Dry eye management with diquafosol 3% eyedrops before and after cataract surgery: a retrospective observational case series

Introduction

Background

Dry eye disease (DED) can develop following cataract surgery, causing foreign body sensations, soreness, poor visual acuity, dryness and ocular fatigue (1-3). Post-operative DED may result from a loss of tear film homeostasis (4), manifesting as ocular surface changes, including reduced tear production and altered lipid, protein and mucin profiles. The transection of corneal nerves during cataract surgery can also disrupt neural feedback loops, leading to reduced tear production, altered tear film composition, and significantly impacted tear film homeostasis, resulting in DED (5,6).

Consequently, tear film instability and hyperosmolarity, ocular surface inflammation and damage, and neurosensory abnormalities (4,7) occur. In one study, DED severity peaked 1 day post-operatively and persisted for up to 12 months (8).

Increasing age is accompanied by an increasing prevalence of cataracts (9) and DED, particularly in the elderly, with the Dry Eye Workshop (DEWS) Committee (10) estimating a DED prevalence of 20.0–52.4% in Southeast Asia alone. DED is more common in females and is generally associated with various systemic and ocular health conditions (8,11). The diagnostic criteria for DED, based on the Tear Film and Ocular Surface Society (TFOS) DEWS II, include positive scores for symptoms [e.g., via the Ocular Surface Disease Index (OSDI) questionnaire (12) or the Dry Eye Questionnaire (13)] and a minimum of one abnormal marker (e.g., tear film break-up time, ocular surface staining (11).

Currently, the American Academy of Ophthalmology recommends patient education, ocular lubricants, modification or elimination of offending medications and prescription drugs to manage DED (14). Artificial tears are an effective and well-tolerated therapy suitable for milder disease, to reduce evaporation and inflammation by enhancing tear stability (14,15).

P2Y2 purinergic receptors are found in the meibomian gland (16) and are abundant in the conjunctiva, where they facilitate the production of fluids and chloride ions. Diquafosol is an agonist of the P2Y2 purinergic receptor and stimulates its secretion of tear components (17). P2Y2 receptor expression in conjunctival epithelial cells increases after diquafosol administration, and in turn, increases the production of tear constituents such as mucins from goblet cells and aqueous components from conjunctival accessory lacrimal glands (18). The clinical efficacy of diquafosol in DED has been documented in human (19-21) and animal studies. In animal models (19-21), diquafosol increased secretions and mediated ocular surface improvements post-operatively by increasing the levels of intracellular lipids in meibomian gland cells (20,22). In addition, diquafosol stimulated the cell proliferation mediated by epidermal growth factor receptor/extracellular-signal-regulated kinase signalling, and facilitated wound healing of damaged cornea (23). In human patients with DED, diquafosol was superior to sodium hyaluronate at improving rose Bengal staining scores, with a similar efficacy in improving fluorescein staining scores (24). Diquafosol 3% significantly improved subjective symptoms related to pre-existing DED, increased tear break-up time (TBUT), lowered corneal and conjunctival staining scores, reduced higher-order aberrations, and improved Schirmer test results in post-operative patients (17). Diquafosol 3% also reduced DED prevalence post-cataract surgery (55.7%) compared with before surgery (69.7%) (25).

Rationale and knowledge gap

Cataract surgery can cause new-onset DED but can also exacerbate pre-existing DED and decrease corneal sensitivity and tear production post-operatively (26). In fact, nearly 40% of cataract surgery candidates demonstrated positive corneal staining, and over half had abnormal tear osmolarity or levels of matrix metalloproteinase-9 (27). Data on the pre-operative use of diquafosol 3% ophthalmic solution is scarce, and there are few attempts to improve the pre-operative ocular surface or dry eye, even though pre-existing DED worsens post-operative outcomes among routine cataract patients (26,28), and causes refractive error measurements. As the pre-operative ocular surface status has significant post-operative impacts (29), it must be optimised before cataract surgery.

