Effect of bathing with 2% chlorhexidine gluconate every other day on healthcare-associated infections in the medical intensive care unit

Summary

Background

Healthcare-associated infections (HAIs) cause morbidity and mortality in patients at medical intensive care units (MICUs). However, current literature reports inconsistent findings on the effect of daily bathing with 2% chlorhexidine gluconate (CHG) on reducing HAIs and that the solution can cause skin harm. This study aimed to explore the effect of bathing with 2% CHG every 2 days on HAIs in the MICU.

Methods

This study used a quasi-experimental design (experimental group) and a medical record review (control group). Patients in the control group were admitted to the MICU at a medical centre in Taiwan from March 2018 to February 2019 and used general soap for bathing every other day as part of the unit’s routine. The experimental group was recruited from March 2019 to February 2020 and used 2% CHG wet wipes for bathing every other day. The study outcome was to compare the effects on HAIs, catheter-associated urinary tract infections (CAUTIs), central line–associated bloodstream infections (CLABSIs), and ventilator-associated pneumonia (VAP) between these two groups.

Results

A total of 731 patients in the MICU participated in the study over 12 months. HAIs were significantly different between the experimental (5.9‰) and control (8.9‰) groups, and CAUTIs were also considerably different between the experimental (1.1‰) and control (5.2‰) groups. In contrast, CLABSIs and VAP did not show differences between these two groups.

Conclusions

Bathing with 2% CHG every 2 days for 12 months was associated with reduced HAIs and CAUTIs in the MICU. However, strict aseptic procedures still should be followed during routine care.

Introduction

Healthcare-associated infections (HAIs), also referred to as ‘nosocomial infections’ or ‘hospital infections’, are infections that occur in a patient during care in a hospital or other healthcare facility and were not present or incubating at the time of admission from 48 h post admission until 3 days and continue to pose a substantial burden in intensive care units (ICUs) [1]. Two recent systematic reviews and meta-analyses showed that 7.4% of ICU patients hospitalized for more than 2 days developed at least one ICU-acquired HAI, with pneumonia (4%), bloodstream infections (BSIs) (3%), and urinary tract infections (UTIs) (2%) being the most common [2]. Ventilator-associated pneumonia (VAP) prevalence was 54.0%, that of BSI was 34.0%, and that of UTI was 26.0% [3]. Notably, 96% of pneumonia cases were associated with intubation, 44% of BSIs with central lines, and 94% of UTIs with indwelling urinary catheters, highlighting the critical roles of invasive devices in infection risk [2].

The rate of central line–associated bloodstream infections (CLABSIs) per 1000 central line days was 1.5, and the rate of catheter-associated urinary tract infections (CAUTIs) was 5.3. VAP was observed in 23.7‰ of medical intensive care units (MICUs) in Vietnam [4]. In Taiwan, national surveillance data from the Taiwan HAIs and Antimicrobial Resistance Surveillance System (THAS) in 2022 reported an ICU HAI incidence rate of 6.2‰ in medical centres. Device-associated infections remained a significant concern, with CLABSI rates of 4.2‰, CAUTI rates of 3.1‰, and VAP rates of 0.5‰ in medical centres [5]. Therefore, they are responsible for increased morbidity, mortality, and healthcare costs [6]. Invasive medical procedures increase the risk. Studies suggest that reducing the incidence of HAIs can be achieved by lowering device usage time and strengthening infection control measures [5,6].

Chlorhexidine gluconate (CHG) is a disinfectant with broad bactericidal activity, low toxicity, and prolonged antibacterial efficacy [6]. Chlorhexidine bathing was mainly influential in preventing BSIs and those caused by Gram-positive bacteria. Thus, its use may be effective in ICUs with a high prevalence of infections caused by this type of microorganism [7]. Generally, daily bathing with 2% CHG significantly affects the incidence of HAIs and multi-drug-resistant organisms (MDROs). One study reported a decrease in HAIs from 3.43‰ to 0.58‰ (P < 0.05), accompanied by a significant reduction in CAUTIs and CLABSIs (P < 0.05) [8]. Subgroup analyses indicate that bathing with 2% CHG is effective in preventing BSIs but not in preventing CAUTIs, VAP, or Clostridioides difficile infections [9]. Moreover, daily bathing with 2% CHG alone or in combination with other interventions has a significant impact on the incidence of HAIs and MDROs in the ICU [8,9].

