Development of a cellular assay as a personalized model for testing chronic wound therapeutics.

Exudates of non-healing wounds contain drivers of pathogenicity. We utilized >800 exudates from non-healing and healing wounds of diverse etiologies, collected by three different methods, to develop a wound-specific, cell-based functional biomarker assay. Human dermal fibroblast proliferation served as readout to a) to differentiate between healing and non-healing wounds, b) follow the healing process of individual patients, and c) assess the effects of therapeutics for chronic wounds ex vivo. We observed a strong correlation between wound chronicity and inhibitory effects of individual exudates on fibroblast proliferation, with good diagnostic sensitivity (76-90%, depending on the sample collection method). Transition of a clinically non-healing to a healing phenotype restored fibroblast proliferation and extracellular matrix formation while reducing inflammatory cytokine production. Transcriptional analysis of fibroblasts exposed to ex vivo non-healing wound exudates revealed an induction of inflammatory cytokine- and chemokine pathways and the unfolded protein response, indicating that these changes may contribute to the pathology of non-healing wounds. Testing the wound therapeutics platelet derived growth factor and silver sulfadiazine yielded responses in line with clinical experience and indicate the usefulness of the assay to search for and profile new therapeutics.

Illuminating characteristic patterns of inflammatory dermatoses: A comprehensive dual-imaging approach using Optical coherence tomography and Line-field confocal optical coherence tomography.

BACKGROUND: Inflammatory skin diseases, such as psoriasis, atopic eczema, and contact dermatitis pose diagnostic challenges due to their diverse clinical presentations and the need for rapid and precise diagnostic assessment. OBJECTIVE: While recent studies described non-invasive imaging devices such as Optical coherence tomography and Line-field confocal OCT (LC-OCT) as possible techniques to enable real-time visualization of pathological features, a standardized analysis and validation has not yet been performed. METHODS: One hundred forty lesions from patients diagnosed with atopic eczema (57), psoriasis (50), and contact dermatitis (33) were imaged using OCT and LC-OCT. Statistical analysis was employed to assess the significance of their characteristic morphologic features. Additionally, a decision tree algorithm based on Gini's coefficient calculations was developed to identify key attributes and criteria for accurately classifying the disease groups. RESULTS: Descriptive statistics revealed distinct morphologic features in eczema, psoriasis, and contact dermatitis lesions. Multivariate logistic regression demonstrated the significance of these features, providing a robust differentiation between the three inflammatory conditions. The decision tree algorithm further enhanced classification accuracy by identifying optimal attributes for disease discrimination, highlighting specific morphologic criteria as crucial for rapid diagnosis in the clinical setting. CONCLUSION: The combined approach of descriptive statistics, multivariate logistic regression, and a decision tree algorithm provides a thorough understanding of the unique aspects associated with each inflammatory skin disease. This research offers a practical framework for lesion classification, enhancing the interpretability of imaging results for clinicians.

Sensitization against medical hyaluronidase in patients with confirmed hypersensitivity against hymenoptera species and its clinical implications.

BACKGROUND: Hyaluronidase is an ubiquitious enzyme, present, amongst others, in hymenoptera venom and in medical formulations. The latter include use as an emergency treatment or to correct undesired outcomes of medical and aesthetic procedures using hyaluronic acid fillers. By performing detailed allergy work-ups including prick-testing we investigated here if patients with a history of allergic reaction to hymenoptera venom are also sensitized to medical grade hyaluronidase. METHODS: Ninety patients with a history of type-1 reaction to hymenoptera venom with and without a history of previous specific venom immunotherapy were included in the study. All underwent skin prick tests for medical hyaluronidase. All patients also underwent serological analysis for Api m2, the only commercially available IgE-test for a hymenoptera hyaluronidase. RESULTS: Of the 90 patients with previous type-1 reactions to hymenoptera venom hyaluronidase included in the study, 60 had undergone previous venom immunotherapy, 30 did not. A majority (73/90) were allergic to wasps, followed by honeybees (14/90) and 3 were allergic to both. Neither patients having undergone previous immunotherapy nor those allergic to bees showed positive skin prick tests to medical hyaluronidase. Of those with a wasp allergy and naïve to immunotherapy, over 20% (5/23) showed positive skin prick tests to medical hyaluronidase. Healthy controls (0/30) without previous allergic reactions to hymenoptera did not show positive skin prick tests to medical hyaluronidase. CONCLUSION: Sensitization to hyaluronidase is most common in wasp-allergic patients who have not had previous specific immunotherapy. As allergic reactions to medical hyaluronidase are reported to be scarce, this group is probably at the highest risk to develop anaphlaxis to medical hyaluronidase. While all patients with untreated anaphylaxis to hymenoptera venom should consult an allergy specialist, particularly those with untreated wasp allergies need to seek a specialist's advice before treatment with medical hyaluronidase is initiated.

