Silver-Catalyzed Cascade Radical Bicyclization Reaction: An Atom- and Step-Economical Strategy Accessing γ-Lactam Containing Isoquinolinediones.

An efficient and convenient method for the cascade radical bicyclization of N-phenyl-4-pentenamides with N-methyl-N-methacryloylbenzamides under silver-catalyzed conditions is described. Based on this newly developed strategy, a variety of valuable γ-lactam containing isoquinolinediones can be effectively synthesized in one step within 0.5 h, during which two C-C bonds, one C-N bond, and two new N-heterocycles were formed concurrently. With N-aryl allyl carbamates, similar 2-oxazolidinone substituted isoquinolinedione compounds can likewise be produced. The approach demonstrates wide functional group compatibility, high step- and atom-economy, and the ability to be scaled up to gram quantities in a satisfactory yield. It marks the first instance of introducing γ-lactams into isoquinoline-1,3(2H,4H)-diones to construct linked hybrid drug-like molecules, thereby making this strategy highly attractive to drug discovery.

Paroxetine is an effective treatment for refractory erythema of rosacea: Primary results from the Prospective Rosacea Refractory Erythema Randomized Clinical Trial.

BACKGROUND: Patients with refractory erythema of rosacea have limited treatment options. OBJECTIVE: To evaluate the efficacy and safety of a 12-week course of paroxetine for moderate-to-severe erythema of rosacea. METHODS: In a multicenter, randomized, double-blinded, placebo-controlled trial, patients with refractory erythema of rosacea were randomly assigned (1:1) to receive paroxetine 25 mg daily or placebo for 12 weeks. RESULTS: Overall, 97 patients completed the study (paroxetine: 49; placebo: 48). The primary end point was the proportion of participants achieving Clinical Erythema Assessment success (defined as Clinical Erythema Assessment score of 0, 1, or ≥2-grade improvement from baseline) at week 12; this was significantly greater in the paroxetine group than in the placebo group (42.9% vs 20.8%, P = .02). Some secondary end points were met, such as flushing success with point reductions ≥2 (44.9% vs 25.0%, P = .04) and improvement in overall flushing (2.49 ± 3.03 vs 1.68 ± 2.27, P = .047), burning sensation (46.9% vs 18.8%, P = .003), and depression (P = .041). The most reported adverse events associated with paroxetine were dizziness, lethargy, nausea, dyspepsia, and muscle tremors. LIMITATIONS: Only a single-dosage regimen of paroxetine within a 12-week study was evaluated. CONCLUSIONS: Paroxetine is an effective and well-tolerated alternative treatment for moderate-to-severe erythema of rosacea.

lncRNA PRR34-AS1 knockdown represses neuroinflammation and neuronal death in traumatic brain injury by inhibiting microRNA-498 expression.

OBJECTIVE: Traumatic brain injury (TBI) can result in motor and cognitive dysfunction and is a possible risk factor for the subsequent development of dementia. However, the pathogenesis of TBI remains largely unclear. This study investigated the roles of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) in inflammation and neuronal apoptosis following TBI. METHODS: The lncRNA expression profiles in the cerebral cortices of TBI model mice and sham-operated mice were analyzed using microarray. We focused on an upregulated lncRNA, PRR34-AS1, because of its known modulatory role in apoptosis and inflammation. RESULTS: Our findings indicated that the knockdown of PRR34-AS1 inhibited inflammation and neuronal apoptosis and improved long-term neurological function. Using an in vitro, cell-based model of etoposide-induced primary cortical neuronal injury, we demonstrated that PRR34-AS1 levels were higher in injured model cells than in untreated control cells. Silencing of PRR34-AS1 suppressed etoposide-induced apoptosis and the production of inflammatory mediators in primary cortical neurons. PRR34-AS1 directly targets microRNA-498 (miR-498) in primary cortical neurons. Importantly, the inhibition of miR-498 expression counteracted the effects of PRR34-AS1 silencing on neuronal apoptosis and inflammation. CONCLUSIONS: These findings indicate that PRR34-AS1 may be a useful therapeutic target for TBI.

Multidimensional evaluation of offline and online education in dermatology teaching during the COVID-19 pandemic in a chinese teaching hospital: a cross-sectional study.

