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Coronary artery lesion risk and mediating mechanism in children with complete and incomplete Kawasaki disease
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  1. Hongying Shi1,2,
  2. Huixian Qiu2,3,
  3. Zengyou Jin4,
  4. Chen Li2,3,
  5. Xinjun Yang1,
  6. Chenping Huang1,
  7. Rongzhou Wu2,3,
  8. Guihua Zhuang5,
  9. Maoping Chu2,3
  1. 1 Department of Preventive Medicine, School of Public Health and Management, Wenzhou Medical University, Wenzhou, China
  2. 2 Institute of Cardiovascular Development and Translation Medicine, Wenzhou Medical University, Wenzhou, China
  3. 3 Children’s Heart Center, Second Affiliated Hospital & Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, China
  4. 4 Department of Pediatric Cardiology, First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
  5. 5 Department of Public Health, Xi’an Jiaotong University, Xi’an, China
  1. Correspondence to Dr Maoping Chu, Institute of Cardiovascular Development and Translation Medicine, Wenzhou Medical University, Wenzhou 325000, China; chmping{at}126.com

Abstract

To compare the risk of coronary artery lesions (CAL) in children with complete and incomplete Kawasaki disease (KD) before and after immunoglobulin therapy and explore the mediation mechanisms underlying this association. All patients with KD admitted to the Wenzhou Medical University affiliated Yuying Children’s Hospital were divided into complete and incomplete KD groups. The independent effect of KD type on the risk of CAL and the intermediate effect of admission time on the association between KD type and CAL were assessed. The incidence of CAL in children with incomplete KD was higher than that in children with complete KD (33.9% vs 23.0%, p<0.001), and was also higher before therapy (27.5% vs 14.8%). Among children without CAL before therapy, there was no statistical difference in the incidence of CAL after treatment between the two groups. Mediation analysis found that the mediating effect of admission time was 1.07 (95% C: 1.01 to 1.13), and the direct effect of KD type on CAL was 1.59 (95% CI 1.17 to 2.16); proportion mediated was 15.71%. In conclusion, the risk of CAL among patients with incomplete KD was higher than that for complete KD, especially before therapy. In patients without CAL before treatment, the risk of CAL after treatment was equivalent for the two groups. Delayed admission may be one of the important mediating mechanisms for the higher risk of CAL in incomplete KD children.

  • cardiology
  • risk

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Significance of this study

What is already known about this subject?

  • Coronary artery lesions (CAL) are the most common complication of Kawasaki disease (KD).

  • Difference in the prognosis of complete and incomplete KD is controversial.

  • To date, there are very few published reports explaining whether the difference between the incidence of CAL in incomplete and complete KD children occurs before or after treatment and whether the time at admission has a mediating effect on the relationship between KD type and CAL.

What are the new findings?

  • In this study, we discussed the risk of CAL during the entire course of KD and  the separate risk of CAL before and after treatment and quantitatively evaluated the mediating effect of admission time on the relationship between KD type and CAL using mediation analysis.

  • The risk of CAL in incomplete KD children was higher than that in children with complete KD.

  • In patients without CAL before treatment, there was no significant difference in the incidence of CAL between the two groups after treatment.

  • Delayed admission may be one of the important mediating mechanisms for the higher risk of CAL in incomplete KD children.

Significance of this study

How might these results change the focus of research or clinical practice?

  • The incidence of CAL among incomplete KD children is higher than that in children with complete KD. This is mainly reflected before immunoglobulin therapy. More attention should be given to children with incomplete KD, especially focusing on the risk of CAL before treatment.

  • One of the mediation mechanisms of the increased risk of CAL in patients with incomplete KD is the delay in admission to hospital; the proportion mediation is about 15%. Timely admission to hospital and prompt treatment may reduce the effect of incomplete KD on CAL, which provides scientific evidence for individualized intervention for children diagnosed with KD.