Targeting IL-1 controls refractory pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease with a poorly understood pathogenesis. Through a molecularly driven precision medicine approach and an extensive mechanistic pathway analysis in PRP skin samples, compared to psoriasis, atopic dermatitis, healed PRP, and healthy controls, we identified IL-1ß as a key mediator, orchestrating an NF-κB-mediated IL-1ß-CCL20 axis, including activation of CARD14 and NOD2. Treatment of three patients with the IL-1 antagonists anakinra and canakinumab resulted in rapid clinical improvement and reversal of the PRP-associated molecular signature with a 50% improvement in skin lesions after 2 to 3 weeks. This transcriptional signature was consistent with in vitro stimulation of keratinocytes with IL-1ß. With the central role of IL-1ß underscoring its potential as a therapeutic target, our findings propose a redefinition of PRP as an autoinflammatory keratinization disorder. Further clinical trials are needed to validate the efficacy of IL-1ß antagonists in PRP.

Exploring the potential of omega-3 fatty acids in acne patients: A prospective intervention study.

BACKGROUND: Omega-3 fatty acids (ω-3 FA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), are essential nutrients known for their anti-inflammatory properties, which involve reducing pro-inflammatory cytokines, eicosanoids, and insulin-like growth factor-1. This suggests their potential to alleviate acne severity, especially when deficits are present. AIMS: To elevate EPA/DHA levels in acne patients through dietary intervention and supplementation, observing subsequent clinical effects. METHODS: Over 16 weeks, 60 patients without prescription medication (n = 23 acne comedonica [AC], n = 37 acne papulopustulosa [AP]) adhered to a Mediterranean diet, incorporating oral algae-derived ω-3 FA supplementation (600 mg DHA/300 mg EPA week 1-8, 800 mg DHA/400 mg EPA week 8-16). At four visits (V1-V4), blood EPA/DHA levels were tracked using the HS-omega 3 index® (EPA/DHA (%) of total identified fatty acids in erythrocytes; target 8%-11%, deficit <8%, severe deficit <4%), alongside clinical assessments and standardized questionnaires. RESULTS: At baseline, 98.3% of patients had an EPA/DHA deficit, with the mean HS-omega 3 index® rising from 4.9% at V1 to 8.3% at V4 (p < 0.001). AC showed significantly higher indices than AP at V4 (p = 0.035). Objective improvements in both inflammatory and non-inflammatory lesions were observed (p < 0.001). While self-reported appearance worsened in four patients, overall quality of life improved (p < 0.001), particularly in AP. Dietary triggers were more clearly defined than beneficial foods. Intake of cow's milk and dairy products reduced (p < 0.001). Compliance was good; no adverse events were reported. CONCLUSION: Many acne patients have a ω-3 FA deficit. The HS-omega 3 index® can be increased by a Mediterranean diet and oral supplementation with algae-derived ω-3 FA. Acne severity improved significantly in patients with target ω-3 FA levels.

Stringent monitoring can decrease mortality of immune checkpoint inhibitor induced cardiotoxicity.