However, the current literature reports inconsistent results on the effect of daily bathing with 2% CHG on HAIs, and the solution may cause skin harm [10]. The HAI rate in medical units poses a challenge to the quality of care in these units and incurs significant costs in Taiwan. Therefore, the HAIs are indicators used become routine quality monitoring in the MICU. Before intervention, the rate was 5.6‰, 6.3‰, and 8.9‰ in 2017–2019 for our MICU. Furthermore, nurses in the MICU care for a large number of patients, and routine care includes bathing patients with soap every other day. Infection rates have not improved. If the nurse replaces soapy water with a 2% CHG sponge bath, can infection be reduced? To date, no studies have investigated the role of bathing with 2% CHG every other day in the MICU. This study aimed to examine the effect of bathing with 2% CHG every other day on HAIs and the related influencing factors. The findings of this study may help inform the development of strategies to improve healthcare.

Methods

Study design

This was a quasi-experimental, prospective study with a retrospective design. The study was conducted from 2018 to 2020. Patients admitted to the adult MICU were divided into an experimental group and a control group. The patients from March 2018 to February 2019 were included in the control group. The control group used soap to clean every other day, a routine common in the MICU. Implementation begun immediately upon approval from the institutional review board. From March 2019 to February 2020, all patients were included in the experimental group, and they used 2% CHG wet wipes every other day for bathing.

Participants

The participants were admitted to the adult MICU of the medical centre in Taiwan. The inclusion criteria were (1) age ≧20 years and (2) no damage to the participant’s skin. Exclusion criteria were (1) individuals who were pregnant or lactating; (2) those who were allergic to CHG and skin rashes, damage, ulcers, or infections; and (3) refusal to participate in research. During the research process, to ensure the rights and interests of the research participants, MICU directors and physicians were informed about the program. Additionally, family members were instructed by the hospital to use 2% CHG wet wipes every other day for bed bathing after the patient was admitted to the MICU. They were informed of emergency procedures for allergies. The family members did not have to pay the cost of 2% CHG wet wipes, and the nursing records then documented the patient’s overall skin condition after taking a bath. This study used G∗power (version 3.1.9.7) to calculate the sample size, the software was developed by researchers Faul et al. at the Heinrich Heine University Düsseldorf (HHU) [11]. A t-test was used to compare the difference between two independent means (two groups), with an allowable error of 0.05 and a medium effect size (f = 0.3). If the effect size (f = 0.3) and statistical power reached 95%, the total number of cases was estimated to be 580. There were 290 patients in each group.

Interventions

Before the study, the MICU had ten nurses (a total of eighteen) who received professional lecture training from the manufacturer on how to use 2% CHG and related products, as well as precautions. The MICU (12 beds) bathed six patients daily, with 2% CHG and six packages of bath wipes in the thermostat. The thermostat temperature was set at 41°C. The maximum acceptable temperature, which can reach 34–41°C, should be slowly heated to the set temperature 6 h before bathing. The team leader on duty will continue monitoring the thermostat’s temperature daily to maintain a constant temperature.

The experimental group first used the same CHG antibacterial soap brand for bathing on the day of admission. Simultaneously, a single package of six wipes containing warm 2% Aqua CHG for bathing was used. The bath towel is fast-acting, operates according to different parts (broad spectrum), and maintains antimicrobial activity for at least 24 h after use. It is alcohol free, contains moisturizers, and is rinse free, disposable, and not reusable. A clean 2% CHG wipe should be used on each area of the body to reduce the chance of spreading bacteria from one location to another; the bathing procedure was as follows: first, the neck, shoulders, and chest; second, the arms, hands, finger joints, and armpits; third, the abdomen and groin/perineum; fourth, the right leg, right foot, and proper toe gap; fifth, the left leg, left foot, and between left toes; and sixth, the back of the neck, back, and buttocks [12].

Before using 2% Aqua CHG bath wipes, 2% Aqua CHG was placed in a steam oven with a constant temperature of 41°C and was slowly heated for 6 h. Then, six single-package bath wipes were soaked in 200 mL of warm 2% Aqua CHG and then used, as mentioned earlier. The patient’s body was sequentially wiped, avoiding the patient’s chin and above (the face, head, and mouth). After applying it to each body part, the indwelling urinary catheter and chest tubes were cleaned, ensuring the area was at least 2 inches away from the patient’s skin. When the skin is dry, the same brand of ion lotion can be used to wipe the body gently [12]. The control group followed the MICU routine and received a bath with general soap every other day.