Introduction

Coronary artery lesions (CAL) are the most common complication of Kawasaki disease (KD). Even after intravenous immune globulin (IVIG) and aspirin therapy, 20%–25% of KD children will develop CAL, making it the leading cause of acquired heart disease in children.1

The etiology of KD is unknown, and its diagnosis depends on fever and at least four of five clinical manifestations (changes in the lips or oral mucosa, conjunctival congestion, cervical lymphadenopathy, changes of the distal extremities, polymorphic rash). Medical staff found that some cases that did not meet the diagnostic criteria had similar laboratory characteristics to KD and also had CAL complications; in other words, incomplete KD. In 1987, American scholar Rowley2 reported five such incomplete cases; all had CAL during the course of the disease, and in one case, autopsy found KD-like abnormal artery. Then, a study performed at Kyushu University in Japan, based on a total of 242 KD cases between 1983 and 1991, found that only 4% of the total patients with KD had a transient coronary artery dilatation3; therefore, it was concluded that the risk of CAL in the incomplete KD cases was smaller. Subsequent studies in Canada found that there was no significant difference in the incidence of CAL between complete and incomplete KD.4 A Japanese national KD survey found that patients with incomplete KD were more likely to have delayed treatment and higher CAL incidence than patients with complete KD.5 6 And there was a big discrepancy in the results of similar Chinese research.7–9 Thus, the difference in the prognosis of complete and incomplete KD is controversial.

A small amount of evidence suggests that the vast majority of CAL occurring in the course of KD is already present at initial cardiac examination before treatment.10 11 However, some cases with no CAL before treatment developed CAL after treatment. These are two completely different cases and should be treated differently. To date, there are very few reports on whether the difference between the incidence of CAL in incomplete and complete KD children occurs before or after gamma globulin therapy.

The number of patients with incomplete KD has increased worldwide. Timely admission and IVIG treatment is crucial to improving the prognosis for these patients. Does the delay of medical treatment have a mediating effect on the relationship between incomplete KD and CAL?

The aim of this study is: to compare the incidence of CAL between complete and incomplete KD children; specifically to compare the incidence of CAL before and after therapy between the two groups; quantify how much of the effects of incomplete KD on CAL are mediated through delayed treatment and to quantify the direct effect of KD type.

Methods

Participants

All children diagnosed with KD from January 1, 2009 to December 31, 2014, at the Wenzhou Medical University affiliated Yuying Children’s Hospital were selected for this study. According to the Japanese KD diagnostic guide (Fifth Edition) and the KD diagnosis and treatment guide formulated by the American Heart Association, the diagnosis of KD is based on six clinical manifestations: (1) fever persisting at least 5 days, (2) bilateral conjunctival hyperemia, (3) changes in lips and oral cavity, (4) polymorphic rash, (5) changes in extremities, (6) nonsuppurative cervical lymph node enlargement.12 13 Depending on the number of clinical manifestations at admission, patients in our study were classified as having complete KD if they had at least four clinical signs in addition to fever for at least 5 days and were classified as having incomplete KD if they presented with only two or three clinical signs in addition to fever.4–6 14 15

Exclusion criteria: patients without echocardiography findings during hospitalization and at outpatient follow-ups after discharge were excluded because we were unable to determine the occurrence of CAL in these patients.

The study was conducted according to the principles of the Declaration of Helsinki and approved by the Wenzhou Medical University affiliated Yuying Children’s Hospital’s Research Ethics Board. Requirement for individual consent was waived for this retrospective study.

CAL

Judgment of CAL: Using echocardiography results, two pediatric cardiologists independently assessed the occurrence of CAL. Both cardiologists were blind to the patients’ medical records, hospital identification, and other clinical information. When intercardiologist judgments were inconsistent, a senior pediatric physician was requested to make a determination. Considering racial differences in coronary artery diameter,16 we used Chinese criteria. CAL was defined as one of the following conditions17 18: (1) internal lumen diameter of >2.5 mm in children younger than 3 years old, >3 mm in children 3–9 years, and >3.5 mm in children 9–14 years; (2) internal diameter of a segment measuring≥1.5 times that of an adjacent segment; or (3) lumen was clearly irregular.

Echocardiographic examination: The children were either supine or lying on their left side. The inner diameter of the left and right coronary arteries, aorta, left anterior descending branch, and left circumflex branch were measured by trained, skilled, cardiovascular pediatricians using the Philips IE-33 color Doppler echocardiography. Each position was measured three times, and the average value taken as the final measurement included in the data.

