|Year : 2021 | Volume
| Issue : 5 | Page : 762-769
Methylated spirit versus chlorhexidine gel: A randomized non-inferiority trial for prevention of neonatal umbilical cord infection in Jos, North-Central Nigeria
DD Shwe1, TO Afolaranmi2, CO Egbodo3, J Musa4, S Oguche5, F Bode-Thomas5
1 Department of Paediatrics, Faculty of Clinical Sciences, Nigeria /Jos University Teaching Hospital, Jos, Nigeria
2 Department of Community Health, Faculty of Clinical Sciences, College of Health Sciences, University of Jos, Nigeria /Jos University Teaching Hospital, Jos, Nigeria
3 Department of Obstetrics and Gynaecology, Faculty of Clinical Sciences, College of Health Sciences, University of Jos/Jos University Teaching Hospital, Jos, Nigeria
4 Professor of Obstetrics and Gynaecology, Faculty of Clinical Sciences, College of Health Sciences, University of Jos, Nigeria /Jos University Teaching Hospital, Jos, Nigeria
5 Professor of Paediatrics, Faculty of Clinical Sciences, College of Health Sciences, University of Jos, Jos, Nigeria /Jos University Teaching Hospital, Jos, Nigeria
|Date of Submission||03-Sep-2020|
|Date of Acceptance||12-Mar-2021|
|Date of Web Publication||20-May-2021|
Dr. D D Shwe
Department of Pediatrics, Faculty of Clinical Sciences, College of Health Sciences, University of Jos, Nigeria and Jos University Teaching Hospital, Jos
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Omphalitis is an important cause of neonatal sepsis (NNS) and mortality. Quantitative estimates of risk of omphalitis-related neonatal death is about 10%–19%. Topical applications of antiseptics have been shown to reduce this risk burden but has not been well investigated. Aim: To demonstrate non-inferiority of methylated spirit to chlorhexidine (CHX) gel for prevention of omphalitis, NNS and mortality at day 28. Methods: This was a randomized, non-inferiority trial of methylated spirit versus CHX gel with 161 and 162 mother–baby pairs, respectively, conducted between July 2017 and May 2018. SPSS version 23.0 was used for data analysis to examine for incidence of omphalitis, time-to-cord separation, NNS and mortality. Relative risk and 95% confidence interval were used as point and interval estimates, respectively, with a non-inferiority margin of 10% set for CHX gel while a P values <0.05 was statistically significant. Results: The median age of newborns was 18 h; (IQR: 8–24) h with the risk of omphalitis being 2% higher with CHX gel compared to methylated spirit (RR = 1.020; 95% CI; 0.988-1.053; P = 0.053). The median times-to-cord separation were 7.0 days (IQR: 2–17) and 7.0 days (IQR: 2–18) for methylated spirit and CHX gel, respectively (mean difference: ‒0.2145; 95% CI = ‒0.9085–0.4759; P = 0.544). There was no difference in the risks of NNS and mortality among those treated with methylated spirit compared to those exposed to CHX gel (RR: 1.0; 95% CI = 0.984–1.017; P = 1.000) and (RR: 1.0; 95% CI = 0.994–1.018; P = 0.986) respectively. Conclusions: There is no evidence that 96% methylated spirit is inferior to 4% CHX gel in preventing neonatal omphalitis; hence, it may be considered a safe and effective alternative where CHX gel is unavailable.
Keywords: Chlorhexidine gel, methylated spirit, neonatal sepsis, omphalitis, risk
|How to cite this article:|
Shwe D D, Afolaranmi T O, Egbodo C O, Musa J, Oguche S, Bode-Thomas F. Methylated spirit versus chlorhexidine gel: A randomized non-inferiority trial for prevention of neonatal umbilical cord infection in Jos, North-Central Nigeria. Niger J Clin Pract 2021;24:762-9
|How to cite this URL:|
Shwe D D, Afolaranmi T O, Egbodo C O, Musa J, Oguche S, Bode-Thomas F. Methylated spirit versus chlorhexidine gel: A randomized non-inferiority trial for prevention of neonatal umbilical cord infection in Jos, North-Central Nigeria. Niger J Clin Pract [serial online] 2021 [cited 2022 Dec 3];24:762-9. Available from: https://www.njcponline.com/text.asp?2021/24/5/762/316477
| Introduction|| |
Omphalitis is a significant cause of neonatal sepsis (NNS) and mortality particularly in developing countries of the world., Quantitative estimates of risk of neonatal death following omphalitis is about 10%–19%, suggesting existing disparity in access to newborn care services. Currently, the neonatal mortality rate in Nigeria stands at 39 per 1000 live births, ranking among the highest in the world.
