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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 2  |  Page : 108-115

Intestinal carriage of drug-resistant Gram-negative bacteria belonging to family Enterobacteriaceae in children aged 3–14 years: An emerging threat


1 Department of Microbiology, BPS Government Medical College for Women, Sonipat, Haryana, India
2 MBBS Student, BPS Government Medical College for Women, Sonipat, Haryana, India

Date of Web Publication14-May-2019

Correspondence Address:
Dr. Raminder Sandhu
Department of Microbiology, BPS Government Medical College for Women, Khanpur Kalan, Sonipat, Haryana
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijhas.IJHAS_74_18

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  Abstract 


BACKGROUND: Intestinal colonization by the members of family Enterobacteriaceae represents a major step in the development of systemic infection.
MATERIALS AND METHODS: A total of 100 stool samples were taken from healthy children aged between 3 and 14 years. A structured questionnaire concerning child's lifestyle, predisposing factors as well as risk factors was illustrated. Detection of microorganisms was done by standard laboratory procedures which included microscopy, culture identification, and antibiotic susceptibility testing.
RESULTS: Thirty-three of 100 participants (33%) carried Escherichia coli (66.7%), Klebsiella spp. (27.3%), and Citrobacter freundii (6.1%). Underweight children showed the highest colonization rate (84.8%). Previous exposure to antimicrobial agents (60.6%), rural housing (60.6%), maternal education (57.6%), and nonimmunized status (51.5%) were significantly associated with high carriage among children. The pathogens revealed high resistance to ampicillin (E. coli, 90.9%; Klebsiella spp., 100%; and C. freundii, 100%), co-trimoxazole (E. coli, 81.8%; Klebsiella spp., 88.9%; and C. freundii, 100%), cefuroxime and cefotaxime (E. coli, 81.8% and 63.6%; Klebsiella spp., 100% and 88.9%; and C. freundii, 100% and 100%). Aminoglycoside depicted good susceptibility (gentamicin and amikacin) with resistance rates of 27.3% and 13.6% in E. coli, 33.3% and 44.4% in Klebsiella spp., and no resistance in C. freundii. Carbapenems (imipenem and meropenem) looked promising with low resistance levels (E. coli, 27.3% and 13.6%; Klebsiella spp., 33.3% and 22.2%; and C. freundii, 50% and 00%).
CONCLUSION: High rate of colonization in healthy children with drug-resistant members of family Enterobacteriaceae was observed. The fecal flora of children in the community represents a huge potential reservoir of strains resistant to multiple antimicrobial agents and can be challenging to treat, as their therapeutic options are few.

Keywords: Enterobacteriaceae, Gram-negative, intestinal carriage


How to cite this article:
Sandhu R, Aggarwal A, Sayal P, Kumar S. Intestinal carriage of drug-resistant Gram-negative bacteria belonging to family Enterobacteriaceae in children aged 3–14 years: An emerging threat. Int J Health Allied Sci 2019;8:108-15

How to cite this URL:
Sandhu R, Aggarwal A, Sayal P, Kumar S. Intestinal carriage of drug-resistant Gram-negative bacteria belonging to family Enterobacteriaceae in children aged 3–14 years: An emerging threat. Int J Health Allied Sci [serial online] 2019 [cited 2019 Nov 17];8:108-15. Available from: http://www.ijhas.in/text.asp?2019/8/2/108/258186




  Introduction Top


Antibiotic resistance among bacterial pathogens seems to be on an uninterrupted incline. This increasing trend of antimicrobial resistance is most worrisome, particularly among Gram-negative bacteria (GNB) because there has been little successful development of new antibiotic agents targeting this class of pathogens. Furthermore, we are now in the presence of GNB that have “extreme drug resistance,” indicating complete resistance of strains to first-line and second-line antibiotics creating a therapeutic challenge for clinicians treating patients with a known or suspected infection.[1] Although correlation between in vitro resistance and treatment failure is imperfect, resistance undoubtedly increases mortality, morbidity, and costs in many settings.[2]

Enterobacteriaceae are inhabitants of human intestinal flora, and fecal content with these bacteria is the paradigm of normal circulating strains in a particular time and region. Fecal carriers of extended spectrum beta lactamase (ESBL)-producing Enterobacteriaceae represent an important reservoir, contributing to person-to-person transmission and strengthening their dissemination. Few studies have evaluated intestinal carriage of ESBL-producing Enterobacteriaceae in healthy individuals in the community, especially in children.[3] The main aim of the present study was to investigate the prevalence, phenotypic resistance patterns, and associated risk factors for intestinal carriage of drug-resistant Enterobacteriaceae family from children aged 3–14 years attending the pediatric outpatient department.

