer (NSCLC) in adults whose tumors expressed programmed death-ligand 1 (PD-L1) with a tumor proportion score (TPS) ≥ 50% in the Irish healthcare setting. METHODS: Effectiveness inputs were derived from the 5-year analysis of KEYNOTE-024 phase III clinical trial. The intervention was pembrolizumab monotherapy; the comparator was a weighted average of the 5 chemotherapy regimens from the trial. The population included those with previously untreated advanced PD-L1 TPS ≥ 50% NSCLC. A de novo partitioned survival model was developed. Survival modeling was done using Bayesian model averaging on fitted parametric functions. Costs included drug acquisition, treatment initiation, administration and monitoring, adverse events, subsequent treatments, and terminal care. Costs and health state utilities were sourced from the literature and Irish sources. The model had a 20-year time horizon. The perspective taken was the Health Service Executive. A 4% discount rate was applied. Outcomes were expressed as an incremental cost-effectiveness ratio (ICER), measured in terms of incremental costs per quality-adjusted life-year (QALY). Probabilistic sensitivity analysis and 1-way sensitivity analyses were conducted. RESULTS: The model estimated a base case ICER of €54 237 per QALY. The probabilistic sensitivity analysis estimated an average ICER of €54 568 per QALY and a 11% probability of cost-effectiveness at the Irish cost-effectiveness threshold of €45 000 per QALY. CONCLUSION: At the current list price, first-line pembrolizumab monotherapy is not considered cost-effective for the treatment of advanced PD-L1 TPS ≥ 50% NSCLC in the Irish healthcare setting.

Cost and public reimbursement of cancer medicines in the UK and the Republic of Ireland.

INTRODUCTION/AIMS: There are disparities in the availability of systemic anticancer therapies (SACTs) globally. We set out to investigate the cost and reimbursement of SACTs in the United Kingdom (UK) and the Republic of Ireland (ROI) in conjunction with efficacy and licensing authority decisions in the United States (US) and the European Union (EU). METHODS: We sought data pertaining to licensing in the EU, reimbursement in ROI/UK and cost/efficacy of SACTs licensed by the Food and Drug Administration (FDA) between January 2015 and May 2021. Independent samples t tests, chi-square test and Pearson's correlation were used for statistical analysis. RESULTS: We identified that the majority of FDA-approved regimens are licensed by the European Medicines Agency (EMA) (n = 91, 67.9%). However, only a minority of these are currently reimbursed in the UK (n = 60, 45%) or the ROI (n = 28, 21%) as of the 1st of May 2021. In addition, only a minority of regimens have demonstrated a statistically significant OS benefit (n = 54, 40%). There was no association between cost of regimens and either the presence (t = 0.846, p = 0.40) or duration of OS benefit (t = - 0.84, p = 0.64). CONCLUSIONS: Our study highlights that many licensed systemic anticancer treatments are not currently reimbursed in ROI/UK. The high cost of these medicines is independent of the presence of an OS benefit. Collaboration between regulatory agencies, governments and industry partners is needed to ensure health expenditure is directed towards the most effective treatments.

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.

Mortality, Revascularization, and Cardioprotective Pharmacotherapy After Acute Coronary Syndrome in Patients With Severe Mental Illness: A Systematic Review and Meta-analysis.

