Systematic review and meta-analysis of the efficacy and safety of self-applied topical interventions for melasma

Hintergrund Das Melasma ist eine verbreitete dermatologische Erkrankung, die aufgrund ihrer Prädilektionsstellen im Bereich der sichtbaren Haut das emotionale Wohlbefinden und die allgemeine Lebensqualität der Betroffenen einschränken kann. Ein breites Spektrum an medizinischen, kosmetischen und pflanzlichen Therapieoptionen, bei nach dem heutigen Stand uneinheitlichen Ergebnissen und häufigen Rückfällen, erschwert die Auswahl der am besten geeigneten Behandlung. Ziel Ziel war es, randomisierte, kontrollierte, verblindete Studien zur topischen, selbstapplizierten Therapie bei Melasma systematisch auszuwerten und kritisch zu beurteilen. Methodik Eine systematische Übersichtsarbeit und Metaanalyse wurden im Einklang mit der Cochrane-Methodik und den Empfehlungen der Arbeitsgruppe GRADE erstellt. Es erfolgte eine systematische Literaturrecherche der elektronischen Datenbanken MEDLINE und Cochrane CENTRAL. Um eingeschlossen zu werden, mussten die folgenden Einschlusskriterien erfüllt sein: Eingeschlossen wurden randomisierte, kontrollierte Studien (RCT) mit mindestens 15 Teilnehmer*innen pro Studienarm, in denen ausdrücklich die Methode zur Erstellung der Randomisierungssequenz angegeben wurde und die Ergebnisbewertung verblindet war. Die Daten eingeschlossener Studien wurden, sofern möglich, gepoolt und metaanalysiert. Resultate Die systematische Literaturrecherche erzielte 1078 Treffer, von denen 36 Studien ein-geschlossen wurden. Die 47 berichteten Vergleiche von Interventionen zur Behandlung des Melasmas umfassen medizinische, kosmetische und pflanzliche Therapieoptionen. Für eine Vielzahl von Interventionen waren Direktvergleiche verfügbar, deren Ergebnisse jedoch heterogen waren. Ein Pooling von Daten war möglich für die Vergleiche von Tranexamsäure vs. Hydrochinon und Cysteamin vs. Placebo. Das Vertrauen in die Effektschätzer reichte von sehr gering bis hoch. Schlussfolgerung Die Ergebnisse zeigen, dass die etablierten Therapieoptionen Dreifachkombinationscreme, bestehend aus Fluocinolonacetonid, Hydrochinon und Tretinoin, sowie ihre Einzelkomponenten Hydrochinon und Tretinoin zu einer Aufhellung des Melasmas führen. Es gibt Hinweise, dass die Verwendung eines Breitspektrum-Sonnenschutzmittels, das sowohl das ultraviolette als auch das sichtbare Lichtspektrum abdeckt, die Wirksamkeit der Behandlung mit Hydrochinon erhöht. Wir konnten weitere vielversprechende medizinische, kosmetische und pflanzliche Behandlungsansätze identifizieren. Es sind weitere RCTs erforderlich, in denen die etablierten topischen Therapien verglichen werden, sowie Studien, die deren langfristige Wirksamkeit untersuchen, um unser Wissen über die geeignete Therapie zu erweitern.Background Melasma is a common dermatologic condition that can influence the emotional well-being and overall quality of life of patients due to affecting the visible skin. A broad range of medical, cosmetic, and herbal treatment options, characterized by inconsistent results and frequent relapses is available, making it difficult to select the most appropriate treatment. Objectives We systematically evaluated and critically assessed randomized, investigator-blinded clinical trials on topical self-applied interventions for melasma. Methods A systematic review and meta-analysis were performed in accordance with the Cochrane methodology and the GRADE working group recommendations. A systematic literature search of the MEDLINE and Cochrane CENTRAL electronic databases was performed. For the studies to be included, the following inclusion criteria had to be met: Randomized controlled trials (RCTs) with at least 15 participants per study arm, which explicitly stated the method for generating the random allocation sequence and that the outcome assessment was blinded, were included. Data from included studies were pooled and meta-analysed whenever possible. Results The systematic literature search yielded 1078 hits, of which 36 studies were included. The 47 reported comparisons of interventions for the treatment of melasma included medical, cosmetic, and herbal therapy options. Direct comparisons were available for a variety of interventions, but results were heterogeneous. Pooling of data was possible for the comparisons tranexamic acid (TXA) vs. hydroquinone (HQ) and cysteamine vs. placebo. Confidence in the effect estimates ranged from very low to high. Conclusion The results show that the established therapeutic options triple combination cream (TCC), consisting of fluocinolone acetonide, hydroquinone and tretinoin, and its individual components HQ and tretinoin lead to effective lightening of melasma. There is evidence that the use of a broad-spectrum sunscreen covering both the visible and ultraviolet light spectra increases the efficacy of treatment with HQ. We identified other promising medical, cosmetic, and herbal treatment approaches. Further RCTs comparing these established topical therapies are needed in the future, as well as studies investigating their long-term efficacy to increase our knowledge of appropriate therapy

