Tranexamic acid in melasma: A focused review on drug administration routes

Melasma is a disorder of hyperpigmentation and vascularization often found in women between the ages of 20 and 40. The pathogenesis is unknown, but melasma often occurs in sun‐exposed areas of the face, forearms, and back. Risk factors include family history, increased estrogen/progesterone, certain medications, and UV exposure. Melasma is typically treated with topical hydroquinone (HQ); however, it is often refractory to treatment. Tranexamic acid (TXA) is a plasmin inhibitor used off‐label in the treatment of melasma. TXA can be administered orally, topically, or intralesionally.


| INTRODUC TI ON
Melasma is an acquired pigment disorder with increased melanogenesis and vascularization affecting mostly women aged 20-40. It is characterized as light-to-dark brown macules and patches in sunexposed areas of the face. The etiopathogenesis remains unclear; however, factors implicated include family history, ultraviolet radiation (UV) exposure, medications, and hormonal imbalances. 1 Melasma can be divided into epidermal, dermal, and mixed types based on the depth of melanogenesis. 2 The Melasma Area and Severity Index (MASI) and modified Melasma Area and Severity Index (mMASI) are validated and reliable tools to evaluate melasma severity and are used as a standard outcome measurement of melasma treatment efficacy. 3 This tool considers the surface area, darkness, and homogeneity of melasma in four different areas of the face.
Treatment for melasma is difficult and relapse often occurs. Most treatments aim to decrease melanogenesis and the depth of melanocyte invasion. Conventional first-line treatment methods for melasma include topical lightening agents including hydroquinone (HQ), azelaic acid, mequinol, kojic acid, and retinoids, with triple therapy cream containing hydroquinone, tretinoin, and corticosteroid as the most effective topical treatment. 4 Other second-line therapies include chemical peels and laser therapies. Often, dermatologists will use multiple treatment options with varying levels of efficacies. Sun protection must be used in melasma treatments and all melasma treatment regimens will include a sunscreen.
Tranexamic acid (TXA) is a treatment option for this difficult-totreat condition. It is a synthetic derivative of the amino acid lysine that acts as a plasmin inhibitor and was historically used to treat bleeding disorders. Plasmin plays a key role in melasma since UV light increases plasmin activity in keratinocytes, which can lead to an increase in melanocytic-stimulating mediators, such as arachidonic acid and α-melanocyte stimulating hormone. TXA can inhibit this UV-induced plasmin activity. Additionally, studies have shown that TXA can suppress melanin formation by inhibiting the release of paracrine melanogenic factors that normally act to stimulate melanocytes; therefore, it has been heavily researched as a treatment for pigment disorders in addition to its traditional use in bleeding disorders. An additional effect of TXA is reducing Vascular Endothelial Derived Growth Factor (VEGF) and endothelin-1-induced angiogenesis, therefore decreasing the appearance of pigmentation. TXA can be used orally, intradermally, topically, and transepidermally to treat melasma. 5 The purpose of this review is to characterize the use of different TXA delivery methods and the efficacy of these modalities compared with traditional treatments.

| Technique
Oral TXA is currently FDA-approved for cyclic heavy menstrual bleeding (1300 mg PO TID), hemoptysis (500 mg inhalation TID), and tooth extraction in patients with hemophilia (PO or injection 650 mg). However, oral TXA is being used off-label for the treatment of melasma, particularly cases recalcitrant to conventional first-line treatment options. The most common dosage used in the RCTs is 250 mg twice a day. In clinical practice, TXA is dispensed at 650 mg, which can be split into 325 mg tablets and taken twice a day.

| Safety and side effects
As a systemic medication, this type of therapy must be prescribed with caution due to its mechanism of action as a plasmin inhibitor. 6 Thus, providers must screen any patients for history of thromboembolic events and active thrombotic disease as well as intracranial bleeding, traumatic events, and color blindness. 6 The most common side effects of oral TXA are gastrointestinal side effects.
Additionally, studies with oral TXA saw menstrual irregularities as a side effect. More serious side effects include deep vein thrombosis, acute renal cortical necrosis, acute myocardial infarction, and pulmonary embolism. These are rare given the lower doses of TXA used in melasma patients. However, baseline screening for clotting risk factors via thorough patient history assessment and relevant laboratory screening tests is crucial before initiating this therapy. Further, in the context of the COVID-19 pandemic, providers should be cautious when prescribing oral TXA. The SARS-CoV-2 virus has the potential to progress to respiratory failure, microthrombic events, and hypercoagulability, which could be exacerbated using this medication. 7

