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| CURRENT BEST EVIDENCE |
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| Year : 2016 | Volume
: 3
| Issue : 2 | Page : 116-121 |
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Current best evidence from pigmentary dermatology
Amanjot Kaur Arora, Muthu S Kumaran MD
Department of Dermatology, Venereology and Leprology, PGIMER, Chandigarh, India
| Date of Web Publication | 27-Dec-2016 |
Correspondence Address:
Dr. Muthu S Kumaran
Associate Professor, Department of Dermatology, Venereology and Leprology, PGIMER, Sector-12, Chandigarh - 160 012
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2349-5847.196306
How to cite this article:
Arora AK, Kumaran MS. Current best evidence from pigmentary dermatology. Pigment Int 2016;3:116-21 |
Xiao BH, Shi M, Chen H, Cui S, Wu Y, Gao XH, et al. Glutathione peroxidase level in patients with vitiligo: A meta-analysis. Biomed Res Int 2016;2016:3029810. doi: 10.1155/2016/3029810
Vitiligo is an idiopathic, acquired pigmentation disorder of skin and/or mucosa, with clinical manifestations of porcelain white patches. It is considered to be a multifactorial and polygenic disease caused by the destruction of melanocytes. Among others, oxidative stress is considered to be one of the causative factors in the pathogenesis of vitiligo. Glutathione peroxidase (Gpx) protects cells from oxidative damage through decreasing lipid hydroperoxides to their corresponding alcohols or reducing free hydrogen peroxide to water. Some researchers reported elevated level, whereas others showed no change or reduced level. Owing to the inconsistent results, this group of researchers did a meta-analysis to clarify the GPx level in vitiligo patients. The PubMed, Cochrane Library, Web of Science, Chinese National Knowledge Infrastructure (CNKI), and Wan Fang Med Online were searched by two independent investigators using the search terms (“vitiligo”) and (“glutathione peroxidase” or “GPx” or “GSH-Px” or “oxidant” or “antioxidant”). Additional potential relevant articles were further retrieved through a manual search of references from original reports. The research dated from the earliest time to December 2015. They sought studies published in English or Chinese. Articles were included in this meta-analysis if (1) the case group consisted of vitiligo patients and the control group included healthy individuals and (2) the outcome measures reported quantitative GPx level (mean ± standard deviation). A study was excluded if it (1) was an animal or in vitro experiment, (2) was a case report or a review, and (3) consisted of duplicate data with other study. All studies were deliberately reviewed by two investigators to decide whether to be included. The standard mean difference (SMD) for the effect and corresponding 95% confidence intervals (s) were calculated from the original data. Twenty-three studies with a total of 1076 vitiligo patients and 770 healthy controls were included. The pooled meta-analysis showed that patients with vitiligo had equivalent levels of GPx with the healthy controls (SMD = −0.47, 95% CI: −1.03 to 0.08). Further, subgroup analysis showed that the GPx levels of Asian patients or segmental vitiligo patients were, respectively, lower than those of healthy controls (Asian: SMD = −0.47, 95% CI: −1.08 to 0.14, and; segmental: SMD = −3.59, 95% CI: −6.38 to −0.80, and P = 0.012). This meta-analysis showed a significant association between low GPx level and vitiligo.
Comment
Oxidative stress-inducing vitiligo is based on the fact that some intermediates such as 3,4-dihydroxyphenylalanine (DOPA), dopachrome, and 5,6-dihydroxyindole are created during melanin biosynthesis. The final result of these changes is the continuous increase of hydrogen peroxide (H2O2), which strains the antioxidative enzyme activity leading to the destruction of melanocytes. Therefore, antioxidants are important to nullify the harmful radical-mediated reactions. GPx is a group of antioxidative markers against free radicals by detoxification and has been considered to be involved in the pathogenesis of many skin diseases. The results of the above study are intriguing and at the same time controversial. First, as melanogenesis occurs in skin it is desirable that glutathione activity/levels are measured in the skin rather than in blood/serum. However, only 4 out of 23 studies measured the levels in skin and showed higher levels of GPx activity in patients’ skin compared to controls. Also, there was much heterogeneity in the samples studied, which included blood, serum, blister fluid, and skin thus, making the comparison between studies disputable. Second, various different methods 1: Paglia and Valentine’s method (1967); 2: flameless atomic absorption (graphite furnace) method; 3: DTNB colorimetry; 4: Lawrence and Burk’s method (1976); 5: Najwa’s method (1990); 6: Paglia’s method (2002); 7: Beutler’s method (1989) were used to analyze enzyme activity, which makes the comparison between different studies questionable as there is no consensus if the enzyme activity measured by all these methods are comparable. Third, this study concluded that there are lower levels of GPx in Asians whereas those in Caucasians are similar to controls. This is a new concept indicating a racial difference in the pathogenesis of vitiligo but with such heterogeneity in the samples and methods of measurement, this claim should be accepted with a pinch of salt. Fourth, nothing has been mentioned about allelic heterogeneity in genes determining glutathione peroxidase levels among patients, controls, and different races. Lastly, limited number of studies, small sample sizes of the studies included, and methodological diversities weaken the statistical power of this analysis. More studies with larger sample size and of higher quality should be done to verify the conclusions of this study.