Background: Immune checkpoint inhibitor (ICI)-induced myocarditis is a rare immune-related adverse event (irAE) with a fatality rate of 40%-46%. However, irMyocarditis can be asymptomatic. Thus, improved monitoring, detection and therapy are needed. This study aims to generate knowledge on pathogenesis and assess outcomes in cancer centers with intensified patient management. Methods: Patients with cardiac irAEs from the SERIO registry (www.serio-registry.org) were analyzed for demographics, ICI-related information (type of ICI, therapy line, combination with other drugs, onset of irAE, and tumor response), examination results, irAE treatment and outcome, as well as oncological endpoints. Cardiac biopsies of irMyocarditis cases (n = 12) were analyzed by Nanostring and compared to healthy heart muscle (n = 5) and longitudinal blood sampling was performed for immunophenotyping of irMyocarditis-patients (n = 4 baseline and n = 8 during irAE) in comparison to patients without toxicity under ICI-therapy (n = 4 baseline and n = 7 during ICI-therapy) using flow cytometry. Results: A total of 51 patients with 53 cardiac irAEs induced by 4 different ICIs (anti-PD1, anti-PD-L1, anti-CTLA4) were included from 12 centers in 3 countries. Altogether, 83.0% of cardiac irAEs were graded as severe or life-threatening, and 11.3% were fatal (6/53). Thus, in centers with established consequent troponin monitoring, work-up upon the rise in troponin and consequent treatment of irMyocarditis with corticosteroids and -if required-second-line therapy mortality rate is much lower than previously reported. The median time to irMyocarditis was 36 days (range 4-1,074 days) after ICI initiation, whereas other cardiotoxicities, e.g. asystolia or myocardiopathy, occurred much later. The cytokine-mediated signaling pathway was differentially regulated in myocardial biopsies as compared to healthy heart based on enrichment Gene Ontology analysis. Additionally, longitudinal peripheral blood mononuclear cell (PBMC) samples from irMyocarditis-patients indicated ICI-driven enhanced CD4+ Treg cells and reduced CD4+ T cells. Immunophenotypes, particularly effector memory T cells of irMyocarditis-patients differed from those of ICI-treated patients without side effects. LAG3 expression on T cells and PD-L1 expression on dendritic cells could serve as predictive indicators for the development of irMyocarditis. Conclusion: Interestingly, our cohort shows a very low mortality rate of irMyocarditis-patients. Our data indicate so far unknown local and systemic immunological patterns in cardiotoxicity.

Checkpoint inhibitor-induced lichen planus differs from spontaneous lichen planus on the clinical, histological, and gene expression level.

Background: Although highly efficacious, immune checkpoint inhibitors induce a multitude of immune-related adverse events including lichenoid skin reactions (irLP) that are often therapy-resistant. Objectives: To compare the clinical, histological, and transcriptional features of irLP with spontaneous lichen planus (LP). Methods: Clinical and histological presentations of irLP and LP, as well as the gene expression profiles of irLP and LP lesional and healthy skin were assessed. Results: irLP differed considerably from LP with regard to the distribution pattern of skin lesions with irLP appearing mostly in an exanthematous form, whereas lesions were more localized in the LP group. Histologically, dermal lymphocyte infiltration was significantly lower in irLP compared with LP, whereas lymphocyte exocytosis and apoptotic keratinocytes were significantly higher in irLP. Gene expression analysis revealed irLP to have a more inflammatory profile with elevated IFNG levels and a possible role of phagosome signaling compared with LP. Limitations: The study is descriptive and necessitates further investigation with larger cohorts and broader analyses. Conclusion: irLP differs from spontaneous LP on the clinical, histopathological, and gene expression level. The inflammatory gene signature in irLP suggests that topical JAK inhibitors could be an effective treatment, targeting local skin inflammation without systemic immunosuppression.

Ex Vivo Confocal Laser Scanning Microscopy in Rare Skin Diseases.

While ex vivo confocal laser scanning microscopy has previously demonstrated its utility in most common skin diseases, its use in the assessment of dermatological entities with lower incidence remains unexplored in most cases. We therefore aimed to evaluate the diagnostic efficacy of some rare skin tumors as well as a few inflammatory skin diseases, that have not yet been studied in ex vivo confocal laser scanning microscopy. A total of 50 tissue samples comprising 10 healthy controls, 10 basal cell carcinoma, 10 squamous cell carcinoma, and 20 rare skin conditions were imaged using the newest generation ex vivo confocal microscopy (Vivascope 2500 M-G4, Vivascope GmbH, Munich, Germany). Three blinded investigators were asked to identify characteristic features of rare skin disorders and distinguish them from more common skin diseases in the ex vivo confocal microscopy images. Our findings present the capability of ex vivo confocal microscopy to display distinctive morphologic patterns in common and rare skin diseases. As might be expected, we found a strong correlation between imaging experience and diagnostic accuracy. While the imaging inexperienced dermatohistopathologist reached 60% concordance, the imaging-trained dermatologist obtained 88% agreement with dermatohistopathology. The imaging-trained dermatohistopathologist achieved concordance up to 92% with gold-standard dermatohistopathology. This study highlights the potential of ex vivo confocal laser scanning microscopy as a promising adjunct to conventional dermatohistopathology for the early and precise identification of rare dermatological disorders.