Time of CAL evaluation: In clinical practice, the occurrence of CAL in KD children is evaluated by echocardiography many times including at diagnosis, before discharge, 2 weeks after discharge (about 1 month after disease onset) and 2 months after disease onset. The peak CAL occurrence is 2~4 weeks during the course of the disease. The absence of CAL within 6 weeks after disease onset often indicates that CAL will not occur.4 To avoid missed diagnosis, in this study, any CAL detected by echocardiography within 2 months of disease onset, was coded “yes,” indicating a positive CAL diagnosis. The absence of CAL was coded “no.”

We recorded the CAL status before and after treatment. If patients had CAL before treatment, CALpre was coded “yes”; otherwise, it was coded ‘no.’ For patients without CAL before IVIG, CALpost was coded “yes” if patients had CAL after IVIG; otherwise, the code was “no”. When analyzing the relationship between KD type and CALpost, we included only patients without CAL before IVIG.

Covariates

Covariates included demographics (age, gender, weight, height); clinical features (KD related five main clinical features and seven other secondary clinical manifestations); laboratory indicators (blood routine, liver function, serum electrolytes, c-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and N-terminal pro brain natriuretic peptide (NT-proBNP)); duration of fever at admission to hospital and time of IVIG treatment (duration between the fever onset and IVIG treatment); treatment regimen (IVIG group, antibiotics, steroid). Using the WHO standard, children with height-specific weight>median+2 SD were classified as overweight.19

According to the total dose of immunoglobulin and weight of the children, the use of immunoglobulin was divided into two groups: the standard treatment regimen (2 g/kg, single dose intravenous injection), and the non-standard treatment regimen (eg, 1 g/kg/day for two consecutive days or 2 g/kg/day for 1 day).

We divided the children into two groups according to their visits: those who were treated in one department such as pediatric cardiology were recorded as having no history of referral and those who had been consulted in the emergency department or digestive department before being transferred to pediatric cardiology were recorded as having a history of referral.

Statistical analysis

Two groups of quantitative data were compared with t-test or rank sum test, and two groups of qualitative data were compared with χ² test or Fisher’s exact probability method. The independent effect of KD type on CAL was evaluated with Logistic regression. Confounding was assumed to have occurred if the association of potential covariates and CAL was statistically significant or if the effect size of KD type on CAL changed by ≥10% when the potential covariate was included in the model.20–22 In the analysis of CAL, the confounders selected included age (<36 m, 36–59 m, ≥60 m), gender, overweight, the number of days before admission, history of referral, hemoglobin (<114, ≥114 g/L), alanine aminotransferase (<16, ≥16 U/L); in the analysis of CAL after treatment, platelet count (≥350, <350×109/L), treatment scheme, and immunoglobulin resistance were also selected. Data were analyzed with the use of SPSS software, V.23.0 and EmpowerStats (www.empowerstats.com; X&Y Solutions Inc).

Mediation analysis23 24 was used to explore the mediating effect of the time at admission on the relationship between KD type and CAL. The main evaluation indices include the total effect (TE), the natural direct effect (NDE) and the natural indirect effect (NIE).23–25 In this counterfactual-based approach, TE assesses how much the outcome would change overall for a change in the exposure from level 0 to level 1, and it decomposes into the natural direct and indirect effects even in models with interactions or nonlinearities. NDE captures what the effect of the exposure on the outcome would remain if we were to disable the pathway from the exposure to the mediator. NIE captures the effect of the exposure on the outcome that operates by changing the mediator. Proportion mediated (PM) assesses the extent to which the total effect of the exposure on the outcome operates through the mediator. This measure captures how important the pathway through the mediator is in explaining the actual operation of the effect of the exposure on the outcome, and it measures what would happen to the effect of the exposure on the outcome—by how much it would be reduced—if we were to disable the pathway from the exposure to the mediator. All these mediation analyses were implemented by SAS macro. All tests were two sided and considered significant at the 0.05 level.

Results

A total of 967 cases with discharge diagnosis of KD or mucocutaneous lymph node syndrome were identified. Of these, 13 patients were excluded because of unclear diagnosis, 28 patients were excluded because of no records of echocardiograms at any time. The remaining 926 KD cases were included in this analysis: 64.0% male; median age 19 months (IQR: 9–33 months); 61.5% complete KD; duration between disease onset and admission ranged from 1 to 20 (median=5 days), IQR: 3.75–6.00 days. The median number of days of fever before treatment was 6 days (IQR: 6–8 days); 90.7% received 2 g/kg IVIG.