The data for this study are based on information provided by the study hospital’s infection control centre. The definition of HAIs is based on guidelines from the Taiwan Centers for Disease Control and Prevention [5], which was referred to a definition from the Centers for Disease Control and Prevention, USA [13]. The infection control centre needs to discuss the cases on a case-by-case basis at the meeting and finally determine the cases according to the HAIs guidelines.

Data analysis

The data for this study were confirmed after a meeting at the infection control centre of the research hospital. Data were analysed using IBM SPSS Statistics 22.0. Descriptive statistics were used, including means and standard deviations for continuous variables and percentages for categorical variables. The differences in demographic characteristics between the two groups were analysed using a t-test and a χ² test before the study. The correlation between demographic factors, HAIs, CLABSI, CAUTI, and VAP was examined in the two groups, and the effectiveness of different intervention measures was compared using a paired t-test. A P value <0.05 indicates statistical significance.

Results

This study included 731 MICU patients. In the control group, 341 patients were identified through a review of medical records from March 2018 to February 2019. The experimental group was conducted from March 2019 to February 2020, and a total of 390 patients were included in the study. The demographic characteristics of the 731 participants are as follows: all items included age, length of stay in the ICU, Acute Physiology and Chronic Health Evaluation (APACHE) II score, gender, central venous pressure (CVP) device, endotracheal tube device, and indwelling urinary catheter. No significant differences were observed between the two groups before the study (Table I).

Table I.

Demographic characteristics of the participants (N=731)

Groups	Experimental group	Control group	t/χ2
Items	Mean ± SD; Cases (%) (N=390)	Mean ± SD; Cases (%) (N=341)
Age	68.8±15.3	67.6±15.6	−1.32
Length of stay in the ICU	5.0±1.0	4.9±1.2	1.11
APACHE II score	21.9±8.6	22±8.2	1.47
Gender			0.5
Male	229 (58.7)	209 (61.3)
Female	161 (41.3)	132 (38.7)
CVP device			1.81
Yes	356 (91.3)	301 (88.3)
No	34 (8.7)	40 (11.7)
ET device			2.40
Yes	281 (72.1)	277 (81.2)
No	109 (27.9)	64 (18.8)
IUC device			2.10
Yes	314 (80.5)	274 (80.4)
No	76 (19.5)	67 (19.6)

SD, standard deviation; ICU, intensive care unit; APACHE, Acute Physiology and Chronic Health Evaluation; CVP, central venous pressure; ET, endotracheal tube; IUC, indwelling urinary catheter.

On the other hand, demographic characteristics correlated with infection sides between the two groups. Age had a positive correlation and significantly differed between the two groups in CLABSI, CAUTI, and VAP; however, the length of stay in the ICU and APACHE II scores were not different (Table II).

Table II.

Demographic characteristics are correlated with infection sides between the two groups (N=731)

Groups Items	Experimental group (N=390)			Control group (N=341)
	CLABSI	CAUTI	VAP	CLABSI	CAUTI	VAP
Age	0.22∗∗	0.55∗∗	0.37∗∗	0.18∗∗	0.49∗∗	0.62∗∗
Length of stay in the ICU	0.04	0.04	0.03	0.04	0.004	0.07
APACHE II score	0.07	0.001	0.03	0.08	0.03	0.06

∗∗ P = 0.000.

CLABSI, central line–associated bloodstream infection; CAUTI, catheter-associated urinary tract infection; VAP, ventilator-associated pneumonia; ICU, intensive care unit; APACHE, Acute Physiology and Chronic Health Evaluation.

Comparing the HAIs and infection sites’ effectiveness between the experimental group and the control group, significant differences in overall HAIs (5.9‰ vs. 8.9‰, t = 6.3, P=0.000) and CAUTIs (1.1‰ vs. 5.2‰, t = 8.2, P=0.000) were observed between the two groups, while no improvements in CLABSIs (4.1‰ vs 3.3‰, t = 1.8, P=0.178) and VAP (0.7‰ vs 0.4‰, t = 2.4, P=0.956) were observed before and after the study (Table III).

