Systemic and local effect of oxidative stress on recurrent aphthous stomatitis: systematic review.

Recurrent aphthous stomatitis (RAS) is a chronic and recurrent inflammatory disease of the mouth. It is characterised by the appearance of painful ulcers in the oral mucosa. RAS is believed to be a multifactorial disease with genetic predisposition, environmental factors and alterations in the immune system. Oxidative stress, caused by an imbalance between free radicals and the antioxidant system, also appears to be involved in the pathogenesis of RAS. Several risk factors, such as smoking, iron and vitamin deficiency and anxiety, may contribute to the development of the disease. Understanding the underlying mechanisms may help in the prevention and treatment of RAS. We searched PubMed, Scopus and Web of Science databases for articles on oxidative stress in patients with RAS from 2000 to 2023. Studies analysing oxidant and antioxidant levels in the blood and saliva of RAS patients and healthy controls were selected. Of 170 potentially eligible articles, 24 met the inclusion criteria: 11 studies on blood samples, 6 on salivary samples and 7 on both blood and salivary samples. Multiple oxidative and antioxidant markers were assessed in blood and saliva samples. Overall, statistically significant differences were found between RAS patients and healthy controls for most markers. In addition, increased oxidative DNA damage was observed in patients with RAS. Patients with RAS show elevated levels of oxidative stress compared to healthy controls, with a significant increase in oxidative markers and a significant decrease in antioxidant defences in saliva and blood samples.

Exploring the complex relationships between coping strategies, locus of control and self-esteem with psychopathology: structural equation modeling with a special focus on clinical high-risk of psychosis.

BACKGROUND: Coping strategies, competence, and locus of control (LOC) beliefs are important predictors of mental health (MH). However, research into their complex interactions has produced mixed results. Our study investigated them further in the previously unexplored context of clinical high-risk (CHR) of psychosis. METHODS: We tested six alternative structural equation models in a community sample (N = 523), hypothesizing a mediating role of coping and treating CHR symptoms as (i) an additional mediator or (ii) a specific outcome. Our measurement model included two latent factors of MH: (1) psychopathology (PP), consisting of presence of mental disorders, global and psychosocial functioning, and (2) self-rated health (SRH) status. RESULTS: In the model with the best Akaike Information Criterion and the latent factors as outcome variables, maladaptive coping completely mediated the impact of maladaptive LOC on PP and SRH. Additionally, CHR symptoms partially mediated the effect of maladaptive coping on PP and SRH in the community sample, as long as sex was not entered into the model. In the clinical sample (N = 371), the model did not support a mediation by CHR symptoms, despite significant pathways with both coping and MH outcomes; further, competence beliefs directly impacted SRH. CONCLUSIONS: Coping strategies are an important intervention target for MH promotion, especially in the community. In clinical populations, interventions focusing on coping strategies may improve CHR symptoms, thus potentially supporting better MH, especially SRH. Additionally, due to their mostly cascading effects on MH, improving competence and LOC beliefs may also promote psychological well-being.

In Silico and In Vitro Analysis of IL36RN Alterations Reveals Critical Residues for the Function of the Interleukin-36 Receptor Complex.

Generalized pustular psoriasis is a potentially life-threatening skin disease, associated with IL36RN disease alleles. IL36RN encodes the IL-36 receptor antagonist (IL-36Ra), a protein that downregulates the activity of IL-36 cytokines by blocking their receptor (IL-36R). Although generalized pustular psoriasis can be treated with IL-36R inhibitors, the structural underpinnings of the IL-36Ra/IL-36R interaction remain poorly understood. In this study, we sought to address this question by systematically investigating the effects of IL36RN sequence changes. We experimentally characterized the effects of 30 IL36RN variants on protein stability. In parallel, we used a machinelearning tool (Rhapsody) to analyze the IL-36Ra three-dimensional structure and predict the impact of all possible amino acid substitutions. This integrated approach identified 21 amino acids that are essential for IL-36Ra stability. We next investigated the effects of IL36RN changes on IL-36Ra/IL-36R binding and IL-36R signaling. Combining invitro assays and machine learning with a second program (mCSM), we identified 13 amino acids that are critical for IL-36Ra/IL36R engagement. Finally, we experimentally validated three representative predictions, further confirming the reliability of Rhapsody and mCSM. These findings shed light on the structural determinants of IL-36Ra activity, with potential to facilitate the design of new IL-36 inhibitors and aid the interpretation of IL36RN variants in diagnostic settings.