Although many patients with DED have concurrent significant cataract requiring surgery, studies on their peri-operative management are scarce. While one study hypothesized an increased post-operative incidence of dry eye to be related to the misuse of eyedrops (1), it is unknown if this was due to the presence of preservatives. In contrast, other studies (30-32) indicate that peri-operative anti-inflammatory treatments, such as topical immunosuppressants (e.g., cyclosporine), mucosal protectants or steroid drops, may benefit the ocular surface before cataract surgery and reduce the risk of post-operative dry eye. For example (33), in cataract surgery patients administered rebamipide or artificial tears from 4 weeks pre-surgery to 3 months post-surgery, perioperative dry eye management and ocular parameters were found to be significantly better with rebamipide than with artificial tears, especially at 1 week and 1 month post-surgery, with some effects persisting at 3 months.

Objective

Through a retrospective observational analysis of medical health records (MHR), we assessed the efficacy of diquafosol 3% ophthalmic solution at improving and managing pre-existing DED symptoms when used by patients before and after cataract surgery. This article is presented in accordance with the STROBE reporting checklist (available at https://aes.amegroups.com/article/view/10.21037/aes-24-14/rc).

Methods

This retrospective observational case series collected and analysed MHR data from patients who underwent cataract surgery between January 2021 to January 2022 at a single private ophthalmic health facility in Malaysia (LEC Eye Centre, Ipoh, Malaysia; ClinicalTrials.gov registry identifier NCT04952987). During this period, patient data was recorded as per routine clinical practice and all data collection and processing were conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Due to the retrospective audit nature of the study, the Malaysian Research and Ethics Council, Ministry of Health Malaysia, Guideline 1 (available at: http://www.nccr.gov.my/index.cfm?menuid=26&parentid=17), did not require ethics approvals, but written informed consents were obtained from all patients. The study was conducted in accordance with relevant Malaysian guidelines and regulations on Good Clinical Practice.

Convenience sampling was performed within the study timeframe. Included MHR were from patients who were aged ≥18 years, in good general health, with a diagnosis of pre-existing, mild-to-moderate DED and visually significant cataract, non-visually significant ocular surface disease (NVS-OSD) defined as corneal and conjunctival fluorescein staining (CFS) score of <3 on the Oxford scale (34), and a TBUT of <10 seconds. These visual criteria were based on the Tear Film & Ocular Surface Society Dry Eye Workshop II guidelines for mild-to-moderate dry eye (7). Patients with more severe DED were excluded from our investigations. The patients also needed to have had baseline measurements (Figure 1; categorised as ‘Visit 0’), received diquafosol subsequently and continuously up to the final assessment (categorised as ‘Visit 5’), and had no eye drop-free period between assessments (Figure 2). Included patients also instilled one drop of diquafosol sodium 3% (Diquas^®, Santen Pharmaceutical, Osaka, Japan) six times daily for 4 weeks, as per label, before surgery (Visit 0). Thereafter, all patients underwent another assessment on the day of surgery (Visit 1, Day 0). Post-operatively, all included patients were those who continued concurrent treatment with diquafosol sodium 3% drops and attended post-surgical follow-up assessments at Day 1 (Visit 2), Week 1 (Visit 3), Week 4 (Visit 4) and Week 12 (Visit 5). Patients were also given prednisolone 1% and ofloxacin 0.3% eye drops for up to 4 weeks post-operatively. All surgeries were performed by a single surgeon to prevent technique or assessment variations. The surgeon has completed over 6,000 cataract procedures since 2009, predominantly in Malaysia.

Figure 1 Pre-data extraction clinical interventions.

Figure 2 Flow diagram of patient screening procedure for study inclusion.

Excluded patients were those who developed post-surgical complications requiring a prolonged course of topical medication [anti-glaucoma treatments or antihistamine eye drops (steroidal or for allergies) used for longer than 3 months, and not related to dry eye treatment], or who had a history of contact lens use in the 3 months prior, a history of regular use of topical eye drops (except artificial tears, we excluded patients using any anti-glaucoma treatment or steroid for longer than 3 months) in the 6 months prior, a treatment history of dry eye beyond artificial tears, significant OSD (defined as CFS score of ≥3 on the Oxford scale (34), lacrimal or eyelid disease or ocular surface infections, any ocular surgery within the 6 months prior, medication use that could cause dry eye (e.g., antihistamines, antidepressants, decongestants, anticholinergic drugs) and hypersensitivity to diquafosol.