Characteristics of Gut Microbiota in Rosacea Patients-A Cross-Sectional, Controlled Pilot Study.

BACKGROUND: Recent studies have suggested a possible connection between rosacea and patients' gut microbiota. OBJECTIVE: To investigate the differences in fecal microbial profiles between patients with rosacea and healthy controls. METHODS: Gut microbiota of 54 rosacea patients (RP) were analyzed using MiSeq 16S rRNA sequencing. Enterotypes, the Firmicutes/Bacteroides (F/B) ratio, the significance of alpha and beta diversity, and differential abundance analysis (DAA) were calculated and compared with age- and gender-matched controls (CP, n = 50). RESULTS: Significant changes in the enterotypes and F/B ratio were observed between the RP and CP (p = 0.017 and p = 0.002, respectively). The RP showed a decreased microbial richness and diversity compared to the CP (Shannon p = 0.012, inverse Simpson p = 0.034). Beta diversity also differed between both groups (PERMANOVA, p = 0.006). Fourteen significantly different taxa were detected according to DAA. Faecalibacterium prausnitzii (coef. -0.0800, p = 0.008), Lachnoospiraceae ND 3007 group sp. (coef. -0.073, p < 0.001), and Ruminococcaceae (coef. -0.072, p = 0.015) were significantly decreased; Oscillobacter sp. (coef. 0.023, p = 0.031), Flavonifractor plautii (coef. 0.011, p = 0.037), and Ruminococccaceae UBA 1819 (coef. 0.010, p = 0.031) were significantly increased in the RP compared to the CP. CONCLUSION: Significant alterations in gut microbiota were present in the RP. Taxonomic shifts and reduced richness and diversity were observed when compared to the CP. Larger prospective studies are needed to investigate correlations with clinical features and to translate these findings into future therapeutic approaches.

Deficit of Omega-3 Fatty Acids in Acne Patients-A Cross-Sectional Pilot Study in a German Cohort.

Omega-3 fatty acids (ω-3 FAs) exert anti-inflammatory effects, including the downregulation of pro-inflammatory cytokines, eicosanoids, and insulin-like growth factor-1. Therefore, they may improve acne severity as an adjunct treatment. However, there is a paucity of data regarding patients' existing deficits. The aim of this study was to determine ω-3 FA levels in acne patients in correlation with self-reported dietary preferences and clinical severity. A single-center, cross-sectional study of 100 acne patients was conducted. Patients' blood parameters, including ω-3 FAs levels, were assessed using the HS-omega-3 Index® in erythrocytes (Omegametrix® GmbH, Martinsried, Germany). Dietary preferences were assessed using a standardized food frequency questionnaire. Clinical dermatologic evaluation was performed using the Investigator Global Assessment (IGA) of acne. The values of the HS-omega-3 Index® were outside the recommended range of 8-11% in 96 patients (mean 5.15%), independent of the clinical severity or affected anatomic sites. A severe deficit (HS-omega-3 Index® < 4%) was seen more commonly in men than in women (p = 0.021). The regular consumption of legumes was significantly associated with higher ω-3 FA levels (p = 0.003), as was oral ω-3 FA supplementation (p = 0.006) and the lack of sunflower oil intake (p = 0.008). This pilot study demonstrated a deficit of ω-3 FAs in a German acne cohort. Higher ω-3 FAs levels were observed in patients with regular legume intake and oral ω-3 FAs supplementation. Further prospective studies are needed to investigate whether the clinical severity of acne improves in patients with normal HS-omega-3 Index®.

