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Abstract

Background

Recent advances in the diagnosis and treatment of pulmonary thromboembolism (PTE) have significantly improved survival rates. This progress has shifted greater attention to long-term prognosis, highlighting the need for holistic management that integrates acute care, systematic follow-up, and continuous monitoring.

Methods

The Optimal Follow-Up in Pulmonary Embolism (OFUPE) is a prospective randomized study comparing two follow-up strategies in acute PTE patients: (1) the optimal follow-up strategy, which comprises a systematic protocol incorporating evidence-based education, individualized care planning, and telemedicine support; and (2) the routine follow-up strategy, consisting of standard monitoring. Eligible patients with acute PTE are randomly assigned in a 1:1 ratio to each group. Primary endpoints include all-cause mortality and adverse events.

Discussion

The OFUPE study examines the role of holistic management in PTE and proposes a systematic framework for post-PTE care.

Trial registration Chinese Clinical Trial Registry ChiCTR2200064675.

Keywords

pulmonary embolism follow up studies prognosis prospective studies

Background

Pulmonary thromboembolism (PTE), the third leading cardiovascular cause of death, affects 39–115 per 100 000 annually.^1–3 Although advances in acute management have reduced short-term mortality, a substantial proportion of survivors develop chronic complications.^4–6 Studies show that nearly 50% of PTE patients experience persistent functional limitations—such as exertional dyspnea, exercise intolerance, and reduced health-related quality of life (HRQoL)—one-year post-diagnosis, with outcomes significantly worse than age-matched controls.^7,8 These findings highlight the critical need for holistic management to detect and manage chronic complications beyond initial anticoagulation therapy.^9–12

However, long-term follow-up after acute PTE is often based on periodic outpatient visits. It mainly focuses on symptom review and anticoagulation management but lacks proactive elements such as systematic patient education, individualized care planning, and telemedicine support. This approach may delay the recognition of important sequelae like post-PTE syndrome, chronic thromboembolic pulmonary disease (CTEPD), or chronic thromboembolic pulmonary hypertension (CTEPH).

Recent registry studies, including the ASPIRE and SYSPPE trials, have introduced systematic follow-up strategies. ASPIRE demonstrated improved early detection of mild CTEPH through assessments at 3 months, while SYSPPE reported a 300% increase in CTEPH diagnoses using telemedicine follow-up.^13,14 However, both studies focused primarily on CTEPH as the primary endpoint and used fixed follow-up protocols, with insufficient attention to individual patient disease progression or personalized follow-up approaches. The prognostic impact of optimized follow-up strategies remains unclear.

To address these gaps, the Optimal Follow-Up in Pulmonary Embolism (OFUPE) study proposes a comprehensive, proactive follow-up protocol integrating systematic education, telemedicine support, and multidimensional monitoring. We hypothesize that this study will: (1) improve early detection of high-risk patients, (2) enable timely intervention for emerging complications, (3) ultimately improve long-term outcomes.

Objectives

This study aims to establish an optimal follow-up strategy for patients with acute PTE and to evaluate its superiority over routine follow-up by comparing their effects on clinical prognosis. The proposed strategy is expected to help physicians promptly identify high-risk patients and initiate timely interventions, thereby improving patient outcomes.

Study Design

This prospective, randomized, parallel group study evaluates two distinct follow-up strategies for acute PTE patients. Using computer-generated randomization with stochastic tables, eligible patients will be allocated in a 1:1 ratio to either: (1) the optimal group, receiving a comprehensive, protocol-driven follow-up program; (2) the routine group, continuing standard care. The complete study protocol, including enrollment criteria, intervention details, and assessment timelines, is presented in Figure 1.

Figure 1.

Flowchart showing the patient flow through the study.

Methods

Study Setting

Patients will be primarily recruited from Shandong Provincial Hospital Affiliated to Shandong First Medical University, China.

