Hospital-acquired venous thromboembolism (HA-VTE) in children comprises multiple risk factors that should not be evaluated separately due to collinearity and multiple cause and effect relationships. This is one of the first case-control study of pediatric HA-VTE risk factors using a Directed Acyclic Graph (DAG) analysis.Retrospective, case-control study with 22 cases of objectively confirmed HA-VTE and 76 controls matched by age, sex, unit of admission, and period of hospitalization. Descriptive statistics were used to define distributions of continuous variables, frequencies, and proportions of categorical variables, comparing cases and controls. Due to many potential risk factors of HA-VTE, a directed acyclic graph (DAG) model was created to identify confounding, reduce bias, and increase precision on the analysis. The final model consisted of a DAG-informed conditional logistic regression.In the initial conventional univariable model, the following variables were selected as potential risk factors for HA-VTE: length of stay , immobility, ICU admission in the last 30 days, LOS in ICU, infection, central venous catheter (CVC), number of CVCs placed, L-asparaginase, heart failure, liver failure, and nephrotic syndrome. The final model using the set of variables selected by DAG analysis revealed LOS , L-asparaginase , and nephrotic syndrome  as independent risk factors for HA-VTE.The DAG-based approach was useful to clarify the influence of confounders and multiple causalities of HA-VTE. Interestingly, CVC placement—a known thrombotic risk factor highlighted in several studies—was considered a confounder, while LOS, L-asparaginase use and nephrotic syndrome were confirmed as risk factors to HA-VTE. Large confidence intervals are related to the sample size; however, the results were significant. In the past two decades, venous thromboembolism (VTE) has been recognized as an essential complication in pediatric patients. In the last ten years, VTE incidence has reached 42–58 cases of venous thromboembolism (VTE) for every 100,000 children admitted, according to information from the database of pediatric patients admitted to hospitals in the United States of America (USA). This same database showed that VTE incidence is much higher in hospitalized children . Deep venous thrombosis (DVT) is currently considered the second leading cause of preventable harm in hospitalized patients, according to a study conducted in 80 pediatric hospitals in the USA . The cliHospital-acquired venous thromboembolism (HA-VTE) comprises multiple risk factors that should not be evaluated separately due to collinearity and multiple cause and effect relationships . For thiWe conducted an observational, case-control study to evaluate risk factors for the development of hospital-acquired venous thromboembolism (HA-VTE) in children.The study was approved by the Institutional Review Board (CAAE 58056516.0.0000.5264).th, 2012 to August 31st, 2018, who developed hospital-acquired venous thromboembolism (cases) and randomized controls on a ratio of 1:3, matched by age (range), sex, unit of admission, and period of hospitalization . The study was held at a university hospital in Rio de Janeiro, Brazil , a 65-bed, tertiary care hospital , with 25 pediatric subspecialties.Children (newborn to 16 years old) hospitalized from May 24For the case-control study, 22 cases and 76 controls were selected on a ratio of 1:3 after statistical power calculation considering previous studies.http://www.random.org). Cases and controls criteria were confirmed by two independent reviewers (MP and LRC).Cases were defined as patients who developed hospital-acquired venous thromboembolism (HA-VTE) according to the International Society of Thrombosis and Hemostasis (ISTH)  criteriaCases that only had thrombotic events other than VTE (deep venous thrombosis and/or pulmonary embolism) such as isolated superficial venous thrombosis, isolated thrombotic microangiopathy, and isolated arterial thrombosis were excluded from the study.Patients (cases or controls) that did not have adequate chart information during data collection were excluded.Variables were categorized in baseline, follow-up, and outcome. Baseline variables evaluated in cases were case selection strategy , case thrombotic event , vessel involved in VTE by radiological reports . Variables evaluated in both cases and controls included: demographic variables , date of VTE diagnosis, length of stay, hospital unit location, and comorbidity using ICD-10 codes), clinical data on VTE prophylaxis , putative risk factors  definition , surgeryDescriptive statistics were used to define distributions of continuous variables, frequencies, and proportions of categorical variables, which were then compared between cases and controls using Mann-Whitney U and χ2 tests. Fisher’s exact test was used in place of χ2 in instances of a two-by-two table with a five or under frequency value in at least one cell. Results were expressed as odds ratios (ORs), with accompanying 95% confidence intervals (95% CIs) calculated by the Wald method. To evaluate the trend rate of HA-VTE incidence in the last years, we implemented a temporal series analysis with data from 2012 to 2017. The Autoregressive Integrated Moving Average (ARIMA) was adopted. The cases were divided into three different age categories: all ages, less than six years, and 6 to 15 years old. The linear correlation between the HA-VTE rate and the years was evaluated by R-square (coefficient of determination).Due to a large number of potential variables that could confound or mediate the causal effect of the exposure (risk factors of HA-VTE) on the outcome (VTE), a directed acyclic graph (DAG) model was created to reduce bias, improve transparency, and increase precision on the analysis.http://www.dagitty.net) (Variables included in DAG were clustered in four different groups: (1) exposure variables , (2) forced-variables , (3) non-forced variables  and (4) non-observed variables . We selected eight main exposure variables: central venous catheter, intensive care unit stay, mechanical ventilation, and length of stay were based on the systematic review and meta-analysis of risk factors and risk-assessment models published by Mahajerin A et al. . Other rtty.net) . Variabltty.net) . A famil® (2016) software, and the two last traditional methods, using SPSS Statistics®  Interestingly, all methods resulted in the same Final Model  of Universidade Federal do Rio de Janeiro (UFRJ) Review Board (CAAE 58056516.0.0000.5264). Because of the study’s ambidirectional design, in the retrospective arm, the requirement to obtain informed consent from the legal persons responsible for the individuals under study was waived by our institutional review board. In the prospective arm, the written parental or guardians informed consent, and the child assent was obtained. It is a merely observational and descriptive analysis, and it does not offer physical and/or biological risk. The researchers assured the confidentiality of individuals identification, and the data were delinked entirely from any personal identifiers before they were analyzed to ensure confidentiality.Given the 6,295 hospitalizations during six years of the study, this yielded an average HA-VTE of 5.73 per 10,000 hospitalized children per year. Twenty-six cases of hospital-associated venous thromboembolism (HA-VTE) were diagnosed during the six years of observation. However, only 22 cases were enrolled after applying the validation criteria for venous thromboembolism (VTE) cases selection and loss due to missing data . The flo® software . The remaining three cases (13.63%) that were not anticoagulated were detected by active screening  and Radiology report . These twenty-two cases were matched to 76 randomly selected controls. There was no difference in VTE’s frequency between cases and controls regarding sex, age, and unit of admission as expected due to matching  were found using data bank of the pharmacy sector stored in MV 2000matching . We did The median time from hospital admission to VTE diagnosis was 28.5 days (IQR 32 days), and the most frequently associated signs and symptoms of DVT were edema , pain , discoloration of the limb  and warmness . Two patients  had PE and presented with the following symptoms: one with cough and hemoptysis and the other with dyspnea, tachypnea, cough, and tachycardia. Only one patient had cerebral venous sinus thrombosis (CVST) and presented with seizures. He had a diagnosis of acute lymphoblastic leukemia (ALL) and was treated with L-asparaginase. DVT cases were diagnosed using Doppler ultrasound and PE with a CT scan. The 22 patients had 42 sites of VTE  which inOnly one patient  developed VTE while on the prophylactic use of subcutaneous low molecular weight heparin (LMWH) in a dosage of 1 mg/kg, once daily, on day 30. She was a 15-years old adolescent with encephalitis admitted in the ICU with several risk factors, including immobilization (30 days), mechanical ventilation (14 days), and catheter on the same site of VTE . Another patient developed recurrent VTE even on therapeutic LMWH. She was a 3-year old patient with Down syndrome with several risk factors, including high-risk ALL treated with L-asparaginase and corticosteroids, gastrointestinal infection and febrile neutropenia, obesity, and thrombophilia (combined heterozygosity for methylenetetrahydrofolate reductase and factor V Leiden). DVT occurred on the left femoral common vein with previous attempting of catheter insertion. In our cohort, there were no cases or controls diagnosed with disseminated intravascular coagulation (DIC).versus controls are presented in The risk factors for HA-VTE among cases For estimating the direct effect of the exposure variables  on the outcome (venous thromboembolism), the software recommended an adjustment on corticosteroids, hematologic malignancies, immobilization, infection, L-asparaginase, local trauma, nephrotic syndrome, and surgery  Tables. We found a significant increase in HA-VTE incidence across all age groups from 2012 to 2017, with a similar trend rate reported in a multicenter study in the United States [The DAG is a visual representation of a process understudy’s theoretical assumptions that the reader quickly interprets, encouraging an iterative process of updating and revising theories about causal relationships. A DAG-informed approach helps researchers in avoiding unintentional confounds and colliders , that is represented in DAG by the two arrows pointing toward it , arousinlength of stay (LOS), L-asparaginase use, and nephrotic syndrome to be independent risk factors for hospital-associated venous thromboembolism in children. A recent systematic review and meta-analysis of risk factors and risk-assessment models by Mahajerin A et al. [We found the A et al. , a centrLength of stay (LOS) has been a consistently identified risk factor, but the mechanism by which it increases VTE’s risk is not fully understood. It works as a proxy that also covers unknown risk factors not yet investigated. We postulate some theoretical relationships that were represented by DAG analysis  is the most common pediatric cancer and, therefore, the most frequent malignancy associated with VTE in childhood. The incidence of VTE ranges from 5 to 70% when imaging studies identify asymptomatic cases. thrombin . Most ththrombin  with a pthrombin  in ALL pthrombin  or protethrombin  has receNephrotic syndrome is another prototype for pediatric VTE with multifactorial and complex pathophysiology. The nonselective proteinuria results in hemostatic abnormalities mainly due to loss of anticoagulant and fibrinolytic proteins  and increase of prothrombotic substances  produced by the liver to balance the loss of anticoagulant elements contributing to a procoaguable state [le state . Other rle state . In our le state .Mechanical ventilation was not statistically significant in the final model but remained to adjust confounding factors.The limitations of our study include the small sample size (as a result of single-center research) and the retrospective nature and the missing of some information on patient’s charts, i.e., lack of data on hypercoagulability, absence of radiological documentation of all VTE events—a real-life situation in underdeveloped countries. One of the reasons our sample was not larger was that our hospital does not admit patients with solid malignancies, does not perform cardiothoracic and orthopedic surgery, and the emergency department is referred only for patients who are attended in the outpatient clinic . There are some explanations about why the findings in our study were different from other publications. Potential covariates, unmeasured confounding, and lower statistical power could be fundamental reasons that justify these differences. On the other hand, we evaluated the comorbidities in our DAG model, which could have lessened medical interventions’ significance as the leading risk factor of HA-VTE. We hope that the more extensive ongoing studies that will probably consider the role of comorbidities can establish the medical intervention’s real weight in HA-VTE in children.Our study has some important strengths. To our knowledge, this is the first case-control study of pediatric HA-VTE using DAG analysis worldwide, and the first pediatric case-control HA-VTE study in Brazil. Our study’s DAG-based approach highlighted the importance of medical conditions, appeared as the most critical variables, and made us question if therapeutic interventions would be only triggers or proxies "tip of the iceberg" for the observed thrombosis. Researchers should consider medical conditions  in risk-assessment models besides directing spotlights to interventions .We reported the importance of medical conditions on the genesis of HA-VTE using a DAG-based approach, which makes it possible to clarify the influence of confounders and multiple causalities, such as a catheter, a significant risk factor highlighted in several studies. This approach is rational since children that use intravenous devices are sick, so it is not reasonable to put all the weight on a catheter since other risk factors play an essential role in VTE. Besides that, we reported an increase of HA-VTE events along the years of the study, which suggests that educational actions should be performed to prepare the clinical team to deal with these patients and teach medical students and residents since it is a university hospital. Finally, an international effort should be made to increase the robustness of data and balance the different characteristics of pediatric hospitals globally to create offset risk-assessment models and, therefore, adequate protocols for HA-VTE prophylaxis in children. We suggest that the DAG methodology used in this article be applied in future HA-VTE multicenter studies.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.