Protocol to dissociate healthy and infected murine- and hamster-derived lung tissue for single-cell transcriptome analysis

In infectious disease research, single-cell RNA sequencing allows dissection of host-pathogen interactions. As a prerequisite, we provide a protocol to transform solid and complex organs such as lungs into representative diverse, viable single-cell suspensions. Our protocol describes performance of vascular perfusion, pneumonectomy, enzymatic digestion, and mechanical dissociation of lung tissue, as well as red blood cell lysis and counting of isolated cells. A challenge remains, however, to further increase the proportion of pulmonary endothelial cells without compromising on viability. For complete details on the use and execution of this protocol, please refer to Nouailles et al. (2021), Wyler et al. (2022), and Ebenig et al. (2022)

MicroRNA-223 Dampens Pulmonary Inflammation during Pneumococcal Pneumonia

Community-acquired pneumonia remains a major contributor to global communicable disease-mediated mortality. Neutrophils play a leading role in trying to contain bacterial lung infection, but they also drive detrimental pulmonary inflammation, when dysregulated. Here we aimed at understanding the role of microRNA-223 in orchestrating pulmonary inflammation during pneumococcal pneumonia. Serum microRNA-223 was measured in patients with pneumococcal pneumonia and in healthy subjects. Pulmonary inflammation in wild-type and microRNA-223-knockout mice was assessed in terms of disease course, histopathology, cellular recruitment and evaluation of inflammatory protein and gene signatures following pneumococcal infection. Low levels of serum microRNA-223 correlated with increased disease severity in pneumococcal pneumonia patients. Prolonged neutrophilic influx into the lungs and alveolar spaces was detected in pneumococci-infected microRNA-223-knockout mice, possibly accounting for aggravated histopathology and acute lung injury. Expression of microRNA-223 in wild-type mice was induced by pneumococcal infection in a time-dependent manner in whole lungs and lung neutrophils. Single-cell transcriptome analyses of murine lungs revealed a unique profile of antimicrobial and cellular maturation genes that are dysregulated in neutrophils lacking microRNA-223. Taken together, low levels of microRNA-223 in human pneumonia patient serum were associated with increased disease severity, whilst its absence provoked dysregulation of the neutrophil transcriptome in murine pneumococcal pneumonia

Single-cell-resolved interspecies comparison shows a shared inflammatory axis and a dominant neutrophil-endothelial program in severe COVID-19

A key issue for research on COVID-19 pathogenesis is the lack of biopsies from patients and of samples at the onset of infection. To overcome these hurdles, hamsters were shown to be useful models for studying this disease. Here, we further leverage the model to molecularly survey the disease progression from time-resolved single-cell RNA sequencing data collected from healthy and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected Syrian and Roborovski hamster lungs. We compare our data to human COVID-19 studies, including bronchoalveolar lavage, nasal swab, and postmortem lung tissue, and identify a shared axis of inflammation dominated by macrophages, neutrophils, and endothelial cells, which we show to be transient in Syrian and terminal in Roborovski hamsters. Our data suggest that, following SARS-CoV-2 infection, commitment to a type 1- or type 3-biased immunity determines moderate versus severe COVID-19 outcomes, respectively

A pulmonologist's guide to perform and analyse cross-species single lung cell transcriptomics