Basic characteristics of patients with complete and incomplete KD

The average age of patients with incomplete KD was lower, the number of days before admission was longer, the number of days before therapy was longer, and the proportion of the nonstandard treatment scheme was higher than that of patients with complete KD, p<0.05 (table 1). The proportion of overweight patients in incomplete KD was slightly higher than that in complete KD, but p=0.08. There was no significant difference in gender, referral history, antibiotics, and steroid use history between the two groups.

Table 1

Basic characteristics of patients with complete and incomplete KD

The percentage of neutrophils, neutrophil count, alanine transaminase, C reactive protein and NT-proBNP in children with complete KD were higher than that of children with incomplete KD. The lymphocyte count, platelet count, blood sodium, and blood potassium were lower than those with incomplete KD (table 2).

Table 2

Laboratory indices between patients with complete and incomplete KD

Comparison of CAL in children with complete and incomplete KD

As shown in figure 1, the incidence of CAL in children with incomplete KD (33.9%) was higher than that in children with complete KD (23.0%), p<0.001. The incidence of CAL before treatment (27.5%) was also higher than that of complete KD (14.8%), p<0.001. The results of stratified analysis also showed that the incidence of CAL in the incomplete KD group was higher than that in complete KD.

Figure 1

Incidence of CAL in children with complete and incomplete KD. CAL, coronary artery lesions; KD, Kawasaki disease.

Among children without CAL before immunoglobulin treatment, there was no statistically significant difference in the incidence of CAL after treatment (8.9%, 9.7%) between incomplete and complete KD, p=0.718.

Independent effect of KD type on CAL risk

Logistic regression was used to evaluate the independent effect of incomplete KD on CAL after controlling for age(<36 m, 36–59 m, ≥60 m), gender, overweight, the number of days before admission, history of referral, hemoglobin (<114, ≥114 g/L), alanine aminotransferase (<16, ≥16 U/L); and it was found that the incidence of CAL in incomplete KD children was still higher than that of children with complete KD, aOR=1.57 (95% CI 1.15 to 2.14). The incidence of CAL before treatment in incomplete KD children was also higher than that of children with complete KD, aOR=2.00 (95% CI 1.42 to 2.81). Among the patients with KD without CAL before treatment, the independent effect of KD type on CAL after treatment was not statistically significant, aOR=0.86 (95% CI 0.50 to 1.48) (table 3).

Table 3

Independent effect of KD type on CAL risk

Mediating effect of the number of days before admission on the relationship between KD type and CAL

In order to better illustrate the relationship between KD type, the number of days before admission to hospital and CAL, we first analyzed the interaction between KD type and admission time first. As shown in figure 2 and table 4, the patients with incomplete KD and admission time larger than 4 days had highest risk of CAL and also had highest risk of CAL before treatment. However, the risk of CAL after treatment among the four different groups was not statistically significant (figure 2, table 4). As table 4 shows, there was no significant interaction between KD type and the number of days before admission to hospital.

Figure 2

KD type, number of days before admission and CAL. CAL, coronary artery lesions; KD, Kawasaki disease.

Table 4

Interaction between KD type and admission time to hospital on CAL

Then, the mediating effect of admission time on the relationship between KD type and CAL was analyzed, and the total effect of KD type on CAL was cORTE=1.72 (95% CI 1.28 to 2.33), which indicated that the risk of CAL in children with incomplete KD is higher than that in children with complete KD; the direct effect of KD type was ORNDE=1.61 (95% CI 1.20 to 2.17); the number of days before admission had some indirect effects, the NIE was ORNIE=1.07 (95% CI 1.02 to 1.13); PM=15.3%, indicating that in the total effect of KD type on the risk of CAL, the proportion mediated by the number of days before admission was 15.3%. After controlling for gender, age, overweight, referral history, hemoglobin, and other confounding factors, the results of mediation analysis were consistent: the total effect of KD type on CAL was aORTE=1.70 (95% CI 1.25 to 2.32), p=0.001; the direct effect of KD type on CAL was ORNDE=1.59 (95% CI 1.17 to 2.16), p=0.003; the mediation effect of the number of days before admission was ORNIE=1.07 (95% CI  1.01 to 1.13), p=0.013, PM=15.7% (table 5).