More than two-thirds of youth experience trauma during childhood, and up to 1 in 5 of these youth develops posttraumatic stress symptoms that significantly impair their functioning. Although trauma-focused cognitive behavior therapy (TF-CBT) has a strong evidence base, it is rarely adopted, delivered with adequate fidelity, or evaluated in the most common setting where youth access mental health services—schools. Given that individual behavior change is ultimately required for successful implementation, even when organizational factors are firmly in place, focusing on individual-level processes represents a potentially parsimonious approach. Beliefs and Attitudes for Successful Implementation in Schools (BASIS) is a pragmatic, motivationally focused multifaceted strategy that augments training and consultation and is designed to target precise mechanisms of behavior change to produce enhanced implementation and youth clinical outcomes. This study protocol describes a hybrid type 2 effectiveness-implementation trial designed to concurrently evaluate the main effects, mediators, and moderators of both the BASIS implementation strategy on implementation outcomes and TF-CBT on youth mental health outcomes.Using a cluster randomized controlled design, this trial will assign school-based mental health (SMH) clinicians and schools to one of three study arms: (a) enhanced treatment-as-usual (TAU), (b) attention control plus TF-CBT, or (c) BASIS+TF-CBT. With a proposed sample of 120 SMH clinicians who will each recruit 4–6 youth with a history of trauma (480 children), this project will gather data across 12 different time points to address two project aims. Aim 1 will evaluate, relative to an enhanced TAU condition, the effects of TF-CBT on identified mechanisms of change, youth mental health outcomes, and intervention costs and cost-effectiveness. Aim 2 will compare the effects of BASIS against an attention control plus TF-CBT condition on theoretical mechanisms of clinician behavior change and implementation outcomes, as well as examine costs and cost-effectiveness.This study will generate critical knowledge about the effectiveness and cost-effectiveness of BASIS—a pragmatic, theory-driven, and generalizable implementation strategy designed to enhance motivation—to increase the yield of evidence-based practice training and consultation, as well as the effectiveness of TF-CBT in a novel service setting.NCT04451161. Registered on June 30, 2020.ClinicalTrials.gov registration number The online version contains supplementary material available at 10.1186/s13012-020-01064-1. Contributions to the literatureResearch has demonstrated that even when organizational factors are firmly in place, individual behavior change is critical to implementation. However, few implementation strategies have been designed and tested surrounding their impact on precise, theoretically derived mechanisms of individual behavior change.This study will be the first to test a pragmatic, theory-driven, and generalizable implementation strategy in the context of improving clinician use of an evidence-based trauma intervention in the education sector, the most common setting for youth mental health service delivery.Findings will contribute to gaps in the implementation literature surrounding the utility of pragmatic implementation strategies, the mechanisms through which strategies operate, and the effectiveness of trauma interventions in accessible service settings.More than two-thirds of youth experience trauma during childhood, with one-third experiencing multiple traumatic events . Up to 1Trauma-focused cognitive-behavioral therapy (TF-CBT) has the strongest evidence base of any child trauma treatment, with over 16 randomized trials demonstrating a range of positive outcomes across sex, age range, and ethnic and cultural groups for reduced symptoms of PTSD, anxiety, depression, and trauma-related behavioral problems , 5. EvidEfficacious mental health services such as TF-CBT are unlikely to yield public health impact unless they are consistently implemented in accessible settings. School-based mental health (SMH) services account for 50–80% of all youth mental health services in the USA –11. DespAs outlined in the Exploration, Preparation, Implementation, Sustainment (EPIS) framework , implemeResearch on individual-level implementation strategies has largely focused on training and consultation, which are necessary but insufficient to ensure successful EBT implementation , 26. ManTo influence provider behaviors in response to EBT training and consultation, the current project applies two well-established theories of behavior change: the Theory of Planned Behavior (TPB) and Health Action Process Approach (HAPA) –32, whicThe ability to predict behavior using TPB significantly increases with the addition of volitional strategies that support individuals in enacting the behaviors they are motivated to exhibit . HAPA arEven when TPB has been used to guide process evaluations, efforts have explored traditional implementation strategies such as clinician education and performance-based feedback –47. AspeGrounded in TPB and HAPA see Fig.  30, 31,,31, 35, Figure d = 1.03) [d = .51; d = .67). In a small-scale randomized trial with SMH clinicians, 23 results indicated that BASIS was highly feasible, acceptable, and contextually appropriate. Further, moderate to large effects at post-training for BASIS mechanisms of change encouraged the current trial.In previous pilot work, BASIS has demonstrated large effects on target mechanisms and overall feasibility . For ins = 1.03) . AttitudThe objective of this hybrid type 2 randomized effectiveness-implementation trial is to simultaneously examine the theoretical mechanisms through which a clinical intervention (TF-CBT) and an implementation strategy (BASIS) impact clinical and implementation outcomes, respectively .Aim 1 will evaluate, relative to control, the effects of TF-CBT conditions on TF-CBT’s identified mechanisms of change , differences in child mental health outcomes, and intervention costs and cost-effectiveness.Aim 2 will evaluate the main effects of BASIS, relative to control, on its theoretical implementation mechanisms, implementation outcomes, as well as costs and cost-effectiveness. We will also evaluate “hypothesis-defying residuals”  to further refine our BASIS theory of change.In this hybrid type 2 effectiveness-implementation stratified cluster randomized trial, a single clinician from each participating school will be randomized to BASIS plus TF-CBT (BASIS+TF-CBT), attention control plus TF-CBT (AC + TF-CBT), or enhanced treatment as usual (TAU) . SMH providers will consist of school psychologists, social workers, mental health counselors, etc. recruited from elementary, middle, and high schools from economically and ethnically diverse districts. One clinician per school will be recruited with the assistance of district administrators. The research team will contact eligible participants to describe the purpose of the study, research procedures, and incentives. Clinicians will be included if they (a) serve in a professional role to provide school-based mental health services, (b) hold a graduate degree or equivalent certification or experience, (c) have not previously received formal training in TF-CBT, and (d) are not actively receiving support to implement another related intervention.Youth participants will include 480 students (160 per wave), recruited by TF-CBT and TAU therapists. Youth will meet TF-CBT eligibility criteria, including (a) be enrolled in grades 3–12 and (b) have traumatic event exposure  and (c) significant post-traumatic stress symptoms. SMH clinicians will recruit students by screening through their standard referral pathways  for PTSD symptoms. Once students are identified, clinicians will ask caregivers whether they are open to being contacted by the research team. For caregivers who agree, contact information will be relayed to the team, who will follow-up by phone to describe the research project, estimated time to participate, participant compensation, and obtain consent . We will collect baseline clinician data on implementation intentions and mechanisms , clinician years of experience, and school characteristics . We will use the nearest neighbor algorithm to generate paired distance estimates between each clinician and then select matched groups of three based on smallest distance estimates. Each group of three will be randomly assigned to each of the three conditions.Both BASIS and AC will bookend a TF-CBT virtual training and will be followed by TF-CBT consultation and online booster session.TF-CBT is a 12–16 session intervention for children aged 3 to 18 years with trauma-exposure and related mental health sequelae. TF-CBT includes individual sessions for the youth, individual sessions for parents, and conjoint sessions that include both the youth and parent. TF-CBT has established training and consultation protocols, as well as a psychometrically strong objective fidelity instrument  hypothesized to be responsible for its effects. TAU scaffolding will be provided via an online presentation with a live question and answer section at the conclusion.The BASIS multifaceted implementation strategy is group-based and interactive, with a pre-training session (~ 3 h) delivered prior to TF-CBT training, a post-training session (~ 90 min) delivered immediately after training, and an online booster ~ 15 days post-training. Below, we describe BASIS motivational and volitional components, as well as the BASIS structure and fidelity assessment. Table strategic education focused on increasing beliefs and attitudes about the benefits of EBT and intervention fidelity to improve attitudes. Examples of popular but ineffective practices  are used to help clinicians identify cognitive shortcuts that enhance vulnerability to adopting non-EBTs. In addition, participants are prompted to reflect on the importance of fidelity across a range of professions .The first BASIS component involves Second, BASIS includes social influence techniques to alter perceptions of subjective norms. Evidence-based social influence strategies consist of two broad categories: (1) social proofing messages that use data or testimonials to describe the behavior or attitudes of others and (2) strategies to induce cognitive dissonance. Social proofs are most influential from individuals with whom they closely identify , especiaThird, motivational interviewing (MI) is used to enhance self-efficacy. MI is a nondirective, patient-centered approach with strong evidence for building engagement and commitment for behavior change –68. The To address the intention-behavior gap, BASIS includes volitional planning interventions derived from HAPA to increase the likelihood that clinicians will maintain self-efficacy and act upon their intentions by enacting implementation behaviors. Specifically, action planning and problem-solving planning have been shown to facilitate health behaviors such as breast cancer self-examinations, medication adherence, exercise, and healthy eating –77. Actipre-training session targets attitudes, subjective norms, and self-efficacy via the motivational components listed above. The pre-training opens with the facilitator engaging SMH providers in an activity to clarify their professional values (MI component). Strategic education components are not delivered didactically, but rather to facilitate interaction among participants. Open-ended questions are used to elicit change talk. Testimonials are interspersed