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Actas Dermosifiliogr. 2022 May 10:S0001-7310(22)00391-X. doi: 10.1016/j.ad.2022.05.008. Online ahead of print. ABSTRACT BACKGROUND AND OBJECTIVE: Rosacea is a chronic acneiform skin disorder in which impaired skin barrier function can lead to sensitization to allergens. We aimed to analyze contact allergies in our patients with rosacea. MATERIAL AND METHODS: Retrospective cohort study of all patients who underwent patch testing in our skin allergy clinic between May 1991 and May 2019. RESULTS: A total of 200 patients with rosacea were referred to our clinic for patch testing during the study period; they represented 2.1% of all patch tested patients in the period. Eighty-one percent were women (mean age, 44.7 years). At least 1 positive patch test was recorded for 46.5%; 15% were of current relevance. The most frequent positive reaction was to nickel (26%), followed by cobalt chloride (6.5%), isothiazolinones (6%), p-phenylenediamine (5.5%), fragrance mix II (5%), and thimerosal (3.5%). The most common currently relevant patch test reactions were to isothiazolinones in 10 of the 200 patients (5%); to phenylenediamine, fragrance mix II, and toluensulfonamide formaldehyde resin in 4 patients (2%) each; and to tixocortol and fragrance mix I in 2 patients (1%) each. The allergen groups most often implicated were metals (of current relevance in 12.6%) and drugs (of current relevance in 25.8%). Preservatives and fragrances were the next most common allergen groups, and 70.8% and 43.7% of the positive reactions in these groups, respectively, were of current relevance. Cosmetics were the most frequent source of sensitization, followed by topical medications - notably corticosteroids and antifungal agents. CONCLUSIONS: We emphasize the high prevalence of allergic contact dermatitis in patients with rosacea, a finding which supports patch testing, especially if eruptions worsen when these patients use cosmetics and topical medications. PMID:35562047 | DOI:10.1016/j.ad.2022.05.008 {url} = URL to article

Photodiagnosis Photodyn Ther. 2022 May 7:102897. doi: 10.1016/j.pdpdt.2022.102897. Online ahead of print. ABSTRACT A 72-year-old woman suffering from multiple actinic keratosis (AK) complicating steroid-induced rosacea received 5-aminolevulinic acid-photodynamic therapy (ALA-PDT) in our outpatient clinic. Both AKs and rosacea got remission after one session of PDT. However, adverse effect of severe acute inflammatory response emerged with lasting hyperpigmentation. We then terminated the following PDT sessions in time. After skin care and closely follow-up for a half year, most symptoms and lesions of AK and rosacea disappeared with mild hyperpigmentation left. ALA-PDT is commonly recommended for multiple AKs based on effectiveness and noninvasiveness, but has controversial efficacy and safety for rosacea. The unusual excessive inflammation in this patient after ALA-PDT may due to skin barrier destruction, vasomotor dysfunction and the immune response by dead Demodex after PDT. This case indicated that carefully evaluation before ALA-PDT is of great importance, especially for those patients with complicated skin situation. For AKs complicating rosacea, modified parameters of ALA-PDT such as less ALA incubation time or reduced light dose should be further studied to achieve the optimal efficacy and safety of ALA-PDT and offer the best benefit. PMID:35537699 | DOI:10.1016/j.pdpdt.2022.102897 {url} = URL to article

Skinmed. 2022 Apr 30;20(2):157-158. eCollection 2022. NO ABSTRACT PMID:35532775 {url} = URL to article

Skin Therapy Lett. 2022 May;27(3):5-7. ABSTRACT Tetracycline-class drugs have been used for first-line treatment of moderate-to-severe acne and rosacea for decades. Recently, a new third generation tetracycline, sarecycline, was US FDA-approved for the treatment of moderate-to-severe acne. This narrow-spectrum tetracycline-derived antibiotic has been shown to be effective with an improved safety profile. PMID:35533371 {url} = URL to article More information

J Cosmet Dermatol. 2022 May 9. doi: 10.1111/jocd.15066. Online ahead of print. NO ABSTRACT PMID:35534917 | DOI:10.1111/jocd.15066 {url} = URL to article Purchase

