Long-term cardiovascular events and risk factors in adults sepsis survivors: A systematic review and meta-analysis

doi:10.21203/rs.3.rs-4296440/v1

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Long-term cardiovascular events and risk factors in adults sepsis survivors: A systematic review and meta-analysis

https://doi.org/10.21203/rs.3.rs-4296440/v1

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Background Hospitalization for sepsis may be associated with an increased riskfor cardiovascular events. We aim to explore the relationship between sepsis hospitalization and long-term of cardiovascular events, and describe risk factors for cardiovascular events in adults sepsis survivors.

Methods MEDLINE, EMBASE, Cochrane Library, Wanfang, and CNKI were searched, from inception to Aug 2023, and no language limitation. Cumulative incidence and hazard ratios (HRs) with 95% confidence interval (CI) was used to assess the strength of the association.

Results 25 observational studies were included in this meta-analysis. The pooled cumulative incidence of major cardiovascular was 9.0%, myocardial infarction was 2.4%, stroke was 4.9% and congestive heart failure was 8.6%. Sepsis hospitalization was associated with a higher long-term risk of major cardiovascular(HR, 1.54; 95% CI 1.32- 1.79), myocardial infarction (HR, 1.41; 95% CI 1.29- 1.54), stroke (HR, 1.45; 95% CI 1.32- 1.60) and congestive heart failure (HR, 1.51; 95% CI 1.46- 1.56) compared to non-sepsis controls. Pooled analysis indicate that age≤ 45 years, male gender, hyperlipidaemia, and some comorbidities were significantly associated with increased hazards of cardiovascular events.

Conclusions Adults sepsis survivors may be experience a higher hazard of cardiovascular events compared to non-sepsis controls. And both common cardiovascular risk factors and sepsis-related variables can significantly increase this correlation.

Sepsis

Sepsis survivors

Cardiovascular events

Stroke

Risk factors

Sepsis is defined as a life-threatening acute multiple organ dysfunction syndrome caused by a disordered body’s immune response to infection which can result in high mortality and disability rate[1–3]. Currently, sepsis has been recognized as a global health priority[4]. Even if some sepsis patients manage to overcome the various complications during the acute phase and survive, they still face numerous long-term challenges in the future[5, 6]. The advanced diagnostic techniques and treatment approaches are mainly focused on reducing the mortality rate during sepsis hospitalization, while less attention is given to the long-term survival conditions of sepsis survivors after discharge. The long-term survival rates are improving, with approximately 14 million survivors each year in developed countries[7]. Therefore, it is important to pay more attention to their quality of life after discharge and reduce the risk of related sequelae and re-hospitalization.

Recent studies have demonstrated that some sepsis survivors remain in a state of immune dysfunction and systemic inflammation for a considerable period [8]. These residual risks can lead to the potential of subsequent cardiovascular adverse events, including myocardial infarction, acute heart failure, or stroke[8, 9]. Survivors of sepsis showed a high risk of mortality and major cardiovascular events that may last for years after discharge[10]. Jentzer et al found sepsis survivors had an excess risk of all-cause cardiovascular re-hospitalization in late discharge periods with more than a decade of nationwide follow-up data[11]. However, two recent meta-analyses of observational studies indicated the overall quality of evidence supporting this relationship was low due to wide variability in effect estimates and methodologic limitations of the published research [12, 13]. Moreover, the risk factors for major adverse cardiovascular events remain unclear, and it’s still confusing to what extent subsequent cardiovascular events in survivors are attributed to sepsis-related factors[14].

Thus, this meta-analysis performed a comprehensive evaluation of the link between surviving sepsis hospitalization and cardiovascular events and explored the potential risk factors for cardiovascular events in adult sepsis survivors.

This meta-analysis was performed and reported according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) (Supplement file 1)[15] and Preferred Reporting Items for Systematic Review and Meta-analysis (PRISMA) (Supplement file 2 )[16] and the Cochrane Handbook for Systematic Reviews of Interventions. The study protocol was registered in the International Prospective Register of Systematic Reviews on Sep 20th, 2023 (registration number, CRD42023462016).