Resistance phenomenon is related to many other factors, including excessive antibiotic use in both human and veterinary medicine and cross-transmission of resistant strains from humans to humans and from animals to humans.[4] One of the possible ways for entry of various microbes could be handling of meat and meat products by adopting improper hygienic measures during handling and processing. Furthermore, vegetables are often contaminated through insufficiently treated water and fertilizers and by the use of biocides during cultivation. Therefore, raw meat and vegetables are likely to carry large numbers of bacteria. The transfer of drug resistance within the gastrointestinal tract is still possible; if our food contains substantial numbers of resistant bacteria, it could be an important source of resistance in fecal flora.[5] Acquisition of integrons and beta-lactamase genes by Enterobacteriaceae is increasingly recognized, being associated with resistance to multiple antibiotics. Colonization of healthy individuals with antibiotic-resistant Enterobacteriaceae could contribute to the amplification of resistant bacteria both at community and nosocomial settings. High rates of antibiotic-resistant  Escherichia More Details coli fecal isolates of healthy humans have been reported in different countries.[6] As commensal bacteria constitute as reservoir of resistance genes for potentially pathogenic bacteria, their level of resistance is considered to be a good indicator for selection pressure by antibiotic use and for resistance problems to be expected in pathogens.[7] Changes in the composition of the gut flora can happen silently, leading to the selection of highly resistant bacteria. These resistant organisms may remain for months in the gut of the carrier without causing any symptoms or translocate through the gut epithelium, induce health-care-associated infections, undergo cross-transmission to other individuals, and cause limited outbreaks.[4]

Age is the major driver of differences in gut microbiota in several human studies. Using sequential fecal sampling from one infant during the first 2½ years of life and two large cohort human microbiome studies across North America, Africa, South America, and Europe, it is apparent that the gut microbiome is highly unstable during the first 3 years of life. Although the gut microbiota is rather resilient to disruptive factors such as antibiotics, the ecology of this dense microbial population can be severely altered if exposed to antibiotics too early in its development and/or for long periods of time. This ecological disruption combined with the decreased microbial diversity of the infant's gut can provide opportunities for enteric pathogens. A full understanding of these disease-related changes could allow us to create interventions that rationally shift the microbiota in infants to construct a healthy intestinal environment from a young age. A “critical window” exists early in life where interventions could have more of a profound, long-lasting impact on health. Thus, understanding the microbiota changes during this critical window of time will be of great importance for disease prevention.[8]

Aims and objectives

  1. This study shall aim to provide baseline information on the prevalence of intestinal colonization and resistance in members of family Enterobacteriaceae from reported children aged 3–14 years in the community, toward commonly used antibiotics
  2. The aim of this study is to describe the clinical and microbiological characteristics of intestinal carriage
  3. The secondary aim remains to investigate the association of above-mentioned intestinal colonization and resulting antimicrobial resistance with various demographic variables and other underlying predisposing/risk factors.


The objectives of this study will answer the following questions: what is the overall intestinal bacterial colonization rate in children aged 3–14 years? What is the major leading factor for this gut colonization by drug-resistant bacteria? What will be the priority areas for interventions to prevent and control these infections and curtail antimicrobial drug resistance in low-resource settings that shall decrease the impending health-care costs?