Actas Dermosifiliogr. 2022 Mar;113(3):326-328. doi: 10.1016/j.ad.2020.03.018. Epub 2021 Jul 26. NO ABSTRACT PMID:35527381 | DOI:10.1016/j.ad.2020.03.018 {url} = URL to article

Actas Dermosifiliogr. 2022 Mar;113(3):T326-T328. doi: 10.1016/j.ad.2022.02.004. Epub 2022 Feb 11. NO ABSTRACT PMID:35526939 | DOI:10.1016/j.ad.2022.02.004 {url} = URL to article

J Cosmet Dermatol. 2022 May 4. doi: 10.1111/jocd.15044. Online ahead of print. ABSTRACT BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has led to a dramatic increase in the use of personal protective equipment (PPE). However, the increased use of PPEs may lead to facial skin complaints. AIMS: This survey study aims to evaluate the effect of the COVID-19 pandemic on facial dermatoses and complaints. METHODS: A total of 1017 volunteers (age 18 to 60 years), consisting of healthcare workers (HCWs), participated in the study. In the present study, healthcare professionals were screened for facial dermatoses and complaints between 1-15 April 2021 with an online survey. RESULTS: The vast majority in survey were women (82.4%) and between 26 and 35 years old (49.2%). The most new-onset facial complaints were acne (25.3%) and lip dryness (29.2%). Along with the pandemic, 50.9% of patients with seborrheic dermatitis had an increase in lesions. Another remarkable result was a 60.5% increase in acne complaints. Moreover, the rate of exacerbations of rosacea, melasma, and lip dryness was increased after the COVID-19 pandemic (39.1%, 22.0%, and 42.7%, respectively). Exacerbations of seborrheic dermatitis, acne, and lip dryness have occurred more frequently in females when compared males (p<0.001). CONCLUSIONS: The current pandemic has had serious impacts on facial dermatoses which had to be managed carefully. Compared to the pre-pandemic period, there was a significant increase in the frequency and severity of complaints in facial dermatoses related to PPE. If the complaints that may develop due to PPE are known in advance, their development can be prevented by taking precautions against them. PMID:35509253 | DOI:10.1111/jocd.15044 {url} = URL to article

Exp Dermatol. 2022 May 2. doi: 10.1111/exd.14584. Online ahead of print. NO ABSTRACT PMID:35491738 | DOI:10.1111/exd.14584 {url} = URL to article

J Am Acad Dermatol. 2022 Apr 28:S0190-9622(22)00703-4. doi: 10.1016/j.jaad.2022.04.037. Online ahead of print. NO ABSTRACT PMID:35490832 | DOI:10.1016/j.jaad.2022.04.037 {url} = URL to article

Actas Dermosifiliogr. 2022 Mar 2:S0001-7310(22)00185-5. doi: 10.1016/j.ad.2020.04.024. Online ahead of print. NO ABSTRACT PMID:35473802 | DOI:10.1016/j.ad.2020.04.024 {url} = URL to article

Photodiagnosis Photodyn Ther. 2022 Apr 22:102875. doi: 10.1016/j.pdpdt.2022.102875. Online ahead of print. ABSTRACT OBJECTIVE: To systematically review the efficacy of photodynamic therapy (PDT) in the treatment of rosacea. METHODS: PubMed, Embase, and Cochrane Library databases were searched for articles published by February 5, 2022, using "photodynamic therapy" and "rosacea" as the keywords. RESULTS: Nine studies were included in the review. The number of patients varied from 1 to 30 in each study, with ages ranging from 18 to 76 years. Methyl aminolevulinate (MAL) and aminolevulinic acid (ALA) were used as the photosensitizer, and red light, blue light, intense pulsed light (IPL), long-pulsed dye laser (LPDL), pulsed dye laser (PDL), and tungsten lamp were used as the light or laser source. The follow-up time ranged from one month to 25 months. Most of the studies showed a satisfactory clinical response, and the side effects were tolerant and temporary. CONCLUSION: Current studies have provided preliminary evidence that PDT is an efficient and safe therapy in treating rosacea. However, rigorous randomized control trials (RCTs) with a larger sample size and longer follow-up time are warranted to verify the certain curative effects of PDT in treating rosacea and explore the most appropriate treatment schedule. PMID:35470124 | DOI:10.1016/j.pdpdt.2022.102875 {url} = URL to article