Literature search strategy and selection

A comprehensive electronic search of MEDLINE, EMBASE, Cochrane Library, Wanfang, and CNKI using relevant keywords. All resources were searched from inception to Aug 2023, and no language limitation. The full search strategy is provided in the Supplement (Supplement file 3).

One author (HF Chen) reviewed the abstracts of all studies that describe the occurrence and risk factors of cardiovascular events in sepsis survivors. Identification of studies meeting the exclusion and inclusion criteria (eTable 1) by the other 2 authors (ZS Wu and YS Xu). Any conflicts over inclusion were resolved by a third author(X Zhao). Reference lists of included studies and related review articles were also retrieved. If duplicate studies, the most recent or complete study was included in this meta-analysis.

Risk of Bias and Quality Assessment

We assessed the validity and quality of the included studies using the Newcastle-Ottawa quality assessment scale (NOS)[17]. This grading system assigns star ratings based on predetermined criteria which include the methods of study selection, comparability of the study subjects, and outcome/ exposure. The total number of quality stars ranged from 1 to 9. The quality of the study is indicated by the number of stars (eTable 2 ). The methodological quality of studies and evidence for each outcome were evaluated by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines[18] (eTable 3). We evaluate the bias in prognostic factor studies using the Quality In Prognosis Studies (QUIPS) tool[19] (eTable 4).

Main exposure and outcomes of interest

Our exposure of interest was hospitalization for sepsis, identified using a previously validated algorithm or International Classification of Diseases (ICD) codes[20, 21]. The composite primary outcome included any myocardial infarction, congestive heart failure, stroke, or cardiovascular death.

Based on clinical knowledge, prespecified potential risk factors included baseline demographics (age, gender), comorbidities (hypertension, diabetes, coronary artery disease, atrial fibrillation, chronic lung disease, etc), and statin prescription rate.

Data analysis

Baseline characteristics are reported as counts and percentages. Continuous variables are presented as medians and IQRs (inter-quartile range). The pooled cumulative incidences of cardiovascular events (stroke, myocardial infarction, transient ischemia attack, congestive heart failure) were analyzed using a random effects model. A hazard ratio (HR) with a 95% confidence interval (CI) was conducted for the estimates of the relationship between sepsis hospitalization and the outcomes of interest. The risk ratios (RRs) and odds ratios (ORs) were considered hazard ratios (HRs) due to their close approximation to each other[22], assuming a low occurrence of the primary outcome(< 10%) ) in the unexposed group[23]. The HRs were pooled based on the multivariable model adjusted for confounding factors. Q-test and I² index were used to evaluate the clinical heterogeneity between studies [24]. If the heterogeneity was significant(I² > 50% and P < 0.05), the random-effects model was used for analysis. Otherwise, the fixed effects model was used. Egger’s regression test and Begg’s funnel plot were used to diagnose potential publication bias[25, 26].

To evaluate the stability of the conclusions of this article, a series of sensitivity analyses were performed. First, meta-regression was conducted to assess potential sources of heterogeneity. The effect of covariance was investigated including control for subjects (population-based or hospitalized), mean age, mean follow-up time, and study designs. Second, we did sensitivity analyses to evaluate each study’s influence by eliminating each study in turn to check the robustness of our findings. Third, Galbraith plots were used to assess the heterogeneity of the studies and find potential outliers. All data were analyzed using STATA 11.

The literature search identified 15,472 results, of which 214 were screened for eligibility. After reviewing the full text, twenty-five studies[10, 11, 27–49] that overall included 7,525,271 participants were selected for quantitative synthesis(Fig. 1).

Characteristics of included studies are summarized in Table 1. Of these observational