Lee HC, Thng TG, Goh CL. Oral tranexamic acid (TA) in the treatment of melasma: A retrospective analysis. J Am Acad Dermatol 2016;75:385-92
Melasma is a common pigmentary disorder among Asians and treatment is challenging. Its exact pathogenesis remains unknown, but it has been hypothesized to be induced by biologically active melanocytes. Genetic predisposition has been noted in several studies. Other studies have found increased vascularity in affected skin and increased expression of angiogenic factors in the epidermis that may play a role in the pathogenesis of melasma. Tranexamic acid (TA), a synthetic derivative of lysine, has been commonly used as a hemostatic agent. In recent years, off-label oral TA has emerged as potential treatment for melasma. However, large-scale studies on the use of oral TA in melasma are limited. This study was a retrospective analysis conducted in a tertiary dermatologic center on Asian patients from January 2010 to June 2014 to review the clinical characteristics of melasma and treatment outcomes along with adverse effects of treatment with oral TA. A total of 561 patients (91.4% female, 8.6% male) were enrolled. Median duration of treatment was 4 months (range 0.03–22 months), during which the patients were given oral TA 250 mg twice a day whereas the duration of follow-up was a median of 7 months (range 1–48 months). The majority (503 [89.7%]) improved, 56 (10.0%) had no improvement, and two (0.4%) worsened. Patients without family history of melasma had better response rates than those with family history (90.6% vs 60.0%, P = 0.01). Those cases with an older age of onset and longer duration of melasma also had better response rates (P < 0.05). Of the 503 who improved, response was seen within 2 months of TA initiation, with a relapse rate of 27.2%. Adverse events occurred in 40 (7.1%). Most were transient, but one developed deep vein thrombosis requiring prompt discontinuation. She was later given the diagnosis of familial protein S deficiency.
Comment
Melasma is a common disorder of Asians, with a female preponderance. This condition can be psychologically distressing, and although various treatment modalities can be offered, no mode of treatment guarantees satisfactory results. Treatment remains a challenge, and the search for safe and effective therapy continues. The exact pathogenesis of melasma is unclear, but genetic influences, sun exposure, and hormonal therapy have been reported as possible causative factors. Increased dermal vascularity and expression of angiogenic factors seem to play a role in melasma, and have remained important areas of interest in pigment research. The most plausible mechanism of action of TA in melasma is inhibition of melanin synthesis by inhibition of plasminogen/plasmin pathway, thereby blocking the interaction between melanocytes and keratinocytes. This particular study highlights the use of oral TA as an adjuvant for the treatment of melasma as in the majority (98.2%) of their patients oral TA was used with various combinations of topical treatment, which included tretinoin, triple combination, and hydroquinone. These topical medications are known to effectively treat melasma on their own and their use in combination with oral TA could be responsible for such great results with oral TA. In only 10 patients, oral TA was used as a monotherapy, which is too small a number to assess the actual efficacy of TA for the treatment of melasma. This study also highlights the importance of ruling out any risk for thromboembolic disorders by taking a detailed personal and family history and necessary investigations. Being a retrospective study, this study had several limitations. The duration of treatment and follow-up were not standardized and also no objective score for measuring improvement in pigmentation such as the Melasma Area and Severity Index score and no pigment measuring device was used. A prospective, randomized controlled trial should be done to address these limitations and to evaluate the efficacy and safety of oral TA in melasma.
