Topical frankincense treatment for frostbite based on microcirculation improvements.

ETHNOPHARMACOLOGICAL RELEVANCE: The Chinese traditional medicine frankincense, which can promote blood circulation, is often used to treat skin lesions, including frostbite. AIM OF THE STUDY: To explore the properties of frankincense oil extract (FOE) and its active ingredients and their effect on frostbite wound recovery as an approach to understand the mechanism associated with microcirculation-improvement therapy. MATERIALS AND METHODS: The microcirculation-improving effects of FOE and its active ingredients were evaluated using liquid nitrogen-induced frostbite animal models. The rewarming capacity of FOE on the skin was determined through infrared detection, and frostbite wound healing was evaluated following haematoxylin and eosin (H&E) staining and fibre analysis. Moreover, related factors were examined to determine the anti-apoptotic, anti-inflammatory, and microcirculatory properties of FOE and its active ingredients on affected tissue in the context of frostbite. RESULTS: FOE and its active ingredients rapidly rewarmed wound tissue after frostbite by increasing the temperature. Moreover, these treatments improved wound healing and restored skin structure through collagen and elastin fibre remodelling. In addition, they exerted anti-apoptotic effects by decreasing the number of apoptotic cells, reducing caspase-3 expression, and eliciting anti-inflammatory effects by decreasing COX-2 and ß-catenin expression. They also improved microcirculatory disorders by decreasing HIF-1α expression and increasing CD31 expression. CONCLUSIONS: FOE and its active components can effectively treat frostbite by enhancing microcirculation, inhibiting the infiltration of inflammatory cells, decreasing cell apoptosis, and exerting antinociceptive effects. These findings highlight FOE as a new treatment option for frostbite, providing patients with an effective therapeutic strategy.

Clinical Efficacy and Safety of Low-Energy Extracorporeal Shock Wave Therapy for Various Conditions of Deep Dermal and Subdermal Fibrosis.

BACKGROUND: Extracorporeal shock wave therapy (ESWT) enhances extracellular matrix remodeling and tissue regeneration by promoting growth factor release, regulating blood and lymphatic flows, and reducing fat and fibrotic tissues. Focused shock wave therapy (F-SWT), radial shock wave therapy (R-SWT), and combined F-SWT and R-SWT have been used to deliver different patterns of shock energy depending on the characteristics of the target lesions. METHODS: We investigated the efficacy and safety of ESWT in patients with dermal and subdermal fibrosis. Fifty-two patients treated with F-SWT and/or R-SWT for dermal and subdermal fibrosis caused due to various reasons were retrospectively analyzed by reviewing their medical records, clinical images, and ultrasound study images. RESULTS: The mean number of pulses administered for F-SWT on the cheek, temple, and chin were 2600.0 ± 1040.8 shocks/session and for R-SWT were 5080.0 ± 2234.6 pulses/session, and the number of treatment sessions were 8.0 ± 4.4. In patients who were treated with ESWT on the abdomen, the mean number of pulses for F-SWT were 2600.0 ± 2408.3 shocks/session and for R-SWT were 8400.0 ± 894.4 pulses/session, and the number of treatment sessions were 3.2 ± 1.6. Most patients were satisfied with the results. Pain during ESWT was well tolerated and post-ESWT edema was more common in R-SWT than in F-SWT. CONCLUSION: Our data demonstrated that ESWT effectively and safely improved the clinical appearance and functional movement of patients with dermal and subdermal fibrosis caused due to various reasons.

Artificial Intelligence Smartphone Application for Detection of Simulated Skin Changes: An In Vivo Pilot Study.

