|Year : 2022 | Volume
| Issue : 2 | Page : 55-62
Detection and reporting of Carbapenemase producing Gram negative bacilli in Clinical Microbiology: A survey of practices in laboratories across India
Kavita Raja1, Chiranjay Mukhopadhyay2, Anup Kumar Shetty3, Jily P Chinnan4, J Sudarsana5, Reena Anie Jose6, N Saritha7, C Ravindranath8, G Goel9, Chithra Valsan10, Subha Sundaramoorthy11, Sapna Joy12, SG Sagila13, Ramakrishna Pai Jakribettu14, KL Sarada Devi15, Dinoop Korol Ponnambath1, Ashish Jithendranath16, Kavitha R Dinesh17, Roopika Berry18, Ranganathan N Iyer19, Anu P John20, Sanjay Bhattacharya9
1 Department of Microbiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Thiruvananthapuram, Kerala, India
2 Department of Microbiology, Kasturba Medical College, MAHE, Manipal, Karnataka, India
3 Department of Microbiology, Father Muller Medical College, Mangaluru, Karnataka, India
4 Department of Microbiology, VPS Lakeshore Hospital and Research Centre LTD, Kochi, Kerala, India
5 Department of Microbiology, Baby Memorial Hospital, Kozhikode, Kerala, India
6 Department of Microbiology, Believers Church Medical College, Thiruvalla, Kerala, India
7 Department of Microbiology, Government Medical College, Thiruvananthapuram, Kerala, India
8 Department of Microbiology, Mysore Medical College and Research Institute, Mysuru, Karnataka, India
9 Consultant, Department of Microbiology, Tata Medical Center, New Town, Kolkata, West Bengal, India
10 Department of Microbiology, Jubilee Mission Medical College and RI, Thrissur, Kerala, India
11 Clinical Laboratory Service, Dr.Rela Institute and Medical Centre, Chromepet, Chennai, TamilNadu, India
12 Department of Microbiology, Renai Medicity Hospital, Kochi, Kerala, India
13 Department of Microbiology, Regional Cancer Centre, Thiruvananthapuram, Kerala, India
14 Department of Microbiology, Malabar Medical College Hospital and Research Centre, Kozhikode, Kerala, India
15 Department of Microbiology, Sree Uthradom Thirunal Academy of Medical Sciences, Thiruvananthapuram, Kerala, India
16 Department of Microbiology, Sree Gokulam Medical College and Research Foundation, Thiruvananthapuram, Kerala, India
17 MVR Cancer Centre and Research Institute, Kozhikode, Kerala, India
18 Department of Microbiology, Narayana Multispeciality Hospital, Ahmedabad, Gujarat, India
19 Department of Microbiology, Gleneagles Global Hospitals, Lakdi Ka Pul, Hyderabad, Telangana, India
20 Department of Microbiology, Government Medical College, Thrissur, Kerala, India
|Date of Submission||17-Nov-2022|
|Date of Acceptance||19-Nov-2022|
|Date of Web Publication||13-Dec-2022|
Department of Microbiology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala
Source of Support: None, Conflict of Interest: None
|How to cite this article:|
Raja K, Mukhopadhyay C, Shetty AK, Chinnan JP, Sudarsana J, Jose RA, Saritha N, Ravindranath C, Goel G, Valsan C, Sundaramoorthy S, Joy S, Sagila S G, Jakribettu RP, Sarada Devi K L, Ponnambath DK, Jithendranath A, Dinesh KR, Berry R, Iyer RN, John AP, Bhattacharya S. Detection and reporting of Carbapenemase producing Gram negative bacilli in Clinical Microbiology: A survey of practices in laboratories across India. J Acad Clin Microbiol 2022;24:55-62
|How to cite this URL:|
Raja K, Mukhopadhyay C, Shetty AK, Chinnan JP, Sudarsana J, Jose RA, Saritha N, Ravindranath C, Goel G, Valsan C, Sundaramoorthy S, Joy S, Sagila S G, Jakribettu RP, Sarada Devi K L, Ponnambath DK, Jithendranath A, Dinesh KR, Berry R, Iyer RN, John AP, Bhattacharya S. Detection and reporting of Carbapenemase producing Gram negative bacilli in Clinical Microbiology: A survey of practices in laboratories across India. J Acad Clin Microbiol [serial online] 2022 [cited 2023 Nov 30];24:55-62. Available from: https://www.jacmjournal.org/text.asp?2022/24/2/55/363477
| Introduction and Methods|| |
Carbapenems are semi-synthetic derivatives of Thienamycin, a natural product from Streptomycetes. The Carbapenems such as Meropenem and Ertapenem are stabilised by a beta-methyl group, whereas Imipenem needs cilastatin to stabilise it in vivo, as it is susceptible to hydrolysis by the dehydropeptidases in the body.