MÕry-Bossard L, Bagny K, Chaby G, Khemis A, Maccari F, Marotte H, et al. New-onset vitiligo and progression of pre-existing vitiligo during treatment with biological agents in chronic inflammatory diseases. J Eur Acad Dermatol Venereol 2016. doi: 10.1111/jdv.13759. [Epub ahead of print]
Various biological agents such as tumor necrosis factor alpha (TNFα) inhibitors, anti-lymphocyte B (rituximab), and co-stimulatory blockers have been used for many years in the treatment of different chronic inflammatory diseases. More recently, biological therapies targeting the Th17/IL-12/23 pathway have been developed and ustekinumab, an anti-p40 IL-12/23 product, is currently on the market for the treatment of psoriasis and psoriatic arthritis. This study was undertaken to describe the clinical characteristics and evolution of patients developing new-onset vitiligo following initiation of a biological agent for chronic inflammatory disease and also to report the clinical course of pre-existing vitiligo. It was a retrospective, multicentre study, conducted between July 2013 and January 2015, which described the characteristics of 18 patients who developed new-onset vitiligo while receiving a biological agent. TNFα inhibitors were the most common biological agent involved (13/18) while anti-IL-12/23 and anti-IL-17 agents or abatacept were less common (4/18 and 1/18 respectively). Non-segmental vitiligo was diagnosed in 17 patients and leucotrichia in one. No patient had any previous personal/family history of depigmenting or thyroid disease but one had developed paradoxical psoriasis during a previous course of biological treatment. Mean duration of biological agent exposure before vitiligo onset was 13.9 ± 16.5 months. Fifteen out of 18 patients (83.3%) experienced stabilization or partial repigmentation, while the skin disease progressed in two cases. Outcome was favorable for most patients (15/17) while maintaining the biological agent. Data were also collected for 18 patients who had pre-existing vitiligo when treatment with a biological agent was started (TNFα inhibitors N = 15, ustekinumab N = 1, rituximab N = 1, tocilizumab N = 1). Vitiligo progressed in seven patients and was stable or improved in eight cases. Thus, vitiligo may emerge and/or progress during treatment with various biological agents, mainly TNFα inhibitors and could be a new paradoxical skin reaction. De novo vitiligo displays a favorable outcome when maintaining the biological agent, whereas the prognosis seems worse in cases of pre-existing vitiligo.
Comment
Biologics have been used for many years in the treatment of different chronic inflammatory diseases including inflammatory bowel diseases, inflammatory rheumatic diseases, and psoriasis. All these different biological agents have been associated with various adverse events affecting the skin, with a frequency ranging from 10 to 60%. The development of new-onset vitiligo upon initiation of a biological agent is an unusual event and only a few isolated cases have been reported so far. Also, biological agents given for an autoimmune disease may potentially influence the outcome of pre-existing vitiligo. In this particular study, TNFα inhibitors, particularly the monoclonal antibodies, were the most common biological agents involved in the causation of both de-novo vitiligo as well as worsening of pre-existing vitiligo. Associated inflammatory conditions and a family history of depigmenting disorder were more often observed in patients with pre-existing vitiligo. , the exact pathogenesis of the mechanism, by which a biological agent may be associated with the development/progression of vitiligo is unknown as TNFα is a pro-inflammatory cytokine that plays a central role in the pathogenesis of vitiligo and its blockade should ideally improve vitiligo. On the contrary, results on the effects of TNFα inhibitors in patients with vitiligo are not convincing. Indeed, small series of patients receiving infliximab, adalimumab, or etanercept showed no or mild improvement of depigmenting lesions. The underlying mechanisms for explaining this unexpected reaction are that the biological agent may lead to local changes in the cytokine balance and/or activation of alternative pathways such as type I interferon, as is described for TNFα induced psoriatic lesions. A dual role for TNFα inhibitors on Th1/Th2 cytokine balance has been reported in spondyloarthritis, reducing (infliximab) or enhancing (etanercept) IFN γ production. IFN γ signal transduction occurs through JAK1/2, and IFN γ induces the expression of CXCL10 chemokine in keratinocytes that can interact with CXCR3 on autoreactive CD8+ T cells. The IFN γ/JAK 1/3/chemokine CXCL10-CRCX3 pathway seems to be a key determinant in vitiligo development. NALP1 genetic variants have been linked to vitiligo and thus, another hypothesis is that the biological agent may interfere with innate immunity in selected and genetically predisposed patients. Larger studies are required to know the exact incidence of this ironical cutaneous side effect of biologics along with insights into the molecular pathogenesis of this side effect.