Cureus. 2022 Mar 19;14(3):e23308. doi: 10.7759/cureus.23308. eCollection 2022 Mar. ABSTRACT Rosacea granulomatosis is a common, chronic skin disorder that primarily affects the central face, namely the cheek, nose, chin, and central forehead. Although rosacea is mainly a disorder of innate and adaptive immunity, a variety of endogenous and exogenous triggers such as Demodex may stimulate it. Often found as commensal organisms in human skin, Demodex ​​​​​​​can be parasitic if there is a change in the host's cutaneous environment. This is especially relevant for immunosuppressed patients, who need prompt treatment to prevent further complications. We review the literature regarding rosacea granulomatosis in immunosuppression and present an acute myelogenous leukemia patient with severe neutropenia, which may have promoted the development of rosacea due to Demodex ​​​​​​​mite proliferation. This local proliferation of the ectoparasite on the face can cause an atypical skin rash that mimics severe infections in the setting of neutropenia. PMID:35464516 | PMC:PMC9015070 | DOI:10.7759/cureus.23308 {url} = URL to article

J Clin Aesthet Dermatol. 2022 Apr;15(4):12. NO ABSTRACT PMID:35465034 | PMC:PMC9017669 {url} = URL to article

Dermatol Ther. 2022 Apr 20:e15528. doi: 10.1111/dth.15528. Online ahead of print. ABSTRACT During the COVID-19 pandemic, teledermatology services were set up and enhanced to take care of those benign conditions like cutaneous warts (CWs) which if undiagnosed or treated with delay, could have worsened, enlarged, and potentially spread to the community. The aim of this hybrid exploratory trial was to combine face-to-face clinical and dermoscopic evaluation with teledermatology follow-up in the management of CWs with a cryogenic pen based on nitrous oxide for home treatment. Twelve adult patients affected by CWs were enrolled. During the first face-to-face visit, single CWs were selected for the study by clinical and dermoscopic evaluation. The home schedule consisted of 1 application to be repeated after 2 weeks, when signs of CWs were still evident. Patients were also asked to send a clinical photo of the treated lesion at weekly intervals. A final face-to-face evaluation was scheduled to verify the response to home treatment by clinical and dermoscopy evaluation. A total of 20 CWs located on the trunk and the extremities were treated: a complete clinical and dermoscopic resolution was observed in 16 out of 20 lesions (80%), and a partial response in 2 cases. The adverse events observed during treatment were comparable to those normally observed with cryotherapy of CWs. In conclusion, home treatment of CWs with the cryogenic pen, that should be always preceded by dermatologist diagnosis and prescription, is safe and effective, especially if combined with face-to-face and teledermatology consultations, pointing out its important role during pandemic times or in any other environmental limitations that may impair the access to medical care services. The combination of face-to-face consultations for initial and final visits and teledermatology during the treatment phase could represent a model for other dermatologic conditions as well (e.g. acne, rosacea, psoriasis, atopic eczema etc.). This article is protected by copyright. All rights reserved. PMID:35441776 | DOI:10.1111/dth.15528 {url} = URL to article

J Dermatolog Treat. 2022 Apr 18:1-4. doi: 10.1080/09546634.2022.2062282. Online ahead of print. ABSTRACT Zinc has numerous pharmacological uses in dermatology. Its antioxidant and immunomodulatory properties are thought to correlate with its efficacy in acne vulgaris and leishmaniasis, amongst other cutaneous conditions. We conducted a review of the literature on the use of zinc in dermatology; in particular, we investigated its role in acne vulgaris, hair loss, hidradenitis suppurativa, leishmaniasis, and warts. We searched MEDLINE selecting only articles in English and evaluating the evidence using the Oxford Center of Evidence-Based Medicine 2011 guidance. This review has found evidence to support the use of zinc in patients in infectious conditions (leishmaniasis and warts), inflammatory conditions (acne rosacea, hidradenitis suppurativa) and in hair loss disorders.Ppatients with zinc deficiency should also receive oral supplementation. Further research and large randomized controlled trials are required to investigate the role of zinc as a monotherapy. PMID:35437093 | DOI:10.1080/09546634.2022.2062282 {url} = URL to article Do Rosacea Sufferers have Nutritional Deficiencies? (members only)