Second-line therapies for steroid-refractory immune-related adverse events in patients treated with immune checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) induce adverse events (irAEs) that do not respond to steroids, i.e. steroid-refractory (sr) irAEs, and irAEs in which steroids cannot be tapered, i.e. steroid-dependent (sd) irAEs, in about 10% of cases. An evidence-based analysis of the effectiveness of second-line immunosuppressive agents with regard to irAE and tumor control is lacking. METHODS: The international web-based Side Effect Registry Immuno-Oncology (SERIO; http://serio-registry.org) is a collaborative initiative with the Paul-Ehrlich-Institute to document rare, severe, complex or therapy-refractory immunotherapy-induced side effects. The registry was queried on August 1, 2023 for cases of irAEs which were treated with second-line therapies. RESULTS: From a total of 1330 cases, 217 patients (16.3%) received 249 second-line therapies. A total of 19 different second-line therapies were employed, including TNF-alpha antagonists (46.5%), intravenous immunoglobulins (IVIG; 19.1%), mycophenolate mofetil (15.9%), and methotrexate (3.6%). Therapy choices were determined by the type of irAE. The time to onset of sr-/sd-irAEs after ICI initiation did not consistently differ from steroid-responsive irAEs. While 74.3% of sr-/sd-irAEs resolved and 13.1% had improved, 4.3% persisted, 3.9% resulted in permanent sequelae, and 4.3% in death with ongoing symptoms. Infliximab exhibited potential for earlier symptom improvement compared to mycophenolate mofetil or IVIG. Tumor response in patients with second-line treated sd-/sr-irAE was similar to patients with irAEs treated with steroids only. CONCLUSION: Several second-line therapies are effective against sr-/sd-irAEs, the second-line therapies show no clear negative impact on tumor response, and infliximab shows potential for faster improvement of symptoms. However, prospective comparative data are needed.

Extracorporeal Photopheresis as a Treatment Option for Immune-Related Adverse Events: Two Case Reports and a Prospective Study.

The wide use of immune checkpoint inhibitors has increased the frequency of immune-related adverse events (irAEs). While many are managed with corticosteroids or hormone substitution, up to 14.9% of irAEs are steroid-refractory or steroid-dependent and thus require second-line treatment. These should reduce irAE-related morbidity and mortality and induce a few side effects of their own while maintaining the antitumor response. There is little comparative data on second-line therapies for irAEs. Two cases of irAEs could not be sufficiently managed with corticosteroids and subsequently received treatment with extracorporeal photopheresis (ECP), including one patient with immune-related erosive oral lichen planus and one patient with immune-related colitis. In both cases, the irAE resolved with ECP in combination with immunosuppressive drugs, that is 4 weeks and 10 weeks after the start of ECP, respectively. To investigate this approach, a prospective clinical study that compares ECP and other second-line therapies for the treatment of steroid-refractory and steroid-dependent irAEs with regard to immunophenotype and therapy response has been designed. ECP could be a treatment option for steroid-refractory and steroid-dependent irAEs, given its good safety profile and lack of adverse effects on antitumor response. Comparative prospective studies are needed to generate an evidence base.

Federated Learning for Decentralized Artificial Intelligence in Melanoma Diagnostics.