In order to reduce the burden of omphalitis-related neonatal deaths, the World Health Organization (WHO) and the Nigeria Every Newborn Action Plan (NiNAP) recommended the application of 4% chlorhexidine (CHX) gel for the care of neonatal umbilical cord stump in settings of poor environmental hygiene or where neonatal mortality is high.,, However, the wide spread use of this essential medicine has been grossly hampered by unavailability, poor acceptability and effectiveness concerns in Nigeria.,
A Cochrane review of eight studies conducted remote from the study area suggested superiority of CHX gel in prevention of omphalitis and mortality to dry-cleansing methods, olive oil, and triple-dye. Previous studies on methylated spirit and CHX gel in Jos North-Central Nigeria reported comparable newborn cord separation time. However, the study did not quantify the magnitude of risk of omphalitis-related. Magnitude of risk of omphalitis to the development of neonatal sepsis or mortality. In addition, none of the studies cited above examined the safety profile of the CHX gel versus methylated spirit.
To contribute to filling this gap in knowledge, we hypothesized that 96% methylated spirit will have comparable effectiveness to 4% CHX gel in the prevention of newborn cord infections, with similar safety profile and time-to-cord separation.
| Materials and Methods|| |
Ethical considerations and confidentiality: The study was approved by the Jos University Teaching Hospital (JUTH) Institutional Health Research Ethics Committee (IHREC) (Protocol approval N0: (JUTH/DCS/ADM/127/XXV/162). Written informed consent was obtained from parents. Data were de-identified in line with good clinical practice (GCP) regulations.
Study design, sites and date: This was a randomized, open-labelled, parallel-group, trial to demonstrate non-inferiority of topical 96% methylated spirit to 4% CHX gel (goal-standard comparator) in prevention of omphalitis. Non-inferiority margin for CHX gel was set at 10% from the previous work.
It was conducted at the postnatal wards of the JUTH and Fertile Ground Hospital (FGH), which are located in the cosmopolitan city of Jos, Plateau State, Nigeria, both of which provide maternal and newborn health services.
The JUTH is a 600-bed capacity tertiary center with an average of 2809 deliveries in 2016. Fertile Ground Hospital on the other hand, is a privately owned 29- bed capacity and multi-specialist hospital which, in addition, provides in vitro fertilization (IVF) services with an average of 384 deliveries in 2016. The study was conducted between 20 July 2017 and 18 May 2018.
Study population: It comprised newborns in the postnatal wards of JUTH and FGH, in Jos, Plateau State, North-Central Nigeria.
Sample size estimation: The sample size was determined using the appropriate sample size formula for non-inferiority study with continuous efficacy outcome (cord separation time);
n = f (α, β) × [πs × (100 − πs) + πe × (100 − πe)]/(πs − πe − d),2 where πs and πe are the true percent “success” in the standard and experimental treatment groups respectively, and f (α, β) = [Φ‒1() + Φ‒1(β)]2, Φ‒1 is the cumulative distribution function of a standardized normal deviate. Significance level α set at 5%, power (1–β) = 90%, percentage “success” in intervention group = 10%, d = non-inferiority margin was set at 10%. Minimum sample size required per group = 155. Therefore, the total sample size required = 310 to detect a true difference in the efficacy outcome. Assuming 14% attrition rate = 43 (from previous studies) we required a total accrual size of 353 eligible neonates to detect any difference in effectiveness between the intervention and comparison groups.