Case Rep Dermatol Med. 2022 Apr 14;2022:9944727. doi: 10.1155/2022/9944727. eCollection 2022. ABSTRACT To date, the occurrence of adverse events following immunization after COVID-19 vaccine is rare, and their report is still very poor; however, causality assessment is conducted to identify the associated cause, if they occur. In this case report, we present a case of an association of three cutaneous manifestations (maculopapular exanthem with enanthem, site injection reaction, and rosacea exacerbation) occurring three days after taking the first dose of AstraZeneca AZD1222 vaccine. PMID:35433058 | PMC:PMC9008489 | DOI:10.1155/2022/9944727 {url} = URL to article

Dermatol Ther. 2022 Apr 14:e15517. doi: 10.1111/dth.15517. Online ahead of print. NO ABSTRACT PMID:35426191 | DOI:10.1111/dth.15517 {url} = URL to article

J Invest Dermatol. 2022 Apr 9:S0022-202X(22)00273-1. doi: 10.1016/j.jid.2022.03.026. Online ahead of print. ABSTRACT Rosacea is a chronic inflammatory skin disorder that manifests abnormal enhanced sensitivity to environment stimuli. The decreased prevalence of rosacea in aged population has been reported, but the underlying mechanism is unclear. Here we confirm that the rosacea-like skin inflammation induced by Cathelicidin LL37 is alleviated in aged mice and mice with progeria. Primary mouse keratinocytes isolated from aged mice and human dermal fibroblasts (HDFs) that undergo senescence present a much lower sensitivity to pro-inflammatory stimuli. Mechanistically, toll-like receptor 2 (TLR2) is downregulated in the skin of both aged population and mice. Knockdown of TLR2 in young HDFs mimics the attenuated immune response to LL37 and TNFα evidenced in aged HDFs, while overexpression of TLR2 in aged HDFs rescued this attenuation. At the molecular level, in response to inflammatory stimuli SIRT7 mediates the upregulation of TLR2, which promotes the activation of NF-κB signaling. The decay of SIRT7 confers age-related decline of TLR2-NF-κB signaling. While overexpression of exogenous Sirt7 abrogates skin immune reactivity reduction in aged mice, loss of Sirt7 alleviates the rosacea-like features in mice. Thus, we reveal a SIRT7-TLR2-NF-κB axis that can be targeted for the improvement of rosacea. PMID:35413292 | DOI:10.1016/j.jid.2022.03.026 {url} = URL to article

Int J Dermatol. 2022 Apr 10. doi: 10.1111/ijd.16162. Online ahead of print. ABSTRACT BACKGROUND: Data on Demodex in the immunosuppressed state is limited, focusing mainly on patients with human immunodeficiency virus and hematological malignancies. The aim of this study was to describe the manifestations of facial demodicosis in diverse immunosuppressive states. METHODS: The medical records of all patients followed at a Demodex outpatient clinic of a tertiary medical center from January 2008 to November 2020 were retrospectively reviewed. Data on patients who were immunosuppressed while with demodicosis were retrieved. RESULTS: The cohort included 28 patients (17 women and 11 men; median age, 58 years). Types of immunosuppression included treatments with hydroxyurea for polycythemia vera/essential thrombocytosis, mycophenolic acid, tacrolimus, and prednisone for liver and/or kidney transplantation, prednisone with cyclosporine/methotrexate/azathioprine/rituximab mainly for autoimmune diseases, mercaptopurine with/without anti-tumor necrosis factor alpha (TNF-α) for Crohn's disease, chemotherapy for neoplasms, anti-TNF-α for psoriasis, and Cushing's syndrome. The clinical types of demodicosis included: papulopustular, erythematotelangiectatic and fulminant rosacea, hyperpigmented, pityriasis folliculorum, pustular folliculitis, and dermatitis. The diverse clinical presentations led to various differential diagnoses. Topical treatment with ivermectin (monotherapy/combination with other treatments) was effective. CONCLUSION: Clinicians treating immunosuppressed patients should be familiar with the different forms of demodicosis and include them in the differential diagnosis of facial eruptions. PMID:35398883 | DOI:10.1111/ijd.16162 {url} = URL to article https://irosacea.org/demodectic/