Between baseline (Visit 0) and 12 weeks post-operatively (Visit 5), changes in TBUT, CFS, and Standard Patient Evaluation of Eye Dryness (SPEED) questionnaire score were recorded. This data was subsequently extracted and evaluated as the primary outcomes of the effects of diquafosol sodium 3% drops. Data on uncorrected distance visual acuity (UDVA) and corrected distance visual acuity (CDVA), respectively, were also recorded at 12 weeks (Visit 5) post-operatively. This data was subsequently extracted for analysis as secondary outcomes of diquafosol sodium 3% drops. Appendix 1 provides more information on cataract surgery, TBUT, CFS, SPEED questionnaires, and UDVA and CDVA measurements.

Statistical analysis

To determine the effectiveness of diquafosol sodium 3% on all outcomes (changes in TBUT, CFS, SPEED, UDVA and CDVA, between baseline and 12 weeks post-cataract surgery), means, medians and standard deviations (SD) were calculated and paired t-tests were performed with a statistically-significant threshold P value of <0.05 (two-sided) in Excel. Continuous variables were categorized by time periods, normally distributed and reported as mean ± SD. Categorical data on changes in ocular signs and dry eye symptoms at different times were expressed as percentages. Comparisons of continuous data on the different outcomes between the different timepoints were represented graphically.

Results

Demographics and clinical characteristics

From the 26 patients (39 eyes) initially enrolled by convenience sampling during the study timeframe, 5 patients (7 eyes) were subsequently excluded and 21 patients (32 eyes) progressed to completion. The majority of the patients were female (n=18, 85.7%), and the mean age was 64.06±8.93 years (range, 45–77 years). Of the 32 eyes studied, 10 were from unilateral patients and 22 from bilateral patients. The complete preoperative parameters at Visit 0 are as shown in Table 1.

Change in TBUT up to 12 weeks post-cataract surgery versus baseline

Compared to Visit 0 (4.60±1.99), the mean TBUT improved from <5 seconds to >5 seconds from Visit 1 (5.29±2.03) onwards, indicating improvement of tear film stability. Although the improvement was not significant at Visit 1 (P=0.20), the change was significant at Visit 4 (6.11±2.38) (P=0.001) and Visit 5 (5.93±1.78) (P=0.01) versus Visit 0 (Figure 3).

Figure 3 Mean TBUT (in seconds) at Visit 0, Visit 1, Visit 4 and Visit 5. ^a, P=0.01 versus Visit 0; ^b, P=0.18 versus Visit 1; ^c, P=0.62 versus Visit 4; ^d, P=0.001 versus Visit 0; ^e, P=0.15 versus Visit 1; ^f, P=0.20 versus Visit 0. Visit 0, before the surgery; Visit 1, the day of surgery (Day 0); Visit 4, Week 4; Visit 5, Week 12. TBUT, tear break-up time.

Change in CFS score up to 12 weeks post-cataract surgery versus baseline

The mean CFS score was significantly better on Visit 1 (3.28±1.59) (P=0.009), Visit 4 (2.91±1.97) (P<0.001) and Visit 5 (1.63±1.32) (P<0.001) compared to Visit 0 (4.75±2.27). The mean CFS score was also significantly improved at Visit 5 compared to Visit 4 (P=0.02). In fact, the CFS score showed a significant improvement at all time points except when comparing Visit 4 to Visit 1 (P=0.374) (Figure 4).

Figure 4 Mean CFS score at Visit 0, Visit 1, Visit 4 and Visit 5. ^a, P<0.001 versus Visit 0. ^b, P<0.001 versus Visit 1. ^c, P=0.02 versus Visit 4. ^d, P=0.35 versus Visit 1. ^e, P=0.009 versus Visit 0. Visit 0, before the surgery; Visit 1, the day of surgery (Day 0); Visit 4, Week 4; Visit 5, Week 12. CFS, corneal and conjunctival fluorescein staining.

Change in SPEED score up to 12 weeks post-cataract surgery versus baseline

Mean SPEED scores showed significant improvement at Visit 1 (1.5±1.74) (P<0.001), Visit 4 (2.97±3.51) (P<0.001) and Visit 5 (1.94±2.19) (P<0.001) versus Visit 0 (6.41±3.62). The SPEED score showed slight worsening at Visit 4 compared to Visit 1 (P=0.03), before returning to preoperative levels at Visit 5 (Figure 5).

