Clinical outcomes and nephrotoxicity of colistin methanesulfonate in critically ill patients with carbapenem-resistant organisms infections: a retrospective study

doi:10.21203/rs.3.rs-4978828/v1

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Clinical outcomes and nephrotoxicity of colistin methanesulfonate in critically ill patients with carbapenem-resistant organisms infections: a retrospective study

https://doi.org/10.21203/rs.3.rs-4978828/v1

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Background

Carbapenem resistant organisms (CRO) infection is one of the most common causes of high mortality among critically ill patients. Colistin methanesulfonate (CMS) represents a significant treatment option for CRO infections, yet the available data on CMS in the Chinese population remains limited. This study aimed to analyze the clinical outcomes and nephrotoxicity of CMS in treating critically ill patients with CRO infections in China.

Methods

A retrospective study was conducted from June 2022 to September 2023 in critically ill patients with CRO infections who received CMS treatment. The clinical outcomes were assessed by clinical effective, microbiological eradication, infection-related hospital mortality, the length of ICU stay, and total hospital stay. A sub-group analysis was conducted on patients with lung infection. The nephrotoxicity was assessed by the acute kidney injury (AKI).

Results

A total of 96 critically ill patients with CRO infections were enrolled in the study. The overall clinical effective, microbiological eradication and infection-related hospital mortality rates were 67.90%, 60.49% and 8.33%, respectively. The median length of ICU and total hospital stays was 28 and 32.5 days, respectively. In patients with lung infection, 70.31% and 61.19% achieved clinical effective and microbiological eradication, respectively. The younger patients (< 65 years old), patients who received intravenous combined nebulized CMS, and infections caused by CRE benefitted more from CMS treatment. The incidence of acute kidney injury (AKI) was 28 cases (30.43%), with the majority (82.14%) occurring in stage 1.

Conclusions

CMS treatment in Chinese critically ill patients with CRO infections achieved favorable outcomes, with acceptable nephrotoxicity, providing a promising option for this fatal disease.

Carbapenem-resistant organisms

Critically ill patients

Colistin methanesulfonate

Clinical outcomes

Nephrotoxicity

According to predictive statistical models, antibiotic resistance caused 1.27 million deaths in 2019, nearly twice the 700000 deaths reported in 2016 [1]. The incidence rate of carbapenem resistant organisms (CRO) infections is rising rapidly worldwide, which were listed as the highest priority category (i.e. critical) by the World Health Organization (WHO) [2]. Patients in the intensive care unit (ICU) are typically immunocompromised, with an infection rate of more than 50% [3]. Furthermore, due to the widespread adoption of carbapenems, the incidence of CRO infections in ICU patients has been significantly higher than in non-ICU settings, with an in-hospital mortality of up to 46.1% [4–6]. Therefore, the control of CRO infections has become a key issue to save ICU patients with severe infections.

The clinical management of CRO infections is severely hampered by the extensively drug-resistant or pan-drug-resistant nature of CRO isolates [7]. Although extensive efforts have been made to identify new drugs that counteract the mechanisms underlying this phenomenon, most have been unsuccessful. Consequently, the reintroduction of old potent drugs into clinical practice may be a necessary effort [8]. Despite the cessation of polymyxins utilisation due to the elevated prevalence of adverse effects, including nephrotoxicity, its robust bactericidal efficacy and lowest resistance rate to multidrug-resistant Gram-negative bacterial infections render polymyxins the “last line of defence” for the treatment of CRO infections [9]. Currently, three injectable polymyxins are available in both domestic and international markets, including colistin methanesulfonate (CMS), polymyxin B sulfate (PBS), and polymyxin E sulfate (PES). As the earliest polymyxin launched internationally, CMS has the highest attention and lower nephrotoxicity than PBS [10].