Table 1

Characteristics of included studies in this meta-analysis. DM, diabetes mellitus; CVD, cardiovascular disease; CHF, congestive heart failure; PVD, peripheral vascular disease; TIA, transient ischaemic attack; MI, myocardial infarction; CHD, coronary heart disease; IHD, ischemic heart disease.
Study (year) [inf.]	Study design	Overall	Age (year)	female	Control	Main confounding adjustment	Follow-up	Outcome
Study (year) [inf.]		sample size		(%)	subjects	(mean/ maximum)
Ishani 2005 [27]	Prospective cohort	2,311	62.5 (15.5)	46.7	Population	Age, sex, and race, multiple	3 years	MI, stroke, CHF
						comorbidities		PVD
Lee 2013 [28]	Matched cohort	23,027	55.1 (25)	47.3	Population	Age, sex, multiple comorbidities	10 years	Stroke
Yende 2014 [29]	Retrospective cohort	1,638,566	77.4 (7.8)	55.8	Population	Age, sex, multiple comorbidities	1 year	CVD, MI, stroke
Walkey 2014 [30]	Retrospective cohort	138,722	80.0	57.5	Hospital	NO	5 years	Stroke, CHF
Jafarzadeh 2016 [31]	Prospective cohort	47,009	59.0	47.8	Hospital	Age, sex, and race, multiple	5 years	CVD, MI, stroke
						comorbidities, demographics		TIA
Ou 2016 [32]	Retrospective cohort	204,643	64.7 (17.1)	47.4	Hospital	Age, sex, multiple comorbidities	6.7 years	MI, stroke, CHF
Wang 2017 [33]	Matched cohort	6,420	67.2 (9.2)	53.7	Population	Age, sex, and race, multiple	10 years	CHD
						comorbidies
Boehme 2017 [34]	Case-Crossover	50,194	71.7 (14.6)	52.2	Population	Age, sex, and DM	1 year	Stroke
Shih 2017 [35]	Matched cohort	130,530	71.0 (13.2)	47.4	Hospital	Age, sex, multiple comorbidities	2.5 years	MI, stroke, CHF
Cheng 2017 [36]	Retrospective cohort	68,324	67.3 (17.4)	47.8	Hospital	NO	1 year	Stroke
Cheng 2017 [37]	Retrospective cohort	7,419	69.8 (12.2)	46.7	Hospital	NO	4.6 years	Stroke
Lai 2018 [38]	Retrospective cohort	42,316	67.7 (17.6)	40.8	Hospital	Age, sex, and Charlson	0.5 year	MI, stroke
						Score, multiple comorbidities
De Geer 2018 [39]	Matched cohort	13,669	66.4 (15.5)	44.4	Hospital	Age, sex, illness severity	2 years	CVD, CHF
Vallabhajosyula 2018 [40]	Retrospective cohort	434	68.0	47.2	Hospital	NO	2 years	CHF
Gadre 2019 [41]	Retrospective cohort	898,257	66.0 (17.6)	51.8	Hospital	NO	30 days	CVD, CHF
Shao 2019 [42]	Retrospective cohort	121,947	65.3 (20.3)	49.2	Hospital	NO	1 year	Stroke
Hsieh 2019 [43]	Prospective cohort	42,316	70.4 (16.6)	40.9	Hospital	NO	0.5 year	MI, stroke
Wu 2019 [44]	Matched cohort	84,467	74.3 (12.5)	42.4	Hospital	Age, sex, and race, multiple	1 year	MI, stroke
						comorbidities		CVD, MI
Sebastian 2019 [45]	Case-crossover	152,356	NO	NO	Hospital	NO	1 year	Stroke
Hsiao 2022 [46]	Retrospective cohort	4,323	60.1 (17.5)	47.2	Hospital	NO	0.5 year	CVD, IHD, stroke
Angriman 2022 [10]	Matched cohort	508,482	68.3 (17.4)	57.5	Population	Age, sex, demographics, CVD	5 years	CVD, MI, stroke
						risk factors, comorbidities
Walkey 2023 [47]	Retrospective cohort	82,748	78.0 (11.0)	47.0	Hospital	NO	1 year	Stroke, TIA
Jentzer 2023 [11]	Retrospective cohort	2,258,464	68.7 (13.2)	54.2	Hospital	Age, sex, race, CVD risk	12 years	CVD
						factor, comorbidities, index
						hospitalization characteristics
						health plan, pharmacy coverage
Angriman 2023 [48]	Retrospective cohort	268,259	72.0	57.7	Population	Age, sex, and race, multiple	5 years	CVD, MI, stroke
						comorbidities
Angriman 2023 [49]	Matched cohort	157,276	71.3 (14.2)	54.8	Population	Age, sex, and pre-existing diabetes	5 years	CVD, MI, stroke

studies, there were 23 cohort studies and 2 case-crossover studies. The median number of included participants in the study was 98,824 (IQR 42,316 − 161,788). The mean age of participants ranged from 55.1 to 80.0 years. The median period of follow-up was 2 years (IQR 1–5 years). The NOS scores of included studies ranged from 5 to 7, which indicated the studies had low to moderate quality. Due to observational study designs and lack of adequate adjustment for confounding, there was a low to moderate risk of bias for each domain. The GRADE assessment suggested the overall methodological quality of the outcomes was very low to moderate.