Real-World Implementation and Outcomes of Adalimumab Therapeutic Drug Monitoring in Psoriasis: A National Specialized Center Experience.

Serum adalimumab concentration is a biomarker of treatment response but therapeutic drug monitoring (TDM) is yet to be implemented in routine psoriasis care. We incorporated adalimumab TDM in a national specialized psoriasis service and evaluated it using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, and Maintenance) implementation science framework. We undertook pre-implementation planning (validating local assays) and implementation interventions targeted to patients (pragmatic sampling at routine reviews), clinicians (introduction of a TDM protocol), and healthcare systems (adalimumab TDM as a key performance indicator). Over 5 months, 170 of 229 (74%) individuals treated with adalimumab received TDM. Clinical improvement after TDM-guided dose escalation occurred in 13 of 15 (87%) nonresponders with serum drug concentrations <8.3 µg/ml (median PASI reduction of 3.2 [interquartile range = 2.2-8.2] after 23.4 weeks) and in all nonresponders who had TDM-guided switch in biologic due to supratherapeutic drug concentrations (>8.3 µg/ml; n = 2) or positive antidrug antibody (n = 2) (PASI reduction of 7.8 [interquartile range = 7.5-12.9] after 20.0 weeks). Proactive TDM led to dose reduction in five individuals with clear skin and subtherapeutic or supratherapeutic drug concentrations; four (80%) sustained clear skin after 50 weeks (range = 42-52). Adalimumab TDM based on pragmatic serum sampling is clinically viable and may lead to patient benefit. Context-specific implementation interventions and systematic implementation assessment may bridge the biomarker research-to-practice gap.

Fish Erythrocyte Extracellular Traps (FEETs) are an evolutionarily conserved cellular process triggered by different stimuli.

Fish erythrocytes remain nucleated, unlike mammalian erythrocytes that undergo enucleation during maturation. Besides oxygen transport, fish erythrocytes are capable of several immune defence processes and thus these cells are candidates for carrying out ETotic responses. ETosis is an evolutionarily conserved innate immune defence process found in both vertebrates and invertebrates, which involves the extrusion of DNA studded with antimicrobial effector proteins into the extracellular space that traps and kills microorganisms. In this present report, we demonstrate that erythrocytes from Danio rerio (zebrafish) produce ETotic-like responses when exposed to both chemical and physiological inducers of ETosis. Furthermore, erythrocytes from Salmo salar (Atlantic salmon) behaved in a similar way. We have termed these ET-like formations, as Fish Erythrocyte Extracellular Traps (FEETs). Several inducers of mammalian ETosis, such as the protein kinase C (PKC) activator phorbol 12-myristate 13-acetate (PMA) and the calcium ionophore ionomycin, induced FEETs. Moreover, we found that FEETs depend on the activation of PKC and generation of mitochondrial reactive oxygen species (mROS). This present report is the first demonstration that fish erythrocytes can exhibit ETotic-like responses, unveiling a previously unknown function, which sheds new light on the innate immune arsenal of these cells.

An Inhaled Galectin-3 Inhibitor in COVID-19 Pneumonitis: A Phase Ib/IIa Randomized Controlled Clinical Trial (DEFINE).

Rationale: High circulating galectin-3 is associated with poor outcomes in patients with coronavirus disease (COVID-19). We hypothesized that GB0139, a potent inhaled thiodigalactoside galectin-3 inhibitor with antiinflammatory and antifibrotic actions, would be safely and effectively delivered in COVID-19 pneumonitis. Objectives: Primary outcomes were safety and tolerability of inhaled GB0139 as an add-on therapy for patients hospitalized with COVID-19 pneumonitis. Methods: We present the findings of two arms of a phase Ib/IIa randomized controlled platform trial in hospitalized patients with confirmed COVID-19 pneumonitis. Patients received standard of care (SoC) or SoC plus 10 mg inhaled GB0139 twice daily for 48 hours, then once daily for up to 14 days or discharge. Measurements and Main Results: Data are reported from 41 patients, 20 of which were assigned randomly to receive GB0139. Primary outcomes: the GB0139 group experienced no treatment-related serious adverse events. Incidences of adverse events were similar between treatment arms (40 with GB0139 + SoC vs. 35 with SoC). Secondary outcomes: plasma GB0139 was measurable in all patients after inhaled exposure and demonstrated target engagement with decreased circulating galectin (overall treatment effect post-hoc analysis of covariance [ANCOVA] over days 2-7; P = 0.0099 vs. SoC). Plasma biomarkers associated with inflammation, fibrosis, coagulopathy, and major organ function were evaluated. Conclusions: In COVID-19 pneumonitis, inhaled GB0139 was well-tolerated and achieved clinically relevant plasma concentrations with target engagement. The data support larger clinical trials to determine clinical efficacy. Clinical trial registered with ClinicalTrials.gov (NCT04473053) and EudraCT (2020-002230-32).