| Evidence
One randomized controlled trial separated 37 patients with 20 receiving 250 mg TXA twice a day and 17 receiving a placebo for 12 weeks.
Melasma improved in 50% of the patients taking TXA versus only 5.9% in the placebo group using MASI, Melasma Quality of Life score, and colorimetry as parameters. No severe side effects were reported. 8 Another randomized controlled trial compared 18 participants taking 250 mg TXA twice daily and 21 participants taking placebo for 12 weeks, followed by 12 weeks of only sunscreen. The MASI scores in both groups decreased over time, with only the TXA group improving significantly, especially in patients with severe melasma. Both groups saw an increase in MASI scores after stopping treatment between weeks 12 and 24, but the scores did not return to baseline. The same trend occurred with the melanin index scores. There was no difference in quality-of-life scores between the two groups. Two-thirds of patients taking oral TXA experienced some side effects, most commonly GI disturbances, changes in menses, and headaches. There were no severe side effects noted. The authors noted that the treatment effects lasted beyond the 3 months of treatment in patients with moderate melasma; however, patients with severe melasma had a relapse, suggesting that patients with more severe melasma may require a longer duration of treatment. 9 A multicenter clinical trial compared 500, 1000, 750, and 1500 mg of oral TXA over an initial 8-week stage followed by a 2-year phase in 72 patients with severe melasma. Even though there was a trend of higher reduction in MASI scores and melanin index in the higher dose groups, these did not reach statistical significance. There was also no difference in patient satisfaction.
Side effects included insomnia, stomach upset, and menstrual changes; however, no one discontinued the medication due to these symptoms. 10 A study comparing 250 mg TXA once daily to 500 mg TXA twice daily in 132 patients showed a significant reduction in mean MASI score in the 500 mg twice a day group when compared to the 250 mg group after 16 weeks. There was also higher satisfaction in the 500 mg twice daily group as there was noted clinical improvement earlier than in the other group. Neither group had significant adverse events, but minor transient side effects were noted in both groups.
The authors recommend starting patients on 500 mg twice a day to quickly improve melasma and then maintaining results on 250 mg once daily. 11 Another trial enrolled 74 participants to take 250 mg of TXA twice daily for 6 months. Every patient demonstrated clinical improvement; however, only one patient was an "excellent" responder in mMASI score, while 14 were considered "moderate-good." The Melasma Quality of Life score was moderate-good in 26 patients and mild in four patients.
Out of the patients biopsied, 13/14 saw decreased epidermal pigmentation, and 7/14 saw reduced number of melanocytes. Some patients also demonstrated a reduction in inflammation and edema.
The effects of the TXA treatment were maintained in all patients over the 2-month follow-up period. 13

| Summary of clinical evidence
Oral TXA has been shown to be an effective and fast-acting treatment for melasma, especially in severe or refractory cases. The effectiveness of oral TA depends on the duration of therapy, which is more important than the dose used. A minimum trial of 3 months is recommended before improvement is noted, although skin lightening may be seen before this time frame. Additionally, even though the typical therapeutic dose in melasma is at least 500 mg twice daily, some authors have found lower doses of 250 mg once daily and 125 mg once daily to be effective and propose the utility of these lower doses as a maintenance treatment to prevent relapses. Though many patients experienced transient menstrual, GI, and sleep disturbances, none of the studies reported any severe adverse events. These studies highlight that the effects of oral TXA may not last long beyond cessation of treatment, and studies with longer follow-up periods should be conducted.

| Technique
Topical TXA allows for a direct delivery of TXA to the skin and is a good alternative option for people who cannot tolerate oral TXA or those who do not wish to take oral medication for melasma. TXA 5% and 2% are most commonly prescribed. Several studies have been done comparing topical TXA to traditional topical treatment.

| Safety and side effects
Topical TXA is a safe treatment that has been shown to be better tolerated than topical HQ.