Importance: The development of artificial intelligence (AI)-based melanoma classifiers typically calls for large, centralized datasets, requiring hospitals to give away their patient data, which raises serious privacy concerns. To address this concern, decentralized federated learning has been proposed, where classifier development is distributed across hospitals. Objective: To investigate whether a more privacy-preserving federated learning approach can achieve comparable diagnostic performance to a classical centralized (ie, single-model) and ensemble learning approach for AI-based melanoma diagnostics. Design, Setting, and Participants: This multicentric, single-arm diagnostic study developed a federated model for melanoma-nevus classification using histopathological whole-slide images prospectively acquired at 6 German university hospitals between April 2021 and February 2023 and benchmarked it using both a holdout and an external test dataset. Data analysis was performed from February to April 2023. Exposures: All whole-slide images were retrospectively analyzed by an AI-based classifier without influencing routine clinical care. Main Outcomes and Measures: The area under the receiver operating characteristic curve (AUROC) served as the primary end point for evaluating the diagnostic performance. Secondary end points included balanced accuracy, sensitivity, and specificity. Results: The study included 1025 whole-slide images of clinically melanoma-suspicious skin lesions from 923 patients, consisting of 388 histopathologically confirmed invasive melanomas and 637 nevi. The median (range) age at diagnosis was 58 (18-95) years for the training set, 57 (18-93) years for the holdout test dataset, and 61 (18-95) years for the external test dataset; the median (range) Breslow thickness was 0.70 (0.10-34.00) mm, 0.70 (0.20-14.40) mm, and 0.80 (0.30-20.00) mm, respectively. The federated approach (0.8579; 95% CI, 0.7693-0.9299) performed significantly worse than the classical centralized approach (0.9024; 95% CI, 0.8379-0.9565) in terms of AUROC on a holdout test dataset (pairwise Wilcoxon signed-rank, P < .001) but performed significantly better (0.9126; 95% CI, 0.8810-0.9412) than the classical centralized approach (0.9045; 95% CI, 0.8701-0.9331) on an external test dataset (pairwise Wilcoxon signed-rank, P < .001). Notably, the federated approach performed significantly worse than the ensemble approach on both the holdout (0.8867; 95% CI, 0.8103-0.9481) and external test dataset (0.9227; 95% CI, 0.8941-0.9479). Conclusions and Relevance: The findings of this diagnostic study suggest that federated learning is a viable approach for the binary classification of invasive melanomas and nevi on a clinically representative distributed dataset. Federated learning can improve privacy protection in AI-based melanoma diagnostics while simultaneously promoting collaboration across institutions and countries. Moreover, it may have the potential to be extended to other image classification tasks in digital cancer histopathology and beyond.

Line-field confocal optical coherence tomography, a novel non-invasive tool for the diagnosis of onychomycosis.

BACKGROUND AND OBJECTIVES: Onychomycosis is common and important to distinguish from other nail diseases. Rapid and accurate diagnosis is necessary for optimal patient treatment and outcome. Non-invasive diagnostic tools have increasing potential for nail diseases including onychomycosis. This study evaluated line-field confocal optical coherence tomography (LC-OCT) as a rapid non-invasive tool for diagnosing onychomycosis as compared to confocal laser scanning microscopy (CLSM), optical coherence tomography (OCT), and conventional methods. PATIENTS AND METHODS: In this prospective study 86 patients with clinically suspected onychomycosis and 14 controls were examined using LC-OCT, OCT, and CLSM. KOH-preparation, fungal culture, PCR, and histopathology were used as comparative conventional methods. RESULTS: LC-OCT had the highest sensitivity and negative predictive value of all methods used, closely followed by PCR and OCT. Specificity and positive predictive value of LC-OCT were as high as with CLSM, while OCT scored much lower. The gold standard technique, fungal culture, showed the lowest sensitivity and negative predictive value. Only PCR and culture allowed species differentiation. CONCLUSIONS: LC-OCT enables quick and non-invasive detection of onychomycosis, with advantages over CLSM and OCT, and similar diagnostic accuracy to PCR but lacking species differentiation. For accurate nail examination, LC-OCT requires well-trained and experienced operators.

MHC-I upregulation safeguards neoplastic T cells in the skin against NK cell-mediated eradication in mycosis fungoides.

Cancer-associated immune dysfunction is a major challenge for effective therapies. The emergence of antibodies targeting tumor cell-surface antigens led to advancements in the treatment of hematopoietic malignancies, particularly blood cancers. Yet their impact is constrained against tumors of hematopoietic origin manifesting in the skin. In this study, we employ a clonality-supervised deep learning methodology to dissect key pathological features implicated in mycosis fungoides, the most common cutaneous T-cell lymphoma. Our investigations unveil the prominence of the IL-32ß-major histocompatibility complex (MHC)-I axis as a critical determinant in tumor T-cell immune evasion within the skin microenvironment. In patients' skin, we find MHC-I to detrimentally impact the functionality of natural killer (NK) cells, diminishing antibody-dependent cellular cytotoxicity and promoting resistance of tumor skin T-cells to cell-surface targeting therapies. Through murine experiments in female mice, we demonstrate that disruption of the MHC-I interaction with NK cell inhibitory Ly49 receptors restores NK cell anti-tumor activity and targeted T-cell lymphoma elimination in vivo. These findings underscore the significance of attenuating the MHC-I-dependent immunosuppressive networks within skin tumors. Overall, our study introduces a strategy to reinvigorate NK cell-mediated anti-tumor responses to overcome treatment resistance to existing cell-surface targeted therapies for skin lymphoma.