Outcomes of Locally Advanced Rectal Cancer Patients Treated with Total Neoadjuvant Treatment: A Meta-Anaysis of Randomized Controlled Trials.

BACKGROUND & AIMS: Determining outcomes using the total neoadjuvant therapy (TNT) in patients with local advanced rectal cancer is important for stratifying patients according to expected outcomes in future studies in the era of treatment combination. The present meta-analysis estimated the pathological complete response, disease-free survival, and overall survival probabilities of rectal cancer patients and identified predictors of outcomes. METHODS: Studies reporting pathological complete response rate and time-dependent outcomes (progression or death) after total neoadjuvant treatment of locally advanced rectal cancer (LARC) were identified in MEDLINE through January 2022. Three independent observers extracted data on patient populations and outcomes and combined the data using a distribution-free summary survival curve. The primary outcomes were actuarial probabilities of recurrence and survival. RESULTS: Fourteen RCTs, including 18 TNT arms, met the inclusion criteria. The pooled estimate of pathological complete response (pCR) probability was 23.6%, with moderate heterogeneity between studies. The pooled estimates of actuarial disease-free survival rate were 70.6% at 3 years and 65.4% at 5 years. The pooled estimates of actuarial survival rates were 93% at 3 years and 81.6% at 5 years. In both these outcomes, heterogeneity between studies was highly significant. CONCLUSION: This meta-analysis showed that Total Neoadjuvant Therapy is an optimal approach for LARC patients. The results provide a useful benchmark for future comparisons of the benefits of combinations of other drug families as target therapies or immunotherapies.

Low fat diet versus low carbohydrate diet for management of non-alcohol fatty liver disease: A systematic review.

Although there is a consensus on beneficial effects of a low calorie diet in management of non-alcoholic fatty liver disease, the optimal composition of diet has not yet been elucidated. The aim of this review is to summarize the results of current randomized controlled trials evaluating the effects of low fat diet (LFD) vs. low carbohydrate diet (LCD) on NAFLD. This is a systematic review of all the available data reported in published clinical trials up to February 2022. The methodological quality of eligible studies was assessed, and data were presented aiming specific standard measurements. A total of 15 clinical trial studies were included in this systematic review. There is an overall lack of consensus on which dietary intervention is the most beneficial for NAFLD patients. There is also an overall lack of consensus on the definition of the different restrictive diets and the percentage of macronutrient restriction recommended. It seems that low calorie diets, regardless of their fat and carbohydrate composition, are efficient for liver enzyme reduction. Both LCD and LFD have similar effects on liver enzymes change; however, this improvement tends to be more marked in LFD. All calorie restrictive dietary interventions are beneficial for reducing weight, liver fat content and liver enzymes in individuals with NAFLD. Low fat diets seem to be markedly successful in reducing transaminase levels. Further research is needed to explore diet intensity, duration and long-term outcome.

A Systematic Review and a Meta-analysis of Randomized Controlled Trials' Control Groups in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

PURPOSE OF REVIEW: Determining the risk for progression or survival after standard androgen deprivation treatment (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) is essential for stratifying patients according to expected outcomes in future studies of treatment combination. This systematic review and meta-analysis aims to estimate the progression-free survival (PFS) and overall survival (OS) probabilities in the control group of randomized controlled trials (RCTs) of different regimens of standard androgen deprivation treatment (ADT) in mHSPC and to identify possible predictors of outcomes. RECENT FINDINGS: Studies reporting time-dependent outcomes (progression or death) after standard ADT treatment of mHSPC were searched in MEDLINE, CANCERLIT, the Cochrane Controlled Trials Register, and the Cochrane Library from inception through June 2021. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using a distribution-free summary survival curve. Primary outcomes were actuarial probabilities of disease progression and survival. Fifteen studies met the inclusion criteria. The pooled estimate of the actuarial PFS rate was 35.2% at two years. The pooled actuarial OS rate was 62.5% at three years. Heterogeneity among studies was highly significant for all outcomes. By univariate meta-regression analyses, high-volume disease and the presence of visceral metastases were associated with shorter survival. Our findings show that PFS and OS are highly variable in patients with mHSPC treated with ADT, providing a helpful benchmark for indirect comparisons of the benefits of the combination of chemotherapy and second-generation hormonotherapy.