BACKGROUND AND HYPOTHESIS: People with severe mental illness (SMI) may experience excess mortality and inequitable treatment following acute coronary syndrome (ACS). However, cardioprotective pharmacotherapy and SMI diagnoses other than schizophrenia are rarely examined in previous reviews. We hypothesized that SMI including bipolar disorder (BD) is associated with increased post-ACS mortality, decreased revascularization, and cardioprotective medication receipt relative to those without SMI. STUDY DESIGN: We performed a meta-analysis to quantitatively synthesize estimates of post-ACS mortality, major adverse cardiac events (MACEs), and receipt of invasive coronary procedures and cardioprotective medications in patients with SMI, comprising schizophrenia, BD, and other nonaffective psychoses, relative to non-SMI counterparts. Subgroup analyses stratified by SMI subtypes (schizophrenia, BD), incident ACS status, and post-ACS time frame for outcome evaluation were conducted. STUDY RESULTS: Twenty-two studies were included (n = 12 235 501, including 503 686 SMI patients). SMI was associated with increased overall (relative risk [RR] = 1.40 [95% confidence interval = 1.21-1.62]), 1-year (1.68 [1.42-1.98]), and 30-day (1.26 [1.05-1.51]) post-ACS mortality, lower receipt of revascularization (odds ratio = 0.57 [0.49-0.67]), and cardioprotective medications (RR = 0.89 [0.85-0.94]), but comparable rates of any/specific MACEs relative to non-SMI patients. Incident ACS status conferred further increase in post-ACS mortality. Schizophrenia was associated with heightened mortality irrespective of incident ACS status, while BD was linked to significantly elevated mortality only in incident ACS cohort. Both schizophrenia and BD patients had lower revascularization rates. Post-ACS mortality risk remained significantly increased with mild attenuation after adjusting for revascularization. CONCLUSIONS: SMI is associated with increased post-ACS mortality and undertreatment. Effective multipronged interventions are urgently needed to reduce these physical health disparities.

Automating Access to Real-World Evidence.

Introduction: Real-world evidence is important in regulatory and funding decisions. Manual data extraction from electronic health records (EHRs) is time-consuming and challenging to maintain. Automated extraction using natural language processing (NLP) and artificial intelligence may facilitate this process. Whereas NLP offers a faster solution than manual methods of extraction, the validity of extracted data remains in question. The current study compared manual and automated data extraction from the EHR of patients with advanced lung cancer. Methods: Previously, we extracted EHRs from 1209 patients diagnosed with advanced lung cancer (stage IIIB or IV) between January 2015 and December 2017 at Princess Margaret Cancer Centre (Toronto, Canada) using the commercially available artificial intelligence engine, DARWEN (Pentavere, Ontario, Canada). For comparison, 100 of 333 patients that received systemic therapy were randomly selected and clinical data manually extracted by two trained abstractors using the same accepted gold standard feature definitions, including patient, disease characteristics, and treatment data. All cases were re-reviewed by an expert adjudicator. Accuracy and concordance between automated and manual methods are reported. Results: Automated extraction required considerably less time (<1 day) than manual extraction (∼225 person-hr). The collection of demographic data (age, sex, diagnosis) was highly accurate and concordant with both methods (96%-100%). Accuracy (for either extraction approach) and concordance were lower for unstructured data elements in EHR, such as performance status, date of diagnosis, and smoking status (NLP accuracy: 88%-94%; Manual accuracy: 78%-94%; concordance: 71%-82%). Concurrent medications (86%-100%) and comorbid conditions (96%-100%), were reported with high accuracy and concordance. Treatment details were also accurately captured with both methods (84%-100%) and highly concordant (83%-99%). Detection of whether biomarker testing was performed was highly accurate and concordant (96%-98%), although detection of biomarker test results was more variable (accuracy 84%-100%, concordance 84%-99%). Features with syntactic or semantic variation requiring clinical interpretation were extracted with slightly lower accuracy by both NLP and manual review. For example, metastatic sites were more accurately identified through NLP extraction (NLP: 88%-99%; manual: 71%-100%; concordance: 70%-99%) with the exception of lung and lymph node metastases (NLP: 66%-71%; manual: 87%-92%; concordance: 58%) owing to analogous terms used in radiology reports not being included in the accepted gold standard definition. Conclusions: Automated data abstraction from EHR is highly accurate and faster than manual abstraction. Key challenges include poorly structured EHR and the use of analogous terms beyond the accepted gold standard definition. The application of NLP can facilitate real-world evidence studies at a greater scale than could be achieved with manual data extraction.

Parametric Survival Extrapolation of Early Survival Data in Economic Analyses: A Comparison of Projected Versus Observed Updated Survival.