Eligibility Criteria

Inclusion criteria include the following: (1) Provision of written informed consent by the patient and/or legal guardian(s); (2) Age > 14 years at enrollment; (3) Confirmed PTE by computed tomography pulmonary angiography (CTPA) or ventilation/perfusion (V/Q) scanning according to the guideline.³

Exclusion criteria include the following: (1) Concurrent life-threatening comorbidities with potential to compromise short-term prognosis; (2) History of severe psychiatric disorders, substance dependence, or other conditions impairing capacity to provide consent or comply with study procedures; (3) Inability to communicate verbally with investigators; (4) Anticipated inability to complete required follow-up assessments.

Interventions

Eligible patients will be assigned to one of two groups: (1) the optimal group, which undergo a comprehensive, protocol-driven follow-up program, or (2) the routine group, which maintain routine follow-up procedures.¹⁵ The routine group involves a 3-year follow-up with assessments at eight predefined time points: baseline (enrollment), hospital discharge, and at 3, 6, 12, 18, 24, and 36 months (Table 1). Each assessment will include: patient-reported health status, clinical and functional evaluations, laboratory tests and imaging studies (including echocardiography). For patients unable to attend in-person visits, telephone follow-ups will be performed to ensure data collection.

Table 1.

Schedule of Enrolment, Interventions, and Assessments.

	STUDY PERIOD
	Enrolment	Allocation	Post-allocation
TIMEPOINT	-t₁	0	t₁	t₂	t₃	t₄	t₅	t₆
ENROLMENT: Eligibility screen Informed consentPatient informationAllocation
	X
	X
	X
		X
INTERVENTIONS:
Optimal group
Routine group
ASSESSMENTS:
Baseline demographics, Medical history	X
Vital signs, Laboratory tests, Echocardiography, PFT, ECG, 6MWD, WHO-FC, PEmb-QoL, Concomitant medication, Adverse events	X		X	X	X	X	X	X
CTPA or V/Q scan*	X		X	X	X	X	X	X

Abbreviations: 6MWD, 6-min walk distance; CTPA, computed tomographic pulmonary angiogram; ECG, Electrocardiograph; PEmb-QoL, Pulmonary Embolism Quality of Life Questionnaire; PFT, pulmonary function test; V/Q, scan ventilation and perfusion scintigraphy; WHO-FC, World Health Organization functional class.

t₁ 3 months ± 7 days after allocation, t₂ 6 months ± 7 days after allocation, t₃ 12 months ± 7 days, t₄ 18 months ± 7 days, t₅ 24 months ± 7 days, t₆ 36 months ± 7 days.

*CTPA or V/Q scans are performed according to the patients’ conditions during follow-up period.

In addition to these routine follow-up procedures, patients in the optimal group will receive an enhanced strategy comprising three key components: (1) Health Education, delivered through monthly evidence-based handbooks (addressing anticoagulation adherence, symptom recognition [eg, dyspnea ≥ NYHA Class II or unilateral leg swelling], and lifestyle modifications) supplemented by digital materials on a secure platform; (2) Personalized Care Management, involving regular telephone consultations with standardized Pulmonary Embolism Quality of Life Questionnaire (PEmb-QoL) assessments, symptom monitoring, and adherence tracking. In addition, a protocolized approach for physician escalation is implemented in cases of clinical deterioration (manifested as new or worsening symptoms), biomarker abnormalities (such as D-dimer > 0.5 mg/L or NT-proBNP > 300 pg/mL), or safety concerns; and (3) Real-time Clinical Support via WeChat platform, where pulmonologists provide 24-h responsive triage, with all collected data de-identified for subsequent analysis (Figure 1).

Outcomes

Primary Outcomes

All-cause mortality

Adverse events, including major bleeding, recurrent venous thromboembolism (VTE), right ventricular dysfunction (RVD) and CTEPH.