Figure 5 Mean SPEED questionnaire scores at Visit 0, Visit 1, Visit 4 and Visit 5. ^a, P<0.001 versus Visit 0. ^b, P=0.11 versus Visit 1. ^c, P=0.30 versus Visit 4. ^d, P=0.03 versus Visit 1. Visit 0, before the surgery; Visit 1, the day of surgery (Day 0); Visit 4, Week 4; Visit 5, Week 12. SPEED, Standard Patient Evaluation of Eye Dryness.

Change in UDVA and CDVA up to 12 weeks post-cataract surgery versus baseline

Mean CDVA and UDVA at Visit 4 were 0.15±0.12 and 0.24±0.16, respectively, and at Visit 5 were 0.15±0.12 and 0.26±0.19, respectively. Both post-operative UDVA and CDVA were significantly better at Visit 4 (both P<0.001) and Visit 5 (both P<0.001) compared to Visit 0 (0.57±0.27 and 0.34±0.20, respectively) (Figure 6A). At Visit 5, 90.9% had a CDVA of 6/12 [logarithm of the minimum angle of resolution (logMAR) 0.3] or better, and 63.6% had a CDVA of 6/9 (logMAR 0.18) or better. In addition, 72.4% had a UDVA of 6/12 or better, and 44.8% had a UDVA of 6/9 or better (Figure 6B).

Figure 6 UDVA and CDVA before and up to 12 weeks (Visit 5) post-operatively. (A) Mean UDVA and CDVA (logMAR) values at Visit 0, Visit 4 and Visit 5. ^a, P<0.001 versus Visit 0. (B) Percentage of eyes with UDVA and CDVA values of 6/9 (logMAR 0.18) or better and 6/12 (logMAR 0.3) or better at 12 weeks post-cataract surgery. CDVA, corrected distance visual acuity; logMAR, logarithm of the minimum angle of resolution; UDVA, uncorrected distance visual acuity; VA, visual acuity.

Changes in ocular signs and dry eye symptoms at different times post-diquafosol

The percentage of patients showing changes in ocular signs and dry eye symptoms between different evaluation periods after topical 3% diquafosol is also shown in Figure 7. Notably, compared to baseline, pre-surgical use of diquafosol for 4 weeks improved TBUT in 66.7% of patients, CFS improved in 61.9% of patients, and SPEED score improved in 95.2% of patients, with no patient worsening.

Figure 7 Graphical representation of the percentage of patients showing changes in ocular signs and dry eye symptoms (TBUT^a, CFS, and SPEED score) among different evaluation periods after pre-surgical (Visit 1) or post-surgical (Visits 4 and 5) treatment with topical 3% diquafosol ophthalmic solution. ^a, an increase in tear film break-up time after treatment was defined as “Improved”, and a decrease as “Worsened”. The same values of tear film break-up time before and after treatment were defined as “No change”. Visit 0, before the surgery; Visit 1, the day of surgery (Day 0); Visit 4, Week 4; Visit 5, Week 12. CFS, corneal and conjunctival fluorescein staining; DQS, diquafosol sodium; SPEED, Standard Patient Evaluation of Eye Dryness; TBUT, tear breakup time.

Patients then applied diquafosol for 12 weeks post-surgically. At the Visit 4 follow-up, compared to Visit 0, improvements in TBUT had declined from 66.7% to 61.9%, in CFS from 61.9% to 52.4%, and in SPEED scores from 95.2% to 19%. By 12 weeks post-surgery, TBUT, CFS and SPEED score had improved in all patients who continued with diquafosol use. Specifically, 80.9% of patients had improved TBUT, 90.5% of patients had improved CFS, while 80.9% of patients had improved SPEED score. Similarly, the proportion of patients with worse TBUT, CFS and SPEED score at Visit 4 compared to baseline (23.8%, 33.3% and 61.9%, respectively) had also improved at Week 12 (to 9.5%, 9.5% and 9.5%). Also, between post-surgical weeks 4 and 12, use of diquafosol led to TBUT improving in 42.9% of patients and being maintained in 19% of patients; CFS improving in 57.1% of patients and being maintained in 28.6% of patients; and SPEED score improving in 33.3% of patients and being maintained in 38.1% of patients. Overall, the results show that patients can worsen in the first post-surgical month, but improve by 3 months post-surgery.