Inclusion criteria: Male and female newborns, with written informed consent of the parent. Exclusion criteria: Severe perinatal asphyxia, clinically significant structural birth defects (omphalocele and gastroschisis) that could potentially compromise the topical application of the treatment agent, known risk factors for sepsis (premature rupture of fetal membranes, maternal peri-partum fever), which could confound NNS.,
Sampling Technique A two-stage approach to sampling was used in this study. Stage 1: Jos North and Jos South Local Government Area (LGAs) were purposively selected out of the 17 LGAs in plateau state because, they are homes to the largest public and private hospitals in the state. Stage 2: JUTH was selected from the two tertiary level hospitals using simple random sampling technique by balloting. And FGH was selected from the list of four largest privately owned hospitals providing maternal-newborn health services with at least 324 deliveries per annum using simple random sampling technique by balloting.
Selection of enrollees: Proportion-to-size technique was used to determine the number of eligible mother–baby pairs for the study. Thus, 290 (90.3%) and 31 (9.7%) mother–baby pairs were recruited from JUTH and FGH hospitals, respectively. Furthermore, from the sample frame in each of the health facilities, the starting point was determined using simple random sampling technique by balloting within the sampling interval of 3, and thereafter, sampling was continued until the required minimum accrual size of selected facility was met.
Subject identification, screening, and recruitment: Prior to enrollment, full clinical history was obtained and thorough physical examination carried out by the investigators. Relevant health information of mothers and babies (age, parity, highest educational attainment, occupation of husband, ANC attendance and place, age of newborns, sex, gestational and mode of delivery, risk for sepsis,, family history of sensitivity to test agents, weight, temperature, and more) were obtained and documented on case report forms (CRFs)., Mothers received education on WHO-recommended handwashing technique before each cord care process in addition to demonstration on procedures for topical application of the treatment agents. They were also counseled to avoid the application of harmful substances to cord stump.
Randomization and treatment allocation procedure: Eligible enrollees were then randomized (1:1) to receive either 2-hourly applications of 96% methylated spirit or 12-hourly topical application of CHX gel treatment group from computer-generated blocks of random numbers. The randomization was done centrally by a physician who was not directly involved in the study. The first eligible enrollee was selected by a simple random technique by balloting within the blocks of random numbers which was continued until the required minimum accrual size was reached.
Mothers had telephone interviews on day 2 (D2) following enrollment into the study. Relevant health information on the symptoms-checklist were as follows: fever, redness around cord stump, bleeding, bad odor or purulent discharge, swelling, frequency of cord care, cord separation time, evidence of omphalitis, and or sepsis.,
Information were solicited regarding the use of non-recommended disinfectants applied to the cord. Enrollees had return hospital visits on days 7, 14 and 28 or any other days within study protocol when there were study-related concerns. If subjects failed to return for follow-up visit, they were visited at their home by study team for clinical review. Newborn was deemed lost-to-follow-up after three failed efforts to reach them by home visit and telephone calls.
On each clinic visit, clinical evaluation was carried out for evidence of omphalitis, cord separation or sepsis, and mortality. In the event of diagnosis of probable sepsis, based on the WHO guidelines for omphalitis (erythema, foul-smelling discharge around the cord), the patients were hospitalized, screened for sepsis and received the hospital's standard of care.
Antiseptic agents: Topical CHX digluconate 7.1% (equivalent to 4% CHX gel): 4% CHX (25 g of 4% chlorxy-G gel, Batch N0 CGH2, was applied to the cord stump according to manufacturer's instructions.
Topical 96% methylated spirit: This was obtained from the Compounding Pharmacy Unit of the Pharmacy Department of the JUTH to ensure quality and standard.
Demonstration on topical applications of test agents Demonstration sessions for mothers were carried out by the investigators. They were conducted one-on-one or at some cases in small groups of five whenever there were more than five eligible newborns at recruitment.
Administration of treatment agents: In all, 4% topical CHX gel was applied on the umbilical stump and spread around the abdominal wall area that comes into direct contact with the stump using the index finger. This was carried out twice daily and any other times of the day the stump appeared wet. On the other hand, a clean piece of cotton wool soaked in dispensed 50-ml container of 96% methylated spirit was used in cleaning of stump and the cord clamp every 2 h. Cleansing procedure started from the tip of the stump towards the cord clamp and proximally to the base of the stump.