  Materials and Methods Top


Study design and site

The present study is a cross-sectional interviewer-administered questionnaire-based prospective study, carried out in the Department of Microbiology, BPS Government Medical College (BPSGMC) for Women, Khanpur Kalan, Sonepat, for 2-month duration from August 2017 to September 2017. This teaching institute is a tertiary care center catering to a wide population of North West region of Haryana and neighboring states. The study population consisted of children both boys and girls aged 3–14 years who were visiting the pediatric outdoor of our tertiary care institute. Approvals and formal authentications were acquired from the ethical and scientific committee to whom proposal and detailed research methodology were presented and agreed on, according to the Declaration of Helsinki roles and policies. The Ethical Clearance was granted wide letter no. BPSGMCW/RC218/IEC/17 dated May 31, 2017.

Before starting the study, the purpose of the study was explained to the parents/legal guardians, and informed consent was obtained for their participation. Medical history was obtained from the parents/guardian, who was interviewed in the local language. Children were excluded if they had diarrhea during the previous 24 h and those who have traveled outside the country. Parents who consented for their children to participate were included and interviewed using a structured questionnaire to investigate about the demographic detail of the child and family, reason of hospital visit, predisposing factors, and risk factors along with previous treatment details.

Inclusion criteria

Children aged 3-14 years who were attending outdoor section of the paediatric department, whose parents/ guardians consented for their children to participate in the study were included. Only those who had not had diarrhea (as defined by the WHO during the previous 24 h) were eligible for inclusion in the study.[9]

Exclusion criteria

Children below 3 years and whose parents/guardians were unavailable for interview as well as those who remained unwilling to participate were excluded.

Specimen collection and microbiological procedures

A rectal swab or freshly passed sterile fecal sample was obtained randomly from each child enrolled in the study, after informed consent being obtained from parents or other legal guardians. Before obtaining the sample, parent/guardian was interviewed using a structured questionnaire, which included information on the family's socioeconomic and cultural setting, paternal and maternal education and occupation, the household antimicrobial drug use, recent illness among the child and health-seeking behavior in event of illness, immunization, nutritional and HIV status, previous 3-month exposure to various antimicrobials, and general health status of the selected child.

Rectal swabs/stool samples collected from enrolled children were transported to microbiology laboratory for culture and antibiotic sensitivity testing, to know the prevalence of intestinal colonization and resistance pattern among family Enterobacteriaceae from reportedly children aged 3–14 years in the community toward commonly used antibiotics. Processing of the samples was started within 4 h of sample collection. All the stool samples were processed and isolates obtained were identified using standard microbiological techniques.[10]

Processing of specimen, identification of organisms, and antibiotic sensitivity testing

The samples were processed by the routine standard laboratory procedures which included microscopy (wet mount), culture identification, and antibiotic susceptibility testing. Stool samples were streaked on MacConkey agar and blood agar for isolation of members of family Enterobacteriaceae. All the culture plates were incubated at 37°C aerobically for 18–24 h, and the culture-positive isolates were identified by their colony morphology and Gram staining and characterized biochemically for species identification by standard biochemical tests.[11]

Susceptibility of the bacterial isolates to different antimicrobials was determined using the Kirby–Bauer disk diffusion method as per the Clinical and Laboratory Standards Institute guidelines.[12] The antimicrobial drugs tested were as follows: ampicillin (10 μg), co-trimoxazole (1.25/23.75 μg), amoxyclav (20:10 μg), cefuroxime (30 μg), cefotaxime (30 μg), doxycycline (30 μg), gentamicin (10 μg), amikacin (30 μg), ciprofloxacin (5 μg), piperacillin/tazobactam (100/10 μg), meropenem (10 μg), and imipenem (10 μg). All the antimicrobial agents were purchased from HiMedia Laboratories, Mumbai, India.

Statistical Analysis

Descriptive statistics were used to evaluate the prevalence of intestinal carriage of drug-resistant Gram-negative organisms among children.