Adverse outcomes

Five instances of adverse drug reactions in 5 different patients were recorded in this study. One patient reported itchiness with the use of diquafosol after 4 weeks, which resolved after discontinuation. Another patient developed significant punctate corneal erosions after surgery and was switched to preservative-free lubricants, with resolution of erosions. Three patients had developed either post-operative corneal oedema, recurrent anterior uveitis or cystoid macular oedema, all of which resolved with additional appropriate treatment whilst still continuing with diquafosol eyedrops. Diquafosol was otherwise well-tolerated and there were no severe ocular or systemic adverse reactions recorded. All adverse reactions were mild and resolved with treatment or cessation of diquafosol.

Discussion

Our main objective was to determine the effect of diquafosol sodium 3% treatment (starting 4 weeks prior to surgery and continuing until 12 weeks post-operatively) in patients with pre-existing DED who underwent cataract surgery.

Key findings

Our observational analysis detected improvements in all primary and secondary outcomes. Improved CFS scores indicate that diquafosol benefit the ocular surface, even post-operatively. Improved post-operative use of diquafosol also persistently increased tear film stability. Diquafosol also significantly improved SPEED scores, with symptom improvements maintained post-operatively.

Strengths and limitations

Strengths of this study included its focus on the peri-operative management of dry eye disease in patients undergoing cataract surgery, at 4-week pre-operative and 12-week post-operative follow-up periods, thus allowing evaluation of both short-term and longer-term effects, and its real-world setting in a private ophthalmic clinic, thus reflecting typical clinical practice. There were several limitations to this study. This was an observational study of a small sample of patients with no comparative arm, and is therefore open to bias. The subjects in the study, comprising a high proportion of females, also had only mild to moderate DED; hence, the efficacy of diquafosol in patients with more severe DED undergoing cataract surgery is not known. The use of post-operative topical steroids and antibiotics may be a confounding factor as these anti-inflammatory medications may improve dry eye symptoms. Moreover, there was no objective measure of mucus (impression cytology) or tear osmolarity, which will have been affected by a P2Y2 agonist such as diquafosol. Due to its real-world, retrospective, observational nature, a control group could not be included to conclusively demonstrate the effect of diquafosol. There was also no measure of higher-order aberrations, which may have impacted the final visual outcomes.

Comparison with similar research

Diquafosol has previously been shown to improve corneal and conjunctival staining scores, TBUT and dry eye symptoms (24). In a previous study (35), 4 weeks of diquafosol use improved subjective DED symptoms in 78.6% of eyes, with TBUT improving in 65.7% of eyes, and corneoconjunctival staining improving in 62.8% of eyes, but Schirmer I values were unchanged. In our evaluation of ocular parameters (TBUT, CFS and SPEED) and dry eye symptoms at different post-surgical periods, we found minor deteriorations in the immediate 4-week period post-surgery, even with diquafosol use, similar to results observed elsewhere (5). By 12 weeks post-surgery, the parameters had improved in the majority of patients who persisted with diquafosol use. Beyond 12 weeks, diquafosol could potentially continue to benefit patients with worsening or unchanging symptoms, who may require longer recovery times.

Multiple reports have demonstrated superior effectiveness in DED with post-operative topical diquafosol than with artificial tears (17). Lee et al. (21) found that DED-associated surface changes were mitigated by applying diquafosol 3% peri-operatively, 1 week before and up to three months after cataract surgery. TBUT, OSDI and Oxford Scheme scores were significantly improved, with significantly decreased Schirmer’s test I scores at three months, compared to patients without diquafosol. This underscores the importance of including the treatment of pre-existing DED in cataract management, and before conducting cataract surgery.