Data collection tool: CRF was used to document clinical information. It had four sections: Section A - biodata and obstetric information of the mother, Section B - biodata, perinatal health information, temperature and anthropometric measurement of the newborns. Section C - comprised social and family histories of the neonate and Section D - comprised clinical follow-up visits of the enrollees from day 0 Day 0 (D0), day 1 (D1), day 2 (D2), day 7 (D14), day 21 (D21) and day 28 (D28) including NNS and omphalitis symptoms checklist.
Definition of key terms of the study
Protocol violation: A study subject was adjudged to have violated protocol if there was evidence to suggest – the use or application of a different treatment agent outside study protocol, umbilical stump was cut manually or burnt-off for any reason and or did not apply treatment agent according to approved protocol.
Adverse reaction: A response to a drug which is noxious, unintended, and occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of disease, or for the modifications of physiological function.
Adverse events (AEs): Medical occurrence temporally associated with the use of a medicinal product, but not necessarily causally related. An AE was considered a serious adverse event (SAE) if it (1) resulted in death or it is life-threatening in an enrolled patient, (2) required hospitalization/admission or prolongation of hospitalization, and (3) results in permanent or significant disability.,
Solicited adverse reactions: These reactions such as dermatitis, anaphylaxis were recorded on CRF. Any neonate who developed such events were given alternative (rescue) antiseptic per protocol and then followed-up for safety in line with GCP requirements.,
Time-to-cord separation: This was defined as the time (days) taken for the umbilical cord to dry and completely fall off from the cord stump.
Neonatal mortality: Neonatal mortality was defined as death within the first 28 days after birth.
Outcome measure: Denotes whether or not a study subject benefited from the application of the treatment agent provided.
Determination of socio-economic status of respondents: Olusanya's scoring of social indices was used to determine the socio-economic status of the enrollees, which was categorized into upper, middle, and lower classes.
Outcome measures: The primary outcome measure was omphalitis. The secondary outcomes were time-to-cord separation (days), NNS, and occurrence of mortality by D28.
Blinding: Investigators and parents were not blinded to the study medications. Only the physician who generated the randomization blocks and medical biologist both of whom were not in direct contact with study subjects were blinded to the biological specimens.
Data Processing: All CRFs used to obtain clinical information were serialized by type of facility codes and double checked for adequacy and completeness. A total of 355 (85.7%) CRFs had completed information and were available for processing and final data analysis. The information was extracted and entered into Excel spreadsheet and then exported to Licensed IBM SPSS Inc. Delaware, Chicago, IL, USA, version 23.0. 1989, 2015, for analysis.
Primary analysis was performed on Day 28 per protocol population (PP) of newborns. It was restricted to the intention-to-treat (ITT) newborns. These were all enrollees randomized to treatment groups who had at least one topical application of test medications.
Univariate analysis of socio-demographic and perinatal characteristics of the mother–baby pairs were done. Basic descriptive statistics were presented in frequency and percentages. Continuous variables were described using mean ± standard deviation if the data were normally distributed but median and interquartile range (IQR) for data not fulfilling the assumptions of normality. Qualitative variables were described using frequencies and proportions, and then presented in tables. Independent Samples t-Test was used to determine the mean difference in time-to-cord separation between the comparison groups. Relative risk was used to quantify the magnitude of risk as estimates for primary and secondary outcomes; 95% confidence interval was used as the interval estimate and calculated by normal estimates of binomial distribution. All tests of significance were two-tailed. P values <0.05 was deemed statistically significant.
| Results|| |
Out of 355 mother–baby pairs screened for study eligibility, 328 (92.4%) met the enrolment criteria of which 321 (97.9%) consented and were recruited for the study. The mean age of the mothers was (31 ± 6) years with the majority of 167 (53.2%) being 20–34 years. The median age of newborns at enrollment was 18 h (IQR: 8–24) of which 185 (52.1%) were males. The socio-economic status of the respondents cuts across the three levels of which 126 (35.5%) were in the upper stratum [Table 1].
Participants' flow: The ITT population comprised 321 randomized patients; 162 randomized to 96% methylated spirit and 161 to 4% CHX gel treatment groups, respectively. The proportion of premature withdrawals was dissimilar in each treatment group [Figure 1].
The per protocol population. The per protocol analysis is useful for comparison of treatment groups that includes only those patients who completed the treatment originally allocated. In non-inferiority trials, both per protocol and intention-to-treat analysis are recommended, because they should support non-inferiority. consisted of 160 (98.8%) newborns in the methylated spirit group and 140 (87%) in the CHX group (see study profile, [Figure 1] above).
