Conclusions: By this SEM pathway analysis, there is the correlation between the disruptive, more aggressive subtype of ADHD in children/adolescents and the existence of psychopathological symptomatology of their parents. ADHD + ODD + aggression in children should be classified as an irritable subtype of ADHD, warranting early diagnosis and intensive treatment.Background: Children with attention deficit hyperactivity disorder (ADHD) co-occurring with Oppositional Defiant Disorder (ODD) further present aggressive behavior and may have a depressive parent. A child with co-occurring ADHD and ODD has differentially higher levels of behavioral and emotional difficulties. Little is known about how the irritable subtype of ADHD in children mediates the development of parental symptomatology. This study aims to elucidate the direct or indirect influence of childhood disruptive ADHD with aggressive behavior on their parental symptom using Structural Equation Modeling (SEM). Methods: A total of 231 ADHD children and their parents completed the Swanson, Nolan, and Pelham Version IV questionnaire for symptoms of ADHD, Oppositional Defiant Disorder (ODD) scale for irritable symptoms, Child Behavior Check List (CBCL) for aggression, and Symptom Checklist (SCL) for parental symptom. Results: The three-factor confirmatory factor analysis (CFA) model found symptoms of inattention, hyperactivity/impulsivity, irritable ODD, and aggression were inter-related. Mediational analyses demonstrated ODD mediates symptoms directly predicting the risk of increasing ADHD severity. Disruptive child symptoms (ADHD + ODD + aggression) may increase the risk of depression-related symptoms in the parent. When the child’s aggression increases by one standard deviation (SD), parental psychiatric symptoms increase by 0.235 SD ( Attention deficit hyperactivity disorder (ADHD) is the most common neurodevelopmental disorder, with a reported high prevalence of 5% to 12.76% among children and adolescents ,4. FamilBy the developmental-transactional model, it is reasonable to find the cause-and-effect relationship between ADHD in children and maternal depressive disorder through multiple psychosocial and biological risks . As an eNot every family has a difficult time. When reviewing ADHD symptom severity, we found a clinically heterogenous picture, especially when ADHD is complicated by extensive comorbid conditions . Up to 8Previous studies on psychopathological spectrum disorders have focused more on the symptom profiles of ADHD, ODD, and Conduct Disorder (CD) , not aggStructural equation modeling (SEM) is an appropriate method for analyzing a set of interactive factors simultaneously . TraditiThe authors first hypothesize a bidirectional association between the symptoms of the child and parental symptoms. Following this, we examined the direct effect between ADHD, ODD, aggression, and parental symptoms. This allows us to further examine whether disruptive symptoms in children have a more direct effect on parental depression-related symptoms compared to families with kids that only have ADHD. To discover the relationship between ADHD, ODD, and aggression, the authors also hypothesized ODD is a mediating risk factor that causes children with ADHD to become aggressive and has a significant, direct effect on parental depression-related psychiatric symptoms. With these results, mental health professionals can take steps earlier to manage ODD and develop more intensive parenting programs to prevent further occurrences of conduct disorder in the future.This study recruited patients from the outpatient unit of a major medical center in Taipei, Taiwan. The Mackay Memorial Hospital Institutional Review Board (IRB) approved the design of the study, with IRB No. MMH-I-S-489 under the project “exploring the symptomatology on children with internet addiction and attention deficit hyperactivity disorder and their parent”. After receiving a complete description of the study, participants provided written informed consent in line with the IRB guidelines. A total of 231 children with a clinical diagnosis of ADHD, based on the Diagnostic and Statistical Manual of Mental Health Disorders, Fourth Edition (DSM-IV), were recruited in this study. The senior child and adolescence psychiatrist confirmed the clinical diagnosis of ADHD based on the DSM-IV criteria. After obtaining signed consent from the legal guardian, each subject recruited for this study was invited to participate in the following programs and was interviewed to derive the following measures.The Swanson, Nolan, and Pelham version IV scale, Chinese (SNAP-IV-C) consists of the following items: inattention (9 items), hyperactivity/impulsivity (9 items), and oppositional symptoms (8 items). These items reflect the core symptoms of ADHD and ODD, as defined in DSM-IV . The inaWe used the Child Behavior Check List (CBCL) to determine competencies and behavioral/emotional problems of children aged 4–18 years. The questionnaires, completed by the parents, included 118 items to assess specific behavioral and emotional problems. The CBCL was translated into Chinese via a two-stage translation . The intThe ODD score from SNAP plus an aggressive behavior score from CBCL was used to indicate Disruptive Child Symptoms (DCS) and to differentiate general irritable ODD or aggressive symptoms from symptoms of ADHD. We used the Symptom Checklist-90-Revised (SCL-90-R), a 90-item self-report system developed in the 1980s by Derogatis , to determine the parental psychiatric symptom score. The SCL-90-R has previously been proven as a reliable psychometric measurement. The Cronbach α coefficient range of the SCL-90-R is 0.77–0.90, according to the study by Derogatis . The ChiThe nine primary dimensions are somatization, obsessive–compulsive disorder, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism. We used a five-point scale (0–4) for symptoms, ranging from “not at all” to “extremely”. We chose five parental symptoms  for this SEM analysis to explore the association between parental depressive/anxiety symptoms and disruptive behavior symptoms of children.SEM can be used to evaluate and to explain how the relationships among unobserved variables and their influence on their parental psychiatric symptom. SEM is directly adequate latent pathway analysis to elucidate the hypothesis test. This paper reviews the role of latent variables in multiple regression, factor analysis, and structural equation models. SEM process centers around two steps. One is validating the measurement model: accomplished primarily through confirmatory factor analysis (CFA). Other is fitting the structural model: accomplished primarily through path analysis with latent variables .The first SEM process was using factor loadings to specify the association between an unobservable construct (latent variables) and its theoretically related measures (indicator variables). Multiple linear regression methods were used to determine the relationships among the aforementioned latent variables and were indexed by standardized path coefficients. 2; (2) the comparative fit index, CFI; (3) the Bentler–Bonett [2 (p > 0.05), GFI and CFI greater than 0.95, TLI greater than 0.96, and RMSEA less than 0.06 each indicated a good fit between the data and the hypothesized model [The second step is to use absolute model fit indices determining how well a priori model fits the sample data. The six following indices were used to evaluate model fit: (1) the chi-square test, χr–Bonett  normed fr–Bonett . All theed model . We used the following two models to establish the potential direct effect of a diagnosis of worse ADHD severity with related disruptive child symptoms (ODD and aggression) on the development of parental psychiatric symptoms (SCL-90). Among three latent variables, named ADHD, Disruptive Child Symptoms (DCS), and parental symptom (SCL), we used a three-factor confirmatory factor analysis (CFA) model to explore the existence of bivariate correlations. For the direct effect model of DCS on ADHD and parental symptoms (SCL-90), we used the SEM model to find the relationship. Furthermore, a mediational effect model, analyzed by SEM, was used to elucidate the relationship among ADHD, ODD, and aggression. We used Amos 21.0 and SPSS v.21.0 packages (SPSS Inc.) to perform all statistical analyses .There are some limitations in using the SEM method. The most severe one is that all measurement variables (represented by rectangles) are normally distributed. In other words, the demographic factors, such as gender, marriage status, and socioeconomic status, etc., cannot be put into the structure part to control for their potential influence on the relationships in the modeling.Overall, 231 eligible patients with ADHD were enrolled. In p < 0.001). However, the covariance between perceived ADHD symptoms in children and SCL-90 parental symptoms was not significantly different from zero at the 0.05 significance level . Based on the aforementioned six indices, this model provides a good fit for the data, as suggested by the results of the non-significant chi-square test and the other five indices of good fit . The results of the three-factor CFA, in p < 0.001). In other words, when DCS increased by one standard deviation, ADHD significantly increased by 0.85 standard deviations. This SEM model also provided a very good fit for the data .p < 0.001) and is predictive of aggression in children . On the other hand, children’s aggression had a significant, direct effect on pa-rental somatization, obsessive–compulsive disorder, interpersonal sensitivity, depression, and symptoms of anxiety. More specifically, the standardized direct effect of a child’s aggression on parental symptom was 0.235 (p < 0.001). That is, when aggression in children increased by one standard deviation, parental psychiatric symptoms in-creased by 0.235 standard deviations. The mediation model also provided an excellent fit for the data .The mediational effect model analyzed by SEM is shown in Our study used exploratory SEM to elucidate the association between ADHD, ODD, and aggression in children with parental psychiatric symptoms. We found a potential bi-directive influence between symptoms from children with ADHD and parental depression-related symptoms. This Confirmatory Factor Analysis (CFA) conceptualized ADHD, ODD, and aggression in children interact with parental depression-related symptoms. We have known that adolescents with ADHD have more family-related impairments due to higher ADHD severity and parenting stress . This stp < 0.001). ODD, being a serious intermediate diagnosis, plays a role in increasing the severity of hyperactive/impulsive symptoms of ADHD. The symptoms of ADHD were not significantly associated with parental depression-related symptoms. However, if ADHD co-occurs with ODD and aggressive behavior, the inter-relevance of symptoms of the child and parental depression-related symptoms became significant, 0.23 (p = 0.006). Higher ADHD severity with disruptive behavior problems in children, or so-called the psychopathologic spectrum, could be used to predict the depression- and anxiety-related psychiatric symptoms in their parents, according to this SEM analysis.According to this study result, so-called higher ADHD severity is a form of ADHD in children that co-occurs with disruptive behavior symptoms (ODD and aggression). Importantly, these three behavior symptoms  are inter-correlated with each other, with a ratio of 0.86  need an intensive program combining pharmacotherapy and parenting programs , here ouAnother contribution of our study is the zero-order correlation, which highlighted aggressive behavior as closely correlated with the severity of hyperactivity/impulsivity symptoms  and with ODD (0.587) in children. As other studies have found, the severity of the children’s hyperactivity/impulsivity symptoms, but not inattention in ADHD, influence parenting stress . This SEThis study has the following limitations. First, a symptom-by-symptom checklist (SCL-90) was used to assess parental psychiatric status, rather than directly interviewing parents. Therefore, construction of the subscale seems to be arbitrary in symptom expression. Another limitation is the cross-sectional design, which may not necessarily represent the longitudinal developmental relationship among ADHD, ODD, aggression, and parental depression-related symptoms. In addition, most of the information was from the primary caregiver (mainly mothers), which may lead to sampling deviations. Finally, since the objective of this study was to explore the relationship between symptom severity in children and parental depression-related symptoms, we used the presence of any aggressive behavior in the CBCL, instead of a formal diagnosis of Conduct Disorder, which is a well-known diagnosis of childhood disruptive behavior symptoms. Evaluating aggressive behavior symptoms in the outpatient setting may be particularly challenging for some families because parents may refuse to report their child’s aggression symptoms during interview. Despite these limitations, we still suggest using the CBCL aggression scale as a tool to screen for these high-risk patients .This study used SEM to conceptualize the intergenerational transmission of ADHD in children and parental psychiatric symptoms. We first provide this view to understand how ODD moderately enhances the severity of ADHD symptoms. In summary, this study conceptualized symptoms of ADHD, ODD, and aggression interact with parental depression-related symptoms. It is important and requires low costs to routinely screen ADHD children with ODD and aggressive behavior using the CBCL in a clinical setting. ADHD children on the severe end of the psychopathologic spectrum require a more intensive biopsychosocial model of treatment to help them earlier in clinical psychiatric practice .