Table III.

Compare the HAIs and infection sites between the two groups (N=40)

Groups	Experimental group		Control group		t
Items	Cases	HAIs (N=16)	Cases	HAIs (N=24)
HAIs	16	5.9	24	8.9	66.3∗∗
CLABSI	11	4.1	9	3.3	1.8
CAUTI	3	1.1	14	5.2	8.2∗∗
VAP	2	0.7	1	0.4	2.4

HAI, healthcare-associated infection; CLABSI, central line–associated bloodstream infections; CAUTI: catheter-associated urinary tract infections; VAP: ventilator-associated pneumonia.

HAIs: device-associated infection rates per 1000 patient-days.

Total infection rates per 1000 patient-days formula: number of infected cases/days of hospitalization.

Days of hospitalization: experimental group 2707; control group: 2694.

∗∗ P = 0.000.

Further analysis of the sites and strains causing infections in the two groups is needed. The infection sites in the experimental group were CLABSIs in ten cases (62.5%), followed by CAUTIs in four cases (25%) and VAP in two cases (12.5%). In the control group, CAUTIs had thirteen cases (54.1%), followed by ten cases of CLABSIs (41.7%), and VAP had one case (4.2%). As for the infectious strains, the experimental group had the most Gram-negative bacteria with nine cases (56.3%), followed by yeast with six cases (37.5%); the control group also had Gram-negative bacteria with ten cases (41.7%), followed by yeast with ten cases (41.7%) (Table IV).

Table IV.

Classification of bacterial strains infected in the two groups (N=40)

Experimental group (N=16)			Control group (N=24)
Infectious strain	Side	Cases	Infectious strain	Side	Cases
Gram (+) bacteria			Gram (+) bacteria
Veillonella species	Sputum	1	VRE	CAUTI	3
			MRSA	CLABSI	1
Gram (−) bacteria			Gram (−) bacteria
CRKP	CLABSI	1	CRKP	CLABSI	2
Stenotrophomonas maltophilia	CLABSI	2	Stenotrophomonas maltophilia	CLABSI	1
Burkholderia cenocepacia	CLABSI	1	Bacteroides fragilis	CLABSI	1
Bacteroides distasonis	Sputum	1	Pseudomonas aeruginosa	CLABSI	1
Elizabethkingia anopheles	CLABSI	2	Enterobacter cloacae	CLABSI	1
CRAB	CLABSI	2	CRPA	Sputum	1
			Escherichia coli	CLABSI	1
			CRAB	CLABSI	2
Yeast			Yeast
Candida albicans	CAUTI	1	Candida albicans	CAUTI	6
	CLABSI	2	Candida parapsilosis	CAUTI	1
Candida glabrata	CAUTI	3	Candida tropicalis	CAUTI	2
			Candida glabrata	CAUTI	1

VRE, vancomycin-resistant Enterococcus faecium; MRSA, methicillin-resistant Staphylococcus aureus; CRKP: carbapenem-resistant Klebsiella pneumoniae; CLABSI, central line–associated bloodstream infection; CRPA, carbapenem-resistant Pseudomonas aeruginosa; CRAB: carbapenem-resistant Acinetobacter baumannii.

Discussion

In this study, the experimental group was bathed with 2% Aqua CHG every other day for 12 months, while the control group was cleansed with soap. The results showed that the experimental group had a device-associated HAI rate of 5.9‰, significantly lower than the control group’s rate of 8.9‰. The results are consistent with a recent single-centre study from Taiwan, which demonstrated that the implementation of daily bathing with 2% CHG for 12 months significantly reduced the incidence of HAIs [8] and decreased risk [14], including CAUTIs, with effects sustained over time [8]. Therefore, a long duration of bathing with 2% CHG may be beneficial for HAI prevention, regardless of whether it is performed daily or every other day.