throughout . At the end of the pre-training session, providers collaborate with each other to develop an individualized menu of potential solutions to common implementation barriers that they can select from when encountering challenges to adopting and delivering new practices with fidelity. Last, they set value-congruent goals related to participation and engagement in the upcoming EBT training.The BASIS post-training session includes volitional strategies shown in prior research to maintain implementation intentions and facilitate actual enactment of behavior change. Specifically, clinicians are supported to develop action plans and problem-solving plans. Clinicians are provided with an action planning template to detail precisely what TF-CBT components, how, with whom, where/when, and the environmental cues and resources needed to initiate delivery of TF-CBT with fidelity. The problem-solving plan involves clinicians anticipating situational and internal barriers and generating solutions to overcome those barriers to develop personalized if-then plans that can be used when confronted with specific barriers.The BASIS The BASIS online booster is delivered at approximately 15 days post-training, a time point when clinicians’ implementation intentions and behaviors may first weaken . The aimA BASIS fidelity tool  will be Providers randomly assigned to AC condition will receive a 3-h pre-training, 90-min post-training session, and an online booster roughly 15 days post-training to mirror the duration of BASIS and control for dose, information provided, and interventionist effects. The AC condition will be delivered by the same facilitator as BASIS to control for facilitator effects. Content will be didactic, as is typical in trainings for SMH clinicians , 82. TheClinician data collection will span the active implementation and sustainment phases . Data will include clinician quantitative surveys and qualitative interviews, fidelity assessments of recorded TF-CBT sessions (via objective coding), and ratings of TF-CBT case presentations completed by TF-CBT consultants. Data collection will be incentivized in both the implementation and sustainment phases.Clinician surveys will be administered via a secure web-based system at 12 time points for BASIS/AC and 9 time points for TAU, beginning in the fall of each year. Clinicians will self-report their demographic characteristics, BASIS mechanisms , implementation intentions, organizational moderators , and TF-CBT sessions delivered. For BASIS/AC, surveys will be administered at baseline through post-training , 2 months from baseline and after the BASIS/AC booster (T6), winter (T7), spring (T8), and end of school year (T9), as well as three sustainment time points during the subsequent year . For TAU, we will administer the T1, T5, and T6–T12 surveys..To assess TF-CBT fidelity, clinicians will record all sessions for participating TF-CBT and TAU students. Three sessions (one from each phase of TF-CBT) will be randomly selected and coded for fidelity using an established, systematic TF-CBT coding protocol Table .Table 2Adoption and sustainment data will be collected via the TF-CBT “Toolkit,” an online TF-CBT tracking system used by clinicians to determine client eligibility, log client sessions, and facilitate consultation.unexplained residuals from aim 2 mediation analyses will be explored qualitatively via semi-structured phone interviews at the end of the active implementation phase. Residuals are defined as clinicians whose implementation behavior is insufficiently accounted for by our mediation model . Clinicians from aim 2 will be identified at the end of their first year of participation based on the results of aim 2 quantitative modeling. Participants will include those whose predicted probability score is greater than 1.0 standard deviations of the mean from their predicted behavior, balanced between implementers and non-implementers and TF-CBT and AC conditions . The mixed methods design will be sequential in structure; the functions are sampling and expansion; and the process is connecting [To fully address aim 2 and identify factors unaccounted for by our BASIS theory of change Fig. , unexplannecting –100. We nnecting  to examinnecting  determinActivity-based costing will estimate the respective, incremental costs of enhanced TAU, TF-CBT, and BASIS. For TF-CBT/TAU costs, we will estimate direct costs of TF-CBT and enhanced TAU, such as training, consultation and delivery of services, and indirect costs, such as lost opportunities for alternative activities. For BASIS costs, we will directly measure the resource use and incremental costs associated with BASIS and TF-CBT training as compared to status quo TF-CBT training  . We willWe will combine incremental costs collected for BASIS, TF-CBT, and TAU with estimates of effectiveness on implementation and clinical .Youth data collection will focus on mental health and functional outcomes targeted by TF-CBT, with evidence of effectiveness in previous studies. Youth will complete surveys via telephone prior to their first TF-CBT session (ST1) and at 3- (ST2) and 6-month (ST3) follow-ups. These surveys will assess PTSD, depression, and psychosocial functioning. On the same time frame, caregivers will complete a measure of their students’ psychosocial functioning and provide information regarding family income and parent occupation. At the end of each school year, academic records will be requested for all participants who received TF-CBT or TAU during that year. Attendance, discipline, and achievement  will be extracted from these academic records.Measures evaluate basic demographics and aspects of each school’s context, mediators (mechanisms) and moderators, implementation outcomes, and youth clinical outcomes. Table We will test the direct main effects of TF-CBT on the hypothesized intervention mechanisms  and child mental health outcomes , via longitudinal mixed effects models (time within client within clinician) for each mechanism, using effect coding for each of the 3 conditions  in an intention-to-treat approach, and focusing our comparisons on the main effect of TAU vs. TF-CBT conditions. To increase statistical power to detect an effect of TF-CBT, we will include as covariates any variables at the client, provider, or school level that are associated with the mechanism variable, as indicated during preliminary bivariate analyses. Path analysis will then be used to test the mediated effect of mechanisms. Mixed effect models will estimate standardized coefficients for each path separately, as well as together, and any significant reduction in the condition to outcome coefficient when including the other paths will be suggestive of partial or full mediation, using the bias-corrected bootstrap method to test significance .For aim 2, clinicians assigned to the enhanced TAU condition will be excluded from analyses. We will test for the impact of BASIS on proximal implementation mechanisms of change via a series of piecewise longitudinal mixed effects models (time within clinician) to examine between-condition differences on the rates of change across all twelve time points pieced into three epochs  for each of the five primary BASIS mechanisms of change. As compared to AC, we hypothesize steeper gains for BASIS from T1 to T5, smaller rates of decline for BASIS from T6 to T9, and higher levels of sustainment for T10 to T12. The impact of BASIS on fidelity will be tested using mixed effects models, with fidelity measurement occurrence nested within clinician. Adoption and sustainment will be tested using logistic regressions using condition as a predictor . We will stratify sustainment analyses (T10–T12) as follows: (1) the entire population of participants, regardless of year 1 implementation, in order to capture any sustained impact of BASIS, (2) the subgroup of clinicians who implemented in year 1, to examine the sustainment of TF-CBT implementation. Mediation will be tested as in aim 1.Based on aim 2 quantitative models, we will identify clinicians who have a difference between predicted and actual implementation behavior of ≥ 1 SD. Transcribed data will be coded using an integrated directed content analysis  approachIn all main effects analyses, the Benjamini-Hochberg procedure adjusts for familywise error within outcome families . Missing data will be addressed in modeling using restricted maximum likelihood estimation.For both aims, cost data collection and analyses of TF-CBT and BASIS will estimate incremental total and unit costs for TAU, BASIS+TF-CBT, and TF-CBT during both the implementation and sustainment periods . We willd > .35 for direct effects on student mechanisms and outcomes, assuming an intraclass correlation of .05, paired two-group  tests with 35 schools/clinicians in each group (to account for attrition/missing data) and 4 clients served by each provider. Assuming some variance in the number of clients per clinician ranging from 1 to 7, a Monte Carlo simulation estimated that the maximum detrimental impact on power will be less than 10% [d > .2  [Our conservative power analyses indicate that we are powered to detect minimum detectable effect sizes (MDES) of Cohen’s than 10% . Using beffects) .d of .68 for clinician implementation outcomes, which is lower than most significant effects during our pilot study [d > .59 (as expected) and mechanisms to implementation outcomes has at least small/moderate effects (d > .31) [Conservatively assuming 35 clinicians in each group and 12 time points, we will have sufficient power to detect a Cohen’s ot study . We willd > .31) .This hybrid trial will address significant gaps in implementation science surrounding the impact of pragmatic, individually focused implementation strategies and their mechanisms. It is also the first project to conduct an effectiveness trial of TF-CBT in schools. Existing compilations of implementation strategies , 113 conFurthermore, relative to many existing implementation strategies that unfold over months or years –118, theFinally, much of what has been written about the sustainment phase of implementation comes from conceptual models , 126, anThe current study only recruits one clinician per school site, which does not allow for robust evaluation of organizational covariates. We considered randomizing multiple clinicians from site to different conditions to increase sample size; however, given that BASIS is designed to target clinician perspectives of social norms, this would have presented significant risk of contamination.This research will generate critical knowledge about the effectiveness and cost-effectiveness of BASIS—a pragmatic, theory-driven, and generalizable implementation strategy—to support provider behavior change, as well as the effectiveness of TF-CBT in SMH. Trial results will be disseminated via publications, presentations, via traditional  and social  media, and through networks of practitioners. If effective, BASIS could be adapted for use in initiatives across service sectors and evaluated in subsequent trials with additional interventions. Finally, evidence supporting the effectiveness of TF-CBT in schools would be cause for increased scale-up of this EBT in the most common setting where youth with history of trauma are likely to access needed mental health services.Additional file 1. CONSORT 2010 Checklist of Information to Include When Reporting Cluster Randomised Trial.Additional file 2. SPIRIT 2013 Checklist.Additional file 3. IRB Approval.Additional file 4. Study Consents.Additional file 5. Detailed Measures Table.