J Inflamm Res. 2022 Mar 31;15:2141-2156. doi: 10.2147/JIR.S356551. eCollection 2022. ABSTRACT OBJECTIVE: Rosacea is a chronic inflammatory skin disease with high morbidity. Previous studies have described the contribution of skin barrier dysfunction (SBD) in the progression of rosacea, but the specific mechanism remains unclear. In this study, we aim to investigate the key genes that may involve SBD-mediated rosacea aggravation. METHODS: In this study, we evaluated the SBD patterns of rosacea based on the expression of 23 skin barrier-related genes (SBRGs) using a consensus clustering analysis, and revealed the SBD-mediated immune cells infiltration in rosacea using GSE65914 dataset. The key genes associated with SBD and rosacea progression were identified using WGCNA analysis and then verified in rosacea mice model. RESULTS: Two distinct SBD patterns (moderate- and high-SBD patterns) were determined in rosacea. GO, KEGG and GSEA analysis revealed the differently immune-related signal pathways between two SBD patterns in rosacea. The XCell immune cell assays showed that the increased immune infiltration with SBD. Subsequently, the WGCNA analysis identified STAT3 as the hub gene related to rosacea and SBD, and correlation analysis revealed that STAT3 could contribute to the progression of rosacea partly by dysregulating immune infiltration via activating the cytokine/chemokines signal. Finally, the up-regulated STAT3 was verified in the epidermis of rosacea tissues and correlated with SBRGs expression using IHC and epidermal transcriptome data of rosacea. The vivo experiment showed that tape stripping-induced SBD evidently induced the expression of STAT3 and increased CD4+ T cell infiltration in LL37-induced rosacea-like skin lesion in mice. CONCLUSION: In conclusion, our results showed that the destruction of the skin barrier aggravates the inflammation levels and immune infiltration of rosacea partly by activating STAT3-mediated cytokine signal pathways in keratinocytes. PMID:35392024 | PMC:PMC8980297 | DOI:10.2147/JIR.S356551 {url} = URL to article More information on Cytokines and Rosacea (you will need to subscribe to view this article)

J Cosmet Dermatol. 2022 Apr 7. doi: 10.1111/jocd.14972. Online ahead of print. ABSTRACT BACKGROUND: Acne is a chronic, inflammatory skin disorder of pilosebaceous units. Tranexamic acid (TXA) acts as a plasmin inhibitor to reduce blood loss, and is also used to treat rosacea due to its anti-inflammatory effects. Some parts of the pathogenesis of rosacea are similar to inflammatory acne. OBJECTIVES: The study aimed to evaluate the efficacy of 10% TXA serum in treating acne and its adverse effects. METHODS: A randomized, double-blind, placebo-controlled, split-face study was performed on 18 mild to moderate acne patients. Patients applied 10% TXA serum on one side of the face and placebo on another side twice daily for 8 weeks. Acne lesion counts and adverse effects were evaluated every 2 weeks. RESULTS: Significant differences in total inflammatory acne counts were observed between TXA and placebo since week 4 (p = 0.008). TXA mainly reduced papules and pustules, as papule counts significantly decreased since the 8th week (p = 0.046) and pustule counts significantly reduced since week 8 (p = 0.033). Moreover, physicians also found that TXA serum reduced the redness of the skin, corresponding with the imaging from VISIA® Skin Analysis. The anti-inflammatory effect of TXA resulted in less PIE and PIH. Adverse effects, including erythema and scaling, were treated by applying any moisturizing cream. CONCLUSION: Topical 10% TXA can reduce inflammatory acne effectively. Adverse effects were minor and treat easily. PMID:35388589 | DOI:10.1111/jocd.14972 {url} = URL to article https://irosacea.org/forums/topic/4145-tranexamic-acid-solution/