The CAUTI rate was significantly reduced in the experimental group compared with the control group in our study, consistent with the findings from Chang et al. [8]. However, many studies have shown no effect of 2% CHG on reducing CAUTIs in the ICU [15,16]. A possible reason is that in our research, the area within 2 inches of the exposed urinary catheter must also be cleaned when bathing with 2% CHG. Meanwhile, the perineal skin care was also a crucial part of cleaning in our study. CHG has a broad antimicrobial effect, can adhere to skin proteins for an extended period, and maintains bactericidal activity for 24 h, significantly reducing the bacterial load on the skin around the catheter and decreasing the likelihood of bacteria entering the urinary tract [17]. Additionally, the unit randomly checked the sterile technology procedure as part of the MICU routine in this study. One guideline recommended is implementing a CAUTI insertion and maintenance bundle care, which is best done using a quality improvement approach with a multi-disciplinary team. This approach includes a standardized methodology for performing CAUTI surveillance, as well as regular feedback and reporting on unit-specific CAUTI rates for nursing and clinical care staff [18]. Therefore, healthcare facilities should strive to provide excellent care for patients who have urinary catheters in place. A CAUTI prevention program should be recommended as part of their infection prevention and control program.

On the other hand, no significant reduction was observed between the two groups regarding CLABSIs and VAP in our study. A systematic review with meta-analysis verified that daily bathing with 2% CHG wipes can reduce the risk by 40% [16] and 48% of CLABSIs, and this is moderate evidence; factors affecting evidence include period of ICU, hospital stay, mortality rate, and cost-effectiveness [19]. However, for effective prevention of CLABSIs compared with conventional bathing with soap in the ICU, no difference was observed between the groups in the other study [15]. In our research, the CVP must be covered with a dressing containing antibiotics, which costs more than ordinary dressings. The dressing was changed every three days, and exudate was present in the wound. No changes were made at the same time as bathing may have been the reason for the failure to improve the infection. One study showed that the use of tissue adhesive (rich in 2-octyl blended with n-butyl cyanoacrylate) can significantly reduce CLABSIs, the oozing rate was considerably lower, and no serious adverse events occurred during use [20]. It can be used as a basis for improving our study, yet an article showed that within 7–10 days of the main route of contamination of CLABSIs, bacteria migrated from the micro-organisms present on the patient’s skin to the insertion site, towards the intravascular space, which causes contamination of the catheter tip due to a breach of standard aseptic precautions [21]. Therefore, it is recommended that the Centers for Disease Control standards be followed for the insertion of tubes. Educating healthcare personnel about the indications for use, proper procedures for inserting and maintaining intravascular catheters, and infection control measures to prevent intravascular catheter-related infections are critical. To avoid infections, priority selection of sites such as the subclavian vein, the use of ultrasound to guide intubation to reduce intubation frequency and complications, and skin cleaning preparation with 0.5% CHG preparation with alcohol before CVP should be used; there is no need to replace it routinely and remove it as soon as possible [22].

HAIs are common and have a high prevalence in adult ICU patients, especially those with VAP. The primary risks include invasive medical devices and chronic diseases [3]. A trial study with sequential meta-analysis demonstrated that bathing with 2% CHG did not reduce the incidence of VAP in the ICU [9,15,16], a finding consistent with our results. A possible reason for this observation is that wiping the patient’s chin, face, head, and mouth with 2% CHG should be avoided; therefore, there is no improvement in VAP in our study. In contrast, one meta-analysis found that daily bathing with 2% CHG significantly decreased the incidence risk of VAP; however, the exact mechanism for the association between daily bathing with CHG and VAP reduction remains unknown [23]. Reduced rates of VAP are related to the residual effect of bathing with CHG on both the patient and the environment, thereby reducing the risk of colonization and subsequent infection from medical devices associated with the patient [24]. Some studies suggest that it may be related to lowering cross-infection through the patient’s skin, environment, and healthcare workers’ hands [23]. Some scholars have recommended avoiding intubation, minimizing the duration of intubation, and preventing reintubations and daily toothbrushing, considering early tracheostomy; and they do not recommend oral care with chlorhexidine and taking probiotics, tapered endotracheal tube cuffs, ultrathin polyurethane endotracheal tube cuffs, automated control of endotracheal cuff pressures, and frequent endotracheal cuff pressure monitoring as part of a VAP prevention strategy [25]. It is an excellent way to reduce VAP. We also strongly recommend installing the device during endotracheal intubation. Strict aseptic techniques and nursing care must be implemented, such as washing hands and using sterile sputum suction, or new care models must be developed to reduce VAP infections.

Yet, skin rashes in patients were also considered a side-effect of using 2% CHG. Results showed that no severe skin reactions were noted in either the experimental or control group in our study or other studies [8,15,20]. The occurrences of adverse skin reactions in the two groups are similar [26]. Therefore, no relevant studies have reported the side-effects of bathing with 2% CHG on patients’ skin.