Background: To date, too little attention has been paid to monitoring and estimating the risk of incident multidrug-resistant tuberculosis (MDR-TB) among individuals with a previous tuberculosis history (PTBH). The purpose of this study was to assess the incidence of and risk factors for MDR-TB in those individuals.Methods: Between 2005 and 2020, a large, retrospective, population-based cohort study was performed in Hangzhou, China. A multivariable Cox regression model was used to evaluate independent predictors of incident MDR-TB among individuals with PTBH.Results: The incidence density of MDR-TB was 22.6 per 1,000 person-years  for individuals with PTBH. The incidence of MDR-TB increased significantly in individuals who• were under 60 years old.• were male.• had a history of direct contact.• came from low-income families.• worked in high-risk occupations.• lived in rural areas.• had a retreatment TB history.P < 0.05).• had an unfavorable outcome in their previous treatment (P < 0.05):In addition, we found that the following factors were significantly linked to the MDR-TB risk among individuals with PTBH , human immunodeficiency virus infection, unfavorable treatment outcomes, retreated TB history, non-standardized treatment regimens of retreatment TB patients, and duration of pulmonary cavities (DPC).• microbiological factors, such as duration of positive sputum culture.We also found that the 21–30 year age group, low family income, and PMTCF were significantly linked to incident MDR-TB only in males with PTBH, whilst the 41–50 year age group, extended treatment course, and DPC were significantly associated with female MDR-TB only.Conclusion: The incidence of MDR-TB was high, with a higher rate among subjects with a history of direct contact and unfavorable treatment outcomes. There was a gender difference in the incidence density and risk factors of MDR-TB among individuals with PTBH. Long-term monitoring and gender-specific risk-factor modifications should be given to individuals with PTBH. Multidrug-resistant tuberculosis (MDR-TB) is associated with severe and fatal respiratory disease in humans. To date, MDR-TB continues to be a serious global public health issue . AlthougContinuous monitoring indicates that some MDR-TB patients have a previous history of tuberculosis (PTBH)  , 5. The Our literature review concluded that a clear understanding of how previous TB cases contributed to future MDR-TB onset was still lacking. Previous reports focused primarily on the prevalence and predictors of MDR-TB in TB patients , 8–10. FTo reduce the morbidity and mortality of MDR-TB, the government and research institutions must address the potential disease burden and multifactor pathogenesis of MDR-TB among individuals with PTBH. We conducted an extensive, retrospective, population-based cohort study to determine the association between PTBH and incident MDR-TB in Hangzhou City, China, between October 1, 2005, and September 30, 2020. The purpose of this study was to (1) assess the incidence density of MDR-TB among individuals with PTBH, and (2) define specific risk factors for MDR-TB in this population.The study was conducted in Hangzhou, China. The study cohort included individuals with PTBH, including newly diagnosed TB history (NDTH) and retreated TB history (RTH) with drug-resistance test (DRT) who were recruited in the study between October 1, 2005, and September 30, 2020. For this study, we selected MDR-TB cases from all TB designated hospitals in Hangzhou City. MTB-TB cases were diagnosed by clinicians through Gene Xpert (GX) and traditional drug susceptibility testing (DST) .Subjects were divided into incident MDR-TB group  and non-incident MDR-TB group (such as the control group) based on DRT results for participants during the follow-up period. Subjects were selected if theyhad a history of TB but did not have MDR-TB during previous treatment episodes;were surviving during the study;had a history of TB treatment;had a confirmed treatment outcome; andwere available for follow-up.Subjects were excluded ifthey had a history of MDR-TB infection before the previous TB treatment episodes;no DST results were reported;they were a TB patient being treated ;no treatment outcome could be identified;they were not treated  .The starting date of our study referred to the starting date for previous anti-TB treatment. A patient's observation ending date was the end of the incident MDR-TB or September 30, 2020. Incident MDR-TB data for all years were collected between October 1, 2005, and September 30, 2020. Participants were observed until incident MDR-TB was recorded or until September 30, 2020. Treatment regimens (TRs) were formulated based on the treatment history of the TB cases.N = sample size; α = alpha ; β = 1– power ; Z statistics (Z) —Z statistics for confidence level; Zα = standard normal variate for level of significance; Zβ = standard normal variate for power or type 2 error as explained in earlier section; m is the number of control subjects per experimental subject; p0 is the probability of event in controls ; p1is the probability of an event in experimental subjects.To calculate the sample size of cohort study, we used the following formula :N= . The incThe present study mainly used the methods of traditional detection  for diagnosing TB cases from 2005 to 2014 . FurtherThe DST was conducted during follow-up. The detections of conventional DST and GX MTB/rifampicin of collected samples were performed at the TB Program Laboratory of Hangzhou Center for Disease Control and Prevention . We excluded MDR-TB cases with laboratory cross-contamination. Borderline TB drugs resistance was considered resistant.In this study, a binary variable including incident MDR-TB and non-incident MDR-TB categories was defined as the outcome variable. The analysis of subjects' characteristics was conducted by using the descriptive method. Continuous variables were described using the mean with standard deviation (SD) while categorical data were analyzed using percentage (proportion). Markov chain Monte Carlo (MCMC) method of multiple imputation (MI) was used to impute censored missing data in this study . The datUnivariable and multivariable Cox proportional hazards regression models were used to analyze the risk of incident MDR-TB among individuals with PTBH. Subjects who could not be evaluated during the study were excluded from the analysis. A univariable Cox regression analysis was conducted to identify the factors associated with incident MDR-TB. Variables were analyzed using hazard ratio (HR) generated using the same Cox regression analysis.P < 0.05 were included the Cox analysis using the backward stepwise method based on the minimum statistics of the Akaike information criterion. Variables with a P < 0.05 were considered statistically significant in the Cox analysis and included in the final Cox proportional hazards regression model.Subsequently, independent predictors associated with incident MDR-TB were evaluated using HR generated by a multivariable Cox regression model. All variables with a www.R-project.org, 2021) was used for all statistical analyses.R software  because the high-risk group of drug-resistant TB (such as TB patients with sputum smear–positive or unsuccessful treatment) was only asked to do the DRT  in China. Finally, 15,177 subjects were enrolled in this study. A flow diagram summarizing the identified eligible subjects is shown in Of the 13,551 subjects with PTBH, including 12,172 subjects who completed the follow-up study, 89 deaths, the loss to follow-up of 1,004 subjects, and 286 subjects with missing data, were included in the analytic cohort. Of the total, the vast majority was of the Han nationality . Most of the subjects had educational levels of high school and below  and low family incomes . The mean age in the study population was 50.96 ± 21.03, and the ratio of males to females was 2.25–1. The main reason for this was that TB occurred mainly in the elderly population or males in China  ]. In contrast, subjects with favorable treatment outcomes had the lowest incidence . The incidence of MDR-TB increased significantly for subjects under 60 years of age [crude relative risk 2.38 (95% CI 1.88–3.00)]. It also increased for those with a history of direct contact, male, low family income, high-risk occupation, rural areas, repeated treatment for TB, and unfavorable treatment outcomes ( < 0.05) .P < 0.05). The significant covariates were:sociodemographic characteristics, including the 21–30, 31–40, and 41–50 year age groups, male, a history of direct contact, low family income (LFI), high-risk occupation, high school education and below, residence in rural areas, and migrant individuals with PTBH.clinical characteristics, including passive modes of TB case finding (PMTCF), HIV infection, RTH, unfavorable treatment outcome, non-standardized TRs for re-treated TB patients (RTPs), extended treatment course (ETC), and duration of pulmonary cavities (DPC).microbiological characteristics, including frequencies of sputum culture, duration of positive sputum culture (DPSC), frequencies of sputum smear, and duration of positive sputum smear (DPSS).P > 0.05):The remaining 17 covariates were not associated with incident MDR-TB among individuals with PTBH .TB patients with severe infection.comorbidities.family members' management or self-management for TB patients.non-standardized TRs for newly diagnosed TB patients.frequencies of chest X-ray examination.duration of pulmonary miliary tubercles.duration of abnormal imaging findings.duration without chest radiological findings.duration of negative sputum culture.duration without sputum culture.duration of negative sputum smear.duration without sputum smear.To further explore the independent predictors of incident MDR-TB in individuals with PTBH, we conducted a multivariable Cox regression analysis. two age groups: 21–30 and 31–40 years.a history of direct contact.PMTCF.HIV infection.RTH.unfavorable treatment outcome.non-standardized TRs of RTPs.DPC.DPSC.P < 0.001).From this model, we could also see that a history of direct contact was the most striking predictor for incident MDR-TB in this population  and female MDR-TB   were related to incident MDR-TB in both genders . The mod< 0.001) .In this study, we conducted a 15-year retrospective cohort study to explore the incidence and risk factors of MDR-TB in individuals with PTBH. Our findings may provide more reliable evidence in developing prevention and control strategies for MDR-TB among individuals with PTBH. Because the pathogenic mechanism of MDR-TB has not been fully clarified, we can only decrease the risk of incident MDR-TB by modifying potential risk factors. Thus, we anticipate these results will be useful in reducing the disease burden of MDR-TB and improving risk monitoring and management of MDR-TB among