BACKGROUND: The development of artificial intelligence (AI) is rapidly expanding, showing promise in the dermatological field. Skin checks are a resource-heavy challenge that could potentially benefit from AI-tool assistance, particularly if provided in widely available AI solutions. A novel smartphone application(app)-based AI system, "SCAI," was developed and trained to recognize spots in paired images of skin, pursuing identification of new skin lesions. This pilot study aimed to investigate the feasibility of the SCAI-app to identify simulated skin changes in vivo. MATERIALS AND METHODS: The study was conducted in a controlled setting with healthy volunteers and standardized, simulated skin changes (test spots), consisting of customized 3-mm adhesive spots in three colors (black, brown, and red). Each volunteer had a total of eight test spots adhered to four areas on back and legs. The SCAI-app collected smartphone- and template-guided standardized images before and after test spot application, using its backend AI algorithms to identify changes between the paired images. RESULTS: Twenty-four volunteers were included, amounting to a total of 192 test spots. Overall, the detection algorithms identified test spots with a sensitivity of 92.0% (CI: 88.1-95.9) and a specificity of 95.5% (CI: 95.0-96.0). The SCAI-app's positive predictive value was 38.0% (CI: 31.0-44.9), while the negative predictive value was 99.7% (CI: 99.0-100). CONCLUSION: This pilot study showed that SCAI-app could detect simulated skin changes in a controlled in vivo setting. The app's feasibility in a clinical setting with real-life skin lesions remains to be investigated, where the challenge with false positives in particular needs to be addressed.

Skin Tone Analysis Through Skin Tone Map Generation With Optical Approach and Deep Learning.

BACKGROUND: Skin tone assessment is critical in both cosmetic and medical fields, yet traditional methods like the individual typology angle (ITA) have limitations, such as sensitivity to illuminants and insensitivity to skin redness. METHODS: This study introduces an automated image-based method for skin tone mapping by applying optical approaches and deep learning. The method generates skin tone maps by leveraging the illuminant spectrum, segments the skin region from face images, and identifies the corresponding skin tone on the map. The method was evaluated by generating skin tone maps under three standard illuminants (D45, D65, and D85) and comparing the results with those obtained using ITA on skin tone simulation images. RESULTS: The results showed that skin tone maps generated under the same lighting conditions as the image acquisition (D65) provided the highest accuracy, with a color difference of around 6, which is more than twice as small as those observed under other illuminants. The mapping positions also demonstrated a clear correlation with pigment levels. Compared to ITA, the proposed approach was particularly effective in distinguishing skin tones related to redness. CONCLUSION: Despite the need to measure the illuminant spectrum and for further physiological validation, the proposed approach shows potential for enhancing skin tone assessment. Its ability to mitigate the effects of illuminants and distinguish between the two dominant pigments offers promising applications in both cosmetic and medical diagnostics.

The lncRNA SNHG26 drives the inflammatory-to-proliferative state transition of keratinocyte progenitor cells during wound healing.

The cell transition from an inflammatory phase to a subsequent proliferative phase is crucial for wound healing, yet the driving mechanism remains unclear. By profiling lncRNA expression changes during human skin wound healing and screening lncRNA functions, we identify SNHG26 as a pivotal regulator in keratinocyte progenitors underpinning this phase transition. Snhg26-deficient mice exhibit impaired wound repair characterized by delayed re-epithelization accompanied by exacerbated inflammation. Single-cell transcriptome analysis combined with gain-of-function and loss-of-function of SNHG26 in vitro and ex vivo reveals its specific role in facilitating inflammatory-to-proliferative state transition of keratinocyte progenitors. A mechanistic study unravels that SNHG26 interacts with and relocates the transcription factor ILF2 from inflammatory genomic loci, such as JUN, IL6, IL8, and CCL20, to the genomic locus of LAMB3. Collectively, our findings suggest that lncRNAs play cardinal roles in expediting tissue repair and regeneration and may constitute an invaluable reservoir of therapeutic targets in reparative medicine.

Visible light accelerates skin wound healing and alleviates scar formation in mice by adjusting STAT3 signaling.