MicroRNAs (miRNAs) are evolutionarily conserved short non-coding RNAs that act at post-transcriptional regulation of gene expression by destroying target messenger RNA or inhibiting its translation. Recently, miRNAs have been identified as important regulators in autoimmunity. Aberrant expression and function of miRNAs can lead to dysfunction of immune system and mediate autoimmune disorders. Here, we summarize the roles of miRNAs that have been implicated in three representative ocular autoimmune disorders, including autoimmune uveitis, Grave’s ophthalmopathy, and Sjögren’s syndrome dry eye, and discuss the potential of miRNAs as biomarkers and therapeutic targets for the diagnosis and treatment of these diseases. Caenorhabditis elegans in 1993, miRNAs have been identified as key players in a plethora of cellular processes, such as cell growth, proliferation, differentiation, and apoptosis (MicroRNAs (miRNAs), a class of evolutionarily conserved, short non-coding RNAs, are potent post-transcriptional regulators of gene expression through binding to the 3’ untranslated region of a target mRNA . Since tpoptosis . Besidespoptosis . Recentlpoptosis , includiThe eye, an immune privileged organ, has adapted several negative regulators to prevent inflammation within its tissue microenvironment . These rAutoimmune uveitis is an intraocular inflammatory disease characterized by immune-mediated damage in the uveal tissues and retina. The progressive irreversible photoreceptors’ damage caused by autoreactive T cells eventually leads to visual impairment and even blindness . ExperimDysregulation of certain miRNAs has been shown to be closely associated with the progression of EAU. Upregulation of miR-223 and miR-146a and downregulation of miR-181a were observed in the retina of rats during the course of EAU, corresponding with the score of EAU and the upregulation of IL-1β/MCP-1 . AdditioTh17 cells driven by IL-23 are central to the pathogenesis of EAU . Th17 ceExperimental autoimmune anterior uveitis (EAAU), in which inflammation is restricted to ocular anterior segment while retinal tissues and photoreceptor cells are not involved, resembles human idiopathic anterior uveitis . EAAU isBehcet’s disease (BD) is a systemic inflammatory disease of unknown etiology, characterized by ocular lesions, oral ulcer, genital ulcer, and multiple skin lesions . The eyeThe disturbed miRNA expression in peripheral blood mononuclear cells (PBMCs) from patients with BD has been unveiled, and certain miRNAs have been deemed as potent diagnostic biomarkers. MiR-155 expression was significantly increased in the PBMCs of BD patients with uveitis, whereas miR-146a expression had no significant difference between BD patients and controls . In addiTh17 cells can facilitate neutrophil inflammatory response that underlies the pathogenesis of BD . IncreasGenome-wide association studies have identified that single nucleotide polymorphisms (SNPs) in miRNAs are involved in many autoimmune diseases, including BD. For example, there is a strong correlation between rs2910164 in the pre-miR-146a gene and development of BD . DecreasMiRNAs and their SNPs affect cells and molecules involved in BD, which deepens our understanding of BD pathogenesis and sheds new light on the diagnosis and treatment of BD. More in-depth studies are warranted to explore the miRNAs-mediated mechanisms in the development of BD.Vogt–Koyanagi–Harada (VKH) syndrome, one of the sight-threatening diseases, is characterized by bilateral granulomatous uveitis associated with neurological, auditory, and dermatological manifestations, which are presumably caused by T-cell-mediated autoimmune response against melanocyte-associated antigens in multiple organs . Active Sympathetic ophthalmia (SO) is a rare, granulomatous uveitis found in bilateral eyes, occurring after ocular trauma and intraocular surgery. It is mainly characterized by acute or chronic uveitis, accompanied by mutton-fat KP in anterior segments and yellow-white lesions of choroid in the posterior segment . The etiAlthough the accumulating data have demonstrated the crucial roles of miRNAs in immune cell function, the role of miRNAs in SO pathogenesis is still largely unknown and only one research group reported this topic. It was shown that four miRNAs including miR-1, let-7e, miR-9, and miR-182, which are associated with T-cell-mediated inflammatory pathway, were downregulated in globes of patients with SO compared to those in controls. Among them, hsa-miR-9 directly targeted proinflammatory TNF-α and NF-κB1, both of which are crucial factors in the pathogenesis of SO . TherefoGrave’s ophthalmopathy (GO), an extra-thyroidal complication of Graves’ disease, is characterized by the inflammation and extensive remodeling of orbital adipose/connective tissues. Its clinical manifestations include exophthalmos, eyelid retraction, strabismus, and exposure keratitis, which may cause cosmetic and functional deficits . AlthougMiR-146a is a key regulator of orbital tissue fibrosis and GO development. Upregulation of miR-146a in OFs suppressed the production of inflammatory protein [including IL-6 and intercellular adhesion molecule-1 (ICAM-1)] and TGF-β-induced fibrotic markers , suggesting a key role for miR-146a in anti-inflammatory and anti-fibrotic process , 2018. CIn addition to miR-146a, miR-21 also plays a pivotal role in the regulation of fibrosis. in vitro  is a chronic systemic autoimmune disease, mainly characterized by lymphocytic infiltration of lacrimal and salivary glands, which results in ocular and oral dryness . The patThe altered miRNA expression in immune cells from patients with SS was recently reported. The dysregulation of miR-146a may be associated with the pathogenesis of SS. A previous study reported increased miR-146a expression in PBMCs from both SS patients and Sjs-prone mouse, which may affect innate immunity and contribute to the initiation and progression of SS . In addiRegarding other miRNAs, The potential value of miRNAs as biomarkers has gained tremendous interests in recent years. The disease-specific expression pattern makes some of them suitable biomarker candidates. Owing to their encapsulation in extracellular vesicles (EVs) or association with RNA-binding proteins, miRNAs found in various body fluids are highly stable . MoreoveMicroRNAs are emerging as potential molecular targets for the treatment of a variety of diseases owing to their unique expression profiles, crucial regulatory functions, and target specificity . CurrentMicroRNA alterations are closely associated with the pathogenesis of ocular autoimmune disorders. Due to the important roles of miRNAs in regulating inflammation and immune response, miRNAs can be potentially therapeutic targets for autoimmune-mediated eye diseases. Nevertheless, the exact roles of most miRNAs and the underlying mechanisms have not been clarified, requiring further investigation. Additionally, for successful translation to clinical therapies, it is necessary to develop safe and effective delivery system that can transport therapeutic miRNAs specifically to target sites.YW read the literature related to the topic and participated in drafting the manuscript. NL, LZ, and CY participated in searching and archiving the literature related to the topic and discussed the contents of the manuscript. BM, XL, and RW revised the manuscript. HN participated in the design, revision, and final approval of the manuscript. All authors read and approved the final manuscript.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.