individuals with PTBH.The incidence density of MDR-TB reported in this study is high, with 22.6 per 1,000 PYs from individuals with PTBH in Hangzhou, China. This finding broadly supports the work of other studies in this area linking MDR-TB with previously treated patients . One impIn our study, the highest incidence density was found in close contact with the MDR-TB case among individuals with PTBH. A possible explanation for this might be that most subjects did not use personal protective measures when they closely contacted the MDR-TB case . That stTo our best knowledge, this is the first study to examine the associations between MDR-TB and a broad range of potential risk factors  among a large sample of the Chinese population with PTBH. A notable finding in this study was that 10 independent predictors are associated with the increased risk of MDR-TB among individuals with PTBH. These findings were also reported in many previous studies of TB patients , 10, 29.Notably, this study also observed that RTPs are treated using non-standardized TRs , which increased the risk of incident MDR-TB dramatically. Thus, it can be seen that the acquired infection due to poor TRs during TB treatment is one of the main risk factors for MDR-TB. This association might be attributed to the increased chance of drug resistance with longer exposure to anti-TB drugs . FurtherSurprisingly, the present study found a relationship between the PMTCF  and incident MDR-TB. A possible explanation for this association is that the increasing risk of MDR-TB may originate from TB cases who were not diagnosed due to a failure of diagnostics at baseline diagnosis. Further analysis reveals that the main reason for this is that there is inadequate sputum smear and culture, the lack of DST, low sensitivity for detecting TB, and poor patient compliance. This reminds us that adequate medical support  should be considered by the government. The detection sensitivity for TB should be strengthened in the medical institution. In addition, a health communication schedule with the knowledge of TB diagnosis and treatment should be provided to increase patient compliance. Another possible reason is that delayed diagnosis and treatment of TB may increase the risk of MDR-TB . As far Most importantly, we used a stratified comparison to analyze gender differences in the predictors of MDR-TB that were found in individuals with PTBH. There were many differences in predictors for incident MDR-TB between the sexes. These findings might be attributed to certain gender disparities with sociodemographic, therapeutic and managed factors implicated in the development of MDR-TB , 36. In Finally, it should be reminded that the present study indicated that the risk of MDR-TB among individuals with PTBH was attributed mainly to acquired infection via exposure to a case of MDR in the household or community. The present finding showed that there was an urgent need to contain the epidemic of MDR-TB through potential intervention strategies  in individuals with PTBH. Moreover, the government would need to carry out a health education program on the knowledge of TB infection control in the household or community. Although these findings were also reported in many previous studies of TB patients –11. For Our studies had several limitations. First, it was a retrospective study, which might cause recall bias. To reduce recall bias, we collected the first follow-up records  after the diagnosis of MDR-TB through the TB information system. Secondly, we failed to include some long-established impact factors . Thirdly, there are some potential confounders like the psychological health of TB case, the stability, malabsorption, and quality of TB drug could not be controlled. Fourthly, our study might have a selection bias. For example, we might not include all MDR-TB cases, due to non-access or access at other, non-hospital facilities. To reduce selection bias, we have retrieved and collected medical records of MDR-TB cases from hospitals outside Hangzhou through the NTSS. However, we might not include MDR-TB cases with non-access or non-hospital facilities. According to our investigation, there was little for patients with non-access or non-hospital facilities in China. Fifth, the present study has the limitations of using electronic data . Finally, in order to reduce limitations, we performed additional measures such as the multicenter research, follow-up of the participants, and the inclusion of additional predictors. Moreover, we verified the validity and reliability of electronic data by using the face-to-face interview among 100 participants with random selection. Despite several limitations of this study, there are limited reports on impact factors of MDR-TB among individuals with PTBH. We feel these findings would instill some cognition on the novel strategy of prevention and control of incident MDR-TB.In conclusion, our study showed that, in individuals with PTBH, the incidence of MDR-TB is high, with higher rates among subjects with a history of direct contact and unfavorable treatment outcome. Enhanced attention and long-term monitoring should be given to patients who have been treated previously, especially those with a history of direct contact or previous unfavorable treatment outcomes. This study broadens our knowledge of MDR-TB as a growing public health issue in China and underscores the necessity of healthcare plans for the prevention of MDR-TB.provide a personal protection program of close contacts for MDR-TB.increase the rate of favorable treatment outcomes in TB cases.treat TB patients with standardized TRs .strengthen early detection of TB.modify gender-specific risk factors.We identified four primary risk factors for MDR-TB among individuals with PTBH. They included a history of direct contact, unfavorable treatment outcomes, non-standardized TRs for RTPs, and retreated TB history. We also found that there was a gender difference in risk factors of MDR-TB among individuals with PTBH. Therefore, we offer the following recommendations:Such measures are critical to preventing the spread of infection from MDR-TB in individuals with PTBH.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by the Ethics Committee of the Hangzhou Center for Disease Control and Prevention. Written informed consent to participate in this study was provided by the participants' legal guardian/next of kin.All authors contributed to the data analysis, prepared the draft report, revised the report, prepared the final report, gave final approval for the report to be published, and agreed to be accountable for all aspects of the study.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Background and aims: Current guidelines state that infliximab is contraindicated for the treatment of immune checkpoint inhibitor-related hepatitis (ir-hepatitis) due to the risk of inducing further liver damage. As this recommendation is largely based on the use of infliximab for rheumatologic diseases, we evaluated the efficacy and hepatotoxicity of infliximab in patients with steroid-refractory immune-related adverse events (irAEs). Methods: We retrospectively reviewed consecutive patients treated with infliximab for irAEs at Princess Margaret Cancer Centre. To assess hepatotoxicity, we compared the mean value of ALT, AST, and total bilirubin (BT) before and after infliximab treatment. We used logistic regression to assess factors associated with infliximab efficacy. Results: Between January 2010 and February 2019, 56 patients were identified. The median age of the patients was 63 (27–84) years. Colitis was the most frequent toxicity (66%), followed by pneumonitis (11%). Infliximab was used to treat ir-hepatitis in one patient. The median number of infliximab doses was 1 (1–3) and led to toxicity resolution in 43 (76%) patients. The mean ALT, AST, and BT levels before and after infliximab treatment were not statistically different. The patient treated for ir-hepatitis had a complete recovery, with no incremental liver toxicity. Conclusions: In this dose-limited setting, infliximab was effective in resolving irAEs and did not induce hepatotoxicity. Immune checkpoint inhibitors (ICI), such as anti-programmed cell death 1 (anti-PD1), anti-programmed cell death-ligand 1 (anti-PD-L1), and anti-cytotoxic T-Lymphocyte associated protein 4 (anti-CTLA-4) agents, act by disrupting inhibitory mechanisms of T-cell activation facilitating T-cell mediated cytotoxicity to cancer cells ,3. InfliIn this work, we examined the efficacy and hepatotoxicity of infliximab in a single institution series of cancer patients with steroid-refractory irAEs, with the aim to evaluate a possible revision of recommendations regarding the use of infliximab as a treatment for ir-hepatitis.https://www.R-project.org/ accessed on 8 March 2021), and a two-sided alpha level of 0.05 was used for determining statistical significance.Following Research Ethics Board approval, we retrospectively identified consecutive patients treated with infliximab for irAEs deemed to be steroid refractory by the attending physician. Patients received infliximab at Princess Margaret Cancer Centre between January 2010 and February 2019. Data regarding tumor type, toxicity, ICI regimen at irAE onset (monotherapy vs. combination of 2 ICIs), toxicity resolution, tumor response to ICI, and survival were collected. Demographic characteristics were summarized as means, medians, and proportions. We assessed hepatotoxicity by comparing mean values of ALT, AST, and total bilirubin (BT) between 0–4 weeks before and after infliximab therapy. When values were not available within 4 weeks, the nearest report was utilized. The Wilcoxon signed rank test was used to compare mean values. We used a logistic regression to investigate characteristics associated with irAE resolution. We performed multivariable analysis to adjust for potential confounders. Treatment efficacy assessed at the time of ICI toxicity onset was recorded as response rate (RR) per attending physician’s assessment and categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Overall survival (OS) was calculated from the date of the first infliximab dose to date of death or last follow-up. All of the statistical analyses were performed in R . The tumor type  and combination vs monotherapy ICI treatment  did not affect the likelihood of an infliximab response (The median number of infliximab treatments was one (1–3). Infliximab treatment led to the resolution of irAEs in 43 (76%) patients. Fourteen patients (25%) required more than one dose of infliximab, which were separated by a median of 40.5 (12–867) days. After multivariable adjustment, colitis was more likely to respond to infliximab compared to all of the other irAEs combined  occurred in 17 (31%) patients, and 46 (82%) patients did not resume ICI treatment