During the wound healing process, the activation of signal transducer and activator of transcription 3 (STAT3) is considered crucial for the migration and proliferation of epithelial cells, as well as for establishing the inflammatory environment. However, an excessive STAT3 activation aggravates scar formation. Here we show that 450 nm blue light and 630 nm red light can differentially regulate the phosphorylation of STAT3 (p-STAT3) and its downstream cytokines in keratinocytes. Further mechanistic studies reveal that red light promotes wound healing by activating the PI3 kinase p110 beta (PI3Kß)/STAT3 signaling axis, while blue light inhibits p-STAT3 at the wound site by modulating cytochrome c-P450 (CYT-P450) activity and reactive oxygen species (ROS) generation. In a mouse scar model, skin wound healing can be significantly accelerated with red light followed by blue light to reduce scar formation. In summary, our study presents a potential strategy for regulating epithelial cell p-STAT3 through visible light to address skin scarring issues and elucidates the underlying mechanisms.

3D bioprinting of fish skin-based gelatin methacryloyl (GelMA) bio-ink for use as a potential skin substitute.

Gelatin methacryloyl (GelMA), typically derived from mammalian sources, has recently emerged as an ideal bio-ink for three-dimensional (3D) bioprinting. Herein, we developed a fish skin-based GelMA bio-ink for the fabrication of a 3D GelMA skin substitute with a 3D bioprinter. Several concentrations of methacrylic acid anhydride were used to fabricate GelMA, in which their physical-mechanical properties were assessed. This fish skin-based GelMA bio-ink was loaded with human adipose tissue-derived mesenchymal stromal cells (ASCs) and human platelet lysate (HPL) and then printed to obtain 3D ASCs + HPL-loaded GelMA scaffolds. Cell viability test and a preliminary investigation of its effectiveness in promoting wound closure were evaluated in a critical-sized full thickness skin defect in a rat model. The cell viability results showed that the number of ASCs increased significantly within the 3D GelMA hydrogel scaffold, indicating its biocompatibility property. In vivo results demonstrated that ASCs + HPL-loaded GelMA scaffolds could delay wound contraction, markedly enhanced collagen deposition, and promoted the formation of new blood vessels, especially at the wound edge, compared to the untreated group. Therefore, this newly fish skin-based GelMA bio-ink developed in this study has the potential to be utilized for the printing of 3D GelMA skin substitutes.

Recombinant ISRAA ameliorates imiquimod-induced psoriasis and knocking out Israa delays its onset.

Psoriasis, an inflammatory disease, is largely mediated by T-helper 17 cytokines. We have previously identified the immune system-released activating agent (Israa) as a novel gene that connects the nervous and immune systems. This research aims to investigate the role of the Israa gene in psoriasis in vivo using the imiquimod-induced psoriasis model. We established the model in C57BL/6 wildtype mice, which were then treated with 200 pg/mouse, 400 pg/mouse, or 800 pg/mouse of recombinant ISRAA compared to methotrexate. Subsequently, we also induced psoriasis in Israa-knockout mice to confirm the effect of Israa. Results consistently showed improvement in psoriasis in all groups receiving recombinant ISRAA. The 200 pg/mouse dose eliminated the disease, reduced the cutaneous release of IL-17 to one-third and TNF-α to one-sixth, increased IL-10 release to over 500 pg, completely resolved parakeratosis, decreased epidermal thickness to one-half, and reduced the expression of CD4 and neutrophil elastase in the skin (all p < 0.05). Israa-knockout mice exhibited less severe psoriasis in all scoring, biochemical, and histological parameters compared to wild-type mice (p < 0.05). This study highlights Israa as a crucial molecule in psoriasis and confirms its immunomodulatory role in inflammatory diseases.

A reconfigurable and conformal liquid sensor for ambulatory cardiac monitoring.

The severe mismatch between solid bioelectronics and dynamic biological tissues has posed enduring challenges in the biomonitoring community. Here, we developed a reconfigurable liquid cardiac sensor capable of adapting to dynamic biological tissues, facilitating ambulatory cardiac monitoring unhindered by motion artifacts or interference from other biological activities. We employed an ultrahigh-resolution 3D scanning technique to capture tomographic images of the skin on the wrist. Then, we established a theoretical model to gain a deep understanding of the intricate interaction between our reconfigurable sensor and dynamic biological tissues. To properly elucidate the advantages of this sensor, we conducted cardiac monitoring alongside benchmarks such as the electrocardiogram. The liquid cardiac sensor was demonstrated to produce stable signals of high quality (23.1 dB) in ambulatory settings.