Due to the dramatic impact of the COVID-19 pandemic, Spain underwent a strict lockdown (March–May 2020). How the lockdown modified older adults’ physical activity (PA) has been poorly described. This research assesses the effect of the lockdown on PA levels and identifies predictors of sufficient/insufficient PA in frail older community-dwellers. Community-dwelling participants from the +ÀGIL Barcelona frailty intervention program, suspended during the pandemic, underwent a phone-assessment during the lockdown. PA was measured before and after the lockdown using the Brief Physical Activity Assessment Tool (BPAAT). We included 98 frail older adults free of COVID-19 . About one third of participants (32.2%) were not meeting sufficient PA levels at the end of the lockdown. Depressive symptoms  and fatigue  decreased the odds of maintaining sufficient PA, whereas maintaining social networks  and reading  increased it. Living alone was associated with the reduction of PA levels . In our sample, pre-lockdown mental health, frailty-related symptoms and social relationships were consistently associated with both PA levels during-lockdown and pre-post change. These data suggest considering specific plans to maintain PA levels in frail older community-dwellers. The COVID-19 global pandemic has had a dramatic impact on the population’s health, especially for older adults [Frailty, a dynamic state of increased vulnerability to internal or external stressors, determines a higher risk of negative health outcomes, such as disability, falls, fractures, institutionalization and death . TherefoPA has been previously described as a risk factor for frailty ,9,10 andAmong the heterogeneous group of older adults, the COVID-19 pandemic posed particular challenges to community-dwelling frail older adults’ approach and care. Nevertheless, the impact and consequences of decreased daily activities and social contacts limitations in this vulnerable group, including community-dwelling, frail older adults with a relatively preserved autonomy before the pandemic, has been poorly described. Focusing on this population group is particularly relevant due to the increased risk of accelerated disability. Therefore, it is crucial to appropriately target at-risk individuals to implement individualized post-pandemic plans to recover PA.In this paper, we describe PA changes due to mobility restrictions in community-dwelling, frail older persons who had not been diagnosed with COVID-19 from a running program, to delay or revert frailty in community-dwelling older adults of Barcelona. Taking advantage of the extensive CGA pre-lockdown, which also included a standardized measure of PA, we explored factors associated with the improvement or maintenance of sufficient PA levels during the lockdown.The study population was derived from the +ÀGIL Barcelona project, an implemented, ongoing, real-life multidimensional intervention program, based on integrating primary care, geriatrics and other community resources. Models and results of the initiative have been previously published ,21. In bIn May 2020, at the end of the Spanish lockdown applied by the Spanish Government (14 March to 2 May), a follow-up visit via phone was performed with each participant in the +ÀGIL Barcelona program who had been assessed face-to-face during the 12 months prior to the lockdown . In case the participant could not complete the phone call assessment, a self-identified proxy or caregiver answered the follow-up interview. The interviews lasted around 20 min and were performed by two trained physiotherapist researchers.During the phone survey, the level of PA was assessed with the Brief Physical Activity Assessment Tool (BPAAT), the same tool used in all the routine visits pre-lockdown ,25. The Data from the last face-to-face CGA pre-lockdown were considered as covariates. These included sociodemographic data , clinical characteristics including the Charlson Comorbidity Index  and currData collected by semi-structured phone interview during the lockdown, included sociodemographic data , COVID-19 related variables . Differences among participants with improvement or sufficient PA level and those with reduction or insufficient PA level, were analyzed using the Student’s t-test or the Mann-Whitney U-test and Chi-square test, as appropriate. Variables showing an association with the outcomes  and those considered clinically relevant, or to have a potential influence on the outcomes, were included in a stepwise multivariable logistic (dichotomous outcome of change) and stepwise linear regression models , as appropriate, to obtain final parsimonious models . All analyses were performed using Stata version 14.Characteristics of the sample before the lockdown are presented as mean values and standard deviation (SD), or median values and interquartile range (IQR) for continuous variables, as applicable, and frequency and percentages for categorical variables. The pre-post lockdown PA level was analyzed by a paired sample The +ÀGIL Barcelona program and study protocol were approved by the Clinical Research Ethics Committee of the Institut Universitari d’Investigació en Atención Primaria, Jordi Gol i Gorina (20/048-P). Before starting the telephone interview, oral informed consent was obtained from all participants or, if the participant could not provide such consent, from a proxy.n = 4), or with incomplete PA data (n = 5), were excluded. Finally, we included in the analyses 98 participants . The vast majority (88.8%) of the phone interviews were answered by the participants. There were no significant differences in terms of age, sex and time since the last face-to-face assessment between those who participated and those who refused to participate or were excluded from the survey.Out of 117 contacted participants from +ÀGIL, 107 (91.5%) agreed to answer the phone survey. To ensure the homogeneity of the population, those previously diagnosed with SARS-COVID-19 (p < 0.001)) and reduction of participants reporting sufficient PA  was reported  points; reported . OverallParticipants with reduced or insufficient PA presented higher pre-lockdown IADLs disability and comorbidity, more prevalent depressive symptoms and previous diagnosis or positive screening for cognitive impairment/dementia than those who improved or maintained sufficient PA . This sap = 0.003), previous depressive symptoms  and self-reported fatigue during the COVID-19 outbreak  were inversely associated with PA levels  during the lockdown. Having social contact with people different from family  and performing reading activities during the lockdown  were associated with higher BPAAT scores during the lockdown  and self-reported fatigue , which were negatively associated with improvement/maintenance of sufficient PA, as well as for social contacts with people different from family networks (friends or neighbors), which increased the odds for a positive outcome . In this model, reading during the lockdown  was positively associated with improving/maintaining sufficient PA , and social-distancing measures. These regulations precluded free and low-cost options to perform PA and might decrease motivation, hampering PA adherence. Interestingly, despite a long time since the last face-to-face visit, a remarkable proportion of our sample followed the personalized PA recommendations derived from the +ÀGIL Barcelona program. This reinforces the need of community-based programs to empower older adults for self-care .The association between depressive symptoms and low PA levels has been previously described  and coulWe also found a negative, independent association between fatigue and total PA levels and its improvement or maintenance during the lockdown. Fatigue, a subjective self-reported global tiredness and lack of energy , has beeSocial relationships are pivotal for healthy aging  and haveReading is a complex activity, which combines both cognitive and mental functions. Previous studies have reported that reading has a positive impact on stress, insomnia, depression symptoms and dementia development. Indeed, all of them related negatively with levels of physical activity . SurprisWe acknowledge the different limitations of our study. First, our pre-lockdown assessment cannot completely reflect the situation immediately pre-lockdown because of the time elapsed since the last face-to-face visit to the telephonic interview. However, it provides the added value of a longitudinal design. Second, the sample size was relatively small, although representing almost 50% of the whole +ÀGIL Barcelona sample. As for strengths, PA levels were assessed by the BPAAT scale, a short validated scale, with good psychometric properties, that was already part of the +ÀGIL Barcelona assessment, allowing us to track pre-post changes. In this same line, the study population had an extended pre-lockdown assessment, which offered a comprehensive sample characterization. The telephone interview was short, which is important for such a vulnerable population, who could get tired easily.Considering that reduced PA is a key risk factor to increased frailty and disability, our results highlight the need to design and adapt strategies for community and home-based PA in older adults, particularly in challenging situations such as the ongoing COVID-19 pandemic. These strategies should likely take into account multifactorial contributors to reduced PA, such as mental status, social relationships and frailty-related symptoms such as fatigue. In light of COVID-19 pandemics, we also believe that there is an increased need for adapted digital solutions to provide PA in the community. These should be adapted through a broad system thinking strategy, particularly for vulnerable older adults with such multidomain contributors to inadequate PA.In our sample, strict home lockdown due to the COVID-19 pandemic had determined a decrease in PA levels. Moreover, pre-lockdown mental health, frailty-related symptoms and social relationships were consistently associated with both PA levels during-lockdown and pre-post change. Our data could be used to design specific person-centered plans to maintain PA levels in frail older community-dwellers. However, larger population studies including dwelling older adults are needed to confirm our results.


More than 50 000 papers have been published about COVID-19 since the beginning of 2020 and several hundred new papers continue to be published every day. This incredible rate of scientific productivity leads to information overload, making it difficult for researchers, clinicians and public health officials to keep up with the latest findings. Automated text mining techniques for searching, reading and summarizing papers are helpful for addressing information overload. In this review, we describe the many resources that have been introduced to support text mining applications over the COVID-19 literature; specifically, we discuss the corpora, modeling resources, systems and shared tasks that have been introduced for COVID-19. We compile a list of 39 systems that provide functionality such as search, discovery, visualization and summarization over the COVID-19 literature. For each system, we provide a qualitative description and assessment of the system’s performance, unique data or user interface features and modeling decisions. Many systems focus on search and discovery, though several systems provide novel features, such as the ability to summarize findings over multiple documents or linking between scientific articles and clinical trials. We also describe the public corpora, models and shared tasks that have been introduced to help reduce repeated effort among community members; some of these resources  can provide a basis for comparing the performance of different systems. Finally, we summarize promising results and open challenges for text mining the COVID-19 literature. Even on the low-end of this estimate, conventional reading methods are challenged and we must rely on automated text mining approaches to address this tidal wave of research output.Since the discovery of the novel coronavirus SARS-CoV-2 , 107 towOne of the major application areas of biomedical text mining is managing information overload , 40, 116In response to the large volume of literature published on COVID-19, the computing community has introduced text mining corpora, modeling resources, systems and community-wide shared tasks specific to COVID-19 to address the mounting challenge. Corpora are collections of documents, preprocessed to extract machine-readable text, that are used for text mining; in this case, we focus on corpora-containing scientific articles. Modeling resources can be incorporated by text mining practitioners into production systems and consist of things such as text embeddings, data annotations, pretrained language models, knowledge graphs and more. Systems are applications that incorporate text mining models and user interfaces to provide functionalities such as the ability to search, discover or visualize article content. Shared tasks are community competitions that promote concentrated work on specific scientific problems.Figure In this review, we summarize the corpora (Section on “Text mining corpora”), modeling resources (Section on “Text mining modeling resources”), systems (Section on “Text mining systems”) and shared tasks (Section on “Shared tasks”) that have been created/implemented to support text mining over the COVID-19 literature. We note standout systems that either provide strong performance on fundamental tasks such as search or question answering (QA) or provide novel functionality such as multi-document summarization or linking between articles and clinical trials. We also discuss strategies for building performant and useful systems, specifically advocating for systems that facilitate the production of systematic reviews, or those that directly address the needs of clinicians, researchers and public health officials.https://www.semanticscholar.org/cord19) [https://www.who.int/emergencies/diseases/novel-coronavirus-2019/global-research-on-novel-coronavirus-2019-ncov) and preprint servers bioRxiv, medRxiv