The first Carbapenemase to be detected was the Klebsiella pneumoniae Carbapenemase (KPC) in the United States in 1996. Three major molecular classes of carbapenemases are recognised now: A, B and D. Classes A and D are serine-beta-lactamases, whereas class B are metallo-beta-lactamases (their hydrolytic activity depends on the presence of zinc), they efficiently hydrolyse not only carbapenems but also cephalosporins, monobactams (except B) and beta-lactam–beta-lactamase inhibitor combinations. Currently, the most important type of class A carbapenemases are KPC enzymes, whereas in class B, it is verona-integron-encoded metallo-β-lactamase (VIM), Imipenem-resistant Pseudomonas-type carbapenemases (IMP) and (particularly) New Delhi metallo-β-lactamase (NDM), and in class D, Oxacillinase-48 (OXA-48) (and related) are the more relevant enzymes. Whereas some enzymes are encoded by chromosomal genes, most carbapenemases are plasmid mediated (with genes frequently located in integrons), which favours the dissemination of the enzymes.
Carbapenems are drugs that are relatively safe to use that have good blood and tissue levels with a potent effect in conditions of sepsis. Hence, the production of a Carbapenemase could lead to a complete dearth of treatment options in the face of life-threatening conditions such as sepsis and meningitis. The practice of clinical microbiology comprises prompt, accurate reporting and giving advice on management in real time based on both clinical and laboratory evidence. The carbapenem group of antibiotics represents an important component for empirical and targeted therapy in patients with Gram-negative bacterial infections and sepsis. However, Carbapenem resistance is on the rise in India and globally, and detection of Carbapenem resistance by the rapid sensitive specific cost-effective method is a diagnostic priority. It is also important to understand the clinical practice scenario of Carbapenem use in the Indian context to facilitate and feedback users on antibiotic stewardship. The current study was to understand actual practices through a survey. It is hoped that the survey would help policymakers, clinicians, administrators and clinical microbiologists in India to take more informed decisions regarding policy matters pertaining to the diagnosis, treatment and prevention of Gram-negative infections.
This special article aims to discuss carbapenemases in the context of clinical microbiology practice, their prevalence, the ways they are detected in different laboratories and the reporting by a clinical microbiology laboratory, which could have a profound effect on the prognosis of the patient.
With this aim in mind, a questionnaire comprising questions in four sections was prepared and sent to medical colleges, multi-speciality hospitals and stand-alone laboratories all over India [Figure 1]. There was a response from 20 centres, mainly from South India, but also a few from east and Western India. The four sections were:
- Laboratory data regarding carbapenem-resistant Gram-negatives for 2021
- Laboratory processing
- Laboratory reports and antimicrobial stewardship.
Demographics helped to determine the type of hospital classified as per the Clinical Establishments (Registration and Regulation) Act, 2010 and Ministry of Health and Family Welfare, Government of India. Laboratory data were analysed to get the number of the common Gram-negatives, namely, Klebsiella species, Escherichia coli, Pseudomonas aeruginosa and Acinetobacter baumannii that were resistant to both Imipenem and Meropenem showing the likely presence of carbapenems. In cases where either one of the two was tested, the number of resistant isolates was noted, and a remark was added. However, when both Imipenem and Meropenem were tested, but not for the same isolate, all efforts were made to get the number of isolates tested for both, out of which isolates resistant to both were determined.