CMS is a pro-drug of colistin, which has a high sensitivity rate against CRO infections [11]. Several clinical studies have confirmed that CMS is an effective antimicrobial agent for CRO infections, with acceptable nephrotoxicity [12–14]. In addition, there is growing evidence that critically ill patients with CRO infections also benefit from CMS treatment. A retrospective study from Vietnam of critically ill adult patients receiving intravenous colistin showed that 68% were clinically effective, with low nephrotoxicity (21%) [15]. Another study from Thailand proposed that, CMS was associated with better clinical outcomes in critically ill patients with CRO infection [16]. However, due to the late listing of CMS in China, there are currently limited studies on CMS for critically ill patients with CRO infection in China. Thus, we retrospectively investigated the clinical outcomes and nephrotoxicity of CMS in critically ill patients with CRO infection in China, aiming to provide a reference for the clinical application of CMS.

Study design

This single-center, retrospective study was conducted to assess the clinical outcomes and safety in critically ill patients with CRO infections who received CMS treatment at the First Affiliated Hospital, Zhejiang University School of Medicine between June 2022 and September 2023. Adult patients aged of 18–90 years were included in the study if they were admitted to the ICU with positive cultures for CRO and received CMS treatment for three or more days. Patients were excluded if they had received other polymyxins treatment one week prior to enrollment, had a known allergy to CMS or its metabolites, pregnancy or lactation, severe liver and kidney dysfunction. The study was carried out in accordance with the Declaration of Helsinki and approved by the clinical research ethics committee of the first affiliated hospital, college of medicine, zhejiang university (IIT20230300B-R1). Written informed consent was waived owing to the retrospective nature of this investigation.

The demographic, clinical, laboratory and microbiological characteristics of each enrolled patient were collected from baseline to the end of treatment. All causative organisms were identified by standard microbiological techniques. The Clinical and Laboratory Standards Institute (CLSI) method was used to evaluate the susceptibility of patients to antimicrobial agents [17].

CMS administration

All enrolled patients were treated with CMS (Chia Tai Tianqing Pharmaceutical Group Co., Ltd, China). Patients receiving intravenous CMS were initially given a loading dose of 300 mg colistin base activity (CBA), followed by a maintenance dose of 2.5–5 mg of CBA/kg/ day[18]. Patients receiving nebulized CMS were given a dose of 75 mg CBA twice a day, and the vibrating mesh nebulizer was used for nebulization[19]. The nebulized CMS was prepared by mixing 75 mg CBA with 3–4 mL of normal saline immediately before nebulization. The specific dosage and duration of CMS was adjusted by clinical physicians based on the renal function of each patient, and the maximum daily dose is not more than 5 mg/kg.

Clinical outcomes

The primary outcomes evaluated in this study were clinical effective and microbiological eradication at the end of treatment. Clinical effective was defined as resolution or significant improvement of presenting symptoms and signs of CRO infection at the end of CMS treatment, or the non-microbiological indicators such as imaging all have returned to normal. Microbiological eradication was defined as the proportion of patients with eradication and presumed eradication in the total population. Eradication was defined as the failure to cultivate pathogenic bacteria from the original infected site of the specimen after treatment, and presumed eradication was defined as the disappearance of symptoms and signs making it impossible to obtain cultivable materials (such as sputum, skin pus, or secretions), or the method of obtaining specimens is too invasive for rehabilitation patients.

Secondary outcomes included infection-related hospital mortality, the length of ICU stay and length of hospital stay. It was not considered that hospital death cases occurring after the improvement of infection symptoms were related to infection. The assessment of hospital and ICU stays did not include patients who died during the course of their hospitalization.

Nephrotoxicity

The nephrotoxicity was evaluated by the development of acute kidney injury (AKI), which was defined in accordance with the Kidney Disease Improving Global Outcomes (KDIGO) criteria based on serum creatinine (SCr) values at the end of treatment [20]. The stage of severity of AKI was also classified in accordance with the KDIGO criteria, as follows: 1) Stage 1, an increase in SCr by ≥ 26.5 µmol/L (0.3 mg/dL) or between 1.5 and 1.9 times the baseline value; 2) Stage 2, an increase in SCr by 2.0 to 2.9 times the baseline SCr value; 3) Stage 3, an increase in SCr by 353.6 µmol/L (4 mg/dL) or > 3.0 times the baseline SCr value, or commencement of renal replacement therapy.