Randomised controlled trial of intravenous nafamostat mesylate in COVID pneumonitis: Phase 1b/2a experimental study to investigate safety, Pharmacokinetics and Pharmacodynamics.

BACKGROUND: Many repurposed drugs have progressed rapidly to Phase 2 and 3 trials in COVID19 without characterisation of Pharmacokinetics /Pharmacodynamics including safety data. One such drug is nafamostat mesylate. METHODS: We present the findings of a phase Ib/IIa open label, platform randomised controlled trial of intravenous nafamostat in hospitalised patients with confirmed COVID-19 pneumonitis. Patients were assigned randomly to standard of care (SoC), nafamostat or an alternative therapy. Nafamostat was administered as an intravenous infusion at a dose of 0.2 mg/kg/h for a maximum of seven days. The analysis population included those who received any dose of the trial drug and all patients randomised to SoC. The primary outcomes of our trial were the safety and tolerability of intravenous nafamostat as an add on therapy for patients hospitalised with COVID-19 pneumonitis. FINDINGS: Data is reported from 42 patients, 21 of which were randomly assigned to receive intravenous nafamostat. 86% of nafamostat-treated patients experienced at least one AE compared to 57% of the SoC group. The nafamostat group were significantly more likely to experience at least one AE (posterior mean odds ratio 5.17, 95% credible interval (CI) 1.10 - 26.05) and developed significantly higher plasma creatinine levels (posterior mean difference 10.57 micromol/L, 95% CI 2.43-18.92). An average longer hospital stay was observed in nafamostat patients, alongside a lower rate of oxygen free days (rate ratio 0.55-95% CI 0.31-0.99, respectively). There were no other statistically significant differences in endpoints between nafamostat and SoC. PK data demonstrated that intravenous nafamostat was rapidly broken down to inactive metabolites. We observed no significant anticoagulant effects in thromboelastometry. INTERPRETATION: In hospitalised patients with COVID-19, we did not observe evidence of anti-inflammatory, anticoagulant or antiviral activity with intravenous nafamostat, and there were additional adverse events. FUNDING: DEFINE was funded by LifeArc (an independent medical research charity) under the STOPCOVID award to the University of Edinburgh. We also thank the Oxford University COVID-19 Research Response Fund (BRD00230).

Triple pass laser therapy for recalcitrant facial port wine stains.

Patients with recalcitrant facial port wine stains (rfPWS) can be challenging to manage, often leaving the clinician with difficult decisions for treatment options. 'Triple therapy' consists of using three different laser wavelengths at each treatment setting. The evidence on outcomes is limited as this treatment approach has not been previously reported to the best of our knowledge. Children who received triple therapy at least once for rfPWS, and for whom SIAscopy readings had been taken, were retrospectively identified. SIAscope readings were compared before the first triple therapy treatment and at final the most recent clinical follow-up. The clinical appearance was also assessed using a Visual Analogue Scale comparing clinical photographs taken before triple therapy to those taken at the most recent clinical follow-up. A total of 47 children were identified and included in our review. The SIAscope readings showed an overall significant (p < 0.001) lightening with 39 (83%) showing lightening and 8 (17%) patients showing a darkening. Scores using the VAS also showed improvement with 55% experiencing an improvement in their clinical appearance, 38% showing no visible change and 6% appearing to have worsened. Triple therapy can offer improvement of rfPWS which have failed to respond to single wavelength laser therapy. SIAscopy and VAS scores correlate well in assessing clinical response; however, the added clinical benefit of SIAscopy in vascular laser clinics remains uncertain.

Neutrophil HIF-1α stabilization is augmented by mitochondrial ROS produced via the glycerol 3-phosphate shuttle.