post-infliximab treatment . In regaIn our study, infliximab was associated with the resolution of 76% of steroid-refractory irAEs in a real-world setting at an academic institution. The median number of infliximab infusions was one, which is in keeping with clinical experience . Within To the best of our knowledge, this is the first study that systematically examined the hepatotoxicity of infliximab in the treatment of steroid-refractory irAEs. Infliximab-induced hepatotoxicity has been described in patients with primary autoimmune conditions or IBD ,9. HowevInfliximab has been previously used to treat autoimmune hepatitis refractory to azathioprine in a cohort of 11 patients leading to a decrease in transaminases, without inducing any additional liver toxicity . In addiThere is no published evidence that infliximab induces hepatotoxicity in a dose-limited setting in oncology patients, or that infliximab may aggravate steroid-refractory ir-hepatitis. On the contrary, the recommendation to avoid infliximab in patients with ir-hepatitis may compromise the optimal treatment of this irAE. The current immunosuppressants of choice for ir-hepatitis—MMF and azathioprine—require tapering, which may delay the re-initiation of ICI treatment for metastatic disease, thus potentially compromising the treatment’s effectiveness. In contrast, infliximab is associated with a rapid kinetics of response and may allow for the earlier re-initiation of ICI treatment . NeverthIn terms of ICI effectiveness, our data is consistent with a report by Burdett et al. in which a cohort of 19 patients required additional immunosuppression (refractory to steroids) for irAEs and an overall response rate to ICI of 35% and a median OS of 9.4 months was found . OverallThe limitations of this work include its retrospective nature, the absence of steroid-refractory disease confirmation in all patients , and the low rate of ir-hepatitis treated with infliximab (one patient). Nonetheless, to date, this is the first study systematically assessing the hepatoxicity of infliximab in the treatment of irAEs and the largest cohort assessing outcomes of patients treated with infliximab in the setting of ICI-induced steroid-refractory irAEs.In our cohort, infliximab was associated with a high rate of resolution of irAEs and was not associated with hepatoxicity development. A patient with ir-hepatitis that was treated with infliximab had his toxicity resolved with no recurrence. Infliximab may be an option for the treatment of ir-hepatitis and should be tested in a randomized trial to determine its efficacy and safety in the dose-limited context of ICI-related toxicity.


Introduction: HIV self-testing (HIV-ST) is an innovative strategy to increase HIV case identification. This analysis shares the outcomes of HIV-ST implementation within the Zimbabwe HIV Care and Treatment (ZHCT) project for the period October 2018–March, 2020.Materials and Methods: We extracted HIV-ST data for the period October 2018 to March 2020 from the project database and assessed (1) the proportion of reactive HIV-ST results; (2) the concordance between reactive HIV-ST results against rapid confirmatory HIV tests using Determine™ and Chembio™ in parallel; and (3) the monthly contribution of HIV-ST to total HIV positive individuals identified within project. The Chi-square test was used to assess for statistical differences in HIV positivity between age groups, by sex and district; as well as the difference in HIV positivity between the HIV-ST and index and mobile testing strategies.Findings: Between October 2018 and March 2020, the ZHCT project distributed 11,983 HIV-ST kits; 11,924 (99.8%) were used and 2,616 (21.9%) were reactive. Of the reactive tests, 2,610 (99.8%) were confirmed HIV positive giving a final positivity rate of 21.9%, and a concordance rate of 99.8% between the HIV-ST results and the confirmatory tests. Proportion of reactive results differed by age-groups (p < 0.001); with the 35–49 years having the highest positivity rate of 25.5%. The contribution of HIV-ST to total new positives increased from 10% in October 2018 to 80% at the end of March 2020 (p < 0.001). Positivity rates from HIV-ST were significantly different by age-groups, sex and district (p = 0.04). Additionally, index and mobile testing had a higher positivity rate compared to HIV-ST (p < 0.001).Conclusion: The ZHCT project has successfully scaled up HIV self-testing which contributed significantly to HIV case finding. Countries should consider using the lessons to scale-up the intervention which will contribute in reaching under-served and undiagnosed populations. In 2016, Zimbabwe had an estimated 1.2 million PLHIV, and an adult prevalence of 14.1% . As of 2HIV self-testing (HIV-ST) is an innovative and high-impact strategy to increase HIV-case identification . It offeIn this study conducted in Zimbabwe, HIV-ST kits were introduced within an established project, the 6-year PEPFAR/USAID funded Zimbabwe HIV Care and Treatment (ZHCT) led by FHI 360, which was implementing HIV testing through (i) mobile clinics in targeted hotspots and (ii) index case testing at homes since 2016. HIV-ST was offered to sexual contacts of newly tested HIV positive individuals referred as index cases at home, and also distributed at hotspots during targeted mobile testing. In this analysis, we assessed the proportion of self-testers screened and confirmed HIV-positive, following a multi-year, large scale implementation of HIV-ST. Results from this real-world approach to scaling up HIV-ST will help demonstrate the approaches of implementing HIV-ST in order to realize its utility in case finding.Using programmatic data, we evaluated HIV-ST uptake and HIV-positivity rates within the ZHCT project by month from October 2018 to March 2020.Through the ZHCT project, HIV-ST was implemented in eight Districts namely Mwenezi, Kwekwe, Makoni, Gutu and Gokwe South, Zaka, Chivi and Mutasa. The project deliberately scaled up HIV-ST in a phased rollout starting with three districts  as a pilot in October 2018. Two districts were added in March 2019 (Gokwe South and Gutu) before further expansion to all eight districts in October 2019. Kwekwe and Makoni Districts are partly urban and partly rural while the rest of the districts are rural. Two of the districts, Kwekwe  and Chivi (14.19%) have an HIV prevalence which is higher than the national average of 14.1%. Mutasa District has the lowest prevalence of 9.46% amongst all the eight districts.After the first 5 months, further rollout of HIV-ST was informed by early lessons from the three-district pilot. For example, because more reactive results were among males, subsequent distribution targeted men; and because most people (75%) who received tests kits during the pilot needed assistance, we offered support more during subsequent rollout. Finally because preliminary data showed that HIV-ST reduced the number of HIV tests conducted by nurse testers thereby reducing workload, we used this information to promote HIV-ST and get further buy in from staff. Prior to introduction of HIV-ST, the ZHCT project had been implementing index testing in the community and targeted mobile testing since 2016. Clients reached were tested by project nurse testers  using rapid HIV Type 1 antibody testing in line with the national HIV testing algorithm. To reduce the number of clients directly tested by nurse testers, the project introduced screening through HIV-ST using the OraQuick test kit  ahead of HIV Type 1 antibody testing within its index and mobile testing strategies.Ahead of index testing, HIV-ST was provided at household level or at targeted hotspots to the sexual contacts of index cases that were aged 16 years and above who were followed up by community outreach workers. Index cases were clients who would have recently returned a confirmed positive HIV test and identified from HIV testing registers at health facilities within the supported districts; and any clients who newly tested HIV positive through index and mobile testing at home or targeted hotspots within the ZHCT project. All index cases whether identified at the facility or community were listed in the index case testing (ICT) register which were based at facility level. Outreach workers [community-based expert clients and described here ] extractThe outreach workers prepared contacts of index cases by making appointments with those who agreed to be tested for HIV, with HIV-ST being offered as the initial test. The date, time, and place for meeting for HIV-ST distribution and testing were recorded in the appointment diaries. The outreach workers, where requested, assisted clients to conduct the HIV-ST and/or interpreted the result. They also collected information on prior HIV testing, demonstrated how the test is done and how the results are interpreted. Clients who did not require direct assistance were given written instructions as well as a video which they could play for guidance for those with compatible phones. After the test, the community outreach workers obtained the results from the clients which they reported daily to the nurse tester responsible for that community. The outreach worker will then contacted those who would have returned a reactive result and book an appointments for a confirmatory test which was done at the household level by the nurse tester. The HIV confirmatory tests are conducted in accordance with national guidelines , using DHIV-ST is also implemented during mobile testing at targeted hot spots, mainly farming and mining communities, and long-distance truck-ins where target populations were famers, artisanal miners, female sex workers and truck drivers. Outreach workers made available HIV-ST kits to individuals who they would have considered at high risk of HIV, based on a screening tool that assessed prior HIV testing and results, assessed clinical symptoms , behaviors or social practices and those who belonged to specific social networks. Apart from those determined as eligible using the screening tool, HIV-ST was also made available on request to other adults found within hotspots. Outreach workers, who are expert patients used their community intelligence and their knowledge on HIV clinical symptoms to initiate conversation with targeted population groups. Targeted and consenting individuals were given HIV-ST kits, instructed how to test and those with a reactive result were confirmed by a project nurse tester as described above. However, the nurse tester was always part of the team that conducted outreaches at hotspots for testing.Children were not offered HIV-ST but were offered HIV Type 1 antibody test conducted by nurse testers. Additionally, adults who decline HIV-ST were directly tested by nurse testers as part of index or targeted mobile testing. Service providers in this project received training on the WHO Five Cs