  Observations and Results Top


The demographic details of the families of 100 children enrolled in the study are shown in [Table 1]. Among the 100 enrolled children, 33 (33%) yielded stool-screening cultures belonging to family Enterobacteriaceae. Stool samples of the remaining 67 (67%) children remained culture negative. Intestinal carriage rate was 33% in the present study after a random screening of stool samples. Overall, among 33 children with culture-positive results, 22 (66.7%) children were identified with E. coli, 9 (27.3%) with Klebsiella spp., and 2 (6.1%) with Citrobacter freundii strains, as shown in [Table 2]. All the 33 culture-positive screened stool samples exhibited growth of a single organism. Clinical characteristics and risk factors for acquisition of drug-resistant Gram-negative organisms revealed that weight by age remained most important risk factor as 84.8% of underweight children had intestinal colonization in comparison to healthy children (15.2%). The other notable risk factors were previous exposure to antimicrobial agents (60.6%) and the housing in rural areas (60.6%). The children of educated mothers (57.6%) remained at higher risk of colonization by resistant bacteria. Non immunized status (51.5%) of the children also remained a fair risk factor. None of the children tested positive for HIV. The previous history of hospitalization accounted for 39.4% as a risk factor, whereas nonhospitalized children were found to be 60.6% at risk of intestinal carriage of Gram-negative pathogens. Children with provisional diagnosis of upper respiratory tract infections (42.4%) and skin infections (27.3%) were those harboring drug-resistant pathogens in their gut, as shown in [Table 3].
Table 1: Demographic characteristics of the study group (n=100)

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Table 2: Prevalence of intestinal carriage among children in stool screening cultures (n=100)

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Table 3: Clinical characteristics and risk factors associated with intestinal colonization of drug-resistant organisms (n=33)

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All the isolates remained resistant to several antibiotic classes tested. The antibiotic sensitivity pattern of isolated pathogens showed very high resistance to ampicillin (E. coli, 90.9%; Klebsiella spp., 100%; and C. freundii, 100%), co-trimoxazole (E. coli, 81.8%; Klebsiella spp., 88.9%; and C. freundii, 100%), cefuroxime and cefotaxime (E. coli, 81.8% and 63.6%; Klebsiella spp., 100% and 88.9%; and C. freundii, 100% and 100%). High resistance was exhibited for amoxyclav (E. coli, 63.6%; Klebsiella spp., 88.9%; and C. freundii, 100%), doxycycline (E. coli, 68.2%; Klebsiella spp., 77.8%; and C. freundii, 100%). All the isolates showed good susceptibility to aminoglycoside (gentamicin and amikacin) with resistance rates of 27.3% and 13.6% in E. coli, 33.3% and 44.4% in Klebsiella spp., and no resistance in C. freundii). The other drugs that looked promising in vitro susceptibility testing were imipenem and meropenem with very low resistance levels in all the three members of family Enterobacteriaceae (E. coli, 27.3% and 13.6%; Klebsiella spp., 33.3% and 22.2%; and C. freundii, 50% and 00%), as shown in [Table 4].
Table 4: Prevalence expressed as percentage of children carrying drug-resistant organisms belonging to the family Enterobacteriaceae

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  Discussion Top


In low-resource countries, the extent and the impact of antibiotic resistance tend to be even larger than in industrialized countries. In fact, high resistance rates have often been reported in surveillance studies dealing with clinical isolates and in prevalence studies of commensal bacteria taken as indicators to estimate the spread of acquired resistance. The high antimicrobial drug resistance rates observed in low-resource countries are likely due to a combination of several factors, among which irrational antimicrobial drug usage and conditions of poor sanitation are thought to play a major role, even if the relative importance of additional factors remains unclear.[13]