| Evidence
One randomized and double-blinded study compared topical TXA 5% to HQ 2% in 60 women over 12 weeks. Participants in both groups were instructed to apply the topical solution twice daily to the affected areas in addition to daily SPF 30. Though the MASI scores decreased significantly in both groups, there was not a significant difference between groups. However, the TXA group reported higher patient satisfaction and fewer side effects than the HQ group. 14 A similar study compared topical TXA 5% solution to HQ 3% cream in 100 participants with skin of color. The participants applied one of the topicals once daily with SPF 30 for 12 weeks. This study found results consistent with the first study, with both groups showing significant improvement in MASI scores, but no significant difference between groups in onset or degree of improvement. They also found that the HQ group experienced a higher incidence of irritation and erythema, leading to significantly higher patient satisfaction in the TXA group. These studies highlight patient satisfaction with the topical formulation of TXA due to its efficacy and fewer side effects than the traditional topical treatment. 15 A split-faced study comparing topical TXA 5% cream twice daily versus HQ 4% cream once daily in addition to SPF 50 found similar results. One hundred patients participated in this trial for 12 weeks.
The hMASI score and the Melasma Quality of Life score significantly improved on both sides of the face, with no significant difference between sides. There was, however, a significant reduction in melanin % surface area on the TXA side shown on biopsy. Both sides had nonsignificant recurrence rates 1 month after cessation of treatment. Similar to other studies, the TXA side reported no side effects, while the HQ side experienced burning, irritation, and postinflammatory hyperpigmentation. 16 Another trial used TXA 2% in both an emulsion and in a sheet mask. Participants were instructed to apply the emulsion twice a day and the mask three times a week for 12 weeks. Twenty-three patients completed the study, and 10 of them consented to a biopsy before and after treatment. There was a significant reduction in mMASI score from baseline and week 4, and week 4 and 8, with Additionally, there was a downtrend in VEGF and endothelin-1, suggesting that topical TXA is effective in decreasing the number of vessels in the dermis and melanogenesis. 17 Cosmeceuticals with skin-lightening properties are often used by patients with skin discoloration. Some studies have investigated the benefits of combining these products with topical TXA. One such study formulated a serum containing 3% TXA, 1% kojic acid, 5% niacinamide, and 5% hydroxyethylpiperazineethane sulfonic acid applied twice daily for 12 weeks in 55 women with mild-moderate melasma. A significant decrease in MASI score was seen as early as 2 weeks after treatment. Ninety percent of patients reported being satisfied with this treatment. The authors hypothesize that the effectiveness of this serum comes from the different mechanisms of action of each drug. Though this was not a controlled trial, this study shows that combining topical TXA with cosmeceuticals is safe and may show results sooner than using TXA alone. 18

| Summary of clinical evidence
Overall, topical TXA is an effective and safe treatment for melasma with fewer side effects than the traditional topical HQ treatment.
HQ treatment is associated with irritation and erythema, and longterm use can cause ochronosis or paradoxical hyperpigmentation.
HQ is sometimes mixed with a topical steroid to combat these side effects, which adds a new set of potential side effects. The studies above highlight the tolerability and patient satisfaction with topical TXA. Topical TXA may lack the same level of efficacy of other methods of TXA; however, topical treatment can often be used in conjunction with other topical medications or cosmeceuticals, making it a useful adjunctive treatment for melasma.

| Technique
Mesotherapy, or intralesional injections, of TXA is the use of small needles to inject TXA into the dermis most commonly at a 4 mg/ml concentration with injections 1 cm apart. The most common concentration for intralesional treatment is 4 mg/ml. The use of intralesional TXA has been shown to be effective in treating melasma.
Benefits to intralesional TXA include direct administration of the target drug and availability of equipment, while disadvantages include limited surface area, increased time to inject, and requirement of a skilled hand ( Table 1).