Single-cell ribonucleic acid sequencing is becoming widely employed to study biological processes at a novel resolution depth. The ability to analyse transcriptomes of multiple heterogeneous cell types in parallel is especially valuable for cell-focused lung research where a variety of resident and recruited cells are essential for maintaining organ functionality. We compared the single-cell transcriptomes from publicly available and unpublished datasets of the lungs in six different species: human (Homo sapiens), African green monkey (Chlorocebus sabaeus), pig (Sus domesticus), hamster (Mesocricetus auratus), rat (Rattus norvegicus) and mouse (Mus musculus) by employing RNA velocity and intercellular communication based on ligand-receptor co-expression, among other techniques. Specifically, we demonstrated a workflow for interspecies data integration, applied a single unified gene nomenclature, performed cell-specific clustering and identified marker genes for each species. Overall, integrative approaches combining newly sequenced as well as publicly available datasets could help identify species-specific transcriptomic signatures in both healthy and diseased lung tissue and select appropriate models for future respiratory research

Temporal omics analysis in Syrian hamsters unravel cellular effector responses to moderate COVID-19

In COVID-19, immune responses are key in determining disease severity. However, cellular mechanisms at the onset of inflammatory lung injury in SARS-CoV-2 infection, particularly involving endothelial cells, remain ill-defined. Using Syrian hamsters as a model for moderate COVID-19, we conduct a detailed longitudinal analysis of systemic and pulmonary cellular responses, and corroborate it with datasets from COVID-19 patients. Monocyte-derived macrophages in lungs exert the earliest and strongest transcriptional response to infection, including induction of pro-inflammatory genes, while epithelial cells show weak alterations. Without evidence for productive infection, endothelial cells react, depending on cell subtypes, by strong and early expression of anti-viral, pro-inflammatory, and T cell recruiting genes. Recruitment of cytotoxic T cells as well as emergence of IgM antibodies precede viral clearance at day 5 post infection. Investigating SARS-CoV-2 infected Syrian hamsters thus identifies cell type-specific effector functions, providing detailed insights into pathomechanisms of COVID-19 and informing therapeutic strategies

Key benefits of dexamethasone and antibody treatment in COVID-19 hamster models revealed by single cell transcriptomics

For COVID-19, effective and well-understood treatment options are still scarce. Since vaccine efficacy is challenged by novel variants, short-lasting immunity and vaccine hesitancy, understanding and optimizing therapeutic options remains essential. We aimed at better understanding the effects of two standard-of-care drugs, dexamethasone and anti-SARS-CoV-2 antibodies, on infection and host responses. By using two COVID-19 hamster models, pulmonary immune responses were analyzed to characterize effects of single or combinatorial treatments. Pulmonary viral burden was reduced by anti-SARS-CoV-2 antibody treatment, and similar or increased by dexamethasone alone. Dexamethasone exhibited strong anti-inflammatory effects and prevented fulminant disease in a severe disease model. Combination therapy showed additive benefits with both anti-viral and anti-inflammatory potency. Bulk and single-cell transcriptomic analyses confirmed dampened inflammatory cell recruitment into lungs upon dexamethasone treatment, and identified a specifically responsive subpopulation of neutrophils, thereby indicating a potential mechanism of action. Our analyses confirm the anti-inflammatory properties of dexamethasone and suggest possible mechanisms, validate anti-viral effects of anti-SARS-CoV-2 antibody treatment, and reveal synergistic effects of a combination therapy, thus informing more effective COVID-19 therapies

Live-attenuated vaccine sCPD9 elicits superior mucosal and systemic immunity to SARS-CoV-2 variants in hamsters

Vaccines play a critical role in combating the COVID-19 pandemic. Future control of the pandemic requires improved vaccines with high efficacy against newly emerging SARS-CoV-2 variants and the ability to reduce virus transmission. Here we compare immune responses and preclinical efficacy of the mRNA vaccine BNT162b2, the adenovirus-vectored spike vaccine Ad2-spike and the live-attenuated virus vaccine candidate sCPD9 in Syrian hamsters, using both homogeneous and heterologous vaccination regimens. Comparative vaccine efficacy was assessed by employing readouts from virus titrations to single-cell RNA sequencing. Our results show that sCPD9 vaccination elicited the most robust immunity, including rapid viral clearance, reduced tissue damage, fast differentiation of pre-plasmablasts, strong systemic and mucosal humoral responses, and rapid recall of memory T cells from lung tissue after challenge with heterologous SARS-CoV-2. Overall, our results demonstrate that live-attenuated vaccines offer advantages over currently available COVID-19 vaccines