Little is known about fecal carriage of organisms belonging to family Enterobacteriaceae among children and their antibiotic resistance in North West region of Haryana, with only a few studies which have been conducted in the northern part of the country. Thus, our study was undertaken in the Department of Microbiology, BPSGMC for Women Khanpur Kalan, to investigate the prevalence of intestinal carriage of drug-resistant GNB belonging to family Enterobacteriaceae in children aged 3–14 years visiting outdoor section of the pediatric department. The intestinal colonization and carriage of such pathogens in the community shall aid in determining their future burden on health-care facilities and transmission rate in the community. The present study comprised 100 stool samples (screening samples) being collected from 100 children enrolled after obtaining informed consent of parents/guardians who answered a structured questionnaire in local language. The samples were collected with proper aseptic precautions as per standard operating procedures. Demographic characteristics of the study participants showed that among 100 enrolled participants, 40% were males and 60% females [Table 1]. Stool screening cultures of the study group revealed that isolates belonging to family Enterobacteriaceae were recovered from 33 children (33%), and the reports of the remaining 67 (67%) children remained culture negative. None of the culture-positive samples contained more than one bacterial species. Overall among 33 children with culture-positive results, 22 (66.7%) children were identified with E. coli, 9 (27.3%) with Klebsiella spp., and 2 (6.1%) with C. freundii strains [Table 2]. Tellevik et al. identified 284 bacterial isolates from 207 children. Of these, 139 were identified as Klebsiella pneumoniae, 129 were E. coli, 11 were Enterobacter cloacae complex, 2 were Klebsiella oxytoca, 2 were Citrobacter spp. and 1 was Proteus mirabilis. Carriage of two different bacteria spp. was detected in 75 (36.2%) participants with a positive screening.[14] A study done by Strysko et al. reported that out of 85 ESBL-producing Enterobacteriaceae isolates, 91% were E. coli, 7% K. pneumoniae, and 2% Klebsiella oxytoca.[15]

Available epidemiological data suggest that intestinal carriage with resistant Enterobacteriaceae may serve as an on-going reservoir for infection, as well as a source for transmission of these bacteria between individuals. Few pediatric studies include the in-depth clinical and molecular characterization required to understand the role that intestinal carriage plays in recurrent infection and to aid in the design of interventions focused on reducing intestinal carriage and limiting transmission.[16]

Intestinal carriage rate was 33% [Table 2] in the present study after random screening of stool samples of children visiting outdoor section of the pediatric department with provisional diagnosis of upper respiratory tract infections, urinary tract infection, pain abdomen, and skin infections. Carriage rate among 3–14-year-old children in our study is comparable to the prevalence found among children in Laos by Stoesser et al., who documented 23% colonization of ESBL among children attending preschool childcare facilities.[17] Another study done by Hijazi et al. quoted that 24.8% of participants carried ESBL producers belonging to the family Enterobacteriaceae that included Lebanese children community between 1 and 5 years age group.[18] As key transmitters of infection within communities children are likely to be important contributors to endemic community resistance.[19]

Risk factors for intestinal carriage included weight for age where underweight children had 84.8% carriage rate as compared to those with normal weight (15.2%). The findings remained consistent with Tellevik et al. who reported the prevalence of fecal carriage of ESBL-screening positive bacteria to be 37.6% in underweight children in Dar es Salaam, Tanzania, in comparison to children having normal weight (31.6%). Malnourished children with impaired immunity are more vulnerable to infections and are hence more likely to be treated with antibiotics.[14]

Prior exposure to various antimicrobials (60.6%) also remained an important risk factor. There has been little research published exploring fecal carriage of bacterial resistance in any asymptomatic population. This could provide important information regarding carriage and transmission of resistant bacteria within and between populations. This is particularly important in low-income countries, where antibiotics are often available over the counter (OTC) without the need for a prescription. The misuse of antibiotics in this way can expose harmless or opportunistic bacteria to a plethora of antibiotics to which they develop resistance.[20] Previous use of antibiotics as far back as 12 months before sampling has been described as a risk factor for carriage.[17],[21] The use of antibiotics in 3 months prior to sampling was identified as the only risk factor that remained significantly associated with ESBL colonization in the multivariate analysis almost doubling the odds, consistent with other data.[22],[23]

Environmental factors may also play a role in the variation of colonization and resistance rates among children living in urban and rural areas. The risk of intestinal carriage by GNB was observed to be higher in children living in rural areas (60.6%) as compared to those residing in urban areas (39.4%) as shown in [Table 3]. Sources of environmental contamination with resistant bacteria include human effluent and farm runoff, which have been detected in low-income countries.[24],[25]

The handling of water storage containers used in different villages may also play a role in occurrence of differing rates of resistance, as contamination of household water with coliform bacteria occurs mostly after collection from water sources.[26]