of HIV testing to assure confidentiality . Consent was sought at the time of booking an appointment, with the client given the opportunity to suggest the best time, day, and place for HIV testing. Privacy was ensured by allowing them to choose alternative private and suitable best places for the testing.During delivery of services, outreach workers compiled data on HIV-ST kits distributed and recorded all clients in the HIV-ST register. Following confirmatory testing for clients, the information was captured in the community HTS register. The district Monitoring and Evaluation Officer (MEO) aggregated data from the HIV-ST registers every month and entered it into the ZHCT project database, a DHIS 2 aggregate-based health information system.Data for this analysis was extracted from the project DHIS 2 aggregate system. The variables extracted were number of HIV-ST kits distributed, HIV-ST results returned, HIV-ST results reactive, and HIV-ST reactive and confirmed by nurse tester. We also extracted HIV testing data for children who were not eligible for HIV-ST and data for adults who declined HIV-ST but received testing from nurse testers through index or targeted mobile testing. The data extracted was disaggregated by age and sex, and it was sent to the district MEO for validation.We started our analysis by assessing the proportion of confirmed HIV positive results following an HIV-ST screening test disaggregated by age-group, sex and district. We also assessed the changes in proportion of reactive HIV-ST results by month since the start of implementation in October 2018 until March 2020, as well as the monthly contribution of HIV-ST to overall case identification within the ZHCT project catchment area. Variables were summarized as frequencies and percentages and Chi-square tests were used for assessing differences in HIV positivity rates by age-group, sex, and month for each test modality separately as well as comparing within the groups. SPSS was used for data analysis .A non-research determination was granted by the Medical Research Council of Zimbabwe , the local institutional review board which reviews research involving human subjects in Zimbabwe. Analysis for this manuscript used aggregate data routinely collected and reported by the ZHCT project, with no personal identifying information. None of the authors accessed patient-level data. Consent with each individual person for testing was obtained following national guidelines during implementation. None of the data can be linked back to the clients. Validation of the data was through the district monitoring and evaluation officers of which none of them are co-authors.The ZHCT project is funded by the United States Agency for International Development under Cooperative Agreement No. AID-613-A-00009 and implemented in collaboration with the Ministry of Health and Child Care Zimbabwe. The funder did not play a role in interpretation of the results.During the period October 2018–March 2020, the ZHCT project distributed a total of 11,983 HIV-ST kits, identifying 2,610 HIV positive individuals. Of the 11,983 HIV-ST kits distributed, 99.5%  were used and had results returned to the health care workers. Among those who returned HIV-ST results, 22.3%  were reactive and 2,610 were confirmed HIV positive by a trained health care worker using the national testing algorithm. This gave a concordance rate of 99.8%  between the HIV-ST positive results and the confirmatory testing an HIV positivity rate of 21.9% .p < 0.001. More females  accessed HIV-ST and had a significantly higher positivity rate  compared to males , p = 0.04. Over a third  of clients who received HIV-ST were in the 35–49 age group. This age group also accounted for 39%  of the newly diagnosed HIV positive and had the highest positivity rate, 25.5%  compared to other age groups. Positivity rate varied across the different age groups, p < 0.001.When comparing districts, the highest positivity rate was reported in Zaka District  but more HIV positive individuals were identified in Kwekwe district , at a positivity rate of 29.5% during the study period. The difference in HIV positivity from HIV-ST varied across districts, The number of HIV-ST kits distributed gradually increased from an average of 200 kits distributed per month in the first 6 months, to more than 1,000 per month in November 2019. The proportion of reactive results averaged 20% in the first 6 months, declining in March 2019 before gradually increasing month-on-month from June 2019 to a high of 30% in March 2020.Overall, positivity rates from index and targeted mobile testing were higher at 34.7%  and in some age groups nearly double those of HIV-ST during the same period. This trend was the same for both age and sex. Within each age-group, index testing and mobile testing were associated with higher HIV positivity rates compared to HIV-ST. This association was statistically significant for all age-groups except among those <15 years .Over time, the contribution of HIV-ST to HIV positives within the ZHCT project increased. Between October 2018 and July 2019, HIV-ST contributed around 25% of the total newly diagnosed cases within the project per month  and incrThe ZHCT project successfully scaled up HIV-ST and through this approach identified many HIV positive individuals who could have previously been undiagnosed. The high concordance rate of 99.8% between HIV-ST and confirmatory testing is reassuring and goes to show that HIV-ST is an accurate and effective strategy for HIV diagnosis. HIV-ST enabled over 2,600 individuals to know their HIV positive status. These findings are important for Zimbabwe and other countries that are close to reaching or have exceeded the 1st 95, where testing approaches need to be nuanced and better targeted. For these countries, HIV-ST should be scaled-up. In Zimbabwe, a gradual implementation allowed the project teams to learn and establish systems to monitor implementation before scale-up to other districts. By so doing, HIV-ST was targeted better and as result, HIV positivity improved month-on-month, and contributed more by month and over time to the overall number of newly diagnosed HIV positive individuals within the project. HIV-ST would reduce the workload for HCW, allowing them to spend more time on those who need care.Multi-country evidence confirms high feasibility, acceptability and accuracy of HIV-ST across many delivery approaches, venues and populations, with minimal risk of harm –8, 14. EThis analysis from the ZHCT project, using routinely collected data has demonstrated how HIV-ST can be optimized at project level, generating lessons over time and targeting it to high-risk individuals. Over time, HIV positivity increased as did its overall contribution to total positives identified. Although the positivity from HIV-ST was lower than from index and targeted community testing in our program, it was at par or similar to that reported in other approaches . We attrA major concern for HIV-ST is the major drop off between test kit distribution, return of used self-test kits and confirmatory HIV testing . We achiOur findings add to the body of evidence supporting the benefits of HIV-ST in general and how it has been used successfully to reach undertested populations. The potential of HIV-ST to increase access to and uptake of HIV testing has been highlighted  within aThis study had some limitations. Firstly, implementation was stopped for 3 months at the start of COVID-19. We missed an opportunity to further scale-up and collect data which would have demonstrated the utility of HIV-ST during COVID-19 or similar emergencies. Secondly, we did not test any individuals who screened non-reactive on HIV-ST to determine if there were any false negatives under field conditions. However, OraQuick® HIV self-test kits have been shown to be very accurate with a specificity of 99.9% and a specificity of 93% . AdditioOur findings on the contribution of HIV case finding using HIV-ST have several implications during this COVID-19 period where major disruptions to healthcare delivery have occurred and health systems have become overwhelmed. Implementation of physical distancing measures and movement restrictions has further reduced access to health services  while thFHI 360, through the ZHCT project has successfully implemented and scaled-up HIV-ST, achieving high return and positivity rates among those tested. These results demonstrate the potential of HIV-ST to supplement other testing modalities toward the achievement of the UNAIDS 95-95-95 goal. HIV-ST should be scaled-up to ensure that the trajectory for countries to reach epidemic control does not stall.The data analyzed in this study is subject to the following licenses/restrictions: The data sets are available on request from the project. Requests to access these datasets should be directed to Auxilia Muchedzi, amuchedzi@fhi360.org.Ethics approval was not required for this study, as according to United States federal guidelines and guidance from the FHI 360's Office of International Research Ethics, this analysis did not constitute human-subjects research. Additionally, a non-research determination was granted by the Medical Research Council of Zimbabwe , the local institutional review board which reviews research involving human subjects. Written informed consent from the participants was not required to participate in this study in accordance with the national legislation and the institutional requirements.AM, MM, and TTaf conceived and designed the manuscript. FM, TM, HS, RD, TZ, TTap, TS, TN, and GN wrote the manuscript. MB participated in the revision of the manuscript. All authors made substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data, critically revised manuscript and approved the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Early recognition and prevention of in-hospital cardiac arrest (IHCA) have played an increasingly important role in the chain of survival. However, clinical tools for predicting IHCA are scarce, particularly in the emergency department (ED). We sought to estimate the incidence of ED-based IHCA and to develop and validate a novel triage tool, the Emergency Department In-hospital Cardiac Arrest Score (EDICAS), for predicting ED-based IHCA.In this retrospective cohort study we used electronic clinical warehouse data from a tertiary medical center with approximately 100,000 ED visits per year. We extracted data from 733,398 ED visits over a seven-year period. We selected one ED visit per person and excluded out-of-hospital cardiac arrest or children. Patient demographics and computerized triage information were included as potential predictors.A total of 325,502 adult ED patients were included. Of these patients, 623 (0.2%) developed ED-based IHCA. The EDICAS, which includes age and arrival mode and categorizes vital signs