Major bleeding, defined according to ISTH criteria as: a decrease in hemoglobin of ≥20 g/L, or transfusion of ≥2 units of packed red blood cells, or symptomatic bleeding in critical sites (intracranial, intraspinal, intraocular, retroperitoneal, intra-articular, or pericardial), or fatal hemorrhage.¹⁶

Recurrent VTE, requires objective confirmation of: new or progressive PTE on CTPA, or new/progressive deep vein thrombosis (DVT) on compression ultrasonography.

RVD, the imaging evidence includes echocardiography or CTPA, with ultrasound findings meeting the following criteria: (a) Right ventricular (RV) dilation, defined as a RV end-diastolic diameter to left ventricular end-diastolic diameter ratio (RVEDD/LVEDD) > 1.0; (b) Hypokinesis of the RV free wall; (c) Increased tricuspid regurgitation velocity; (d) Tricuspid annular plane systolic excursion (TAPSE) < 16 mm; (e) Tricuspid annular peak systolic velocity (S’) < 9.5 cm/s. CTPA findings must satisfy the following condition: RV dilation observed in the four-chamber view (RVEDD/LVEDD >1.0).^2,3

CTEPH, diagnosed per 2022 ESC/ERS guidelines when meeting all criteria: persistent perfusion defects on lung imaging (V/Q scan or CTPA); hemodynamic confirmation by right heart catheterization (RHC): mean pulmonary artery pressure (mPAP) > 20 mm Hg, pulmonary vascular resistance (PVR) > 2 Wood units; exclusion of alternative pulmonary hypertension (PH) causes.¹⁷

Secondary outcomes (as detailed in Table 2)

Simplified pulmonary embolism severity index (sPESI);¹⁸

Laboratory parameters [D-dimer, N-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity troponin-T];

Functional capacity assessment (6-min walk test);¹⁹

Quality of life assessment (Pulmonary Embolism Quality of Life Questionnaire);²⁰

CTEPD.¹⁷

Table 2.

Secondary Outcomes.

Secondary Outcomes	Definition
sPESI	sPESI is a validated prognostic scoring system that incorporates six dichotomous clinical variables (each assigned 1 point): age ≥80 years, history of malignancy or chronic cardiopulmonary disease, heart rate ≥110 beats per minute, systolic blood pressure <100 mm Hg, and oxygen saturation <90% on room air. This tool stratifies patients into two distinct risk categories: those with 0 points are classified as low risk, while any score ≥1 point indicates high-risk status
Laboratory Tests	All biological samples will be collected after an 8–12 h overnight fasting period following standardized collection protocols. Quantitative D-dimer levels will be measured using the STA-R automated coagulation analyzer (Stago, France), with values >0.5 mg/L considered abnormal. NT-proBNP concentrations will be determined by electrochemiluminescence immunoassay (Elecsys 2010, Roche Diagnostics), using a cutoff of >125 pg/mL for abnormality. HS-TnT will be quantified via immunoassay (Cobas E601, Roche Diagnostics) with abnormal levels defined as >14 pg/mL. These biomarker assessments will be systematically performed during each scheduled follow-up visit.
Functional Capacity Assessment	6MWT will be conducted in strict accordance with the 2002 ATS guidelines, utilizing a standardized 30-meter straight walking course marked at 3-meter intervals. Prior to testing, baseline vital signs will be systematically assessed following protocol. During the test, patients will receive continuous standardized verbal encouragement, with the total ambulatory distance precisely recorded upon completion of the 6-min walking period
CTEPD	The diagnosis of CTEPD requires fulfillment of all the following criteria: Patients with acute PTE who received adequate anticoagulant therapy for at least 3 months and those who presented with similar symptoms such as dyspnea, perfusion defects, and organized fibrotic obstructions in patients with or without PH at rest.
Quality of Life Assessment	PEmb-QoL is a validated, disease-specific instrument comprising 40 items across six domains that evaluates HRQoL in post-PTE patients by assessing symptom frequency, temporal patterns of complaints, and the functional impact of pulmonary symptoms on daily activities and occupational performance, with each domain scored 0–100 and the total score (mean of all domain scores) inversely correlated with HRQoL (lower scores indicating better quality of life).