OBJECTIVES: To establish the value of cancer drugs by cost-effectiveness analysis, lifetime parametric survival extrapolations are often fitted to early data. Recent literature suggests that the benefit of cancer agents in primary publications is often different compared with updated data. This study aimed to examine the projected survival based on parametric extrapolations compared with observed survival based on updated data. METHODS: US Food and Drug Administration oncology approvals from January 2006 to December 2015 were reviewed to identify randomized controlled trials, with updated overall survival (OS) or progression-free survival (PFS) data within 5 years. Individual patient data were reconstructed using established methods on initial and updated publications. Projected survival was calculated as the best-fit parametric restricted mean survival time (RMST) based on extrapolated initial Kaplan-Meier curves whereas observed survival was calculated as observed RMST based on updated Kaplan-Meier curves. Mean deviations, mean absolute error (MAE), mean absolute percentage error, and linear regressions were conducted to examine the relationship between projected and observed survival. RESULTS: In total, 32 randomized controlled trials were included. The MAE between the projected RMST and observed RMST was 3.18 months (OS) and 2.84 months (PFS) and absolute percentage error of 100% (OS) and 23% (PFS), suggesting substantial imprecision of the projected RMST in predicting the updated RMST. The linear regression indicated MAE increased as time extrapolated and as the percentage of censored patients increased. CONCLUSIONS: This study demonstrated substantial difference in projected survival between initial and updated publications. Health technology assessment committees need to be aware of the potential uncertainty of incremental effectiveness and resultant value-for-money assessment when making reimbursement decisions based on initial publications with immature survival data.

Aberrant Learned Irrelevance in Patients with First-Episode Schizophrenia-Spectrum Disorder.

Emerging evidence has indicated disrupted learned irrelevance (LIrr), a form of selective attention deficit that may contribute to psychotic symptom formation, in schizophrenia. However, previous research mostly focused on chronic patients. There is a paucity of studies on LIrr in first-episode schizophrenia-spectrum disorder (i.e., schizophrenia and schizophreniform disorder; FES), which were limited by small sample size and have produced mixed results. The current study examined a LIrr effect and its relationship with positive symptom severity in 40 briefly-medicated FES patients and 42 demographically-matched healthy controls using a well-validated computerized LIrr paradigm which has been applied in chronic schizophrenia sample. Positive symptoms were assessed by Positive and Negative Syndrome Scale (PANSS) and Psychotic Symptom Rating Scales (PSYRATS). Our results showed that controls demonstrated intact LIrr, with significantly faster learning about previously predictive (relevant) than previously non-predictive (irrelevant) cues. Lack of such normal attention bias towards predictive over non-predictive cues was observed in FES patients, indicating their failure to distinguish between relevant and irrelevant stimuli. Nonetheless, we failed to reveal any significant correlations between learning scores, in particular learning scores for non-predictive cues, and positive symptom measures in FES patients. Learning scores were also not associated with other symptom dimensions, cognitive functions and antipsychotic dose. In conclusion, our findings indicate aberrant LIrr with impaired allocation of attention to relevant versus irrelevant stimuli in briefly-medicated FES patients. Further prospective research is warranted to clarify the longitudinal trajectory of such selective attention deficit and its association with positive symptoms and treatment response in the early course of illness.

A cost analysis of a community-based support centre for cancer patients and their families in Ireland: the EVeCANs study.

Cancer patients and their families experience a range of physical, psychological and financial adverse effects. Community-based cancer centres offer a range of services and interventions, free of charge, to support those affected by cancer. While shown to be effective, there is a lack of information on the costs of these services. Our aim was to estimate the resource impact of a community-based cancer support centre. Over a 7-month period, there were 2032 contacts with 238 clients whose average age was 60 years. The most frequently used services were transport to treatment (20%), complementary therapies (48%), exercise classes (10%) and counselling (9%). This cost analysis estimated total annual cost to provide all services was €313,744. Average annual cost per person was €1138. Current uptake at the centre represents 8% of all cancer incidences in seven counties surrounding the centre. If uptake increases by 10%, scenario analyses predict an increase in total costs increase to €429,043 and a decrease in costs per patient to €915. As cancer incidences increase, the need for supportive care is growing. Community-based services have been established to meet these needs and fill this gap in national health services. Long-term sustainability of these centres is uncertain as they are entirely reliant on donations and volunteers. This analysis estimates the costs of one such community-based cancer support centre, for the first time in Ireland. Findings can be used to inform future planning of cancer supportive care services, including establishing links between tertiary and community-based centres, and cost effectiveness analyses, nationally and internationally.