Neutrophils are predominantly glycolytic cells that derive little ATP from oxidative phosphorylation; however, they possess an extensive mitochondrial network and maintain a mitochondrial membrane potential. Although studies have shown neutrophils need their mitochondria to undergo apoptosis and regulate NETosis, the metabolic role of the respiratory chain in these highly glycolytic cells is still unclear. Recent studies have expanded on the role of reactive oxygen species (ROS) released from the mitochondria as intracellular signaling molecules. Our study shows that neutrophils can use their mitochondria to generate ROS and that mitochondrial ROS release is increased in hypoxic conditions. This is needed for the stabilization of a high level of the critical hypoxic response factor and pro-survival protein HIF-1α in hypoxia. Further, we demonstrate that neutrophils use the glycerol 3-phosphate pathway as a way of directly regulating mitochondrial function through glycolysis, specifically to maintain polarized mitochondria and produce ROS. This illustrates an additional pathway by which neutrophils can regulate HIF-1α stability and will therefore be an important consideration when looking for treatments of inflammatory conditions in which HIF-1α activation and neutrophil persistence at the site of inflammation are linked to disease severity.

Economic burden of road traffic injuries in sub-Saharan Africa: a systematic review of existing literature.

OBJECTIVE: This systematic review aims to explore and synthesise existing literature on the direct and indirect costs from road traffic injuries (RTIs) in sub-Saharan Africa (SSA), the quality of existing evidence, methods used to estimate and report these costs, and the factors that drive the costs. METHODOLOGY: MEDLINE, SCOPUS, ProQuest Central, Web of Science, Global Index Medicus, Embase, World Bank Group e-Library, Econlit, Google Scholar and WHO webpages were searched for relevant literature. References of selected papers were also examined for related articles. Screening was done following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles were included in this review if they were published by March 2019, written in English, conducted in SSA and reported original findings on the cost of illness or economic burden of RTIs. The results were systematically examined, and the quality assessed by two reviewers using a modified Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklist. RESULTS: Eleven studies met the inclusion criteria. RTIs can cost between INT$119 and 178 634 per injury and INT$486 and 12 845 per hospitalisation. Findings show variability in costing methods and inadequacies in the quality of existing evidence. Prolonged hospital stays, surgical sundries and severity of injury were the most common factors associated with cost. CONCLUSION: While available data are limited, evidence shows that the economic burden of RTIs in SSA is high. Poor quality of existing evidence and heterogeneity in costing methods limit the generalisability of costs reported.

Mass drug administration for endemic scabies: a systematic review.

BACKGROUND: Scabies is an extremely fastidious infestation caused by the Sarcoptes scabiei mite. It causes a persistent itch that can disrupt a person's mental health, sleep, and overall quality of life. In endemic areas, treatment by targeting symptomatic individuals and their contacts is often unsuccessful due to an asymptomatic period and high rates of re-infection. To overcome this, Mass Drug Administration (MDA) is often used to treat the whole community, irrespective of whether individuals presently have scabies. This review summarises the evidence for the effectiveness of MDA in treating scabies. METHODS: An exhaustive literature review was conducted on MEDLINE, EMBASE, Web of Science and Scopus. All peer-reviewed articles published in English January 1990 to March 2020 were eligible and only if the studies were primary and interventional. Furthermore, the intervention had to be a pharmacological MDA method involving human subjects. RESULTS: TWELVE articles that qualified for inclusion were identified. MDA for scabies significantly reduced its prevalence in communities at follow up. Some of the drivers of success were communities with low levels of migration, an uptake of MDA of > 85%, the use of oral Ivermectin therapy, the treatment of children and pregnant women within the treated population, and repeated treatment for participants diagnosed with scabies at baseline. CONCLUSIONS: The average absolute reduction in prevalence of scabies was 22.0% and the relative reduction average was 73.4%. These results suggest MDA is effective in treating scabies in the endemic community. Further evidence is needed surrounding MDA use in urban areas with increased levels of migration. Importantly, MDA should not substitute the tackling of socioeconomic factors which contribute to endemic disease such as good sanitation and hygiene.

A fluorogenic peptide-based smartprobe for the detection of neutrophil extracellular traps and inflammation.