The maternal education (57.6%) was found to be a risk factor for intestinal colonization with drug-resistant pathogens, as shown in [Table 3]. These findings remained concordant with study done by Shakya et al. who observed as association between maternal education and increased antibiotic resistance. Those children whose mothers had attended school were more likely to carry E. coli resistant to these antibiotic groups. Maternal education has previously been regarded as a proxy indicator for socioeconomic status (SES) of a family. It has been seen that children of higher SES are more likely to receive antibiotics, and previous consumption increases the risk of antibiotic resistance. Educated women tend to have a more autonomous role in society compared to illiterate women.[26]

Resistance to different antimicrobials is shown in [Table 4]. All the three bacterial species isolated showed high rates of resistance to commonly used antimicrobials in our North West region of Haryana. E. coli exhibited high resistance to ampicillin (90.9%), co-trimoxazole (81.8%), cefuroxime (81.8%), doxycycline (68.2%), cefotaxime (63.6%), and amoxyclav (63.6%). Lower resistance rates were observed for gentamicin (27.3%) and amikacin (13.6%). Similar resistance pattern was noted by Bartoloni et al., who mentioned high resistance rates for ampicillin (95%), trimethoprim-sulfamethoxazole (94%), and tetracycline (93%) whereas lower resistance rates for gentamicin (21%) and amikacin (<0.5%).[13] The carbapenems remained efficacious in vitro for E. coli, with low resistance rates of 13.6% and 27.3% for meropenem and imipenem, respectively. The higher resistance for imipenem may be due to more frequent use of this drug in hospital settings of this region. Klebsiella spp. showed higher level of resistance to most of the in vitro drugs tested. All nine isolates exhibited high resistance to ampicillin (100%), co-trimoxazole (88.9%), cefotaxime (88.9%), amoxyclav (88.9%), and doxycycline (77.8%). The carbapenem resistance remained at a lower level like E. coli, with 22.2% and 33.3% for meropenem and imipenem, respectively. There is a paucity of data on surveillance cultures from India, with three community-based studies from East, South, and Central India showing 24%–38% prevalence of MDRO isolates in surveillance stool cultures from children. Resistance to carbapenems in these community studies ranged from 0% to 12%.[24],[26],[27] The lower MDRO rates in these studies are due to the community sampling versus hospital-based sampling in our study. Furthermore, these studies studied only E. coli isolates in healthy children.[28]

ESPAUR-2013 data published from the UK estimated the national rate of ESBL E. coli and K. pneumoniae at 10.9% and 11.4%. While the CRE rate for E. coli and K. pneumoniae was low at <1% and 3.8%, respectively.[29] Centers for disease control and prevention (CDC), USA, has recently estimated carbapenem- resistant enterobacteriacae (CRE) in K. pneumoniae and E. coli at 11% and 2%, respectively, together accounting for 600 deaths annually.[30]

All isolates of C. freundii remained sensitive to meropenem, piperacillin/tazobactam, gentamicin, and amikacin whereas 50% sensitivity rate for imipenem. Resistance to all other antimicrobials tested was 100%. Susceptibility to antimicrobial agents for the ESBL screening positive bacteria in a study performed at Dar es Salaam, Tanzania, had similar observations, with all Citrobacter spp. isolates sensitive to meropenem, doxycycline, and co-trimoxazole.[14]


  Conclusion Top


In the current study, the resistance to many commonly used primary care antibiotics among fecal Enterobacteriaceae members in children aged 3–14 years ranged from moderate to very high. The reasons for this local as well as global emergence of antibiotic-resistant bacteria are complex which include interactions between antibiotic prescription, OTC use, patient misuse by suboptimal dosing, community contacts, and transmission. Children are likely to be important contributors to endemic community resistance. There has been very little research aimed to investigate the carriage of fecal Gram-negative pathogens from asymptomatic children resistant to commonly used drugs. There is a need to up regulate local and national research along with surveillance efforts to monitor resistance trends of commensal community in the gut.

Ethical clearance

Approvals and formal authentications were acquired from the ethical and scientific committee to whom proposal and detailed research methodology were presented and agreed on, according to the Declaration of Helsinki roles and policies. The ethical clearance was granted wide letter no. BPSGMCW/RC218/IEC/17 dated 31.05.2017.

Acknowledgment

This study was a part of Short-Term Student 2017 Program of ICMR.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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