Incidence of cardiovascular events

Fifteen studies[10, 28–32, 34, 36, 41–44, 46–48] reported the incidence of cardiovascular events among sepsis survivors. The pooled cumulative incidence of cardiovascular events was as follows: major cardiovascular was 9.0% (95% CI 6.1–11.9%); myocardial infarction was 2.4% (95% CI 1.6–3.1%); stroke was 4.9% (95% CI 3.8–6.1%); and congestive heart failure was 8.6% (95% CI 4.6–12.6%), see eFig. 1.

Risk of cerebrovascular events

Thirteen studies analyzed the relationship between sepsis and long-term cerebrovascular events^{[10,11,27–29,31,32,34,35,38,44,45,49]}. A total of 5,739,229 participants were included in the analysis. Of thirteen studies, seven studies used a hospital-based control, and six used a population-based control. The maximum follow-up period ranges from 0.5 to 10 years. Most studies adjusted for age, sex, and comorbidities, only one study[45] did not provide any adjustment because of the case-cross-over design.

The pooled results indicated surviving sepsis hospitalization was associated with significantly higher risk of major cardiovascular (HR, 1.54; 95% CI 1.32–1.79), myocardial infarction (HR, 1.41; 95% CI 1.29–1.54), stroke (HR, 1.45; 95% CI 1.32–1.60) and congestive heart failure (HR, 1.51; 95% CI 1.46–1.56) compared to non-sepsis hospital or population controls at maximum follow-up (Fig. 2, Table 2).

Table 2

The association of sepsis with major cardiovascular, myocardial infarction, stroke, congestive heart failure. CI, confidence interval; I², measure of heterogeneity.
Outcomes	NO. (studies)	NO. (participants)	Hazard ratio (95% CI)	I²
Major cardiovascular	8	3,776,262	1.54 (1.32, 1.79)	99.6%
Myocardial infarction	8	1,616,592	1.41 (1.29, 1.54)	89.9%
Stroke	11	1,842,169	1.45 (1.32, 1.60)	94.8%
Congestive heart failure	4	2,979,028	1.51 (1.46, 1.56)	74.4%

Risk factors for cardiovascular events

Sixteen studies^{[10,27,28,32–38,41−43,46,48,49]} which included 2,975,602 participants reported the risk factor of long-term cerebrovascular complications following hospital discharge. The maximum follow-up period ranges from one month to 10 years. The mean age of subjects was 62.5 years, and 50.1% were male.

A list provided a complete overview of all potential risks for the development of cerebrovascular in sepsis survivors(Table 3). The pooled analysis found that 10 factors associated with increased hazards of cardiovascular events: Age ≤ 45 years [HR 2.51, 95% CI 1.95–3.23 ], male gender [HR 1.28, 95% CI 1.20–1.37], diabetes mellitus [HR 1.52, 95% CI 1.36–1.70], hypertension [HR 1.41, 95% CI 1.25–1.59], COPD [HR 1.20, 95% CI 1.11–1.30], chronic kidney disease [HR 1.22, 95% CI 1.14–1.31], CHF [HR 1.28, 95% CI 1.18–1.38], coronary artery disease [HR 1.38, 95% CI 1.31–1.47], cerebrovascular accident [HR 1.34, 95% CI 1.30–1.39], hyperlipidaemia [HR 1.60, 95% CI 1.50–1.69].