Diffuse reflectance spectroscopy and RGB-imaging: a comparative study of non-invasive haemoglobin assessment.

Non-invasive assessment of haemoglobin (Hb) level in blood is a hot spot in the point-of-care biomedical diagnostics. Several optical methods are suggested as a solution, some of them being approved for clinical use. Still, there is no consensus on the accuracy of optical techniques, the quality of Hb assessment on different tissue sites, and on the ability of combined use of several optical techniques to improve the quality of Hb level prediction. In this work we examined the capabilities of two optical techniques-diffuse reflectance spectroscopy and RGB-imaging of the skin and fingernails areas-in detecting low blood Hb level. The test sample consisted of 240 adult volunteers with 70 volunteers exhibiting Hb level lower than 120 g/L. We show that using simple descriptors of the diffuse reflectance spectrum of the forearm skin and fingernails is applicable for predicting low blood Hb concentration (ROC-AUC = 0.84 ± 0.08), while RGB-imaging shows similar performance when applied to the fingernail areas (ROC-AUC = 0.83 ± 0.07), which can be considered perspective for clinical use and screening properties. We also report that while the joint use of predictions from two optical methods slightly improves the accuracy of non-invasive Hb level assessment (ROC-AUC = 0.86 ± 0.07), the effect is not as high as one might expect from combining predictions of truly independent modalities, indicating the limit of the accuracy one can expect with multimodal optical approach. We review this case and propose possible solutions towards more sensitive non-invasive optical determination of hemoglobin.

Dataset of human skin and fingernails images for non-invasive haemoglobin level assessment.

Anaemia, a decrease in total concentration of haemoglobin (Hb) in blood, affects substantial percentage of the population worldwide. Currently, the gold standard for determining the Hb level is the invasive analysis of venous blood. Yet, more and more research groups demonstrate the possibility of non-invasive Hb assessment using white light imaging of tissue sites where Hb is the main chromophore, in particular, fingernails. Despite the promising declarations, non-invasive Hb assessment via RGB-imaging is still poorly used in practice. The main reason is the difficulty in establishing the true accuracy of the methods presented in different works since they are tested on private datasets collected under different experimental conditions. Here we present an open dataset containing RGB images of skin and fingernails for patients with a known level of Hb, thus providing a single benchmark for researchers and engineers in the field, aimed at fostering translation of non-invasive imaging methods to the bedside.

The potential of x-ray virtual histology in the diagnosis of skin tumors.

BACKGROUND: Histopathological analysis represents the gold standard in clinical practice for diagnosing skin neoplasms. While the current diagnostic workflow has specialized in producing robust and accurate results, interpreting tissue architecture and malignant cellular morphology correctly remains one of the greatest challenges for pathologists. This paper aims to explore the prospect of applying x-ray virtual histology to human skin tumor excisions and correlating it with the histological validation. MATERIALS AND METHODS: Seven skin biopsies containing intriguing melanoma types and pigmented skin lesions were scanned using x-ray Computed micro-Tomography (µCT) and then sectioned for conventional histology assessment. RESULTS: The tissue microarchitecture reconstructed by µCT offers detailed insights into diagnosing the malignancy or benignity of the skin lesions. Three-dimensional reconstruction via x-ray virtual histology reveals infiltrative patterns in basal cell carcinoma and evaluated invasiveness in melanoma. The technology enables the identification of pagetoid distributions of neoplastic cells and the assessment of melanoma depth in three dimensions. CONCLUSION: Although the proposed approach is not intended to replace conventional histology, the non-destructive nature of the sample and the clarity provided by virtual inspection demonstrate the promising impact of µCT as a valid support method prior to conventional histological sectioning. Indeed, µCT images can suggest the optimal sectioning position before using a microtome, as is commonly performed in histological practice. Moreover, the three-dimensional nature of the proposed approach paves the way for a more accurate assessment of significant prognostic factors in melanoma, such as Breslow thickness, by considering the whole micro-volume rather than a two-dimensional observation.