Statistical analysis

All statistical analyses were conducted using the RStudio version 4.3.1. The descriptive statistics were employed to assess the baseline characteristics of patients. The distribution normality of the continuous variables was tested using the Shapiro-Wilk method. In the event that the variable was normally distributed, it was represented by the mean ± standard deviation (SD). Otherwise, the variable was represented by median (interquartile range, IQR). The categorical variables were represented by the corresponding number of cases and percentage. The Clopper-Pearson method was employed to calculate the 95% confidence interval (CI) for clinical efficacy, microbiological eradication, and other indicators. For patients with lung infection, a subgroup analysis was conducted based on age, medication method and causative organisms.

Patient baseline characteristics

A total of 96 critically ill patients with CRO infections who met the inclusion criteria were recruited for analysis. The characteristics of patient were presented in Table 1. The mean age of all patients was 62.61 ± 17.28 years, with 73.96% being male. The majority of patients (83.33%) had a past medical history. Of these patients, 36 (37.50%) experienced sepsis, and 18 (18.75%) developed septic shock. The majority of patients (77/96, 80.2%) had a lung infection, and the most frequently causative organisms were carbapenem-resistant Acinetobacter baumannii (CRAB) (57/96, 59.38%), followed by carbapenem-resistant Enterobacteriaceae (CRE, 37/96, 38.54%), including 31 patients (32.29%) with carbapenem-resistant Klebsiella pneumonia. Most of patients (87/96, 90.62%) received mechanical ventilation, 33 patients (34.38%) received haemodialysis, and 52 patients (54.17%) were treated with vasoactive agents. All patients received CMS therapy, with 79.17% (76/96) of patients involving the prescription of this treatment in combination with other antimicrobial agents.

Table 1

The demographic and clinical characteristics of patients
Variables	Total (n = 96)
Age, years, mean ± SD	62.61 ± 17.28
Gender, male, no. (%)	71 (73.96)
BMI, kg/m², mean ± SD	23.08 ± 3.96
Past medical history, no. (%)	80 (83.33)
Sepsis, no. (%)	36 (37.50)
Septic shock, no. (%)	18 (18.75)
SOFA score, mean ± SD	7.70 ± 4.18
APACHE II score, mean ± SD	18.03 ± 7.33
Charslon comorbidity index, mean ± SD	3.96 ± 2.59
Glasgow Coma Scale, mean ± SD	10.30 ± 5.41
Site of infection, no. (%)
Lung	77 (80.2)
Others	19 (19.79)
Causative organisms, no. (%)
Carbapenem-resistant Acinetobacter baumannii	57 (59.38)
Carbapenem-resistant Enterobacteriaceae	37 (38.54)
Carbapenem-resistant Pseudomonas aeruginosa	11 (11.46)
Others	2 (2.08)
Laboratory parameters, mean ± SD
Serum creatinine, µmol/L	117.62 ± 89.18
C reactive protein, mg/L	97.76 ± 70.96
Procalcitonin, ng/mL	3.47 ± 7.25
Mechanical ventilation, no. (%)	87 (90.62)
Hemodialysis, no. (%)	33 (34.38)
Vasoactive agents, no. (%)	52 (54.17)
Strategy of CMS use, no. (%)
Monotherapy	20 (20.83)
Combination therapy	76 (79.17)
^*Data are presented as mean ± SD, no. (%), median (IQR), where no. is the total number of patients with available data. SOFA, sequential organ failure assessment; APACHE II, acute physiology and chronic health evaluation II; CMS, Colistin methanesulfonate.

The resistance profiles of the 5 common antimicrobial agents used for the treatment of CRO infections was shown in Table 2. The antimicrobial non-susceptibility rates to meropenem and imipenem were both 96.84% (92/95). 71.25% (57/80) and 69.23% (27/39) of patients were susceptible to tigecycline and ceftazidime/avibactam, respectively. A total of 96.74% of patients exhibited intermediate resistance to colistin, with minimum inhibitory concentrations (MICs) of ≤ 2.0 mg/L (Table 2).