Table 5

Mediating effect of the number of days before admission on the relationship between KD type and CAL

We analyzed the mediating effect of the number of days before admission on the relationship between KD type and CAL before treatment and found that among the total effect of KD type on CAL before treatment (ORTE=2.20 (95% CI 1.57 to 3.07)), the mediation effect of the number of days before admission was ORNIE=1.07 (95% CI 1.01 to 1.12), PM was 11.7%. After controlling for gender, age, overweight, and other confounding factors, the results of mediation analysis were consistent: ORTE=2.16 (95% CI 1.53 to 3.04), ORNIE=1.06 (95% CI 1.01 to 1.12), PM=11.2%.

The mediating effect of the time of admission to hospital on the relationship between KD type and CAL after immunoglobulin therapy was analyzed, and the subjects were restricted to children without CAL before treatment. The results showed that there was no significant direct effect and indirect effect of KD type on CAL after treatment (table 5).

The results were consistent when the number of days before admission was treated as a qualitative variable for mediation analysis. This indicated that the number of days before admission was the stable mediator of the relationship between KD type and CAL, and is also the mediator of the relationship between KD type and CAL before treatment.

Discussion

In this study, we found that the incidence of CAL in incomplete KD children was higher than that in children with complete KD. This difference was mainly caused by a difference in CAL risk before immunoglobulin treatment. In patients without CAL before treatment, there was no significant difference in the incidence of CAL after therapy. The number of days before admission to hospital may play a mediating effect in the relationship between KD type and CAL and also in the relationship between KD type and CAL before treatment.

Our findings corroborate findings in previous studies. Other researchers5 8 have explored the differences in clinical features, laboratory indicators and prognosis between patients with  incomplete and complete KD. They found that patients with incomplete KD had lower age, less clinical symptoms, resulting in late diagnosis and treatment; vascular inflammation persists in these patients, and gradually exacerbates, leading to a higher risk for CAL. Other studies found no significant difference in prognosis between complete and incomplete KD. A study in Canada including 955 KD cases from 1990 to 200715 showed that there was no statistical significance (p=0.58) in the incidence of CAL (maximum coronary diameter Z score>2.5) in patients with complete and incomplete KD (13% and 11%, respectively). A study from the American national children’s medical research center14 analyzed clinical data before and after the publication of KD guidelines by the American Heart Association in 2004 and found that there was no significant difference in the incidence of CAL between patients with complete and incomplete KD (the incidence of CAL in patients with complete and incomplete KD was 13.9%, 20.0% before the publication of the guidelines; 19.4%, 12.5% after the publication of the guidelines). However, most preceding studies did not indicate the specific evaluation time of CAL and could not determine whether it occurred before or after IVIG treatment.

In this study, we discussed the risk of CAL during the entire course of KD and  the separate risk of CAL before and after treatment (excluding patients with CAL before treatment when analyzing CAL after IVIG treatment). We confirmed that the risk of CAL in patients with incomplete KD was higher than that in complete KD children. Additionally, we found that the higher risk of CAL in patients with incomplete KD was mainly caused by CAL before IVIG treatment, which was consistent with a few previous studies.4 A retrospective case study in America4 found that the incidence of CAL in patients with incomplete KD (70%) was higher than that in patients with complete KD (62%), and the incidence of initial CAL (56%) was also higher than that complete KD cases (40%); there was no statistical significance, which may be related to the sample size of only 100 cases in this study. The 20th national KD survey5 in Japan from 2007 to 2008 showed that the incidence of CAL in patients with incomplete KD (within 1 month of onset) was higher than that in patients with complete KD (13.1% and 8.8%, respectively). The incidence of subsequent CAL (1 month after onset) was also higher than that in patients with complete KD (3.5% and 2.5%), p<0.001. All these studies suggest that the risk of CAL in incomplete KD is higher than that in complete KD, especially in the early stage of disease progression. However, the number of symptoms in children with incomplete KD is less and the laboratory index is less serious than that of complete KD, which might easily be overlooked. Clinicians should therefore pay special attention to children with incomplete KD who have fewer clinical manifestations at the early stage of the disease to avoid delayed diagnosis and treatment.