The section on laboratory processing concentrated on the Carbapenems tested and method of susceptibility testing done. All centres do not perform susceptibility testing for all carbapenems. Even if two carbapenems, namely Imipenem and Meropenem are tested in a few centres, the same isolate was not tested for both. Hence, data on the number tested for both were obtained from them. For those centres testing a single carbapenem, the number was used to extrapolate for both, since it was seen that the rate of resistance to one alone was low. Carbapenems production characterised by resistance to both Imipenem and Meropenem was analysed. The centres were then reorganised into those testing at least two Carbapenems for one isolate and ranked based on the number tested for Meropenem and Imipenem. Data on molecular diagnostics used were also obtained.
The section on laboratory reporting was based on whether there was any restriction on reporting of Watch and Reserve antibiotics (AWaRe 2021 classification by the WHO). The various essential aspects of antibiotic stewardship in a hospital are discussed in the past section on stewardship.
| Results|| |
The hospitals were numbered from 1 to 20 based on decreasing number of Gram-negatives isolated in 2021 and to maintain anonymity. There were four sections, namely:
All were laboratories attached to a hospital. There were 13 super speciality teaching hospitals on level 4 of the Clinical Establishment (Registration and Regulation) Act 2010 (CE Act) and seven super speciality hospitals (Level 3 of CE Act) without teaching. Categorising according to bed strength, 10 hospitals were medium sized (100–500 beds) and 10 were large hospitals with bed strength more than 500 (as per American Hospital Association, 2018 https://www.aha.org/statistics/fast-facts-us-hospitals). The largest referral teaching hospital had 3641 beds, comprising adult, paediatric and super speciality blocks. Of these, only 7.7% were intensive care unit (ICU) beds. This hospital also had the largest number of Gram-negative isolates at 5250. It was noted that hospitals with super specialities alone, had a higher proportion of ICU beds, the highest being 58.67%.
Out of 20 centres, 16 had microbiology laboratory service round the clock. Round-the-clock service was not there in three teaching hospitals and one super speciality hospital.
| Laboratory data|| |
It was seen that although centre no. 1 had the highest number of Gram-negative bacilli isolated, it was centre no. 2 that performed testing of both Carbapenems for the greatest number of isolates [Figure 2]. Rearranging the centres based on number of isolates tested for both Imipenem and Carbapenem, showed the prevalence Carbapenem resistance in these hospitals [Table 1]. The mean of the proportions contributed by the common pathogens, namely, E. coli, Klebsiella species, P. aeruginosa and A. baumannii across all the centres was calculated to be 36.56%, 34.47%, 16.93% and 12.04%, respectively [Figure 3]. The mean of the proportions of each species resistant to both Imipenem and Meropenem represented the probable presence of carbapenemase. The means were 12.67% (standard deviation [SD] ± 6.69%), 35.74% (SD ± 17.68%), 22.48% (SD ± 13.03%) and 58.64% (SD ± 23.26%) for E. coli, Klebsiella species, P. aeruginosa and A. baumannii, respectively. The paradox is that although the prevalence of A. baumannii was lower than other common Gram-negative bacilli, the highest rate of Carbapenemase production was encountered in A. baumannii at all centres except one where all were susceptible to Carbapenems [Figure 4]. A prolonged ICU stay was a major risk factor for Carbapenem resistance in many studies. Hence, a correlation between percentage of ICU beds in a hospital with the percentage of resistance to both Carbapenems was done [Table 2]. All hospitals with more than 15% ICU beds of total beds, had prevalence of more than 20% Gram-negative bacteria (GNB) resistant to Carbapenem [Figure 5]a. On the contrary, the hospitals with 10% or less ICU beds, had lesser rate of resistance to Carbapenem [Figure 5]b. Two cancer hospitals and three large teaching hospitals with <11% ICU beds, had infection rates with carbapenem-resistant GNB, higher than 20%, It may be possible to reduce the resistance in these hospitals, since the ICU beds are less in proportion.