Muthu SK, Narang T, Saikia UN, Kanwar AJ, Parsad D, Dogra S. Low-dose oral isotretinoin therapy in lichen planus pigmentosus: An open-label non-randomized prospective pilot study. Int J Dermatol 2016;55:1048-54.
Lichen planus pigmentosus (LPP) is a cosmetically distressing pigmentary disorder often posing a therapeutic challenge. Various therapeutic modalities such as topical tacrolimus, topical and systemic corticosteroids, high doses of vitamin A, and lasers have been tried, giving generally poor outcomes. Isotretinoin has been shown to be effective in oral and cutaneous LP, but its role in LPP is yet unknown. This study was conducted to evaluate the efficacy and safety of isotretinoin in the management of LPP. In this prospective study, 32 clinically and histologically proven patients with LPP were recruited. Subjects were treated with fixed low-dose (20 mg/day) oral isotretinoin once daily for 6 months along with topical sunscreens. Response was graded as mild (<25%), moderate (26–50%), and good (>50%) improvement based on decrease in intensity and progression of hyperpigmentation. Twenty-seven patients (17 females and 10 males), aged 20–62 years, completed the study. Twenty-three (85.2%) patients had active disease and pruritus at presentation. Treatment outcome was moderate improvement in 15 patients (55.7%) followed by good in seven (21.8%) and mild in two (6.2%). Pruritus subsided at the earliest at 9–14 days, and disease stabilized by 4–6 weeks in treatment-responsive patients. Patients with a shorter duration (≤5 years) of disease and limited body area involvement had a better outcome. Thus, in this study, low-dose isotretinoin seems to be a promising treatment modality in stabilizing and decreasing the pigmentation in LPP particularly in early and limited disease.
Comment
Lichen planus pigmentosus (LPP) is considered an infrequent variant of LP clinically characterized by insidious onset of discrete, ill-defined, dark brown, or slate gray macules, primarily appearing over sun-exposed areas and flexures. Pruritus may be present in the early active stage, and disease often runs a prolonged clinical course. LPP is frequently reported in Indians, recently described among Latin Americans, Middle Easterners, Koreans, and Japanese. Many studies have demonstrated a female preponderance, which makes it a bigger cosmetic challenge. However, there is dearth of evidence regarding any effective therapy for LPP. In this study, isotretinoin was used with fairly good results in the treatment of LPP. An effective treatment for LPP is lacking and even 40 years after its initial description, treatment of LPP usually remains unrewarding. Topical isotretinoin has been shown to cause histopathological amelioration of keratin thickness, preservation of the basement membrane zone, and lymphophagocytic infiltrate. Also it has been demonstrated that there is reduced immunostaining for S100 and HLA DR in such patients indicating a reduction in Langerhans cells and immunocompetent cells in the same study. Another study had shown a significant rise of Ki67 and bcl-2 levels and a decrease of apoptotic bodies on immunohistochemical studies of patients with oral LP treated with 0.1% topical isotretinoin. Hence, isotretinoin is believed to act through various immunomodulatory and anti-inflammatory effects explained above, thus stabilizing the disease. Although most of the patients noted a moderate decrease in the intensity of color, none of our patients experienced a complete clearance of hyperpigmentation. Maximum improvement (75%) in pigmentation was noted in three patients with facial and neck lesions. This study was a nonblinded study and thus there could be an observer bias while reporting results. Also, this study had a very short duration of follow-up of 3 months post stopping drug therapy, which is too short for this chronically relapsing disease to advocate the ability of this drug to stabilize the disease process and to establish the sustainability of the results achieved. Also, larger randomized controlled studies with longer follow-ups are required to establish the role of isotretinoin in the management of this enigmatic pigmentary disorder.
Wang P, Li Y, Nie H, Zhang X, Shao Q, Hou X, et al. The changes of gene expression profiling between segmental vitiligo, generalized vitiligo and healthy individual. J Dermatol Sci 2016. pii: S0923-1811(16)30153-0.