A highly sensitive optical probe for the detection of activated neutrophils and Neutrophil Extracellular Traps (NETs) is reported. It is based on a triple-quenched, super-silent tri-branched probe that generates >20 fold increase in fluorescence upon cleavage. The probe was highly specific for human neutrophil elastase, a protease that mediates a variety of inflammatory diseases, and detected NETosis and neutrophil activation in in vitro differentiated neutrophils and isolated human neutrophils.

Relationship Between Vitamin D Level and Mortality in Adults With Psoriasis: A Retrospective Cohort Study of NHANES Data.

PURPOSE: Studies have shown an increased risk for mortality in patients with psoriasis. Furthermore, research has demonstrated an inverse relationship between 25-hydroxyvitamin D (25[OH]D) level and all-cause mortality. This study investigated the association between 25(OH)D level and all-cause mortality in US adults with psoriasis. METHODS: Data from NHANES (1999-2014 and mortality data through December 31, 2015) were analyzed. Quartiles of 25(OH)D level were created based on 25(OH)D levels among patients. Cox proportional hazards models were used for estimating hazard ratios (95% CI) for all-cause mortality. FINDINGS: A total of 82,091 participants were enrolled in the NHANES study from 1999 to 2014. Overall, 610 patients with psoriasis were identified in NHANES. The mean (SD) duration of follow-up was 5.61 (3.38) years (3427.92 person-years). The hazard ratio for mortality in the fully adjusted model was 0.12 (95% CI, 0.02-0.60; Ptrend = 0.01) in patients with a high 25(OH)D concentration compared to those with 25(OH)D deficiency. IMPLICATIONS: The 25(OH)D concentration was significantly inversely associated with all-cause mortality among these patients with psoriasis. Studies have shown an increased risk for mortality in patients with psoriasis compared to the general population. Vitamin D is not regularly metabolized in patients with psoriasis due to their skin abnormality. Vitamin D supplementation has been associated with a reduced mortality in patients with psoriasis. In practice, attention to vitamin D level is crucial, as is the use of vitamin D supplementation, for improving the health of these patients.

Pyogenic granuloma-like Kaposi sarcoma presenting in an HIV-negative man who has sex with men.

A 36-year-old immunocompetent man who have sex with men first presented to the plastics team with an ulcerating lesion on his left first toe. The lesion was suggestive of pyogenic granuloma (PG) clinically and histologically. Two years later, the same patient presented to the dermatology clinic with a new erythematous lesion with intermittent bleeding on the left second toe. Clinically, this lesion was suggestive of another PG. However, the histology of the skin curettage revealed part of a PG merging with an atypical spindle cell proliferation with characteristic 'sieve-like' appearance in keeping with Kaposi sarcoma. This was confirmed with human herpesvirus-8 immunohistochemistry staining. PG-like Kaposi sarcoma is an uncommon variant of Kaposi sarcoma. Often not considered clinically or histologically, a deep skin biopsy is essential to establish the right diagnosis. Our case highlights the need to consider Kaposi sarcoma as a differential diagnosis in all patients, including HIV-negative individuals, presenting with PG-like lesions.

Postmenopausal exogenous hormone therapy and Melanoma risk in women: A systematic review and time-response meta-analysis.

A favourable option to management symptoms during menopausal transition is menopausal hormone therapy (MHT) but relation among MHT and risk of melanoma is controversial. This study aims to identify, analyse and present the evidence surrounding post-menopausal exogenous hormone therapy and the risk for melanoma in women. A systematic searches of database was conducted in PubMed/MEDLINE, Scopus, and Cochrane without time, region, and language restrictions from inception to April 2020. The DerSimonian and Laird random-effects model was used to estimate combined risk ratio (RR) and 95% confidence intervals (CI). Subgroup analysis and time-response analysis was conducted based on the formulation of used hormone and length of hormone therapy. Combined results from fourteen studies that containing 19 arms with 1,164,077 participants which 4273 of them had melanoma cancer showed increase risk of melanoma in the hormone-treated versus control group 1.14 (95% CI 1.05-1.24, I2: 21%). The stronger and significant relationship between MHT and risk of melanoma was in participants who used oestrogen formulation (RR 1.32, 95% CI 1.17-1.49, I2 = 0%). Moreover, a significant non-linear time-response relation between MHT and melanoma was also in initial three years of MHT (Coef1 = 0.2423, p1 < 0.01). This study reveals a significant direct relationship between the MHT and risk of melanoma in postmenopausal women.