| Safety and side effects
Adverse effects of injected TXA include pain and burning at the injection sites, erythema, and hypopigmentation. 19 Two cases were re- showed that 4 mg/ml had significantly decreased mMASI scores than the HQ group in weeks 8 and 12. No significant difference was seen between the 10 mg/ml and HQ group, as well as between the 4 mg/ml and 10 mg/ml TXA mMASI scores. Patient satisfaction was significantly higher in the 4 mg/ml group than in the 10 mg/ml group. 22 This study demonstrates the use of intradermal 4 mg/ml TXA as an effective treatment for melasma. While a larger RCTs are needed, this RCT showed better results for intralesional TXA over HQ, the standard of care treatment.
An assessor and analyst-blinded split-faced clinical trial compared intradermal 100 mg/ml TXA+ 4% topical HQ to topical HQ alone in 55 patients (insulin syringe with 30-gauge needle). There were four rounds of TXA injections spaced 4 weeks apart on one side of the face, and participants applied the HQ nightly to the entire face for 12 weeks. After 16 weeks, the MASI score in both groups decreased significantly, with therapeutic outcomes being significantly better in the combined group. Patient satisfaction was also significantly higher in the TXA+ 4% topical HQ group, demonstrating that combining modalities was more effective than HQ monotherapy. 23 Cysteamine 5% cream, an antioxidant and depigmenting molecule, was compared with 4 mg/ml TXA injections in a singleblind RCT of 54 patients (insulin syringe with 28-gauge needle).
Cysteamine was applied nightly for 4 months, and TXA injections were performed every 4 weeks for 2 months. The study found both treatment groups had significant improvement in mMASI scores compared with baseline with no significant differences between groups. However, the cysteamine group reported fewer side effects compared with the TXA injection group. 24 This study demonstrates that while intralesional TXA is an effective treatment, it is more invasive and has a greater risk of side effects.
A nonrandomized controlled trial compared intradermal plateletrich plasma (PRP) injections to 4 mg/ml TXA injections with injections every 4 weeks for 12 weeks (insulin syringe with 30G needle).
The outcome was measured at 24 weeks and showed a significant difference between groups favoring the PRP group, but both groups had a lower mMASI score at 24 weeks. 25 While PRP may be a more effective intradermal treatment, PRP injections are associated with a high cost and RCTs must be done to further evaluate its effectiveness.

| Summary of clinical evidence
Overall, there are high-quality studies and RCTs, demonstrating that 4 mg/ml TXA injections are an effective treatment for melasma. The authors note that intralesional injections are more invasive than traditional topical medications like HQ and cysteamine and can be more time-consuming and painful for the patient.
We recommend that intralesional TXA be used as an adjuvant to topical medications in difficult-to-treat melasma. However, there are limited data on the longevity of the decrease in mMASI scores after injection and maintenance therapy may be needed to upkeep results.

| Technique
Microneedling creates micro-wounds in the skin at a typical depth Microneedling allows for deeper penetration of topical TXA into the dermis in an even manner. Benefits to this method include a relatively quick and noninvasive method for introducing TXA into the skin.

| Safety and side effects
Microneedling with TXA can cause pain, itching, and erythema, which lasts about 1-2 days for most patients. 27 (Table 1).