Table 2

Susceptibility of patients to antimicrobial agents
Antimicrobial agents	Tested, no.	Susceptibility no. (%)	Intermediate no. (%)	Resistance no. (%)
Meropenem	95	3 (3.16)	0	92 (96.84)
Imipenem	95	3 (3.16)	0	92 (96.84)
Tigecycline	80	57 (71.25)	19 (23.75)	4 (5.00)
Ceftazidime/avibactam	39	27 (69.23)	0	12 (30.77)
Colistin	92	/	89 (96.74)	3 (3.26)

Clinical outcomes analysis

The clinical effective of CMS treatment was achieved in 55 patients (67.90%), and microbiological eradication was achieved in 49 patients (60.49%) (Table 3). The overall infection-related hospital mortality was 8.33% (8/96). The median length of ICU and hospital stays was 28 and 32.5 days, respectively. In patients with lung infection, 70.31% (45/77) and 61.19% (41/77) achieved clinical effective and microbiological eradication, respectively. Furthermore, the infection-related hospital mortality was 7.79% (6/77), with a median length of ICU and hospital stays of 29 and 33 days, respectively.

Table 3

Clinical outcomes of patients treated with CMS
Variables	No. (%) or median (IQR)	95% CI
Total (n = 96)
Primary outcomes
Clinical effective	55 (67.90)	56.60, 77.85
Microbiological eradication	49 (60.49)	49.01, 71.19
Secondary outcomes
Infection-related hospital mortality	8 (8.33)	3.67, 15.76
Length of ICU stay (days)	28 (18.00, 51.75)	27, 41
Length of total hospital stay (days)	32.50 (20.50, 63.75)	35.50, 50.50
Lung infection (n = 77)
Primary outcomes
Clinical effective	45 (70.31)	57.58, 81.09
Microbiological eradication	41 (61.19)	48.50, 72.86
Secondary outcomes
Infection-related hospital mortality	6 (7.79)	2.91, 16.19
Length of ICU stay (days)	29 (18.00, 50.50)	27.50, 42.00
Length of total hospital stay (days)	33 (24,62)	35.00, 50.50

Sub-group analysis

Sub-group analysis based on age, medication method and causative organisms of patients with lung infection were presented in Table 4. The younger patients (< 65 years old) demonstrated superior clinical efficiency (75% vs. 66.67%), lower infection-related hospital mortality (2.94% vs. 11.63%) and shorter ICU stay (24 vs. 31 days). Compared with patients who received intravenous alone, intravenous combined nebulized CMS achieved higher clinical efficacy (61.90% vs. 84.62%), microbiological eradication rate (56.82% vs.78.57%), and lower infection-related hospital mortality rate (9.43% vs. 0). In the sub-groups defined by causative organisms, patients with CRE infections benefitted more from CMS treatment, with a clinical efficiency of 85.71%, a microbiological eradication of 64.29%, and an infection-related hospital mortality of 5.88%.

Table 4

Subgroup analysis of clinical outcomes in patients with lung infection
Variables, no. (%) or median (IQR)
	< 65 years (n = 34)	≥ 65 years (n = 43)
Clinical effective	21 (75.00)	24 (66.67)	/
Microbiological eradication	16 (53.33)	25 (67.57)	/
Infection-related hospital mortality	1 (2.94)	5 (11.63)	/
Length of ICU stay (days)	24 (18, 56)	31 (19.00, 46.75)	/
Length of total hospital stay (days)	32 (19, 61)	33 (27.25, 61.75)	/
	Intravenous	Intravenous combined
	alone (n = 53)	nebulized CMS (n = 14)	/
Clinical effective	26 (61.90)	11 (84.62)	/
Microbiological eradication	25 (56.82)	11 (78.57)	/
Infection-related hospital mortality	5 (9.43)	0	/
Length of ICU stay (days)	27.50 (17.75, 44.00)	40 (24, 69)	/
Length of total hospital stay (days)	32 (18.75, 61.50)	40 (26, 93)	/
	CRAB (n = 49)	CRE (n = 17)	CRPA (n = 6)
Clinical effective	27 (65.85)	12 (85.71)	4 (66.67)
Microbiological eradication	26 (59.09)	9 (64.29)	3 (50.00)
Infection-related hospital mortality	2 (4.08)	1 (5.88)	2 (33.33)
Length of ICU stay (days)	31.50 (19.00, 56.50)	27 (20, 41)	21 (17, 65)
Length of total hospital stay (days)	32.50 (24.75, 64.50)	41 (25, 52)	82 (69, 113)
CRAB, carbapenem-resistant Acinetobacter baumannii; CRE, carbapenem-resistant Enterobacteriaceae; CRPA, carbapenem-resistant Pseudomonas aeruginosa; CMS, Colistin methanesulfonate.