|Figure 2: Centres ranked according to the number of Gram-negatives isolated in 2021 with number evaluated for Imipenem and Meropenem|
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|Figure 3: Means of proportions of four major Gram-negatives in all centres|
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|Figure 4: Mean prevalence of four common Gram-negatives in all centres and mean of the rates of Carbapenem resistance|
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|Figure 5: (a and b) Proportion of ICU beds in a hospital correlated with rates of Carbapenemase production. ICU: Intensive care unit|
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|Table 1: Centres ranked according to the number of Gram-negatives isolated in 2021 with number evaluated for Imipenem and Meropenem|
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|Table 2: Proportion of intensive care unit beds in a hospital correlated with rates of Carbapenemase production|
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Urine was the most common (6 out of 20) specimen with the growth of Carbapenem-resistant GNB. The reason may lie in the fact that it is the most common sample to be received in all laboratories for antimicrobial susceptibility testing. Respiratory samples were reported to be the second highest, 5 out of 20. In three centres, it was blood culture that grew GNB with the highest rate of Carbapenem resistance. However, when blood is a sample, identification (ID) of the source is essential in secondary bacteraemia. Two centres had pus/exudate as the sample with high rate of isolates with Carbapenem resistance.
Susceptibility tests, being so full of fallacies in interpretation, 15 of 20 have adopted combined automated testing and manual testing under different circumstances. Two centres are still doing manual testing, whereas three are fully automated with regard to susceptibility testing. For the manual method, Kirby–Bauer disc diffusion method has completely replaced Stokes' technique at all centres. Among the 20 centres, 18 centres are using VITEK 2 (Biomerieux) and there are two centres using BD Phoenix™ system for microbial ID and antibiotic susceptibility testing (AST).
Only one centre has the full-fledged MALDI-TOF ensemble. Out of the 18 centres, six have upgraded to the newly developed antibiotic cards of VITEK2 (405, 406, 407 and 408). Regarding the kinds of Carbapenems tested, 12 centres test for Ertapenem and five centres test for Doripenem also, in addition to Imipenem and Meropenem. One centre tests Imipenem alone. All laboratories are following standards for AST, 19 are with Clinical Laboratory Standards Institute (CLSI), whereas one centre follows EUCAST, three laboratories followed both CLSI and EUCAST. Out of 20 centres, 11 centres use different methods to detect type of Carbapenem resistance. The methods include Carba-R by Cepheid (rapid genotypic) in three centres, Carba-NP (phenotypic) in two centres and Phoenix CPO panel in one centre. One centre performs multiplex polymerase chain reaction (PCR), whereas another relies on the BCID panel of Biofire (Biomerieux) and a third performs immunochromatographic test. In eight centres, no attempt is made to find the type of resistance, whereas one centre reports that some idea is got from interpreting disc diffusion and Minimum Inhibitory concentration (MIC) values.
The different indications mentioned to attempt finding the mode of resistance include ICU patients, thesis study isolates, on request, bloodstream infections and transplant patients. One centre does the detection routinely by multiplex PCR. Four centres have mentioned the genotypes detected, namely KPC and NDM in all of them, with additional VIM, IMP and Oxa 48 in three of them. Multiplex PCR is used to detect OXA 23, 24 and 58 in addition to others in one centre.
Laboratory reporting and stewardship
All except one centre does selective reporting of antibiotics, i.e., withholding the report of second-and third-line antibiotics. Out of the 20 centres, there are four centres where Carbapenems are reported only if the isolate is resistant to β-lactam–β-lactamase inhibitor combination. In three centres, if the diagnosis is meningitis or invasive infection Carbapenem is reported. On being asked if Carbapenem is reported if it is known that the patient is in sepsis, 11 centres replied in the affirmative, whereas two centres report if the patient is already on carbapenem. Resistance rate changes were not observed in seven centres, some change was observed in the rest with two centres reporting an increase and three centres reporting a decline in resistance. Of the 20 centres, 15 centres followed up with patients on treatment with a carbapenem, with one centre doing it only on selected cases. Using sepsis markers is a method of follow-up but this was done only by nine of the 15 centres. Three centres used both C-reactive protein (CRP) and procalcitonin to follow-up, whereas four centres used only CRP and four centres used only procalcitonin.