Study outcomes and estimation
Primary outcome: Omphalitis at D28. Development of omphalitis was 2 (1.1%) for methylated spirit and 5 (2.9%) for CHX gel treatment groups. Newborns who applied 4% CHX gel had a 2% increase in the risk of getting omphalitis compared to those who applied 96% methylated spirit (RR = 1.020; 95% CI: 0.988–1.053; P = 0.053). Therefore, 96% methylated spirit met the non-inferiority criterion of 10%.
Secondary outcomes: Time-to-cord separation. The median time-to-cord separation was 7.0 days: IQR = (2–17) for methylated spirit and 7.0 days IQR = (2–18) for CHX gel. Thus, mean difference in CST (–0.2145; 95% CI = (‒0.9085–0.4759); P = 0.544). Delayed time-to-cord separation was observed in 16 (9.9%) and 25 (15.5%) subjects in the methylated spirit and CHX gel treatment arms, respectively.
Neonatal Sepsis (NNS). There was little or no difference in the risk of NNS among those treated with methylated spirit compared to those exposed to CHX gel (RR = 1.0; 95% CI = 0.984–1.017; P = 1.000).
Similarly, newborns treated with methylated spirit had little or no difference in the risk of dead compared to newborns who applied topical 4% CHX gel (RR = 1.0; 95% CI = 0.994–1.018; P = 0.986).
All secondary efficacy outcomes examined maintained the non-inferiority margin of 10% [Table 2].
Compliance with treatment agents. A subject was adjudged compliant with study treatment if they received the treatment to which they were randomized as well as the correct frequency per day until the cord stump healed and fell-off. Compliance with study treatment was 99.4% in methylated spirit and 94.4% for CHX gel treatment groups.
Nine (5.6%) newborns exposed to CHX gel developed mild AEs. Extensive peri-umbilical pustules accounted for 3 (37.5%). None was observed in the methylated spirit arm. However, the absolute risk reduction (ARR) = 5.6%. Thus, 1 in every 5.6.6 newborns was needed to be treated with CHX gel to develop an AE; (NNH = 179/1000); [Table 3].
| Discussion|| |
For the primary efficacy outcome at day 28 in this study, 96% methylated spirit was highly effective in preventing omphalitis. It simultaneously demonstrated non-inferiority to 4% CHX gel in the reduction of risk of omphalitis. In addition, non-inferiority of 96% methylated spirit to 4% CHX gel was maintained in all secondary efficacy endpoints. The findings of our study have significant public health policy and clinical practice implications for which policy actors and clinicians need to pay attention to.
The policy recommendations issued by the WHO and subsequent adoption of topical 4% CHX gel for the cord care for the reduction of incidents of omphalitis in middle- and low-income countries which have high neonatal mortality was informed by a community-based studies from Nepal suggesting its effectiveness in reducing incidence of omphalitis.
It is pertinent to note that, in Southeast Asia where significant disparities exist in resource availability, access to newborn health services, social customs, and differences in bacteriologic profile, research findings from other populations may be difficult to apply. Consequently, safe cord care practices with antimicrobial agents in clinical settings with high neonatal mortality has been well recognized.,
For example, a study in Nigeria on trends of newborn cord care practices clearly revealed a lack of access to CHX gel by mothers. In the same report, demand generation, accessibility, and acceptability of CHX gel were barely increased following health awareness campaigns. We speculate that safe and effective alternatives for CHX gel were not recommended by the WHO for clinical settings where access, affordability, and safety of CHX gel were major concerns. Consequently, mothers often resort to harmful home remedies due partly to low awareness and lack of recommended safe alternative cord treatment agents for the prevention and treatment of omphalitis. This assertion is corroborated by several studies within and outside Nigeria.,,,,,
An earlier short report of a randomized trial of methylated spirit and 4% CHX gel in the study area clearly demonstrated a comparable neonatal cord treatment efficacy with similar safety profiles. The report suggested that the methylated spirit could be a safe alternative in clinical settings with high neonatal mortality were 4% CHX gel is unavailable or deemed unsafe. This study further supports the use of topical 96% methylated spirit as a safe alternative to 4% CHX gel for the prevention of newborn umbilical cord infection. Therefore, if relevant regulatory agencies would ensure a quality-assured 96% methylated spirit in pharmaceutical outlets in our clinical settings and mothers, on the other hand, will adhere to 2-hourly cord stump application, it may help to reduce the high incidence of omphalitis-related NNS and mortality in our environment.