Nephrotoxicity analysis

Nephrotoxicity that possibly or probably related to the use of CMS were presented in Table 5. The incidence of AKI among patients received CMS treatment was 28 cases (30.43%), with 23 patients (82.14%) presenting with stage 1 AKI, 2 patients (7.14%) with stage 2 AKI, and 3 patients (10.71%) with stage 3 AKI. The median change in serum creatinine from baseline for patients was 4 µmol/L.

Table 5

Nephrotoxicity possibly or probably related to the use of CMS
Nephrotoxicity	Total (n = 96)
Acute kidney injury, no. (%)
Yes	28 (30.43)
No	64 (69.57)
KDIGO criteria
Stage 1	23 (82.14)
Stage 2	2 (7.14)
Stage 3	3 (10.71)
Serum creatinine change from baseline (Δ), µmol/L, median (IQR)	4 (-31.00, 39.5)
CMS, Colistin methanesulfonate; KDIGO, Kidney Disease Improving Global Outcomes.

To the best of our knowledge, this was one of the first studies to describe the clinical outcomes of CMS use in Chinese critically ill patients. The overall clinical effective rate was 67.9%, the microbiological eradication rate was 60.49%, and the infection-related hospital mortality was 8.33%. Subgroup analysis demonstrated that younger patients (< 65 years old), patients who received intravenous combined nebulized CMS, and infections caused by CRE benefitted more from CMS treatment. 30.43% of patients developed AKI, and most (82.14%) of them were stage 1. In light of these findings, CMS treatment for Chinese critically ill patients with CRO infections achieved favorable outcomes, with acceptable nephrotoxicity.

The increasing of mortality rate associated with CRO infections in critically ill patients has prompted the widespread adoption of CMS. A previous study in critically ill patients investigated the efficacy of CMS and found a clinical effective rate of 68% and a microbiological eradication rate of 62.5%. These findings are similar to those reported there [15]. Additionally, the findings of this study demonstrated that the infection-related hospital mortality rate was 8.33%, which was lower than that observed in previous studies [15, 21]. It is plausible that the mortality in critically ill patients is influenced by factors beyond infectious control, such as disease severity and the presence of comorbidities. It should be noted that this study only counted infection-related hospital mortality, and hospital deaths that occurred after symptom improvement were considered unrelated to infection. Lung infection was the most common site of infection in critically ill patients [22], with 80% of patients with lung infections in our study. Consequently, an analysis of the clinical outcomes of patients with lung infections was condducted, which revealed that 70.31% of patients achieved clinical effective, 61.19% of patients achieved microbiological eradication, and the infection-related hospital mortality was 7.79%, which was comparable to those of the overall population.

A 10-year prospective observational study conducted in China indicated that age ≥ 65 years was independent risk factor for in-hospital mortality among adult patients with lung infection [23]. The sub-group analysis of age < 65 years and ≥ 65 years revealed that younger patients exhibited a higher clinical effective rate and a lower infection-related hospital mortality. Similarly, a previous study has also demonstrated that the patients who responded to treatment were younger than patients who did not respond [15]. However, the microbiological eradication rate of younger patients in this study was slightly lower than that of older patients. It is postulated that this may be due to the fact that some younger patients with improved symptoms have not yet completed microbiological eradication. A previous study demonstrated that nebulized CMS enhanced clinical responses and diminished infection-related mortality [24]. Similarly, the sub-group analysis of medication method in this study demonstrated that, in comparison with patients who received intravenous therapy alone, those who received intravenous combined with nebulized CMS achieved higher clinical efficacy, microbiological eradication rate, and lower mortality rate. Our findings lend support to the combination of intravenous and nebulized CMS for lung infection caused by CRO, a recommendation also made by the most recent guidelines [8]. Prior research has demonstrated the efficacy of CMS in treating infections caused by CRAB, carbapenem-resistant Pseudomonas aeruginosa (CRPA), and CRE [25–27]. In accordance with the findings of this study, the clinical efficacy of CMS for the treatment of lung infections caused by various carbapenem-resistant organisms was consistently above 65%, with a microbial clearance rate was above 50%. It is noteworthy that the clinical effective rate in the CRE group reached 85%, indicating a greater benefit from CMS treatment.