with simple cut-offs, showed excellent discrimination  and maintained its discriminatory ability  in cross-validation. Previously developed early warning scores showed lower AUROC  when applied to our ED population.In-hospital cardiac arrest in the ED is relatively uncommon. We developed and internally validated a novel tool for predicting imminent IHCA in the ED. Future studies are warranted to determine whether this tool could gain lead time to identify high-risk patients and potentially reduce ED-based IHCA. In-hospital cardiac arrest (IHCA) has increasingly been recognized as a separate entity from out-of-hospital cardiac arrest (OHCA).5There has been increasing interest in research on ED-based IHCA.In this study, we aimed to estimate the incidence of cardiac arrest in the ED and to develop and validate a novel triage tool for predicting IHCA in the ED.We conducted a retrospective cohort study using data from the integrated Medical Database of National Taiwan University Hospital (NTUH). This database serves as a central clinical data warehouse for all electronic health records (EHR) in the healthcare system , including inpatient, outpatient, and ED records. The electronic database houses a variety of information, including demographics, diagnosis, treatment, imaging, laboratory, prescription, nursing, billing, and administrative data. The database is maintained and updated by dedicated research personnel and has been used for previous research studies.16For the current study, we retrieved seven years of ED data from the main hospital between January 1, 2009 and December 31, 2015. The NTUH main hospital is a tertiary academic medical center with approximately 2400 beds and 100,000 ED visits per year. The ED also manages an ED observation unit (EDOU), which is staffed by emergency physicians. This study was approved by the NTUH Institutional Review Board, which waived the requirement for patient informed consent.We extracted data from 733,398 ED visits over the seven-year period, including those in the EDOU. For repeat visits, we selected the last visit per patient to maximize statistical power for cardiac arrest analysis. Because cardiac arrest may result in death during an ED visit that became the last visit for the patient. We further excluded patients aged <18 years or those who presented with OHCA. The OHCA population was identified by the structured chief complaint list in the computerized triage system. Few OHCA patients may have a return of spontaneous circulation prior to ED arrival. These patients were still excluded from our study, as we focused on the IHCA population. The subject selection process is shown in What do we already know about this issue?Early recognition of in-hospital cardiac arrest (IHCA) is important in the chain of survival; however, clinical tools for predicting IHCA in the ED are scarce.What was the research question?We sought to develop and validate a novel triage tool for predicting ED-based IHCA.What was the major finding of the study?The Emergency Department In-hospital Cardiac Arrest Score (EDICAS) was developed and internally validated for predicting imminent IHCA in the ED.How does this improve population health?Future studies are warranted to determine whether this novel tool could potentially reduce ED-based IHCA.We extracted patient demographics and the following time-stamped clinical information at triage: chief complaint on presentation; mode of arrival; transfer status; vital signs ; and levels of consciousness coded using the Glasgow Coma Scale (GCS). The data extractors were hospital information technology engineers who were blinded to the study hypothesis. After investigator meetings, data underwent rigorous electronic cleaning, and invalid data were set to missing values . For example, we defined that the respiratory rate ranged between 0–50 breaths per minute.International Classification of Diseases, 9th Revision, Clinical Modification.19At ED triage, when assessing levels of consciousness the triage nurse also indicated whether there was an acute change in levels of consciousness from baseline on the structured EHR. Pain scores were evaluated on a numeric rating scale (NRS) of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable. We further categorized the NRS scores into no (0), mild (1–3), moderate (4–6), and severe (7–10) pain.We extracted the five-level computerized Taiwan Triage and Acuity Scale (TTAS), which contains information on 179 structured chief complaints. Based on computerized algorithms, the TTAS classifies patients in the following order of acuity: level 1, resuscitation; level 2, emergent; level 3, urgent; level 4, less urgent; and level 5, non-urgent. The TTAS was adapted from the Canadian Triage and Acuity Scale and has been validated against hospitalization, length of stay in the ED, and resource utilization.20We identified the primary outcome measure, ED-based IHCA, via a cardiopulmonary resuscitation (CPR) code . Patients with do-not-resuscitate (DNR) status were not counted as treated cardiac arrests. Per the consensus guidelines on reporting IHCA,P <0.10 in bivariate analyses were considered for inclusion in the multivariable analysis. To determine the functional form and cut-off points used for continuous predictors, we grouped these predictors into bins of equal width to see whether log odds of ED-based IHCA changed at certain inflection points. Inflection points were also chosen based on inspection of locally weighted least squares regression smoother. After constructing a full multivariable model, we selected a parsimonious model using the least absolute shrinkage and selection operator. This operator uses a shrinkage parameter to perform the variable selection by penalizing the coefficients of less strong predictors, thereby mitigating potential model overfitting.Summary statistics are presented as proportions , means (with standard deviations), or medians (with interquartile ranges). We examined bivariate associations using Student’s t-tests, Mann-Whitney tests, chi-square tests, and chi-square trend tests, as appropriate. We used complete-case analysis, as the vast majority of variables in the analysis had few or no missing values except for respiratory rate. We used multivariable logistic regression to examine the independent factors associated with ED-based IHCA. Variables associated with the primary outcome measure at We used the variables and their odds ratios (OR) in the condensed model to derive an ED In-hospital Cardiac Arrest Score (EDICAS). The eight-item composite score ranges from 0–13, in which GCS and acute change in consciousness may be used interchangeably. Sensitivity and specificity were calculated with varying cut-off points. We evaluated the discriminatory ability of the final models by using the area under the receiver operating curve (AUROC). The CI of the AUROC was calculated using the DeLong method.P-values are two-sided, with P <0.05 considered statistically significant.All OR and beta-coefficients are presented with 95% CIs. We performed all analyses using Stata 16.0 software . All Of 733,398 ED visits during the seven-year study period, 405,891 unique patient visits were included. After excluding children aged <18 years or patients with OHCA, we included 325,502 patient visits in the analysis. The patient selection process is shown in Multivariable analysis showed that factors associated with an increased risk of ED-based IHCA included older age, arrival by ambulance, transfers, day and night (vs evening) shifts, low systolic blood pressure (<90 millimeters of mercury [mm Hg]), brady- (<60/minute) and tachycardia (>90/minute), low oxygen saturation (<95%), tachypnea (≥22/min), hypothermia (<36°C), and triage levels 1 and 2 . By contP <0.001 for either one vs EDICAS) when applied to our ED population ; brady- (<60/minute [min]) and tachycardia (>90/min); low oxygen saturation (<95%); tachypnea (≥22/min); hypothermia (<36°C); and GCS<15 . This copulation .Based on the condensed model, we developed a predictive tool, the EDICAS . The eigIn this ED-based study of 325,502 patients, we found that a relatively small fraction of patients (2 in 1000) developed IHCA. A novel and simple eight-item triage score predicted imminent ED-based IHCA with excellent discriminatory power, with an AUROC outperforming previous early warning scores. Future prospective studies are warranted to replicate our results and to determine whether the implementation of this tool could actually gain lead time to identify high-risk patients and potentially reduce devastating, ED-based IHCA events.Despite the catastrophic nature of IHCA, the epidemiology of IHCA remains largely unknown worldwide.Regarding seasonal variation, the incidence of ED-based IHCA in our study peaked in the winter, paralleling that in the UK study.As shown in recent resuscitation guidelines,We developed and validated an ED-specific, eight-item EWS that we call the EDICAS, which is intended to be used at ED triage to augment traditional triage in predicting imminent cardiac arrest. After a stringent selection of the strongest predictors, the condensed model comprised older age, arrival mode, and primarily vital signs. Some of the original predictors, such as time of presentation and pain score, were selected out due to concerns of model overfitting. The inclusion of older age in the EDICAS highlights the importance of age in the triage process33We defined an EDICAS of 3–5 as a medium-risk category, which may be used to flag patients needing an urgent physician assessment, particularly those who are initially triaged to lower levels. We also defined an EDICAS of 6 or above as a high-risk category as it corresponded to a specificity of 98% and a positive likelihood ratio of 12.7, both of which could raise the probability of finding rare ED-based IHCA. Similar to the recommendations from the NEWS Working Group,35This study has some potential limitations. First, this was a single-center study at a tertiary medical center, and our findings may not be generalizable to hospitals of different settings. Second, we did not externally validate our prediction model, and further studies are needed to evaluate our model performance in different patient populations. Third, our predictive tool is intended to be used at ED triage; whether a continuous assessment of EDICAS would also be predictive of ED-based IHCA requires further research.In this large study of 325,502 adult ED patients, 0.2% developed IHCA. We developed and validated a novel eight-item ED triage tool for predicting imminent IHCA in the ED with excellent discriminatory ability. While promising, our results need to be replicated in other EDs. Further research is also warranted to test whether this tool could gain lead time to identify high-risk patients and potentially reduce ED-based IHCA and associated deaths.