Vitiligo is a common acquired depigmenting skin disease characterized by loss or dysfunction of melanocytes within the skin lesion, but its pathogenesis is far from lucid. The gene expression profiling of segmental vitiligo (SV) and generalized vitiligo (GV) need further investigation for a better understanding of the common and distinct factors, especially in view of gene expression profile, which are involved in the disease development and maintenance. In this study, peripheral blood samples were collected from SV, GV, and healthy individual (HI) with each group containing 20 samples followed by leukocytes separation and total RNA extraction. The high-throughput whole genome expression microarrays were used to assay the gene expression profiles among HI, SV, and GV. Bioinformatics tools were employed to annotate the biological function of differently expressed genes. Quantitative PCR assay was used to validate the gene expression of array. Compared to HI, 239 over-expressed genes and 175 down-expressed genes were detected in SV, 688 over-expressed genes and 560 down-expressed genes were found in GV, following the criteria of log2 (fold change) ≥0.585 and P value <0.05. In these differently expressed genes, 60 over-expressed genes and 60 down-expressed genes had similar tendency in SV and GV. Compared to SV, 223 genes were up regulated and 129 genes were down regulated in GV. It is reported that the change of cellular immunity is involved in the pathogenesis of GV. Infiltrated T-cells express activator factor and subsequently cause melanocyte death and depigmentation. CD4+ regulatory T-cells (Tregs) expressing cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) regulate auto-aggressive T-cells and regulate the autoimmune response, which Tregs restraining lead to melanocyte killing by CTLs. Parts genes such as HLA-DRB5 and KIR3DS1 involved in above processes were found in the GV but not in the SV group, which suggests that the immune system plays a more important role in GV than SV during the melanocyte dysfunction. Autophagy is essential in the pathogenesis of vitiligo. Compared to HI, they found that fourteen differently expressed genes were involved in the process of autophagy and its regulation. While in the SV with HI as control, only one gene of PAFAH1B2 was differently expressed, which implied that autophagy is crucial for the pathogenesis of GV, but not SV. Numerous differently expressed genes were involved in the apoptosis process in the GV. Different from GV, there were hardly any apoptosis process related genes differently expressed in SV compared to HI, which implied that apoptosis process plays an important role in GV but not in SV. They also found that several up-expressed genes in SV and GV were involved in the oxidoreductase activity. Their results also suggested that CXCL10 may play an important role in progression of vitiligo especially in SV. Twelve genes were involved in the ubiquitin mediated proteolysis while in the SV group, only two genes were up-regulated, which suggested that protein degradation plays different role in SV and GV. This study also concluded that the tyrosine metabolism process may play an important role in the pathogenesis and maintenance of GV, but not SV. The above results suggested that GV and SV not only shared part bio-process and signal pathway, but more importantly, they utilized different biological mechanisms in their pathogenesis and maintenance.
Comment
Vitiligo is a complex depigmenting skin disease with loss or dysfunction of melanocytes within the skin lesions. The etiology of vitiligo is multifactorial, which includes immune, genetic, metabolic, neuro-hormonal, cytotoxic, oxidative stress, and environmental factors. Four major hypotheses are involved in the pathomechanism of vitiligo, which include autoimmune, neural, biochemical, and impaired redox status hypothesis. The autoimmune hypothesis mainly accounts for the pathogenesis of GV. A number of differently expressed genes among SV, GV, and HI are involved in the Toll-like receptor signaling pathway, B and T cell differentiation, lymphocyte proliferation and activation of immune response. The above study provided a comprehensive view on the difference in gene expression between SV and GV especially in leukocytes, and may facilitate the future study on their molecular mechanism and therapeutic targets. It was interesting to know that the regulation of adaptive immune response was an important component of immune process in SV; however, in the GV numerous genes were involved in the regulation of innate immune response, B cell differentiation, and activation. On comparing SV with HI as control, the differently expressed genes were mainly involved in the adaptive immune response, cytokine–cytokine receptor interaction, chemokine signaling, focal adhesion, and sphingolipid metabolism. The differently expressed genes between GV and HI were mainly involved in the innate immunity, autophagy, apoptosis, melanocyte biology, ubiquitin mediated proteolysis, and tyrosine metabolism, which was different from SV. Though larger studies are required to further confirm the results of the above study, this study is a milestone in itself to understand the different behaviors, pathogenesis and prognosis of two opposite poles of vitiligo and thus can form pillars to develop different targeted therapies as per the pathogenesis for the two subtypes. With further understanding of genetics in vitiligo it might be possible to find out the precise genetic aberration in a particular patient and choose a particular targeted therapy for an individual patient. Also it might be possible to consider gene therapy for such patients in future.