Monolithically integrated neuromorphic electronic skin for biomimetic radiation shielding.

Melanogenesis, a natural responsive mechanism of human skin to harmful radiation, is a self-triggered defensive neural activity safeguarding the body from radiation exposure in advance. With the increasing significance of radiation shielding in diverse medical health care and wearable applications, a biomimetic neuromorphic optoelectronic system with adaptive radiation shielding capability is often needed. Here, we demonstrate a transparent and flexible metal oxide-based photovoltaic neuromorphic defensive system. By using a monolithically integrated ultraflexible optoelectronic circuitry and electrochromic device, seamless neural processing for ultraviolet (UV) radiation shielding including history-based sensing, memorizing, risk recognition, and blocking can be realized with piling the entire signal chain into the flexible devices. The UV shielding capability of the system can be evaluated as autonomous blocking up to 97% of UV radiation from 5 to 90 watts per square meter in less than 16.9 seconds, demonstrating autonomously modulated sensitivity and response time corresponding to UV environmental conditions and supplied bias.

Update on protease-activated receptor 2 in inflammatory and autoimmune dermatological diseases.

Protease-activated receptor 2 (PAR2) is a cell-surface receptor expressed in various cell types, including keratinocytes, neurons, immune and inflammatory cells. Activation of PAR2, whether via its canonical or biased pathways, triggers a series of signaling cascades that mediate numerous functions. This review aims to highlight the emerging roles and interactions of PAR2 in different skin cells. It specifically summarizes the latest insights into the roles of PAR2 in skin conditions such as atopic dermatitis (AD), psoriasis, vitiligo and melasma. It also considers these roles from the perspective of the cutaneous microenvironment in relation to other inflammatory and autoimmune dermatological disorders. Additionally, the review explores PAR2's involvement in associated comorbidities from both cutaneous and extracutaneous diseases. Therefore, PAR2 may serve as a key target for interactions among various cells within the local skin environment.

Vitamin C and its derivatives in maintaining the good skin condition / Witamina C i jej pochodne w utrzymaniu dobrej kondycji skóry.

Vitamin C is one of the most important and necessary nutrient for human health, which has great potential as cosmeceutic, which protects health and the skin good condition. Thru the collagen biosynthesis stimulation it affects to the physiology of human skin, participating in the hydroxylation process of proline and lysine, and participates in tissue reconstruction while wound healing. Deficiency of vitamin C causes irregularities in the blood vessels functioning, epidermis and dermis. Is an effective antioxidant neutralizing free radicals, prevents inflammatory and carcinogenic processes. The epidermis and dermis are most exposed to free radicals from the external environment and from the inside of the body. In inflammatory diseases of the skin, such as atopic dermatitis, psoriasis, in the proper skin the levels of vitamin C are reduced. Therefore, delivering it to the skin using cosmetic preparations is important not only for cosmetic, but also health effect. The problem associated with the introduction of vitamin C in cosmetics is its limited penetration through the stratum corneum. Current studies are focused on searching for stable compounds of ascorbic acid and new media, which will allow for better way of delivery of ascorbic acid to the dermis in the future.

Inhibition of Ubiquitin C-Terminal Hydrolase L1 Facilitates Cutaneous Wound Healing via Activating TGF-ß/Smad Signalling Pathway in Fibroblasts.