and arXiv. Paper metadata from these sources are harmonized, PDFs are converted into machine-readable JSON using the S2ORC pipeline described in [One of the earliest and largest literature corpora created to support COVID-19 text mining is the COVID-19 Open Research Dataset  , a corpuribed in  and HTMLribed in . As of 1LitCovid is a curated set of open access COVID-19 papers from PubMed , containhttps://www.cdc.gov/library/researchguides/2019novelcoronavirus/researcharticles.html). These databases overlap with other corpora; for example, the WHO database is ingested by CORD-19 and much of the CDC database overlaps with PubMed and PMC, also sources of papers in CORD-19 and LitCovid. The CDC database also provides a complementary document collection of white papers and technical reports.Other curated sets of COVID-19 papers are also available, e.g. the WHO’s COVID-19 database or the Centers for Disease Control and Prevention (CDC)’s COVID-19 research articles database(https://www.elsevier.com/connect/coronavirus-information-center), Springer Nature’s Coronavirus Research Highlights (https://www.springernature.com/gp/researchers/campaigns/coronavirus), JAMA Network’s COVID-19 Collection  or Science’s COVID-19 Collection (https://www.sciencemag.org/collections/coronavirus). Many publishers have provided COVID-19 literature under temporary open access licenses through PMC’s Public Health Emergency COVID-19 Initiative (https://www.ncbi.nlm.nih.gov/pmc/about/covid-19/), thus making these texts available to the public through PMC and through aggregate corpora like CORD-19 . Full text may also be unavailable in some cases or may only be available in the form of PDFs, which must undergo extensive preprocessing to extract full text for text mining. Finally, the open access status for many articles is under-specified, which could result in unpleasant revocation of licenses and nullification of datasets and systems in the future.Lastly, several publishers have compiled and released collections of their COVID-19 literature, such as Elsevier’s Novel Coronavirus Information Center  or PubAnnotation (http://pubannotation.org/). On PubAnnotation, for example, automatically generated annotations of terms from several ontologies and PICO elements are available for the CORD-19 and LitCovid corpora.Map Lite  or ScispMap Lite ) or manuhttps://github.com/fhircat/CORD-19-on-FHIR), a version of CORD-19 with semantic annotations to clinical entities in the categories of condition, medication and procedure. This version can be more easily integrated into clinical workflows or used to supply evidence for clinical decision support. For the CODA-19 annotation project [Also available is CORD-19-on-FHIR  is perhaps the largest of these, combining literature, case statistics and genomic and molecular data. Another project, the Knowledge Graph Toolkit [https://www.wikidata.org/) and the Comparative Toxigenomics Database (http://ctdbase.org/), as well as the Blender Lab COVID-KG (http://blender.cs.illinois.edu/covid19/) [ Toolkit , integraovid19/) , anotherLanguage models, specifically pretrained contextual language models, are ubiquitous in modern text mining systems. These models are the state-of-the-art in natural language processing and have significantly outperformed previous baselines on the full spectrum of language-based tasks [https://github.com/manueltonneau/covid-berts). Poerner et al. [ed tasks , 53, 67.ed tasks  models sed tasks , which hed tasks  fine-tunr et al.  also disr et al.  vectors r et al. , resultihttps://github.com/allenai/cord19). These text mining systems are collected through a public form on the CORD-19 website, by searching COVID-19 papers and preprints in the CORD-19 corpus and from social media. We omit systems that appear to index documents using off-the-shelf software (e.g. ElasticSearch) without additional data or methodological extensions or without other obvious distinguishing system features.Numerous text mining systems for COVID-19 literature have been released in 2020 thus far. We compile a list of 39 systems in Table All of the included systems facilitate search or exploration over the COVID-19 literature, though some feature more specific text understanding tasks such as summarization, QA and claim verification. To facilitate a comparison between systems, we provide the following in Table The majority of systems we document here make use of public corpora and data resources, which are easily accessible from their source. Corpora like CORD-19 and LitCovid and other commonly used data resources like ClinicalTrials.gov, UMLS and biomedical ontologies adhere to FAIR principles of Findability, Accessibility, Interoperability and Reusability , though The rest of this section is organized as follows: we define the text mining tasks used to categorize and assess the surveyed systems and use these tasks to anchor discussion and comparison of systems described in Table https://aws.amazon.com/kendra/) or Azure Cognitive Search (https://azure.microsoft.com/en-us/services/search/). Systems like COVID papers browser Row S1), Exploration-focused systems assist users with discovery and understanding of documents in a corpus. Such systems may not aim to satisfy a specific informational need but are rather used to help users understand the underlying data source; as such, their interfaces facilitate unfocused data exploration and repeated interactions. Instead of supporting arbitrary user-written queries, these systems may provide a predefined set of topics or keyphrases with which to filter the documents. Keywords or keyphrases can be extracted from documents using supervised biomedical entity extraction (e.g. ScispaCy [ScispaCy  and BERNScispaCy ) or unsuScispaCy ). Paper ScispaCy  (Row S24https://covid-19-navigator.mybluemix.net/), perhaps the best example of this, allows users to perform boolean queries using UMLS concepts and semantic types [Among the systems that leverage KBs, those that use curated domain-specific KBs tend to provide a better user experience, since the entities and relations in these KBs have been vetted by domain experts. IBM Watson’s COVID-19 Navigator  or ontologies (e.g. Gene Ontology). These systems are well positioned to integrate with other data sources that use the same shared vocabularies and to leverage the automated reasoning or inference capabilities of structured KBs. We also observe that very few text mining systems in production have a clinical focus. Those that are better integrated with clinical trial data , participants are asked to extract answers to key COVID-19 scientific questions from the documents in the CORD-19 corpus. Round 1 of the challenge began with nine open-ended questions on COVID-19, seeking information on transmission, diagnostics and treatment. Kaggle partnered with medical experts to identify the most useful contributions from the more than 500 submissions it received.For the Kaggle challenge . An example submission is described in . The tabhttps://www.kaggle.com/covid-19-contributions). Table results have been used to quickly bootstrap QA datasets [Upon the completion of the Kaggle challenge, the community has moved towards repurposing the submitted contributions. Among the contributions are output review tables from Round 2, which provide a useful overview of research findings shared task [The TREC-COVID  and indexers from the NLM. Top submission results are ranked by assessors to produce a partial gold ranking over the input documents.Over 55 teams participated in the TREC-COVID challenge, including several systems from Table https://bionlp.nlm.nih.gov/epic_qa/) challenge, co-located at the 2020 Text Analysis Conference (TAC), motivates the development of QA systems for COVID-19. EPIC-QA focuses on QA over both scientific literature (supplied by the CORD-19 corpus) as well as a corpus of consumer-friendly documents derived from authoritative public-facing sites such as the website of the CDC and various agencies of the NIH.The Epidemic question answering (EPIC-QA, The task is more fine-grained than TREC-COVID in that EPIC-QA evaluates system ability to extract and rank spans of text from documents, rather than full documents, that serve as answers to questions. The evaluation also judges answer comprehensiveness using a ‘nugget’-based evaluation for QA . The CORSystematic reviews aim to synthesize results over all relevant published studies on a topic, providing the highest quality of evidence and recommendations for clinical and public health decisions. They have become a fixture in the biomedical literature, with many established protocol around their registration, production, publication and update , 15, 81.Systematic reviews have played an important role in the scientific response to COVID-19. Rapid reviews, which condense and shorten the typically months- or years-long systematic review process , 89, havAs the number of publications on COVID-19 has grown, it becomes increasingly difficult and expensive to produce and update these reviews. Systems that assist with or automate parts of the review process are needed. Several existing systems focus on automating parts of the systematic review process more broadly . These sThe processes around creating systematic reviews have matured over the past several decades. Reviews provide trusted evidence to clinicians and policymakers and are useful for addressing information overload, as they survey and summarize information across numerous studies. Targeted methods and systems that assist in or automate systematic reviews for COVID-19 could be very impactful going forward.From the start of the COVID-19 pandemic in late 2019 to now, the community has introduced numerous text mining resources and systems aimed at handling the tidal wave of the new COVID-19 literature. Over this time, we have iterated through many versions of corpora, models, systems and shared tasks. Though significant progress has been made, many open questions remain. We summarize some learnings and challenges below.It is helpful to have a centralized corpus of documents, such as CORD-19 or LitCovid, that is maintained and updated regularly. The existence of these corpora free the community to focus on model and system development, encouraging faster iteration and development of novel methodology.Intermediate infrastructure for sharing both automatically and manually produced data annotations, such as PubTator or PubAnnotation, increase the reach of annotation efforts. Annotations shared through these platforms can be reused by many downstream applications.Community shared tasks can be used to pool resources for evaluation and provide expert assessments on the performance of different systems. For COVID-19, the rapid submission and assessment cycles employed by tasks like Kaggle and TREC-COVID emulate the realistic challenges of rapid system development and deployment. These realistic sensibilities, though challenging to implement for organizers, may result in more robust systems that can adapt quickly to changing data and user needs.It is important to engage expert communities early and often, to keep the focus on real-world tasks and user needs. Tasks should be selected to maximize their similarity to relevant workflows, e.g. paper search, or systematic review construction. Because these existing workflows are validated and known to be useful, anchoring shared tasks to these workflows is more likely to result in effective systems.Though much of the infrastructure discussed in this review have existed for decades, the realities of COVID-19 forced us to accelerate the processes around science and research, including in the steps of dataset development, model development and deployment, evaluation and publication. Adapting to these changes has produced difficulties along the way. For example, earlier releases of the CORD-19 corpus were unstable, with formats changing from week to week as we adapted to engineering challenges and user requests. Shared tasks also had to adjust accordingly. TREC-COVID, for example, was organized in five rounds, with one week windows for submission during each round. This required very rapid turnaround from both the participants submitting system for review as well as the expert assessors, who are used to working within more relaxed time constraints.ad hoc retrieval is well defined and has historically been recognized as a useful and important text mining task. The TREC-COVID assessments, though completed in a narrower time window than typical, were still relatively easy for the expert assessors. In the case of Kaggle, however, the first round tasks were very open-ended and submissions were correspondingly diverse and difficult to compare. Medical experts were asked to manually assess more than 500 of these submissions, which was quite time-consuming. As Kaggle converged on a more structured table completion task in Round 2, these assessments became easier and arguably a better use of expert time.It also takes time to identify how best to involve medical experts in assessment. For TREC-COVID, the task of Methods for text mining have matured significantly over the past few decades. With COVID-19, we have an opportunity to test these methods in the sort of time- and resource-constrained setting where automation or computational assistance may be most helpful. Preliminary results are promising. Since early March, several dozen production systems tailored to various aspects of search and retrieval have been released, two shared tasks have completed with more in progress and biomedical experts have been engaged to assess and evaluate many of the systems and tools that have been publicly deployed. Aiming to help researchers manage information overload, some systems use text mining techniques to assist with conducting rapid reviews on the COVID-19 literature. As we move forward, we encourage the community to make further developments in this area. We also remind the community to keep track of practical user needs as we develop text mining systems; though much progress has been made, significant improvements are needed to provide meaningful and actionable results in the fight against COVID-19.