Table 3

The pooled analysis of risk factors associated with cardiovascular events following sepsis hospitalization.
Risk factor	NO. (studies)	NO. (participants)	Hazard ratio (95% CI)	I²
Age ≤ 45 years	7	1519125	2.51 (1.95–3.23 )	78.4%
Male	7	1058459	1.28 (1.20–1.37)	86.0%
Diabetes mellitus	10	1318645	1.52 (1.36–1.70)	97.7%
Hypertension	6	1064976	1.41 (1.25–1.59)	97.3%
COPD	6	1368529	1.20 (1.11–1.30)	91.9%
Chronic kidney disease	6	1461993	1.22 (1.14–1.31)	79.7%
Congestive heart failure	6	1651597	1.28 (1.18–1.38)	83.3%
Coronary artery disease	4	792394	1.38 (1.31–1.47)	61.7%
Cerebrovascular accident	3	601062	1.34 (1.30–1.39)	94.5%
Hyperlipidaemia	3	234435	1.60 (1.50–1.69)	93.3%

Prespecified Sensitivity and Subgroup Analyses

There is high heterogeneity in all primary outcomes. The risk of post-discharge cardiovascular events at different follow-up times were presented in eTable 5. The pooled cumulative incidence of cardiovascular events at different follow-up times was as follows: major cardiovascular was 8.1% (95% CI 3.6–12.1%) less than 2 years, 9.9% (95% CI 4.2–15.7%) at more than 5 years. Moreover, the association of sepsis and the risk of long-term cerebrovascular events was significant across all prespecified subgroups.

The result of the meta-regression is shown in eFig. 2. Meta-regression analysis didn’t find any covariant significantly associated with the primary outcomes. Sensitivity analysis indicated that the overall results were not qualitatively changed correspondingly when the individual studies were eliminated from the analysis (eFig. 3). Finally, the Galbraith plot shows that all studies were distributed in the regression line (eFig. 4).

Publication bias

No significant publication bias was discovered in any analysis according to Egger’s test. Begg’s funnel plot is presented in eFig. 5.

In this meta-analysis of 25 observational studies including 7,525,271 participants, we found that adult sepsis survivors may experience a higher long-term hazard of cardiovascular events compared to hospital or population control. The potential relationship does not degrade over time according to long-term follow-up data. We also observed that there are multiple risk factors (Age ≤ 45 years, diabetes mellitus, hypertension, hyperglycemia, etc) that increase the risk of subsequent cardiovascular events in survivors of sepsis.

The findings of this study are consistent with several previous large cohort studies based on population and two latest systematic reviews [10, 12, 13, 29, 48]. However, Arero et al[13] only analyzed the correlation between survivors of sepsis and stroke occurrence, and their study had incomplete confounding factors adjustment. Kosyakovsky et al[12] included many studies that were of low quality, had small samples and some lacked appropriate non-sepsis controls for comparison. This meta-analysis selected several most recent large cohort research[10, 11, 47–49], among them, Jentzer et al provided the largest study so far (about 2.3 million hospitalized individuals) to exploring the relationship between sepsis and post-discharge cardiovascular complications according to a decade of nationwide follow-up data[11]. Given the influence of confounding factors such as age, disease severity, and basic diseases, we adjusted for various confounding factors to the greatest extent possible and conducted multiple sensitivity analyses. The robust results provide convincing evidence for the association between sepsis survivors and subsequent cardiovascular events.

There are several explanations for the strong relationship between sepsis hospitalization and long-term cardiovascular risk. Recently, clinical and epidemiological research has attracted renewed attention to the many potential approaches in which infections of various types may lead to the risk of cardiovascular disease in sepsis survivors. Pathogens could cause autoimmune disease through the breakdown of self-tolerance, including superantigen cross-linking, innate immune cells activating, and epitopespreading[50]. Mageau[51] et al demonstrated there is a dramatically high risk of immune-mediated inflammatory diseases(IMIDs) after sepsis.