Ubiquitin C-terminal hydrolase L1 (UCHL1) plays vital roles in cell proliferation, angiogenesis, inflammation and oxidative stress. Nevertheless, it is unclear whether UCHL1 could regulate the biologic behaviour of cells and ultimately influences wound healing. We aim to illustrate the roles and the underlying mechanism of UCHL1 in cutaneous wound healing. Murine full-thickness excisional wound model was utilised to study the effects of UCHL1 on wound healing through topical administration of the UCHL1 inhibitor LDN57444, followed by assessment of wound areas and histological alterations. Subsequently, ethynyldeoxyuridine, scratch and transwell assays were performed to examine fibroblast migration and proliferation. The extracellular matrix (ECM)-related genes expression and transforming growth factor-ß (TGF-ß)/Smad signalling pathways activation were investigated by immuno-fluorescent staining, Western blots and quantitative reverse transcription polymerase chain reaction. We identified elevated UCHL1 expression in non-healing wound tissues. The UCHL1 expression displayed a dynamic change and reached a peak on Day-7 post-wounding during the healing process in mice. Cutaneous administration of LDN57444 promoted wound healing by facilitating collagen deposition, myofibroblast activation and angiogenesis. In vitro experiments demonstrated that UCHL1 concentration dependently inhibited migration, ECM synthesis and activation of human dermal fibroblasts, which was mechanistically related to downregulation of TGF-ß/Smad signalling. Furthermore, these effects could be reversed by TGF-ß inhibitor SB431542. Our findings reveal that UCHL1 is a negative regulator of cutaneous wound healing and considered as a novel prospective therapeutic target for effective wound healing.

A Consensus on Staphylococcus aureus Exacerbated Atopic Dermatitis and the Need for a Novel Treatment.

The skin microbiome is essential for skin barrier function because it inhibits pathogen colonization, and decreased microbiome diversity correlates with increased Staphylococcus aureus (S. aureus) burden and atopic dermatitis (AD) severity. Managing S. aureuss-driven AD in clinical practice remains problematic due to complications such as AD exacerbation, impetigo, abscesses, and invasive infections. This project used a modified Delphi process comprising face-to-face discussions followed by a blinded vote to define 5 final consensus statements. A panel of 6 pediatric dermatologists developed a consensus on S. aureus-driven AD exacerbation, challenges in current treatments for AD with secondary bacterial infections, and new developments to improve patient care and outcomes. The panel's 5 consensus statements provide recommendations for dermatologists, pediatricians, and healthcare providers treating patients with secondary infected AD. These recommendations underscore the importance of recognizing and managing S. aureus skin infection in AD clinical practice and promoting antibiotic stewardship to mitigate resistance. The panel defined a significant unmet need for a single topical AD therapy effective against all symptoms, including pruritus, S. aureus-driven AD exacerbation, infection, and inflammation, across AD severity levels. J Drugs Dermatol. 2024;23(10):825-832. doi:10.36849/JDD.8240.

Primary Hyperhidrosis and Sensitive Skin: Exploring the Link with Predictive Machine Learning-Based Classification Models.

BACKGROUND: Primary hyperhidrosis (PHH) is a disorder of excessive sweating caused by aberrant cholinergic signaling. Sensitive skin (SS) is a condition of subjective cutaneous hyperreactivity to innocuous stimuli, impacting 40% to 70% of the population. SS is exacerbated by sweat, stress, and heat, suggesting that cholinergic stimulation may contribute to SS flares. OBJECTIVE: To survey PHH sufferers to assess hyperhidrosis (HH) and SS symptom burden. METHODS: An International Review Board (IRB)-exempt survey was disseminated by the International Hyperhidrosis Society. A predictive classification model for SS was built using random forest machine learning algorithms. RESULTS: Of the 637 respondents with PHH, 89% reported SS; and there was a significant association between HH and SS severity scores. Importantly, SS occurred on body sites affected and unaffected by HH. Predictive modeling designated Sensitive Scale-10 (SS-10), a validated questionnaire to gauge SS severity, to be the most helpful in predicting SS in this cohort. LIMITATIONS: Self-reported data. CONCLUSION: These data are the first to propose and support a relationship between SS and HH. SS occurred with greatest frequency at HH-afflicted body sites, but also occurred on unaffected sites, suggesting that sweat is not the sole causative link. Future work can explore cholinergic signaling as a potential link between these conditions. Screening HH patients for SS may be warranted. J Drugs Dermatol. 2024;23(10):882-888. doi:10.36849/JDD.8461.