Immunotherapy has been focused on by many oncologists and researchers. While, due to technical biases of absolute quantification, few traditional biomarkers for anti-PD-1 immunotherapy have been applied in regular clinical practice of non-small cell lung cancer (NSCLC). Therefore, there is an urgent and unmet need for a feasible tool—immune to data source bias—for identifying patients who might benefit from ICIs in clinical practice. Using the strategy based on the relative ranking of gene expression levels, we herein proposed the novel BRGP index (BRGPI): four BRGPs significantly related with progression-free survival of NSCLC patients treated with anti-PD-1 immunotherapy in the multicohort analysis. Moreover, stratification and multivariate Cox regression analyses demonstrated that BRGPI was an independent prognostic factor. Notably, compared to PD-L1, BRGPI exerted the best predictive ability. Further analysis showed that the patients in the BRGPI-low and PD-L1-high subgroup derived more clinical benefits from anti-PD-1 immunotherapy. In conclusion, the prospect of applying the BRGPI to real clinical practice is promising owing to its powerful and reliable predictive value. Non-small cell lung cancer (NSCLC) is related with the highest cancer-related mortality worldwide. It features a high mortality rate and only 19% of those diagnosed with NSCLC will be alive 5 years later . Over thBiomarkers predicting immunotherapy benefits have recently emerged, including those correlated with the inflammatory tumor microenvironment, such as PD-L1 protein expression in cancer and antigen-presenting cells, and markers demonstrating the increase of tumor-specific neoantigens like tumor mutational burden (TMB) , 15. PD-Opening gene expression sources in public databases enable the development of reliable gene-based biomarkers for cancer research. Some gene expression-based signatures have been proposed for diagnosis and treatment planning for patients with NSCLC. Unfortunately, few of them have been applied in regular clinical practice because of issues such as overfitting in small training datasets and insufficient validation , 23. GenThe objective of this study was to construct a predictive signature based on benefit-related gene pairs (BRGPs)—represented by four BRGPs significantly related with progression-free survival (PFS)—in NSCLC patients who received the treatment of ICIs. Considering all these decisive immune genes that may influence the response to ICIs, we constructed a predictive pattern to remedy the deficiencies of existing biomarkers.We enrolled 74 patients with advanced NSCLC who received the treatment of ICIs in three independent cohorts. We recruited 35 patients from GSE93157 as the signature-training dataset. We then collected 20 patients from the GSE136961 cohort and 19 patients from the CICAMS cohort for signature validation of the prognostic model. The analysis pipeline of the construction and validation of benefit-related gene-pair index (BRGPI) is shown in http://www.ncbi.nlm.nih.gov/geo), and corresponding clinical information were obtained. The CICAMS cohort included 19 LUAD patients who received the treatment of ICIs at the Cancer Hospital/Institute, Chinese Academy of Medical Sciences  from April 2016 to July 2019. Moreover, formalin fixation paraffin embedding (FFPE) specimens of all enrolled patients prior to the initiation of ICIs were available. According to the Response Evaluation Criteria in Solid Tumors, version 1.1, the tumor response to ICIs was categorized as a complete response (CR), a partial response (PR), stable disease (SD), or progressive disease (PD). Noticeably, non-PD refers to the patients with CR, PR, or SD -estimated count data of the GSE93157 cohort and transcripts per million (TPM) data of the GSE136961 cohort from the Gene Expression Omnibus  antibody , an anti-human vascular endothelial growth factor A (VEGFA) antibody , an anti-human cyclin dependent kinase 1 (CDK1) antibody , an anti-human C-X-C motif chemokine ligand 9  antibody , an anti-human major histocompatibility complex, class II, DO beta (HLA-DOB) antibody , an anti-human LCK proto-oncogene, Src family tyrosine kinase (LCK) antibody , an anti-human interleukin 12A (IL-12A) antibody , and an anti-human T-box 21 (TBX21) antibody . Importantly, all IHC slides were assessed based on the evaluation method of the previously published study  and R software (version 3.6.0).Survival was assessed using the log-rank test and Kaplan-Meier analysis. Differences between the two groups were evaluated using Chi-square or Mann–Whitney U test. Notably, all statistical analyses were double-sided, and statistical significance was defined as P values less than 0.05.via the univariate Cox proportional hazards regression modelling. We then used multivariate Cox regression to determine gene pairs with the best prognostic performance to obtain the optimized and practical value. According to the minimum criteria, a novel prognostic signature with four BRGPs was proposed  were chosen  formula : BRGPI sFurthermore, we calculated the AUC value of the ROC and performed Kaplan–Meier survival analysis to validate the predictive performance of the novel BRGPI. The results showed that the AUC value at one-year PFS was 0.842  and BRGPI-high group (n=9) according to the training cohort’s cut-off value. By constructing a ROC curve, the AUC value at a progression-free survival was 0.869. This demonstrated BRGPI had an accurate predictive value for patient prognosis in the testing dataset  for each gene pair. We then calculated the BRGPI score of each patient using the mentioned above formula. Representative staining images of eight genes from the BRGPI model are shown in To verify the reliability of the BRGPI considering pathology for NSCLC, we performed Kaplan–Meier survival analysis in patients grouped by pathological type for each of the three independent cohorts. Notably, the BRGPI remained highly prognostic for the immunotherapy outcome. In the multicohort analysis—in patients with both non-squamous and squamous-cell NSCLC who were treated with anti-PD-1 immunotherapy—those in the BRGPI-low groups had better PFS than those in the BRGPI-high groups  and four BRGPs were selected using multivariate Cox regression to calculate the BRGPI. Remarkably, BRGPI can act as an independent prognostic factor and help identify patients in different response groups. By external validation, the GSE136961 cohort also supports the predictive value of BRGPI. Moreover, we further validated the discriminatory performance of BRGPI using protein expression values, acquired using the IHC technique, in an independent CICAMS cohort. The IHC method might be more suitable and convenient for clinical application because of its simplicity and low cost. Considering pathological type—whether non-squamous or squamous-cell NSCLC—patients in BRGPI-low groups had better PFS times than those in the BRGPI-high groups. This indicated that the BRGPI signature is promising preliminary value. We also investigated the association of BRGPI and PD-L1 expression. The predictive ability of PD-L1 was poor in the analyses of the CICAMS cohort. This might be because multiple immune-related genes may better represent the complex immune microenvironment. When patients were grouped by the PD-L1 expression, we found that—no matter PD-L1 expression level—the BRGPI-low subgroup showed longer PFS. Further analysis demonstrated that the patients in BRGPI-low and PD-L1-high subgroup derived more clinical benefit while the BRGPI-high and PD-L1-low subgroups derived less clinical benefit. The combination with PD-L1 underscores the reliability and predictive validity for predicting immunotherapy response, in addition to clinical utility.BRGPI was constructed by pairwise comparison and the score of each patient was calculated based on his or her own corresponding gene expression. Thus, our prognostic model can avoid the batch effect or bias inherent to different measurement platforms. Additionally, there is no need for data normalization. According to these advantages—and considering the same formula and cut-off value in the training set—this method can be translated into clinical practice as a tool for predicting a patient with NSCLC’s response to immunotherapy.Nevertheless, the limitations of this study should be acknowledged. First, the size of the three datasets was relatively small, despite our attempts to enroll as many datasets as possible, and inclusion of the GEO and CICAMS cohorts increase the rigor of our biomarker validation process. Second, because this was a retrospective study, further validation of this signature should be conducted in prospective paradigms.In conclusion, this study was the first to highlight a BRGPI based on benefit-related gene pairs. This method may emerge as a powerful prognostic tool for immunotherapy and help further optimize the ICI paradigm of personalized medicine for patients with advanced NSCLC.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/The Ethics Committee of CICAMS approved the human tissue study protocol, and the approval number was 20/242-2438. The patients/participants provided their written informed consent to participate in this study.CL and SW designed the study, performed experiments, analyzed data, and wrote the manuscript. SZ, FX, ZC, XF, YW, and XQ performed experiments and analyzed data. JH and NS conceived and designed the study and wrote the manuscript. All authors contributed to the article and approved the submitted version.This work was supported by the National Key Basic Research Development Plan (grant number 2018YFC1312105), the National Natural Science Foundation of China , the Graduate Innovation Funds of Peking Union Medical College (grant number 2019-1002-06), the National Key R&D Program of China , the CAMS Innovation Fund for Medical Sciences , and the Fundamental Research Funds for the Central Universities (grant number 3332018070).