Abbreviations: 6MWT, The 6-min walk test; ATS, American Thoracic Society; CTEPD, Chronic thromboembolic pulmonary disease; HRQoL, health-related quality of life; HS-TnT, High-sensitivity troponin-T; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PEmb-QoL, Pulmonary Embolism Quality of Life Questionnaire; PH, pulmonary hypertension; PTE, pulmonary thromboembolism.

Sample Size

Based on existing epidemiological data indicating a 47.69% prevalence of RVD in PTE patients, we performed sample size estimation using a two-sided α of 0.05% and 80% power (β = 0.20), with reference to effect sizes reported in previous cohort studies.^9,21,22 Using a 1:1 ratio between the optimal group and the routine group, the initial calculated sample size was 234 patients. To account for potential attrition (estimated at 20% due to exclusions or loss to follow-up), we increased the target enrollment to 150 patients per arm (total N = 300).

This sample size provides adequate statistical power for our primary endpoint analysis. While the calculation was anchored to RVD prevalence, our study design - featuring comprehensive 3-year follow-up with standardized assessments - maintains ≥80% power to detect clinically meaningful 15% absolute differences in all primary endpoints, even after applying conservative α adjustment (Bonferroni-corrected threshold of 0.01 for multiple comparisons).

Recruitment

All patients admitted with acute PTE will be systematically evaluated for study participation according to a standardized screening protocol implemented by trained research staff. Recruitment will occur during hospitalization for acute PTE management.

Allocation

Upon obtaining written informed consent, eligible patients will undergo individual-level randomization. The allocation sequence was pre-generated by an independent statistician using computer-based random number generation with a 1:1 allocation ratio, creating unpredictable assignment to either the optimal group or the routine group. The randomization process employs rigorous safeguards including concealed allocation using investigator-inaccessible sequences stored in sealed opaque envelopes until post-eligibility confirmation, stratified implementation with dual independent eligibility verification by trained researchers through comprehensive medical record review, standardized physical examination, laboratory testing, and diagnostic imaging evaluation, and a partial blinding protocol where outcome assessors and data analysts remain masked to group assignment despite inherent intervention visibility; all suspected recurrent VTE events undergo objective confirmation via blinded CTPA interpretation by two independent radiologists.

Data Collection and Management

All baseline and follow-up assessments will be performed by site physicians following standardized study protocols, which encompass: (1) Comprehensive review of medical history and systematic physical examination; (2) Standardized laboratory evaluations including complete blood count and coagulation profile; (3) Multimodal imaging assessment comprising CTPA, V/Q scintigraphy, and transthoracic echocardiography; (4) Functional capacity evaluations through pulmonary function tests (PFT), 6-min walk test (6MWT), and electrocardiography (ECG).

Data will be collected using standardized case report forms and stored in a secure electronic database.

Quantitative Variables

Following data consistency checks and logical error correction, all statistical analyses will be performed using SPSS software. Continuous variables will be summarized using descriptive statistics, including sample size (n), mean, median, standard deviation (SD), interquartile range (IQR), and minimum/maximum values. Categorical variables will be expressed as frequencies and percentages.

Statistical Methods

For comparative analyses, Pearson's chi-square (χ²) test or Fisher's exact test (where appropriate) will be applied to categorical data, while the t-test will be used for normally distributed continuous variables. To assess risk factors and prognostic outcomes, univariate and multivariate Cox proportional hazards regression models will be employed, complemented by Kaplan-Meier survival analysis with log-rank testing for group comparisons.

Missing data will be handled using multiple imputation for variables with <20% missingness after evaluating missing patterns. For sensitivity analysis, complete-case analysis will be compared with the imputed results to assess robustness. All missing data proportions will be reported by variable in the results section.