A small number of existing studies26 have shown that the results usually changed when excluding patients with CAL prior to IVIG therapy. Previous studies comparing the risk of CAL between patients with complete and incomplete KD did not routinely exclude patients with CAL prior to IVIG therapy; this may lead to erroneous conclusions. In this study, among patients without CAL before IVIG therapy, we found that there was no significant difference in the incidence of CAL after IVIG treatment between the patients with complete KD and those with incomplete KD (9.7% to 8.9%). The results of multivariate Logistic regression analysis were consistent, suggesting that even in patients with KD without CAL before treatment, the prognosis of incomplete KD is no better than that in cases of complete KD. A guarded clinical approach should be followed with patients with incomplete KD. Incomplete KD should not be equated with “not serious”.

Different from previous studies, this study quantitatively evaluated the mediating effect of admission time on the relationship between KD type and CAL by using mediation analysis. Admission time was statistically significant; the proportion mediated was about 15%, which confirmed that visiting time was the mediating factor of the relationship between incomplete KD and CAL. Furthermore, in the relationship between KD type and CAL before treatment, visiting time was also a stable mediator. Prompt treatment of children with KD will certainly play a role in preventing the occurrence of CAL, especially CAL before treatment. However, the direct effect of KD type on CAL was 1.59 (95% CI 1.17 to 2.16), indicating that the delay in visiting time could not completely explain the high incidence of CAL in children with incomplete KD. The proportion of incomplete KD cases has been increasing in recent years; this study found that the proportion of incomplete KD is 38.6%. This may be related to the increasing awareness of KD, more sensitive case definition and improved diagnosis. The study of incomplete KD still needs to be further investigated, and the causes of poorer prognosis among these patients still needs to be further explored.

Shortcomings of this study: first, because of the historical data accumulated in clinical practice, the frequency and time of echocardiography in different cases are not standardized. The results of this study need to be further verified by prospective studies. In the same way, based on retrospective data, the genetic factors of KD children were not collected, so it was impossible to study the effect of interaction between KD type and genes on prognosis. In addition, this study is based on single center cases, which may influence the extrapolation of the results. The Yuying Children’s Hospital, affiliated to Wenzhou Medical University, is the central hospital for local pediatric treatment, and the main choice for pediatric medical treatment. Therefore, it should cover the major local pediatric cases, maximizing the representativeness of the study subjects, and our continuous selection of all KD cases that meet the inclusion criteria within the study period also minimizes selection bias. In future, multicenter clinical data for similar studies will be more representative, yield more stable results, and increase the external validity of the research.

Conclusion

In summary, the incidence of CAL among incomplete KD children is higher than that in children with complete KD. This is mainly reflected before immunoglobulin therapy. One of the mediation mechanisms of the increased risk of CAL in patients with incomplete KD is the delay in admission to hospital; the proportion mediation is about 15%. More attention should be given to children with incomplete KD, especially focusing on the risk of CAL before treatment. Timely admission to hospital and prompt treatment may reduce the effect of incomplete KD on CAL, which provides scientific evidence for individualized intervention for children diagnosed with KD.

References

Footnotes

  • Contributors MC and HS designed the study. HQ, ZJ, CL and XY conducted the study. HS analyzed the data. CH, RW and GZ interpreted the results and HS wrote the manuscript. All authors reviewed and approved the manuscript.

  • Funding This study was supported by the project of risk factors and scoring system for predicting the risk of coronary artery lesions in Kawasaki disease, National Natural Science Foundation, China (81502893), the project of study on the mediation mechanism between the type of Kawasaki Disease and Coronary artery lesions from Zhejiang Province Science and Technology Agency (LY19H260004) and the project of development of scoring system for prognosis prediction among Kawasaki disease patients from Zhejiang Province Science and Technology Agency (2014C33160).

  • Competing interests None declared.

  • Ethics approval The study was conducted according to the principles of the Declaration of Helsinki and approved by the Wenzhou Medical University affiliated Yuying Children’s Hospital’s Research Ethics Board.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Patient consent for publication Not required.

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