JAMA Dermatol. 2022 Apr 6. doi: 10.1001/jamadermatol.2022.0526. Online ahead of print. ABSTRACT IMPORTANCE: Four distinct rosacea subtypes have traditionally been recognized, but the frequency of these subtypes among patients with rosacea remains unknown. OBJECTIVE: To assess the frequency of 4 rosacea subtypes. DATA SOURCES: This systemic review and meta-analysis included a search of 2 databases, PubMed and Embase, from inception of the databases to November 2, 2021. The search was filtered to include only studies of human participants published in English, French, and German. STUDY SELECTION: Studies were screened independently by 2 of the authors and were included if they were original with a sample size of 25 or more patients and reported absolute numbers or frequency of patients affected by rosacea subtypes. Studies that did not report sufficient data to calculate the proportions of subtypes were excluded. DATA EXTRACTION AND SYNTHESIS: Data extraction was performed independently and in duplicate by 2 of the authors, using the search term rosacea, according to the Preferred Reporting items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. The search term, objectives, and study protocol methods were defined before the study was initiated. A total of 292 studies were included for full-text assessment. Owing to the heterogeneity of the included studies, a random-effects model was used. MAIN OUTCOME AND MEASURES: The main outcome was the proportion of patients with rosacea in each of the 4 major subtype groups defined by the 2002 National Rosacea Society classification system. Measures were absolute numbers or frequency of patients affected by each of the 4 rosacea subtypes. RESULTS: A total of 39 studies examining 9190 patients with rosacea were included. The pooled proportion of erythematotelangiectatic rosacea was 56.7% (95% CI, 51.4%-62.0%), of papulopustular rosacea was 43.2% (95% CI, 38.8%-47.6%), of phymatous rosacea was 7.4% (95% CI, 6.1%-8.9%), and of ocular rosacea was 11.1% (95% CI, 6.7%-16.3%). Subtype distribution occurred equally among men and women except for phymatous rosacea, which was more prevalent in men. Studies from Africa showed the lowest proportion of erythematotelangiectatic rosacea. Differences in frequency of subtypes were observed when stratification by publication year was performed. CONCLUSION AND RELEVANCE: In this systematic review and meta-analysis, differences were found in rosacea subtypes by patient sex and by continent of origin and publication year of included studies. Erythematotelangiectatic and papulopustular rosacea were the most prevalent subtypes, but data should be interpreted with caution. Future studies should use the phenotype-based rosacea approach. PMID:35385049 | DOI:10.1001/jamadermatol.2022.0526 {url} = URL to article Learn about rosacea phenotypes • More information on Subtypes • RRDi Members Only Subtype classification of rosacea is controversial

Front Immunol. 2022 Mar 14;13:881277. doi: 10.3389/fimmu.2022.881277. eCollection 2022. ABSTRACT [This corrects the article DOI: 10.3389/fimmu.2021.609615.]. PMID:35371112 | PMC:PMC8964351 | DOI:10.3389/fimmu.2022.881277 {url} = URL to article RRDi Members Only Rosacea and Carvedilol

Front Med (Lausanne). 2022 Mar 15;9:820119. doi: 10.3389/fmed.2022.820119. eCollection 2022. ABSTRACT BACKGROUND: Blepharitis is a common eye disorder that may be overlooked by patients and clinical practitioners. The symptoms of blepharitis often manifest as irritation, a burning sensation, grittiness, and itchiness and may decrease visual acuity if not treated promptly. Meibomian gland dysfunction (MGD), a common cause of blepharitis, is believed to be associated with increased inflammatory marker levels that may disrupt the composition of lipids produced by the sebaceous glands in the eyelids and ultimately cause tear film instability. METHODS: This is a retrospective, population-based study using National Health Insurance Research Database (NHIRD) data from a 14-year period (2000-2015). Pearson chi-squared and Student's t-tests were used to assess the differences in categorical and continuous variables, respectively, between statin users and non-statin users. Univariate and multivariate Cox regression analyses were performed to calculate the hazard ratios (HRs) after adjusting for confounders. Kaplan-Meier analysis was used to assess the cumulative risk of blepharitis between the two cohorts. RESULTS: A total of 67,014 patients who used statins were enrolled as the study cohort, and 268,056 patients who did not use statins were enrolled as the comparison cohort. The incidence of blepharitis was 3.04% with statin treatment and 3.72% without statin treatment (p < 0.001). Patients who used statins had a lower risk of developing blepharitis [adjusted hazard ratio (aHR): 0.746, p < 0.001] than those who did not. In addition, diabetes mellitus (DM), hypertension, coronary heart disease (CHD), stroke, chalazion, rosacea, Sjogren syndrome, psoriasis and atopy were found to be possible risk factors for blepharitis. CONCLUSION: Statin use can decrease the risk of developing blepharitis. However, further prospective studies are needed to evaluate statin treatment for various subtypes of blepharitis and to identify the associated mechanism. PMID:35372440 | PMC:PMC8965040 | DOI:10.3389/fmed.2022.820119 {url} = URL to article