Monitoring

The study will implement quarterly data review meetings featuring comprehensive audit trail analyses, supported by a risk-based monitoring framework that specifically evaluates (1) protocol adherence rates, (2) data completeness indicators, and (3) adverse event reporting compliance, with all data modifications permanently recorded in an electronic change log that maintains a complete, timestamped history of every alteration made to the study database.

The sponsor of the study, the hospital, oversees the development of a feasible and compliant protocol, secures ethical approval, and establishes data management plans.

Ethics and Dissemination

This trial was approved by the Institutional Ethics Committee of Shandong Provincial Hospital Affiliated to Shandong First Medical University (Approval No. SWYX: 2022–351). The study is conducted in accordance with the ‘Declaration of Helsinki’. Trial methods and results will be reported according to the Consolidated Standards of Reporting Trials (CONSORT) 2010 guidelines.²³ Prior to enrollment, all patients provided written informed consent after receiving a detailed explanation of the study's objectives, procedures, and potential risks (Trial registration: ChiCTR2200064675, https://www.chictr.org.cn/).

Any protocol modifications will be promptly submitted to the Ethics Committee for approval, with subsequent updates to the ethical approval documentation and patient information materials. Patients experiencing trial-related adverse events may contact the research team during or after their involvement for further support.

The study results will be submitted for publication in high-quality, peer-reviewed journals and presented at relevant national and international conferences on pulmonary circulation. However, the full study protocol, de-identified patient data, and statistical code will not be publicly available to ensure patient confidentiality and intellectual property protection.

Trial status

Recruitment commenced in November 2022 and was completed in November 2024. The study is currently in the follow-up stage.

Discussion

The OFUPE study aims to generate evidence for optimizing follow-up strategies in PTE, with potential implications for guideline development.

Unlike previous studies focused primarily on CTEPH detection or acute-phase outcomes,^13,24–26 the present protocol includes two key features: (1) an integrated care model incorporating patient education, continuous monitoring, and specialist support, and (2) dual evaluation of clinical morbidity and quality-of-life outcomes. This approach implements the 2022 ESC guidelines through systematic and individualized monitoring strategies.¹¹

This study introduces an approach to PTE management that refines routine follow-up with precision monitoring. By integrating evaluation of physiological markers, functional status, and patient-reported outcomes, this model may support earlier complication detection, reduce diagnostic delays for CTEPH, and provide a framework for evidence-based holistic management.

The OFUPE study will provide valuable evidence regarding optimal follow-up strategies for PTE patients. The results may inform clinical practice guidelines and contribute to reduced research waste by improving the quality of PTE follow-up care.

Footnotes

ORCID iDs

Xianming Qiu

Yuanyuan Sun

Consent to Publication

All authors reviewed the final protocol and approved submission for publication.

Authors’ Contributions

LZ and YYS are the Chief Investigators; they conceived the study, led the proposal and protocol development. LZ, YYS and DZL contributed to the execution and accomplishment of the research. MJL, CYL, XMQ and YYW participated in drafting the manuscript, and submitting of the protocol manuscript. ZHY, ML and SJ are responsible for the follow-up of patients. All authors contributed to revise the manuscript, and read and approved the final manuscript.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the Natural Science Foundation of Shandong Province (grant number ZR2022MH138, ZR2023QH200, ZR2024MH084).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability

Any data collected during this study can be acquired from the corresponding author upon a reasonable request.

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Value of Optimal Follow-up in Patients with Pulmonary Embolism (OFUPE): Study Protocol for a Prospective Randomized Study

Abstract

Background

Methods

Discussion

Keywords

Background

Objectives

Study Design

Methods

Study Setting

Eligibility Criteria

Interventions

Outcomes

Primary Outcomes

Sample Size

Recruitment

Allocation

Data Collection and Management

Quantitative Variables

Statistical Methods

Monitoring

Ethics and Dissemination

Trial status

Discussion

Footnotes

ORCID iDs

Consent to Publication

Authors’ Contributions

Funding

Declaration of Conflicting Interests

Data Availability

References