Since the long fluoroscopy time in primary PCI for ST-segment elevation myocardial infarction (STEMI) could be an indicator of delayed reperfusion, it should be important to recognize which types of lesions require longer fluoroscopy-time in primary PCI. The purpose of this study was to investigate the association of the long fluoroscopy-time with clinical factors in primary percutaneous coronary interventions (PCI).A total of 539 patients who underwent primary PCI were divided into the conventional fluoroscopy-time group (Q1-Q4: n = 434) and the long fluoroscopy-time group (Q5: n = 105) according to the quintile of the total fluoroscopy time in primary PCI. Univariate and multivariate logistic regression analyses were performed to find associations between clinical variables and the long fluoroscopy-time.In univariate logistic regression analysis, prevalence of diabetes mellitus, hemodialysis, and previous CABG were significantly associated with the long fluoroscopy-time. In addition, complex lesion characteristics such as lesion length, lesion angle, tortuosity, and calcification were associated with the long fluoroscopy-time. In multivariable logistic regression analysis, lesion length , moderate-excessive tortuosity , and moderate to severe calcification  were significantly associated with the long fluoroscopy-time.In primary PCI for STEMI, diffuse long lesion, tortuosity, and moderate-severe calcification were associated with the long fluoroscopy-time. These complex features require special attention to reduce reperfusion time in primary PCI. Primary percutaneous coronary intervention (PCI) has dramatically reduced the mortality of ST-segment elevation myocardial infarction (STEMI) , 2. AlthWe identified consecutive 624 patients with STEMI in the Saitama Medical Center, Jichi Medical University from January, 2015 to December, 2018. We excluded cases that did not have PCI to the culprit lesion, because of medical therapy alone or surgical therapy to the culprit lesion. We also excluded non-emergent PCI cases, unsuccessful PCI cases, and cases in which ≥2 vessels were treated simultaneously. We defined the long fluoroscopy-time group as the longest quintile of fluoroscopy time (Q5), and defined the conventional fluoroscopy-time group as the other quintiles of fluoroscopy time (Q1-Q4). This study was approved by the Institutional Review Board of Saitama Medical Center, Jichi Medical University, and written informed consent was waived because of the retrospective study design.PCI procedures were performed on a biplane fluoroscopy system , with three magnetic fields  and a standard image acquisition program at 15 frames per second during cine acquisition and 7.5 frames per second during fluoroscopy. Primary PCI was performed using standard techniques via the radial artery, femoral artery, or rarely brachial artery. First, we advanced a conventional guidewire across the lesion, and used a small (2.0-mm diameter) balloon or thrombus aspiration catheter. The choice of devices was at the discretion of the interventional cardiologist. Activated coagulation time was maintained for >250 seconds during PCI. IVUS was routinely used for almost all lesions.Acute myocardial infarction (AMI) was defined based on universal definition of myocardial infarction . STEMI wQuantitative coronary angiography (QCA) parameters were measured using a cardiovascular angiography analysis system . The definition of lesion characteristics including lesion length, eccentricity, tortuosity, lesion angle, ostial lesion, bifurcation lesion has been previously described . In an oData are shown as the mean ± SD or percentage. Categorical variables are presented as numbers (percentage), and were compared using the Pearson χ2 test. Continuous variables were compared between the groups using the unpaired Student’s t test. Univariate and multivariate logistic regression analyses were performed to find the association between clinical variables and the long fluoroscopy-time. In this model, the long fluoroscopy-time, which was defined as ≥33 minute, was used as the dependent variable. In the multivariate stepwise logistic regression model, the selection of independent variables was derived from the results of univariate logistic regression analysis . However, variables with missing values were not included in the model. The multivariate logistic regression analysis with likelihood ratio statistical criteria using backward elimination method was performed. The odds ratio (OR) and the 95% confidence interval (CI) were also calculated. A P value <0.05 was considered statistically significant. We analyzed all data by SPSS ver. 24 for Windows .During the study period, we had 624 STEMI cases in our medical center. We excluded 53 cases that did not have PCI to the culprit lesion, 27 non-emergent PCI cases, 4 cases in which ≥2 vessels were treated simultaneously, and 1 unsuccessful PCI case. Our final study population was 539 patients, and divided into the long fluoroscopy-time group (n = 105) and the conventional fluoroscopy-time group (n = 434). The study flowchart is shown in The comparison of clinical, lesion and procedural characteristics is shown in The univariate logistic regression models to find the factors associated with the long fluoroscopy-time are shown in The multivariate stepwise logistic regression analysis to find the factors associated with the long fluoroscopy-time is shown in The present study included 539 patients who underwent primary PCI for STEMI, which were divided into the conventional fluoroscopy-time group (n = 434) and the long fluoroscopy-time group (n = 105). In the multivariate stepwise logistic regression analysis, serum creatinine, cardiac arrest at prehospital or ER, three vessel disease, diffuse long lesion, moderate to excessive tortuosity, moderate to severe calcification, and big size of guiding catheter were associated with the long fluoroscopy-time, suggesting that complex lesion characteristics required longer fluoroscopy-time in primary PCI.Although there were several studies to find determinants of the long fluoroscopy time in PCI , 15, theIn the present study, moderate-excessive tortuosity was also associated with the long fluoroscopy time. Severe vessel tortuosity has been identified as a predictor of unsuccessful PCI . NikolskSimilarly, calcification was significantly associated with the long fluoroscopy time in the present study. Since severe calcification was closely associated with difficulty of device delivery , 21, it Serum creatinine was associated with the long fluoroscopy-time. Increased serum levels is known to be associated with advanced atherosclerosis , 26. AdvClinical implications of the present study should be noted. Since primary PCI is performed irrespective of on/off-hours , junior First, because this study was a single-center retrospective observational study, there is a risk of patient selection bias. Second, we arbitrary defined the long fluoroscopy-time as the longest quintile of the fluoroscopy time, because there were no established cut-off points for the long fluoroscopy time, which were also used in early literatures –33. MoreIn primary PCI for STEMI, serum creatinine, cardiac arrest at prehospital or ER, three vessel disease, diffuse long lesion, moderate-excessive tortuosity, severe calcification were associated with the long fluoroscopy-time. These complex features require special attention to reduce reperfusion time in primary PCI.S1 File(XLSX)Click here for additional data file.


III-nitride semiconductors have wide bandgap and high carrier mobility, making them suitable candidates for light-emitting diodes (LEDs), laser diodes (LDs), high electron mobility transistors (HEMTs) and other optoelectronics. Compared with conventional epitaxy technique, van der Waals epitaxy (vdWE) has been proven to be a useful route to relax the requirements of lattice mismatch and thermal mismatch between the nitride epilayers and the substrates. By using vdWE, the stress in the epilayer can be sufficiently relaxed, and the epilayer can be easily exfoliated and transferred, which provides opportunities for novel device design and fabrication. In this paper, we review and discuss the important progress on the researches of nitrides vdWE. The potential applications of nitride vdWE are also prospected. Inorganic semiconductors possess many advantages over organic semiconductors, including high carrier mobility, long-term stability, and reliability. Compared with elemental semiconductors , III-nitrides semiconductors, such as AlN and GaN, have higher carrier mobility and radiation recombination rate, which makes III-nitrides perfect candidates for light-emitting diodes (LEDs), lasers (LDs), and high electron mobility transistors (HEMTs) . Additio2/MoS2 structure in 1984  AlN|| [1210]sapphire, which was consistent with the epitaxial relationship of AlN film grown on the bare sapphire substrate  InAs‖(001)[100] SLG  and external quantum efficiency (EQE) of it were increased. The LED’s EQE is the product of internal quantum efficiency (IQE) and light extraction efficiency (LEE). Considering that the as-fabricated device’s IQE was decreased due to the poor crystalline quality of the as-grown GaN film, the LEE played an important role in the significant EQE improvement. It may attribute to the multilayer graphene interlayer. In detail, the high refractive index of graphene and the holes in the as-grown GaN epilayer can both contribute to light scattering, i.e., the direction of the propagation of light may change from being regular to being random and have more opportunities to be extracted to the outside, leading to the enhanced light extraction [The introduction of graphene can also enhance the light extraction of LEDs. In 2017, Li et al. grew the n-GaN/5-period Intraction . 0.55Ga0.45N/Al0.4Ga0.6N/Al0.5Ga0.5N MQWs/p-AlGaN structure. After the characterization, they pointed out that the as-fabricated DUV-LED had a smoother and flatter morphology, as well as better electrical properties than that without the graphene interlayer. Compared to the DUV-LED without the graphene interlayer, its dominant EL peak was located at 280 nm without shifting despite the changing current, and the EL intensity was increased by two orders of magnitude owing to the negligible residual stress [With a better understanding of the van der Waals epitaxy, the performance of III-nitride-based LEDs prepared using the van der Waals epitaxy method is optimized. In 2018, Chen et al. successfully prepared a high-brightness blue LED directly on a graphene-coated substrate and characterized its structure and electrical properties. The as-grown MQWs presented an abrupt interface and uniform In doping a,b. The l stress  , unifor