Sarkar R, Garg V, Bansal S, Sethi S, Gupta C. Comparative evaluation of efficacy and tolerability of glycolic acid, salicylic mandelic acid, and phytic acid combination peels in melasma. Dermatol Surg 2016;42:384-91.
Melasma is an acquired symmetric hypermelanosis characterized by light-to-deep brown pigmentation over cheeks, forehead, upper lip, and nose. Treatment of this condition is difficult and associated with high recurrence rates. Chemical peels have become a popular modality in the treatment of melasma. However, there is a lack of good studies comparing the efficacy of various peels in treatment of melasma. This study was undertaken to compare the efficacy of glycolic acid (GA) with combination peels such as salicylic-mandelic (SM) acid and phytic acid in treatment of melasma in Type IV and Type V skin. Ninety patients diagnosed with melasma were randomly assigned into three groups of 30 patients each. Group A received GA (GA − 35%) peel, Group B received SM acid, and Group C received phytic combination peels. Each group was primed with 4% hydroquinone and 0.05% tretinoin cream for 4 weeks before treatment. Chemical peeling was done after every 14 days in all groups until 12 weeks and patients were followed up for 8 more weeks after that. Clinical evaluation using melasma area and severity index (MASI) score and photography was recorded at every visit and follow-up was done until 20 weeks. There was a decrease in MASI score in all three groups but it was statistically significantly lower in Group A than Group C (P = 0.00), and it was also statistically significantly lower in Group B than Group C (P = 0.00) but there was no statistically significant difference between Groups A and B (P = 0.876). Objective response to treatment evaluated by reduction in MASI scoring after 12 weeks was 62.36% reduction in GA group, 60.98% reduction in SM group, and 44.71% in phytic acid group. They concluded that GA (35%) and SM acid peels are both equally efficacious and a safe treatment modality for melasma in Indian skin, and are more effective than phytic acid peels. Salicylic mandelic peels are better tolerated and more suitable for Indian skin.
Comment
Melasma remains a great therapeutic challenge to dermatologists despite extensive research into the etiology, pathogenesis, and possible treatment options for melasma. Lack of good quality trials make it even more challenging to choose a particular treatment option over the other and those that exist deal with fairer skin types. Chemical peels are very popular these days with walk in patients sometimes asking for chemical peels straight away and paucity of data on comparison of various peels especially in skin of color make it difficult to advocate a particular peel in preference to others. This study can help various dermatologists in choosing chemical peels for melasma patients particularly in Type IV and V skin in whom melasma is commoner and also more difficult to treat. However, there were a few limitations in this study such as uneven distribution of types of melasma in three groups due to which a higher ratio of mixed melasma was allotted in phytic group which might have skewed the results in favor of GA and SM peel. There was no patient with indeterminate or dermal melasma in this study, which is very resistant to treatment. Also in all the groups, although the MASI decreased with peeling till 12 weeks but it increased from thereon during the 8-week follow-up when peeling was stopped. The average MASI score in the GA group decreased from 12.59 ± 7.58 at baseline to 4.56 ± 2.98 at 12 weeks and 7.28 ± 3.890 at 20 weeks. In the SM acid group, the average MASI score decreased from 11.85 ± 7.4 at baseline to 4.37 ± 3.01 at 12 weeks and 6.52 at 20 weeks. In the phytic acid combination peel group, the average MASI score at baseline decreased from 11.04 ± 5.32 to 6.14 ± 3.18 at 12 weeks and 7.83 ± 3.97 at 20 weeks. Thus studies with longer follow-ups are required to understand fully the duration of efficacy of these peels and the need for and frequency of maintenance sittings. Also, a combination with a self-applied topical at home would have been a more real life scenario but could have hampered the interpretation of results. However, such combinations might help in maintaining the remission achieved, for a longer duration.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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