Explanations of findings

In our analyses, CFS scores significantly improved, indicating that diquafosol reduced corneal and conjunctival epithelial damage in DED as early as 4 weeks after starting treatment. Furthermore, the ocular surface showed consistent, continued improvement with continued usage of diquafosol at 4 and 12 weeks post-operatively, despite the trauma following cataract surgery. Continued use of diquafosol also led to a consistent, sustained improvement in TBUT from 4 to 12 weeks post-operatively. Baseline average SPEED scores (an indication of patient’s dry eye symptoms) were low but consistent with these patients having only mild to moderate DED. The most significant improvement in SPEED scores occurred at 4 weeks after starting diquafosol (i.e., on the day of surgery). Although a slight worsening of symptoms was observed at 4 weeks post-operatively, we attribute this to surgery-associated ocular surface disruptions. By 12 weeks post-operatively, the SPEED scores had returned to pre-operative levels. Initiation of diquafosol significantly improved SPEED scores at all time points compared to baseline, indicating that diquafosol’s improvements to patients’ symptoms were maintained even post-operatively. By 12 weeks post-operatively, overall mean logMAR UDVA and CDVA had improved from baseline levels, comparable to a previous study on cataract surgery in DED (36). Significant improvements in UDVA and CDVA by 4 weeks post-operatively were also maintained at 12 weeks.

Implications and actions needed

We showed that diquafosol had a positive impact on patients with mild-to-moderate DED who underwent cataract surgery, and should be integrated into the cataract surgery treatment algorithm. However, further studies are required with a larger sample size, a control group, and robust inclusion and exclusion criteria. Further studies are also needed to ascertain the benefits of peri-operative, preservative-free diquafosol formulations on DED post-surgically, in more male patients, and in those with more severe DED undergoing cataract surgery. Corneal nerve morphology should be assessed by in vivo confocal microscopy to measure pre- and post-operative effects on nerves with 3% diquafosol usage. In addition, further work is needed to examine diquafosol’s effects without post-operative medications, incorporate objective measures for mucus production, assess tear osmolarity changes, evaluate higher-order aberrations, conduct a prospective randomized controlled trial, and perform long-term follow-up.

Conclusions

Diquafosol has been previously shown to improve surgical outcomes by stabilizing the tear film and reducing corneal and conjunctival damage, thus contributing to improved visual acuity and patient comfort post-surgery. Although diquafosol sodium 3% eyedrops were also proven effective in the management of post-cataract surgery dry eye, ours will be the first study to illustrate its benefits when used peri-operatively in patients with pre-existing mild to moderate DED. For such patients, starting diquafosol sodium 3% eyedrops 4 weeks before surgery and continued for up to 12 weeks post-operatively, effectively reduced the signs and symptoms of pre-existing DED, or mitigated DED worsening due to cataract surgery. Diquafosol could thus be included in cataract surgery treatment plans as a simple and cost-effective method for managing post-surgery DED, potentially reducing the need for more complex interventions.

Acknowledgments

The author would like to express gratitude to all staff at LEC Eye Centre and to Ms. Lai Jean Tse, who coordinated the study and provided invaluable support with data collection and storage. Thanks also goes to Ms. Veni Venusha Sakti for her gracious help and guidance and to MediConnexions Consulting Pte Ltd for manuscript writing and Dr. Shawna Tan of Medical Writers Asia for manuscript editing and rewriting.

Footnote

Reporting Checklist: The author has completed the STROBE reporting checklist. Available at https://aes.amegroups.com/article/view/10.21037/aes-24-14/rc

Data Sharing Statement: Available at https://aes.amegroups.com/article/view/10.21037/aes-24-14/dss

Peer Review File: Available at https://aes.amegroups.com/article/view/10.21037/aes-24-14/prf

Funding: This study was supported by a grant from Santen Pharmaceuticals (Malaysia), who also provided the study drug. Santen Pharmaceuticals played no role in conducting the study, data analysis or manuscript preparation. Funding for the rewriting of the original manuscript was provided by Santen Pharmaceutical to Dr. Shawna Tan, Medical Writers Asia.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at https://aes.amegroups.com/article/view/10.21037/aes-24-14/coif). M.W.L. received grants from Alcon Laboratories. He is a speaker for Alcon, Bayer, Novartis, Santen, Topcon, J&J Vision, and Allergan. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. Due to the retrospective audit nature of the study, the Malaysian Research and Ethics Council, Ministry of Health Malaysia, Guideline 1 (available at: http://www.nccr.gov.my/index.cfm?menuid=26&parentid=17), did not require ethics approvals, but written informed consents were obtained from all patients. This study was conducted in accordance with relevant Malaysian guidelines and regulations on Good Clinical Practice.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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