The limit of detection was 3.01 ppm. Two other optical-based approaches, Spectrochip and NanoDrop, were used for comparison. The results suggest that the developed paper-based analytical device is comparable to other colorimetric measurements, as determined by Bland–Altman analysis. The device was clinically validated using urine from six paraquat-poisoned patients. The results prove that the developed paper-based analytical device is accurate, easy-to-use, and efficient for urine paraquat concentration measurement, and may enable physicians to improve clinical management.Paraquat is a highly toxic herbicide. Paraquat poisoning is often fatal and is an important public health threat in many places. The quick identification and timely initiation of treatment based on timely analysis of the paraquat concentration in urine/serum could improve the prognosis for patients. However, current paraquat concentration measurements are time-consuming and difficult to implement due to the expensive and bulky equipment required. To address these practical challenges, paper-based devices have emerged as alternative diagnostic tools for improving point-of-care testing. In this study, we demonstrate the successful use of a paper-based analytical device for the accurate detection of urine paraquat concentration. The developed paper-based analytical device employs colorimetric paraquat concentration measurements. The R N,N′-dimethyl-4,4′-bipyridinium dichloride) is one of the most widely used herbicides in the world. Introduced for agricultural use in the 1960s, this non-selective herbicide became a low-cost, readily accessible, and prevalent product globally. Paraquat is a highly toxic agent and paraquat ingestion, whether intentional or accidental, is frequently fatal. Paraquat has been prohibited in many countries due to its lethality, but paraquat poisoning remains an important public health threat in many regions [Paraquat , and lead to cell death. The most characteristic feature of paraquat poisoning is lung damage. These effects occur during the first several hours following paraquat ingestion. Production of toxic free radicals and subsequent inflammation lead to lung fibrosis and respiratory failure. Paraquat also attacks other organs. In larger doses, paraquat ingestion can cause multi-organ failure and death ,5.The clinical prognosis for acute paraquat poisoning is dose dependent. Paraquat concentrations in plasma and urine are strongly correlated with the prognosis. The ingestion of large doses of paraquat may lead to death due to multi-organ failure and shock within only a few days ,5. The sVarious methods of measuring paraquat concentration have been proposed, including high-performance liquid chromatography (HPLC)/mass spectrometry (MS), gas chromatography (GC)/MS, and photometry coupled with a sodium dithionite assay ,10,11. HIn recent years, paper-based analytical devices have become increasingly well-developed. Microfluidic paper-based analytical devices were introduced in 2007 . The proThis study demonstrates the novel design of a paper-based analytical device for detecting paraquat poisoning. The developed device is compared with other commercially available colorimetric detection methods, i.e., Spectrochip and NanoDrop. The device is also subjected to clinical validation using urine samples from six paraquat-poisoning patients.Paraquat dichloride hydrate , sodium hydroxide (NaOH) , sodium dithionite , phosphate buffered saline (PBS) , and Whatman qualitative filter paper, No. 1  were used in the experiments.The paper-based analytical device was prepared as 96-well plates on paper substrates. Specifically, we designed a 96-well template pattern (8 × 12 circle array) using Microsoft Office software. The diameter of each well was 0.4 cm. We then fabricated the paper-based microzone plates using wax-based printing technology on to paper . We used a wax printer  for printing. Afterward, the paper device with the wax printed wells was heated by an oven for 5 min at 105 °C. In this step, the wax melted and allowed it to penetrate through the highly permeable paper. Finally, the hydrophilic chemical reaction area with complete, well-defined hydrophobic wax barriers was formed. The chemical reaction area impregnated with reactive reagents that produced a color change following the application of the patient test samples. The chemical reaction area was also the detection test zone, which allows us to measure the color intensity change. The schematic diagram of our paper-based analytical device is presented as w/v) sodium dithionite were placed onto each detection zone of the paper-based 96-well plate; (2) 8 μL of the experimental sample was subsequently added to each well before the reagents dried out. Standard samples of various concentrations  and patient samples (diluted in PBS) were applied to the wells.The mechanism of the colorimetric assay is based on the chemical reaction of paraquat and sodium dithionite, which results in the formation of a blue radical ion. The paper-based colorimetric assays were conducted as follows: (1) 5 μL of 5 N NaOH and 2 μL of 20% . The paper-based analytical device was implemented on a white base background. The digital camera was set to auto-focus mode. We captured the image perpendicularly in ambient light.The resulting data were then analyzed using Image J software . The region of interest (ROI) of each detection zone was selected as a circle with a diameter of 0.38 cm (95% of the diameter of each well) to reduce the interference of reflection. We minimized other interferences of inhomogeneous color intensity by maintaining an equal condition in each measurement. Then, we analyzed the RGB color values of each detection zone before and after testing, where R, G, and B are the red, green, and blue coordinates. The ΔRGB value is the mean intensity difference in RGB analysis after 10 min reaction according to the below equation.All samples were analyzed in triplicate. The standard deviation, limit of detection, and limit of quantification of the developed paper-based device were also calculated.Spectral analysis instruments have been used for chemical and biochemical analyses, immunoassays, biosensors, etc. Two spectral detection devices were compared with the developed device, i.e., a spectrophotometer  and a chip-based spectrometric device . The Spectrochip device employs innovative micro-grating technology to create a palm-size portable point-of-care testing (POCT) device for biomedical spectral analysis ,19. The w/v) sodium dithionite solution was diluted in 1 N NaOH, 500 μL was loaded into each test cuvette, and the paraquat samples were added. The paraquat samples included paraquat standard solutions  and patient urine samples. The chemical reaction resulted in a color change from colorless to blue, and the color data were detected using a traditional spectrophotometer  and a new spectrometric device (Spectrochip), respectively.For comparative evaluation of the test samples, 20% .A total of six urine samples were collected from individual patients suffering from paraquat poisoning. Clinical validation of the developed device was conducted by comparing the paraquat concentration determined using the other devices.ΔRGB value  was calculated as described in the Methods section. After reaction of the paraquat sample in the paper-based analytical device, the color intensity was measured and the R2 value) in our system was 0.9989.We then established the calibration function and standard curve using six different concentrations of paraquat . Two spectral detection devices were compared with the developed device, i.e., a spectrophotometer  and a chip-based spectrometric device . Five different paraquat concentrations  were measured using Spectrochip and NanoDrop respectively.A = −log (T), where A and T are the absorbance and transmittance, respectively. The calibration function and standard curve were established (The transmission of white light from a light-emitting diode (LED) was measured with Spectrochip. The transmittance data were converted to absorbance data by using the relation: ablished .The absorption of white light from the LED was also measured with a common UV/visible spectrometer (NanoDrop); the absorbance increased as the color intensity increased. The calibration function and standard curve were established as shown in The spectra of serial concentrations of the paraquat samples were measured using both devices. A transmittance peak at 600.405 nm was noted in the Spectrochip data. An absorbance peak at 603 nm was detected via NanoDrop. Two calibration curves were constructed based on the transmittance of paraquat at 600.405 nm for solutions of differing concentrations and based on the absorbance at 603 nm to create an exponential plot and sigmoidal plot, respectively.The results from the developed paper-based analytical device were compared to the results from the Spectrochip and NanoDrop systems using Bland–Altman analysis and were found to be similar . Bland–AClinical validation of the developed paper-based analytical device was conducted by comparing the results to the measurements using the other clinical devices. 2 value for the standard curve using data from the developed paper-based analytical device was 0.9989, with a concentration range of 0–100 ppm. For paraquat detection, the limit of detection and limit of quantification were 3.01 and 10.02 (ppm), respectively. Standard curves for paraquat detection were also established by using data from the other two methods, Spectrochip and NanoDrop, for comparison. Although the two devices are commercialized, their clinical applications are limited and under-developed now, especially in the clinical toxicology field. As new diagnostics tools for paraquat detection, the standard measuring process of the two devices has not been established. In addition, the devices are not clinically available in hospitals. The R2 values for the standard curves of the data from Spectrochip and NanoDrop were 0.9888 and 0.9941, respectively.This study demonstrates a paper-based analytical device that can be used for detection of paraquat poisoning. The paper-based analytical device employed the chemical reaction of paraquat and sodium dithionite in alkaline solution. The colorimetric method was used for concentration measurement. The RFurthermore, the developed paper-based analytical device was clinically validated by using patient samples. The measurement results from the developed paper-based analytical device, Spectrochip, and NanoDrop were compared using Bland–Altman analysis. The developed paper-based analytical device showed consistency with Spectrochip and NanoDrop, as determined by Bland–Altman analysis. Our experiment indicates that urine paraquat analysis using the developed paper-based analytical device is comparable to that achievable with other traditional colorimetric methods, which are more complicated and time-consuming.Acute paraquat intoxication can be fatal and it remains a clinical challenge. Although there is no gold-standard treatment for paraquat intoxication, except supportive care, recent evidence suggests that timely hemoperfusion is beneficial for resolving acute paraquat poisoning. Hemoperfusion conducted within four to five hours following paraquat ingestion, combined with pulse therapy, could reduce the mortality . A recenWe developed a paper-based analytical device employing a colorimetric method. The whole detection process is simple and the results are of relatively good quality. The accuracy of the paper-based analytical device is superior to that of quick urine sodium dithionite assays currently in clinical use, and the measurement requires only a short time for completion. In addition to its utility as a diagnostic tool, this time-saving and simple detection device could be used for easy follow-up care and may allow physicians to precisely decide on a treatment regimen based on timely concentration analysis. Paper-based analytical devices can also be developed to provide a platform for simultaneous sample analyses, which further underscores their utility, efficiency, and cost-saving features, and supports their potential for commercial product development. Our study proves that paper-based analytical devices can improve point-of-care testing and may improve acute paraquat poisoning treatment.This paper-based analytical device was developed for the analysis of paraquat in urine. Previously, our laboratory developed a paper-based analytical device designed for the rapid assay of paraquat in human serum . The preWe successfully developed a paper-based analytical device for urine paraquat concentration measurement. The analytical device can simplify measurement procedures and provide quantifiable colorimetric results. Our paper-based analytical device is an ideal point-of-care tool that is demonstrably accurate, less-invasive, easy-to-use, and time- and cost-effective. This device could be an efficient tool and enable physicians to improve acute paraquat intoxication management.