Nephrotoxicity represents one of the most prevalent and severe adverse effects observed in patients treated with CMS. Colistin has been demonstrated to increase the permeability of renal tubular epithelial cells, leading to cell swelling and lysis [28]. SCr is a key indicator for detecting renal filtration capacity, and the KDIGO criteria based on SCr are frequently employed to evaluate the nephrotoxicity of CMS[29]. The incidence of nephrotoxicity caused by polymyxins in previous reports ranged from 0–60% [30–32]. The discrepancies in reported incidence rates are likely attributable to variations in the study populations, colistin dosage and duration of treatment, as well as the concomitant use of other nephrotoxic drugs. In this study, 30.43% of patients receiving CMS treatment developed AKI, which is within the ranges reported previously in the literature. A recent systematic review identified a prevalence of approximately 34.7% for polymyxin-induced nephrotoxicity (KDIGO criteria), which is similar to the findings of this study [31]. Additionally, the majority of patients with AKI were classified as stage 1, with mild symptoms, indicating that CMS therapy is a safe treatment for the management of CRO infections in critically ill patients.

The present study was subject to a number of limitations. Firstly, this single-center retrospective study is reliant on the record of events at the time of occurrence, which may result in a degree of bias in the interpretation of clinical response and toxicity. Secondly, the limited sample size and absence of a control group that did not receive CMS in this study restrict the scope for evaluating the true effect; a large-scale controlled study will be conducted to verify our findings. Thirdly, the majority of enrolled patients had lung infection, and therefore, the findings should be interpreted with caution when applied to other infection sites. Notwithstanding these limitations, our study has enhanced the efficacy and safety of CMS used in critically ill patients with CRO infections, thereby provides a reference for the clinical application of CMS.

Our findings corroborated CMS is a relatively safe and effective antimicrobial agent for critically ill patients with CRO infections. Subgroup analysis revealed that younger patients (< 65 years old), patients who received combined intravenous and nebulized CMS, and infections caused by CRE benefitted more from CMS treatment.

CRO, Carbapenem resistant organisms

CMS, Colistin methanesulfonate

AKI, acute kidney injury

WHO, World Health Organization

PBS, polymyxin B sulfate

PES, polymyxin E sulfate

CLSI, Clinical and Laboratory Standards Institute

CBA, colistin base activity

KDIGO, Kidney Disease Improving Global Outcomes

SCr, serum creatinine

SD, standard deviation

IQR, interquartile range

CI, confidence interval

CRAB, carbapenem-resistant Acinetobacter baumannii

CRE, carbapenem-resistant Enterobacteriaceae

MICs, minimum inhibitory concentrations

CRPA, carbapenem-resistant Pseudomonas aeruginosa

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki and approved by the clinical research ethics committee of the first affiliated hospital, college of medicine, zhejiang university (IIT20230300B-R1). Informed consent was obtained from all individual participants included in the study.

Consent for publication

Not applicable.

Availability of data and materials

All data generated or analyzed during this study are included in this published article.

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Authors' contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; HC conceived and designed the study; XR and JX provided materials and samples for this study; XR and JX collected and assembled the data; HZ analyzed and interpreted the data. XR wrote the manuscript.

Acknowledgement

Not applicable.

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No competing interests reported.

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Clinical outcomes and nephrotoxicity of colistin methanesulfonate in critically ill patients with carbapenem-resistant organisms infections: a retrospective study

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Abstract

Background

Methods

Results

Conclusions

Background

Methods

Study design

CMS administration

Clinical outcomes

Nephrotoxicity

Statistical analysis

Results

Patient baseline characteristics

Clinical outcomes analysis

Sub-group analysis

Nephrotoxicity analysis

Discussion

Conclusions

Abbreviations

Declarations

References

Additional Declarations

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Version 1