Antibiotic policy is present in all centres except 3. Of these two centres have a specific policy, one for reserve antibiotics and the other for the newborn ICU. The third centre has a surgical prophylaxis policy. The Carbapenem of first choice is Meropenem in all centres except one, where sensitivity is done only for Imipenem. Carbapenems are started on admission in sepsis at all centres. The other reasons for starting Carbapenem on admission are, melioidosis in three centres, if already on Meropenem in two centres, sepsis in transplant patients, if sepsis is secondary to urinary tract infection or gastrointestinal tract infections, febrile neutropenia and meningitis in two centres. Clinical pharmacology has an active role in 10 centres. Of these, in six centres, they monitor antibiotic use, follow up on reserve antibiotic usage and are involved in making the antibiotic policy. In four centres, they are mainly involved in audit of antibiotic use.
| Discussion|| |
Carbapenem resistance mediated by carbapenemases is encoded by genes that are transferable through plasmids or transposons that also carry other resistance genes for quinolones and aminoglycosides, thus leaving very few options for safe treatment. KPC, VIM, IMP, NDM and OXA-48 types are the most effective and common Carbapenemase genes worldwide. It was in this context that the authors felt that it is time for a review of the present prevalence of carbapenemases, their detection and the role of clinical microbiologists in their treatment and containment.
There were 20 centres ranging from highly specialised transplant hospitals and super speciality centres for cardiology to large multi-speciality teaching hospitals with a massive turnover of specimens. In this survey, the editorial team tried to find the practices prevalent in 2021 concerning the detection and reporting of Carbapenems with special reference to carbapenemases. We can say that clinical microbiology has started to come to the forefront in India, because 16 of the 20 hospitals, have a 24 h laboratory. Clinical microbiology is a dynamic science in that bacteria multiply continuously and the result of a specimen can change if it is kept without processing overnight. Hence, the first step to the implementation of clinical microbiology is a round-the-clock service.
Urine and respiratory samples formed the major source of carbapenem-resistant isolates. In such cases, antibiotic overuse in chronic patients may be a significant cause. Blood is rarely a primary source because blood isolates will always have a source like a central line or secondary to pneumonia, meningitis or pus collection. One centre had routine screening for Carbapenem resistance and hence the rectal swab was the most common source.
The first problem encountered while analysing the responses was the fact that both Imipenem and Meropenem are not done on the same isolate in most laboratories. While there are other modes of resistance to carbapenems, such as the efflux pump mechanism, carbapenemases continue to predominate and they can be suspected if the isolate is resistant to both Imipenem and Meropenem.
Detecting carbapenemases continues to be controversial and error prone. The Performance Standards for Antimicrobial Susceptibility Testing issued annually by the CLSI for 2022 has set revised breakpoints which can be used for reporting clinically as susceptible or resistant. The presence of Carbapenemases is shown by intermediate and resistant range of MICs; hence, the revised breakpoints account for them and give a clear-cut report. Automated bacterial ID and susceptibility systems regularly update their software to account for the revisions done by CLSI. A phenotypic method for detecting carbapenemases is the Carba-NP test. Here, a bacterial lysate hydrolyses Imipenem in the kit turning it yellow from red. This kit claims to have 100% specificity and sensitivity for enterobacterales. However, it may be less sensitive in the presence of enzymes of the OXA group (Class D)., Rapid genotypic methods are now available and the Xpert Carba-R test is now widely used. A new rapid phenotypic method available now is the O.K.N.V.I RESIST 5 test. Briefly, these tests are ready-to-use cassettes which detect the presence of OXA-48/OXA-48 such as variants, KPC, NDM, VIM and IMP carbapenemases in bacterial cultures. The time to result is 15 min. However, the controversy continues as according to CLSI, 'molecular assays can detect the presence of specific β-lactamase genes but cannot exclude the presence of other β-lactamase genes or resistance mechanisms or novel variants with changes in primer or probe annealing sites. Therefore, phenotypic resistance should always be reported'. They also inform us that – 'Current clinical evidence is insufficient to conclude whether Carbapenem monotherapy of carbapenemase-carrying strains (by genotyping) with an MIC in the susceptible range will be effective'.
It was found that the prevalence of Carbapenemase-producing E. coli, Klebsiella species, P. aeruginosa and A. baumannii was more or less the same at all centres. While the bulk of the Gram-negatives was made up of E. coli and Klebsiella species, the prevalence of resistance to both Carbapenems was the highest in A. baumannii followed by Klebsiella species. It was interesting to note that even in centres where only Imipenem (one centre) was tested and where only Meropenem was tested, A. baumannii remained the isolate with the largest rate of resistance. This is probably because it is a common commensal of health-care facilities that causes infection in patients who are on long-term Carbapenems that have already destroyed the normal flora and other sensitive strains.