Inflammatory status may play a crucial role in cardiovascular diseases including myocardial disease, and strokes[52–54]. Both acute or chronic inflammation is a situation characterized by high blood and tissue levels of various pro-inflammatory markers which may confer susceptibility to cardiovascular diseases[55]. Previous studies found that the circulating levels of pro-inflammatory markers still maintained a high level following discharge among sepsis survivors[56, 57]. Similar inflammatory cytokines were proven associated with the occurrence of long-term cardiovascular complications, and critical diseases are considered to induce immunometabolic changes in the relationship with atherosclerotic disease[58]. Wang et al[59] reported that people with long-standing atrial fibrillation(AF) have a trend to show higher levels of C-reactive protein than shorter duration AF, and under the interaction of AF and inflammation, the risk of thrombogenesis increases sharply during follow-up[10, 47]. A randomized and double-blind trial shown that anti-inflammatory therapy targeting the interleukin-1β can significantly reduce the rate of recurrent cardiovascular events compared with placebo in post-myocardial infarction patients[60]. Moreover, infection was found to be related to premature senescence in the aorta tissue in animal experiments[61]. The premature senescence of vascular may be one of the important triggers for human cardiovascular and cerebrovascular diseases.

Many post-sepsis syndromes (PSS) may contribute to this complication risk. PSS is a relatively new concept including chronic pain, cognitive impairment, psychiatric disorders, and neuromuscular weakness[62]. Sepsis survivors frequently experience recurrence of sepsis, new or recurrent infection, and new or progressed symptoms of organ dysfunctions[63]. Kurematsu et al[64] found the health-related quality of life was significantly lower in sepsis survivors compared with non-sepsis survivors. This series of post-sepsis syndrome can increase the generalized vulnerability of sepsis survivors to adverse events. Therefore, careful nursing and rehabilitation are very important for surviving sepsis. Effective post-sepsis nursing and rehabilitation have been proven to reduce cardiovascular events risk and 10-year mortality and improve quality of life and physical functioning.

Finally, our study shows that antecedent health status and comorbidities are associated with a high risk of cardiovascular events after an episode of sepsis. However, different from many other studies[13, 34, 48], we found that younger patients demonstrated a higher prevalence of cardiovascular events. It might be attributed to the low baseline incidence of cardiovascular diseases in young people, the HR is very sensitive to the growth data of patients with cardiovascular complications post-sepsis. Overall, improving the health status and treating basic diseases is an effective measure to prevent cerebrovascular events in survivors of sepsis.

A comprehensive meta-analysis of the associations between hospitalization with sepsis and cardiovascular events has been performed in this study. However, Our study has several limitations. First, all of the included studies were observational design, the overall quality of these studies is low. The evidence provided in these studies might influenced by confounders and recall bias. Second, sepsis was defined according to the ICD codes, none of these ICD codes is perfectly sensitive and specific. In addition, the clinical diagnosis of sepsis has been constantly evolving, this is likely to result in the omission of cases of sepsis but could also lead to some patients being misdiagnosed. Future study needs to use the unified gold-standard sepsis definition to define sepsis. Third, due to the sepsis definition, control populations (Hospital/ population-based), follow-up times, and effect size measure of association, resulting in high heterogeneity between studies. To identify the sources of heterogeneity, a series of sensitivity analyses were performed. Fourth, most observational studies only show associations but cannot prove causation, so the result could not indicate whether sepsis increases the risk of cardiovascular events directly. Finally, most studies didn’t report the individualized treatments during hospitalization for sepsis, as well as rehabilitation measures after discharge, which might potentially make the associations overestimated.

In conclusion, sepsis survivors may be associated with a high long-term hazard of experiencing major cardiovascular events. These associations were strengthened in patients with poor health status and comorbidities. The post-sepsis careful nursing and rehabilitation are needed for high-risk patients.

Funding

This study received no funding.

Author Contribution

ZS Wu collected the data, analysed the data, and wrote the manuscript; X Zhao collected the data and wrote the manuscript; C Xiao analysed the data and wrote the manuscript; YS Xu analysed the data and wrote the manuscript.

Acknowledgement

None.

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No competing interests reported.

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Long-term cardiovascular events and risk factors in adults sepsis survivors: A systematic review and meta-analysis

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Introduction

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Literature search strategy and selection

Risk of Bias and Quality Assessment

Main exposure and outcomes of interest

Data analysis

Result

Incidence of cardiovascular events

Risk of cerebrovascular events

Risk factors for cardiovascular events

Prespecified Sensitivity and Subgroup Analyses

Publication bias

Discussion

Conclusions

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Funding

Author Contribution

Acknowledgement

References

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