| Evidence
A double-blind, split-faced RCT compared microneedling topical 5% TXA to microneedling with a placebo in 3 monthly sessions for 20 patients in addition to a topical treatment regimen of 0.5% retinoic acid, 4% hydroquinone, and 0.01% fluocinolone acetonide (polyethylene roll, 1.5 mm needle length). Results showed improvement in both sides with a better, but not significant, improvement in the TXA side using the hemi-MASI scale. 28 Comparatively, another study performed microneedling to the entire face with the application of 10% TXA to one side and distilled water on the other side in 40 patients (dermaroller, 1 mm depth). This was done four times every 2 weeks with a final visit at week 8. Treatment side had a significant improvement in mMASI when compared to the control. 29 A trial in 42 patients compared topical 10% TXA with microneedling to microneedling alone. Each group received six sessions in two-week intervals (dermapen, 1.5 mm needle length). At week 12, the MASI score was significantly reduced in both groups with a significantly greater reduction in the combination group.
In addition, the authors took biopsies of the regions before and after treatment and found reduction in epidermal hyperpigmentation and dermal melanophages in both groups. These studies show that although microneedling alone is efficacious for treating melasma, the addition of topical TXA after microneedling treatment increases the benefits. 30 One study compared the addition of biweekly 4% TXA microneedling to nightly 4% HQ topical treatment versus nightly 4% HQ treatment alone in 50 participants over 8 weeks (dermapen, 1.5 mm needle length). They found that while both groups had significant improvement, there was no statistically significant difference between the two treatment regimens. 31 A similar study compared microneedling with 4% TXA alone to nightly 4% HQ treatment and had the same result. In this study, patient satisfaction was higher than physician satisfaction in both groups (microneedling device, 1.5 needle length). 32 These studies show that there may not be additive effects of microneedling with TXA and using topical HQ.
A third study compared 1.8% liposomal TXA applied topically to microneedling with 5% TXA and had a control group using nightly 2% HQ (stamp-mode electric microneedling, 100 μm depth). They found that the 5% TXA microneedling showed similar improvement to the nightly HQ, whereas the 1.8% liposomal TXA group showed less improvement in melanin index. They also found that the TXA formulations were better than the HQ treatment at reducing inflammation as shown by the erythema index. Given that microneedling has an added cost and requires more frequent office visits, the authors suggest that patients may be more adherent to topical HQ treatment. 33 Vitamin C is another compound that interferes with melanin formation and has been used to decrease hyperpigmentation.
Several studies have compared microneedling TXA with microneedling vitamin C (dermapen, 1.5 mm depth). A split-face study compared TXA versus vitamin C after microneedling every 2 weeks for 12 weeks. Both sides showed significant improvement although there was no significant difference between sides. Interestingly, only the TXA side showed a significant reduction in vascularity by dermoscopy. This may have contributed to increased patient satisfaction with the TXA-treated side. 34 These results were mirrored in another study, which compared microneedling 100 mg/ml TXA with microneedling 20% vitamin C for five sessions over 10 weeks (dermapen, 1.5 mm needle length) They also found that both vitamin C and TXA significantly decreased pigmentation, dark fine granules, and pseudo reticular brown networks, while only TXA significantly reduced vascularization. 35 Another split-face study comparing microneedling 4 mg/ml TXA and 20% vitamin C in 30 patients found that they both showed significant improvement in melasma, with the TXA side having slightly better improvement and higher patient satisfaction by the 8th week (dermaroller, 1.5 mm needle length). 36 Overall, while microneedling with either TXA or vitamin C significantly improves melasma, TXA generally had higher patient satisfaction, which the authors suggest could be due to its ability to reduce vascularity and therefore erythema in the area.
One study compared microneedling PRP to microneedling 4 mg/ ml TXA in 26 patients (microneedling, 1.5 mm needle depth). Both groups showed statistically significant improvement in MASI score, although participants in the PRP group showed greater improvement. By the end of the fourth session, there was a statistically significant difference in MASI score between the groups. There was no significant difference in patient satisfaction or side effects between groups. 37 Another RCT comparing topical 3% TXA with Q-switched Nd:YAG laser to topical 3% TXA with microneedling in 60 patients (dermaroller, 1.5 mm needle length). Each group received five monthly treatments of laser or microneedling with topical TXA along with daily application of TXA. Results from both groups showed a significant reduction in mMASI score (p < 0.001) with no significant difference between groups. 38 A split-faced trial compared the delivery of 4 mg/ml TXA after microneedling and fractional carbon dioxide laser in 30 patients (dermapen, 0.25-1 mm needle length adjusted to skin thickness).
Patients received six biweekly treatments. Two-week postfinal laser session both groups had a significant reduction in mMASI score from baseline with no difference between sides. 39 These studies show that microneedling may be a comparable alternative to laser treatment, especially since there is no long-term follow-up.

| Summary of clinical evidence
Overall, microneedling with topical TXA has been shown to reduce the appearance of melasma. This treatment is less painful than intralesional injections and has additional skin benefits such as reducing the appearance of scarring and wrinkles. Therefore, we suggest using this treatment in patients who may have these other skin concerns in addition to widespread melasma.