Although our study was designed primarily to determine therapeutic effectiveness and to demonstrate non-inferiority of methylated spirit to topical 4% CHX gel, the most relevant clinical finding related to safety was extensive peri-umbilical pustular lesions reported in about one-tenth of newborns exposed to 4% CHX gel. Curiously, swab culture of the lesions were sterile. The reasons for these findings were not immediately clear to us. Perhaps, they were immunologically mediated. No significant AEs were observed on the comparator group. Our decision to adopt a 1:1 96% methylated spirit: 4% CHX gel randomization schedule probably did not give us sufficient power to detect AEs in the methylated spirit treatment arm. However, the only identifiable risk factor for development of AEs was the exposure to CHX gel. Of particular concern was the 179 in every 1000 newborns who needed to be treated with CHX gel to develop a single AE. This finding highlights the clinical importance of soliciting for family history of adverse drug reactions to CHX gel before prescription for newborn's cord care.
CHX gel is an antiseptic agent with broad-spectrum bactericidal and bacteriostatic properties effective against gram-negative bacteria and fungi, with rapid pathogen killing rates. Through cellular osmosis, destabilization of bacterial cell wall with consequent leakage of cellular components leads to cell death., Methylated spirit on the other hand is both bactericidal, mycobactericidal, fungicidal, and viricidal agent. It causes protein denaturation and coagulation of lipids and lipid structures and cellular metabolism through which it is able to cause pathogen cell death. By these pharmacodynamic mechanisms, CHX gel and methylated spirit are able to prevent and/or treat established omphalitis; whereas not all bio-sensitive pathogens to methylated spirit and CHX gel are clinically relevant in omphalitis or NNS in the study area, their limited bio-profile should thus be recognized.
Our study observed a slight increased risk of omphalitis among newborns exposed to CHX gel compared to those who were not. This increase was not statistically significant. In addition, there was no significant difference on the impacts of both CHX gel and methylated spirit on time-to-cord separation, NNS or mortality outcomes. These findings did not support earlier reports from Nepal, India, Bangladesh, and Pakistan where significant reductions in risk of omphalitis, mortality, and time-to-cord separation were observed.,,
Although these three studies cited above differed significantly in designs and sample size. For example, the study from Pakistan further examined the impact of handwashing before cord cleansing which our study did not, but has a similar methodology and outcome measures. We think that the validity of their data and our findings have further brought to bear the need for efficacious, affordable and accessible multiple topical applications of antiseptics to reduce the incidents of neonatal umbilical cord infections globally.
We observed a dissimilar safety profile in favor of the comparator trial arm. This finding did not agree with our earlier hypothesis. Safety concerns can potentially hamper the acceptability and widespread use of CHX gel by mothers in our clinical setting. There is, therefore, a need for safety monitoring on newborns receiving CHX gel. In addition, further studies on CHX gel risk stratification may be needed on newborns to examine predictors of 4% CHX gel safety. While we wait for such studies, 96% methylated spirit holds a tremendous clinical benefit as an effective, safe and affordable alternative to 4% CHX gel in our environment. However, despite demonstrable non-inferiority of methylated spirit to CHX gel in cord treatment effectiveness and good safety profile, 2-hourly applications still remain a potential challenge to night-to-day adherence. Would fewer applications, for example, 4–6-hourly equally be effective? That requires further study to examine this hypothesis.
| Conclusions|| |
Methylated spirit was highly effective in preventing neonatal omphalitis. It simultaneously demonstrated non-inferiority to CHX gel in cord separation time, reduction of NNS and mortality with better safety profile. It may be considered a safe and effective alternative where CHX gel is unavailable or deemed unsafe.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Jane Brown, Ewa Olugbo and Dr. Kajo for data collection and entry. We equally acknowledge STAMINA Grant project for trainings on research methodology.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3]