Automation has become the most effective way to deal with large specimen loads along with greater accuracy. The Performance Standards for Antimicrobial Susceptibility Testing issued annually by the CLSI is the most popular standard that is followed, although two centres use both the European Committee on Antimicrobial Susceptibility Testing – EUCAST and CLSI standards. Automated instruments change their software according to the CLSI standards generally and there may be some discrepancy between MIC and disc diffusion. In the interests of treatment, it is better to be safe and report resistance; however, we should remember that in some cases we may be denying treatment with an effective agent. Hence, CLSI further remarks that the services of an infectious diseases physician may be needed to advise on the best agent for a particular case. The presence of genotypic resistance markers is not always translated to phenotypic resistance and has to be reported after due consideration of the individual circumstances.
Microbiology reporting has come a long way since the days when all isolates were reported with all antibiotics tested. Selective reporting is the norm now with all centres except one reporting only selected antibiotics. Antibiogram generation is an important part of antibiotic stewardship; hence all antibiotics have to be tested for at all times. Reporting them all would lead to serious antibiotic misuse. Empiric antibiotics are generally broad spectrum and high end. If such antibiotics are reported even when first-line antibiotics are effective, the tendency will be to continue without de-escalation.
The use of Carbapenems seems to be universal in Gram-negative sepsis as reported from all centres. Follow-up of treatment is an important duty of a clinical microbiologist, since once started, Carbapenems may be continued till discharge thus altering the flora of the ICU as a whole. CRP and procalcitonin are the most commonly used markers for sepsis. Of these procalcitonin rapidly increases and rapidly decreases making it a useful marker for discontinuing antibiotics. Proper dosage and mode of administration are important in the effective treatment of a patient. This is another area where both microbiologists and clinical pharmacologists can guide the clinician. It is heartening to note that in 10 out of 20 centres, clinical pharmacology plays an important role in stewardship and antibiotic audit.
Many studies have found that prolonged ICU stay is a risk factor for Carbapenem resistance. Hence, a correlation was made between the proportion of beds in ICU with percentage of overall resistance. This seems to be fairly well correlated as could be shown in [Figure 5]a and [Figure 5]b. Two hospitals with ICU beds <10% with rate higher than 20% are cancer hospitals and three with rates higher than 20% are large teaching hospitals with more than 1000 beds, where some effort is needed to reduce the resistance.
| Conclusion|| |
Clinical microbiology has come of age with round-the-clock service, selective reporting and monitoring of antibiotic use supported by clinical pharmacology (in 50% of the centres). Antibiotic susceptibility standards are followed everywhere with CLSI being the most popular. A. baumannii showed the highest rates of Carbapenem resistance followed by Klebsiella species at all centres, except one. Meropenem is the most commonly used Carbapenem for sepsis. Rates of resistance higher than 20% for Carbapenems due to Carbapenemase are seen mostly in centres with ICU beds making up more than 15% of the total beds.
It is clear from the study that Carbapenem resistance is a problem in India. The study supports findings from previous research in this field. It highlights the need for early detection of Carbapenem resistance by phenotypic and genotypic methods. In the era of genotype-directed antimicrobial therapy (e.g. ceftazidime avibactam against KPC and OXA-48 Carbapenemases) it is important that we acquire the capability of rapid genotype detection across the country, especially in centres where such resistance is common.
Antibiotic stewardship will require close interaction between clinicians and clinical microbiologists, and the role of infectious disease physicians and clinical pharmacologists is yet to be fully explored and utilised in the Indian context.
For medical teachers, especially those in clinical sciences it is of paramount importance that the new generation of doctors is trained in the diagnosis, treatment, and prevention of Carbapenem-resistant Gram-negative bacterial infections, a problem which has emerged as an important cause of morbidity, mortality, hospitalisation and health-care cost across the globe.
The authors are grateful to all the Heads of the Department for giving permission to share the data from their laboratories.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]