| Evidence
Several researchers have directly compared TXA delivery methods in patients with melasma. One RCT compared monthly intralesional therapy (4 mg/ml) and oral therapy (250 mg twice a day) for 3 months.
The 64-person study found that both groups significantly decreased MASI score (Oral p < 0.01, intralesional p = 0.047); however, the oral therapy group had a more significant decrease than the intralesional group (p < 0.001). 40 An additional RCT compared oral therapy (250 mg twice daily) to intralesional injections at both 100 mg/ml and 4 mg/ml concentrations every 2 weeks for 8 weeks with significant decreases in mMASI of all groups. No significant differences were found between groups. 41 A 60-person RCT compared 4 mg/ml bimonthly intralesional injections, 10 mg/ml bimonthly intralesional injections, and topical 10% TXA cream twice daily for 12 weeks. The MASI scores decreased by 39.1% for the 4 mg/ml, 62.7% for the 10 mg/ml group with no significant difference between them (p = 0.070). The topical MASI group decreased by 4.2%, which was significantly different than both intralesional groups. 42 Another RCT compared oral therapy (250 mg twice daily) for 12 weeks to monthly intralesional injections (4 mg/ml) for 3 months.
All groups showed a significant decrease in MASI at 12 weeks with no significant difference between groups. 43 A similar randomized controlled trial compared oral therapy (250 mg twice daily) to topical therapy (unspecified concentration) to an additional group of Modified Kligman's regimen (hydroquinone 2% w/w, tretinoin 0.05% w/w, and fluocinolone 0.01% w/w) for 8 weeks. All three groups had a significant decrease in MASI score at 8 weeks with Modified Kligman's having the largest decrease (30%) followed by oral TXA (25%) and then topical TXA (5%). Of note, the authors described the Modified Kligman's group as having the most adverse effects. 44 Topical TXA can be used with microneedling to achieve a similar result to intralesional injections. Two studies have been done directly comparing intralesional versus microneedling with TXA.
One split-face trial had 56 patients who received intradermal injection of 4 mg/ml TXA on one half of the face and 4 mg/ml TXA with microneedling on the other half. Participants received treatments every 2 weeks for six total sessions. Both sides of the face had mMASI score significantly reduced from baseline with no significant difference between groups. While side effects of pain and erythema were noted in 44.6% of the patients in both groups, all participants completed all six sessions. Pain at the injection site occurred in 42.9% on the injected side, and mild irritation was seen in 19.6% of the microneedling side. However, patient satisfaction was higher for the microneedling side. 45 In another study, 30 patients received microinjections of 4 mg/ ml TXA and 30 received microneedling after topical 4 mg/ml TXA once a month for 3 months. At 20 weeks, both groups had statistically significant endpoints of decreased MASI score; however, the topical TXA microneedling decreased more than the intralesional group (44% versus 36%, but not statistically significant). 27 Neither group experienced severe side effects, but fewer adverse events such as itching and burning were seen in the intralesional group.
These studies highlight the effectiveness of both methods of TXA delivery for melasma and demonstrate that there was not a statistically significant difference in results between the two methods.

| Summary of clinical evidence
These studies indicate that while all delivery methods of TXA decrease the appearance of melasma, oral and intralesional TXA is the most effective while topical TXA is the least effective. When topical TXA is combined with the microneedling technique, its efficacy improves. It is important for providers to discuss the benefits, drawbacks, and efficacy of each method with their patients to determine which may work best for each individual.

| CON CLUS ION
Melasma is a common, difficult-to-treat skin condition with high recurrence rates. TXA is a drug used off-label to combat refractory melasma and comes in topical, intralesional, and oral formulations.
Oral therapy is an effective and safe treatment for melasma with proper screening. While patients may be hesitant to start an oral therapy, intralesional injections and microneedling with topical TXA both have similar efficacy to oral therapy while minimizing systemic side effects. Both methods are effective at reducing the appearance of melasma with similar efficacies and limited adverse reactions.
Microneedling is minimally invasive and relatively painless but may be associated with more itching and irritation and requires purchase of a specific tool. On the contrary, intralesional injections use more universal equipment but require skilled injectors and may be associated with more pain than microneedling and possible hypopigmentation. Topical TXA therapy was the least effective treatment of TXA.
However, this treatment method has minimal side effects and can be combined with other cosmeceuticals for the treatment of melasma.
Clinicians should consider prescribing topical TXA in patients who may not tolerate HQ. Intralesional TXA injections or oral TXA can be utilized as a second-line treatment for refractory or severe melasma or as an alternative to laser/light therapy.
It is important to note that many of the trials did not include further follow-up, so it is difficult to observe the lasting efficacy and long-term safety of these treatments. One limitation of this review is that it is not a comprehensive review and prioritized recent, randomized controlled trials. Further, there is no standard dosing of TXA, and each study used different doses and concentrations, making them difficult to compare. Further randomized and placebocontrolled trials are needed to determine long-term efficacy and safety of each method.

AUTH O R CO NTR I B UTI O N S
HK and EB performed the research and wrote the manuscript. UK and JJ assisted in planning the manuscript and provided necessary edits. KK provided support and essential edits to the manuscript. All authors have read and approved the final manuscript.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this article as no new data were created or analyzed in this study.

E TH I C A L A PPROVA L
Authors declare human ethics approval was not needed for this study.