Retinol semisolid preparations in cosmetics: transcutaneous permeation mechanism and behaviour.

Retinol is widely used to treat skin ageing because of its effect on cell differentiation, proliferation and apoptosis. However, its potential benefits appear to be limited by its skin permeability. Herein, we investigated the transcutaneous behavior of retinol in semisolid cosmetics, in both in vitro and in vivo experiments. In vitro experiments used the modified Franz diffusion cell combined with Raman spectroscopy. In in vivo experiments, the content of retinol in rat skin and plasma was detected with HPLC. Retinol in semisolid cosmetics was mainly concentrated in the stratum corneum in the skin of the three animal models tested, and in any case did not cross the skin barrier after a 24 h dermatologic topical treatment in Franz diffusion cells tests. Similar results were obtained in live mice and rats, where retinol did not cross the skin barrier and did not enter the blood circulation. Raman spectroscopy was used to test the penetration depth of retinol in skin, which reached 16 µm out of 34 µm in pig skin, whereas the skin of mouse and rat showed too strong bakground interference. To explore epidermal transport mechanism and intradermal residence, skin transcriptomics was performed in rats, which identified 126 genes upregulated related to retinol transport and metabolism, relevant to the search terms "retinoid metabolic process" and "transporter activity". The identity of these upregulated genes suggests that the mechanism of retinol action is linked to epidermis, skin, tissue and epithelium development.

Role of histopathological, serological and molecular findings for the early diagnosis of treatment failure in leprosy.

BACKGROUND: Treatment failure (TF) in leprosy following multidrug therapy (MDT) presents a significant challenge. The current World Health Organization (WHO) fixed-duration MDT regimen, based on lesion count, might not be adequate. Leprosy lacks clear-cut objective cure criteria, and the predictive value of post-MDT histopathological findings remains uncertain. This study aims to identify predictive factors for TF among leprosy patients who have completed the WHO-recommended MDT. METHODS: An analysis was conducted on 80 individuals from a national leprosy reference center, comprising 40 TF cases (with a mean relapse at 13.0 months) and 40 controls (with a mean of 113.1 months without disease signs). Various epidemiological and clinical-laboratory parameters were assessed post-MDT. RESULTS: In skin samples, the presence of foamy granuloma (OR = 7.36; 95%CI2.20-24.60; p = 0.0012) and histological bacillary index (hBI) ≥ 1+ (OR = 1.55; 95%CI1. 22-1.99; p = 0.0004) were significantly associated with TF, with odds ratios of 7.36 and 1.55, respectively. Individuals who experienced TF had a mean hBI of 3.02+ (SD ± 2.02), while the control group exhibited a mean hBI of 1.8+ (SD ± 1.88). An hBI ≥ 3 + showed a sensitivity of 73% and a specificity of 78% for TF detection (AUC: 0.75; p = 0.0001). Other histopathological features like epithelioid granulomas, and skin changes did not show significant associations (p > 0.05). Additionally, higher anti-phenolic glycolipid-I (anti-PGL-I) ELISA index (EI) levels were linked to a 1.4-fold increased likelihood for TF (OR = 1.4; 95%CI1.13-1.74; p = 0.0019). A mean EI of 4.48 (SD ± 2.80) was observed, with an EI ≥ 3.95 showing a sensitivity of 79% and a specificity of 59% for TF detection (AUC: 0.74; p = 0.0001). Moreover, the presence of Mycobacterium leprae (M. leprae) DNA in real-time polymerase chain reaction (qPCR) was associated with a 3.43-fold higher likelihood of TF. Multivariate regression analysis indicated that concurrent presentation of neural/perineural lymphocytic infiltrate, foamy granuloma, hBI ≥ 1+, and EI ≥ 1 markedly increased the likelihood of TF by up to 95.41%. CONCLUSION: Persistence of nerve-selective lymphocytic infiltrate, foamy granulomas, and bacilli in skin biopsies, and elevated EI post-MDT, may serve as predictive factors for identifying individuals at higher probability of TF.