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Despite the ample progress made toward faster and more accurate Monte Carlo (MC) simulation tools over the past decade, the limited usability and accessibility of these advanced modeling tools remain key barriers to widespread use among the broad user community.An open-source, high-performance, web-based MC simulator that builds upon modern cloud computing architectures is highly desirable to deliver state-of-the-art MC simulations and hardware acceleration to general users without the need for special hardware installation and optimization.We have developed a configuration-free, in-browser 3D MC simulation platform—Monte Carlo eXtreme (MCX) Cloud—built upon an array of robust and modern technologies, including a Docker Swarm-based cloud-computing backend and a web-based graphical user interface (GUI) that supports in-browser 3D visualization, asynchronous data communication, and automatic data validation via JavaScript Object Notation (JSON) schemas.The front-end of the MCX Cloud platform offers an intuitive simulation design, fast 3D data rendering, and convenient simulation sharing. The Docker Swarm container orchestration backend is highly scalable and can support high-demand GPU MC simulations using MCX over a dynamically expandable virtual cluster.http://mcx.space/cloud.MCX Cloud makes fast, scalable, and feature-rich MC simulations readily available to all biophotonics researchers without overhead. It is fully open-source and can be freely accessed at  First, the adoption of massively parallel computing and graphics processing units (GPUs) have greatly improved the computational efficiency of conventional MC simulations, shortening the simulation run-time by tens to hundreds fold on a modern GPU.,Compared to many published traditional research codes that were developed as single-release static software, an increasing number of new MC software packages have started tackling the challenges of usability and long-term maintainability. Many of these projects openly embrace state-of-the-art software engineering best practices and offer the software as a vibrantly growing platform via continuous enhancements, timely bug fixes, and active user support via flexible feedback channels. Ease-of-use has also become the focus of a number of recently published MC toolkits, where MATLAB-based dynamic library (MEX) interfaces and graphical user interfaces (GUIs) have been reported.,With the exciting progress in developing open-source MC simulators with increasing speed, functionality, accuracy, and user-friendliness, we would like to tackle here the next major challenge in high-performance, general-purpose MC photon simulation software, namely scalability and availability. A number of previous publications, including several from our group, have addressed the challenges in creating scalable simulations that can utilize more than one GPU or run simulations across CPUs/GPUs of multiple vendors. In particular, a number of previous papers reported OpenCL-based MC implementationsIn this work, we report a modern, scalable, high-performance, and fully open-source in-browser MC simulation platform—MCX Cloud—to bring state-of-the-art GPU hardware and our extensively optimized and feature-rich MCX simulator software to the rapidly growing biophotonics research community. Our MCX Cloud platform embraces an array of modern and standardized cloud-computing techniques. In the backend, it utilizes DockerA key advancement that enables us to develop such a compact, scalable and portable software/hardware platform is the adoption of JavaScript Object Notation  data exchange format, and is at the core of most today’s web-based applications. Compared to XML, JSON is extremely lightweight and fast to parse, yet it is capable of storing complex hierarchical data. Numerous free and lightweight JSON parsers are available today for nearly all existing programming languages, permitting plug-and-play implementation of JSON data support in most applications.Despite these aforementioned advantages, adoption of JSON in storing scientific data is largely limited to handling lightweight metadata. This is because JSON does not have explicit rules on how to serialize common scientific data structures such as N-dimensional (N-D) arrays, complex and sparse arrays, tables, graphs, trees, etc. Additionally, JSON does not directly support storage of strong-typed binary data. To bridge this gap, our group published an open-standard—the JData SpecificationIn addition to using JSON to encode input data, we have also completed the migration of MCX volumetric output data as of 2020, converting from the NIfTI data formatA key benefit of adopting JSON based data formats is to enable machine-automatable data validation. This can be readily achieved using the JSON Schema framework. JSON Schema is a systematic approach to defining data types, formats, and properties for each data entry in a JSON data structure, and is currently a proposed Internet standard by the Internet Engineering Task Force (IETF).2.4The front-end, i.e., the web GUI, of MCX Cloud consists of two major components—an in-browser JSON data editor to create JSON-formatted input data for MCX simulations and a 3D data rendering module based on WebGL (see below section). The web-based MCX JSON input editor was derived by combining an open-source general-purpose JSON editor developed by Jeremy Dorn et al. with our JSON-schema of MCX input JSON data format. The JSON editor module is a lightweight (73 kB in size) JavaScript library that enables the creation and editing of arbitrary JSON-formatted data using a user-defined schema. It also simultaneously supports a number of popular web GUI frameworks and icon libraries to improve customizability.A minimalistic design style is used to provide users with a clean and streamlined environment to create, preview, execute, render, and easily share MCX simulations. All front-end functionalities are achieved using a combination of HTML5 and JavaScript programming. Notably, the use of the JQuery library makes the front-end compact  and easy-to-maintain.2.5In the front-end of MCX Cloud, we have developed fully featured 3D shape and volumetric data rendering and download functionalities. In comparison, the web GUI of MCOnline only provides rendering and data downloading for a particular Our MCX JSON input file accepts two methods for defining a heterogeneous simulation domain: (1) a constructive solid geometry (CSG) approach using a list of shape primitive constructs such as spheres, boxes, cylinders, 2.6The client  and the server  communicate via asynchronous data communication, known as AJAX (asynchronous JavaScript And XML). Despite the name, JSON, instead of XML, has been predominantly used in today’s web applications data exchange. User inputs are encoded as lightweight JSONP (JSON with Padding) data packets and sent to the server; the server sends back the response, also encoded as JSON packets, and informs the JavaScript on the web GUI to update the web page content dynamically without needing to reload the entire web page.To facilitate the processing of user submissions and management of Docker Swarm jobs, we developed an ultra-compact common gateway interface (CGI) script, named “mcxserver,” written in the Perl programming language to handle user-submitted job requests. These submitted simulation data are stored in a database using SqliteTo optimize server disk usage, we define a job expiration time window (currently set to 1 h) and configure another recurrent process (known as a cron-job) to automatically clean the expired job folders to save space. If a simulation is frequently executed by users, such as the default simulation or built-in examples, we keep the simulation output folder in a cache folder to avoid repeated computation.2.7Guided by the FAIR principle3Following the methodologies discussed above, we have created a preview version of the MCX Cloud simulation platform. In this initial configuration of the MCX Cloud backend, we have currently included To demonstrate the GUI design in MCX Cloud’s front-end, in To show the 3D domain rendering functions in the web GUI, in Our 3D in-browser rendering tool also automatically renders MCX-computed fluence maps, also encoded in the JSON/JNIfTI format, returned by the server after the computation is completed. In To demonstrate that one can use MCX Cloud to distribute a large simulation across multiple GPU devices installed in the Docker Swarm, we launch the digimouse benchmark simultaneously to 10 GPUs installed on the backend, each running 3.1Over the past decade, MC-based photon transport simulation has gained ample progress in terms of speed and accuracy in modeling increasingly complex anatomical structures. A list of free and open-source MC simulators with various levels of functionalities have been developed, published, and actively maintained by a number of research groups. While some of these open-source toolkits have successfully attracted a sizable user community, most of these tools were disseminated using a conventional download-and-install approach. In addition, many high-performance MC simulators require purchasing and installing high-end graphics cards on users’ own computers to maximize efficiency. For less-experienced users, properly configuring and using these specialized simulation tools can be key barriers.This work specifically addresses challenges regarding the usability and availability of MC simulators as mentioned above. Particularly, we described an in-browser GPU-accelerated MC simulator and cloud-based service that can be launched anywhere a browser is available, including mobile devices such as a smartphone or a tablet. This system combines our decade-long, continual development in MCX light transport simulation software with state-of-the-art cloud-computing platforms, and offers a robust, scalable and forward-looking framework for a standardized, high-demand, high-throughput and community-focused MC modeling platform. Compared to the previously published online MC simulator, this new platform embraces the latest technologies in microservices, cloud-computing (containerization and orchestration), and web-based GUI design , and demonstrates high flexibility and scalability that were not previously available.We can not emphasize enough how adopting a standardized and web-friendly input/output data format in JSON/JData greatly simplified or even directly enabled the implementation of this lightweight yet highly versatile web-based platform. To be more specific, utilizing JSON to encode MCX’s input/output data allowed us to seamlessly integrate them with JavaScript and a web environment. Also, defining MCX’s input data using JSON schema allows the JSON Editor library to automatically create the JSON editing interface in our front-end. This in-browser JSON editor is not only intuitive to use, but also generates JSON data that automatically satisfies the specified schema. Similarly, adopting JSON and JData data annotations also allow MCX to store complex output data records, including volumetric fluence rate, partial-pathlengths, and various lightweight metadata in a unified, easy-to-read JSON format that can be readily transmitted, parsed and rendered inside a browser.Although we use MCX at the backend to perform the underlying MC computation, our cloud computing system can be readily adapted to use any other MC simulators, as long as the alternative simulator also supports JSON/JData as the input/output data format and provides the corresponding JSON schema of the desired input JSON data structure (can be entirely different from those of MCX). For the same reason, our current web GUI can be directly used in combination with MCX-CLFrom the benchmark results shown in Moving forward, we aim to complete the migration of our MMC simulatorThe next step of our project also includes further solidification and dissemination of the JData specificationhttp://mcx.space/cloud.In summary, we report a highly scalable, easy-to-use, and cloud-computing-based in-browser MC simulation platform—MCX Cloud. This platform was built upon an array of modern open-source technologies, including the use of Docker containers and container orchestration to run GPU-based MC simulations across a robust, elastic, scalable, and distributed virtual GPU cluster. It also leverages the latest web-based technologies, such as JSON, JSON schema, AJAX, and WebGL, to create an intuitive, easily expandable, and responsive web GUI. At the core of this cloud computing platform is our significantly improved MCX photon transport simulator, packaging numerous enhancements in GPU optimization and algorithmic features that we have developed and integrated over the past decade. We want to particularly highlight that this platform is fully open-source—we not only provide the source codes for the MCX simulator, but also those for the web GUI and server-side scripts—so that anyone can build a private cloud for internal use or modify these scripts to accommodate other similar solvers. In the meantime, we have built an initial GPU cloud containing