In this study, both groups experienced minimal infections with Gram-positive bacteria in CLABSIs; specifically, the experimental group (0 cases) had fewer infections than the control group (1 case), consistent with previous systematic review and meta-analysis studies [14,27]. In one study, most of these reductions were attributed to a decrease in the incidence of infections. Bathing with chlorhexidine has been shown to reduce CLABSI rates, particularly with Gram-positive bacteria, including coagulase-negative staphylococci [28,29]. However, these data demonstrate a high prevalence of 69% of reduced CHG susceptibility in organisms causing CLABSIs at a large academic medical centre, regardless of whether patients were daily bathed with CHG [30]. Moreover, concerns about reduced CHG susceptibility are increasingly supported by laboratory studies. CHG concentrations led to strains with reduced susceptibility (0.5–8 mg/L); exposure to subinhibitory CHG concentrations may select for strains with enhanced tolerance or resistance [31]. Organisms causing CLABSIs were more likely to be Gram-positive. Many organisms causing CLABSIs have reduced CHG susceptibility, and this proportion is more significant in patients who receive daily bathing with CHG. Thus, continued surveillance of clinical isolates is warranted to identify an epidemiologically considerable trend towards decreasing antiseptic susceptibility [30]. Notably, no CAUTI episodes were caused by MDROs, such as VRE in the experimental group, whereas three VRE-associated CAUTIs occurred in the control group. Although the number of cases was small, the protocol of bathing with 2% CHG every other day – with cleansing of the perineal area and the exposed catheter segment – may have reduced periurethral colonization through CHG’s broad-spectrum and prolonged residual activity [17]. Concurrent adherence to CAUTI insertion and maintenance bundles may also have contributed [18]. However, this finding may reflect random variation and should be interpreted as hypothesis generating rather than evidence of a definitive protective effect. Additionally, using chlorhexidine incurs a cost (each CHG solution with a paper towel bath costs US$4.82), and increased exposure to chlorhexidine may lead to greater microbial resistance, which should be considered when using CHG to reduce HAIs. Thus, bathing in the ICU every two days is an acceptable intervention.

Our study has limitations. First, it was a single-centre before-and-after quality improvement study and not a randomized clinical trial. Second, we did not audit every procedure in urgent situations, especially the aseptic technique. Third, as it was not a intervention, it is susceptible to the Hawthorne effect. Fourth, the size of the HAI cases is small in our study, which led to a small difference between the two compared groups. Regarding the total cost reduction related to HAIs, because Taiwan has universal health insurance, medical expenses require special investigations by medical personnel. It cannot be further analysed in this study.

After the experimental group was bathed with 2% CHG every other day, while the control group was cleansed with soap for 12 months, the experimental group showed lower rates of total HAIs and CAUTIs per 1000 patient-days than the control group. No significant differences were observed between the two groups for CLABSIs and VAP. These findings should be interpreted as associations rather than causal effects. Still, this study recommends that, regardless of bathing strategies, strict aseptic techniques during device insertion and maintenance, as well as the development of new care models, must be implemented to reduce HAIs. Therefore, bathing with CHG every other day can be a feasible and acceptable ICU intervention, and our findings provide hypothesis-generating evidence supporting its use as part of a broader, multi-faceted infection prevention strategy.

CRediT authorship contribution statement

Shu-Fen Hsu: Writing – original draft, Resources, Project administration, Investigation, Data curation, Conceptualization. Pei-Jung Yu: Writing – review & editing, Writing – original draft, Resources, Project administration, Methodology, Formal analysis. Hsing-Yu Yang: Writing – review & editing, Supervision. Te-Yu Wu: Writing – review & editing, Validation, Supervision, Software, Resources, Project administration, Methodology, Investigation, Formal analysis, Data curation, Conceptualization.

Ethics statement

The research was conducted after approval by the MacKay Memorial Hospital Institutional Review Board (19MMHIS049e). The researchers explained that the purpose of the study, method, and content of the information should be communicated to patients and their families in person through the ‘Instructions for Patients and Visitors in the Intensive Care Unit’ health education leaflet.

Funding sources

This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest statement

The authors declare no conflict of interest.