BACKGROUND: The global spread of Coronavirus disease (COVID-19) has led to the use of online teaching methods in universities, but the effect of online education on dermatology teaching remains unclear. METHODS: We designed a multi-dimensional teaching evaluation form for data collection, student teaching feedback evaluation, and assessed the scores of final theoretical and clinical skill tests, to compare the effective difference between online and offline teaching of dermatology. RESULTS: A total of 311 valid questionnaires of medical undergraduates were collected, 116 of which were enrolled for offline learning, and 195 for online learning. The average score of final theoretical test in the online teaching group had no significant difference compared with that in the offline teaching group (75.33 ± 7.37 vs.75.63 ± 7.51, P = 0.734). However, both scores of skin lesion recognition test and medical history collection test in the online teaching group were significantly lower than that in the offline teaching group (6.53 ± 0.86 vs. 7.10 ± 1.11, P < 0.001; 6.70 ± 1.16 vs. 7.62 ± 0.85, P < 0.001). Additionally, the scores of understanding skin lesions in the online teaching group were significantly lower than that in the offline group (P < 0.001), and the scores of overall understanding of skin diseases and evaluating their learning mode in the online teaching group also decreased (P < 0.05). Among the 195 students enrolled in the online learning group, 156 students (80.0%) recognized that the time of offline teaching should be increased. CONCLUSIONS: Both online and offline education can be used in dermatology theory teaching, but online education is less efficient in skin lesion and practical skills learning. More online teaching software with skin diseases characteristic should be developed to improve the online teaching effect.

Relationship Between Tea Drinking Behaviour and Rosacea: A Clinical Case-control Study.

The exact mechanisms of rosacea development are unknown, but it has been suggested that tea consumption may be associated with its development. To determine the relationship between tea drinking behaviour and rosacea, this clinical case-control study recruited 2,063 participants, who completed a questionnaire about tea drinking behaviour. A 1:1 ratio propensity score matching method was used to generate 619 cases and 619 controls. High-frequency tea drinking (3 times/day: adjusted odds ratio (aOR) 2.592; 95% confidence interval (95% CI) 1.225-5.485; ≥ 4 times/day; aOR 8.86; 95% CI 3.43-22.887), non-fermented tea (aOR 2.172; 95% CI 1.562-3.022), and hot tea (aOR 2.793; 95% CI 1.796-1.344) were associated with an increased risk of rosacea. Further results showed that these tea drinking behaviours were significantly associated with an increased risk of flushing (aOR 1.41; 95% CI 1.07-1.87) and erythema (aOR 1.48; 95% CI 1.10-2.00). Tea drinking behaviour is closely related to rosacea and.

Relationship between the exercise and severity of androgenic alopecia. / è¿åŠ¨ä¸Žé›„æ¿€ç´ æ€§ç§ƒå‘ç— æƒ å˜åŒ–çš„å ³ç³».

OBJECTIVES: Androgenic alopecia (AGA) is the most common type of alopecia. At present, the study on AGA mostly focuses on drugs, laser technology and hair transplantation, while the lifestyle factor that may delay the course of AGA and improve the condition of AGA is neglected. This study aims to investigate the relationship between the exercise and severity of androgenic alopecia, and to help AGA patients to choose suitable forms and amounts of exercise. METHODS: Patients, who were diagnosed with AGA from May 13, 2020 to August 25, 2020, were the subjects of the survey. Through the internet online questionnaire survey, the information regarding demographics, exercise forms (lifestyle exercises, stretching exercises, aerobic exercises, and anaerobic exercises), exercise frequency (0-2 times/week, 3-4 times/week, and 5-7 times/week), exercise duration (<30, 30-60, and >60 min/time), and family history (androgenic alopecia, alopecia areata, and scarring alopecia) was obtained. Combination of patient self-assessment and doctor's photo examination was used to evaluate the changes (improvement, aggravation, and natural course) of the condition after 6 months of exercise. Single factor analysis and logistic regression analysis were used to study the factors related to the changes before and after exercise. RESULTS: A total of 592 AGA patients were recruited. Among them, 215 were male patients (36.32%), and 377 were female patients (63.68%); 91 patients (15.37%) were improved after 6 months of exercise, 448 patients (75.68%) were in natural progress, and 53 patients (8.95%) were aggravated. A total of 439 AGA patients were involved in non-life sports. After 6 months of exercise, 137 patients (31.21%) with scalp itching and scaling were reduced, 65 patients (14.81%) with greasy scalp was reduced, and 204 patients (46.47%) with anxiety and depression symptoms were improved compared with the previous period, and 356 patients (81.10%) showed that their sleep quality was improved compared with before. The changes in the condition before and after exercise are related to exercise style (P<0.001), exercise frequency (P=0.033), exercise duration (P=0.044), but not related to gender (P=0.358) and family history (P=0.052). The degree of improvement in AGA patients, who performed aerobic exercise, was 5.416 times of those who only performed life-like exercises (OR=5.416, P<0.001); the degree of improvement in AGA patients with each exercise time >60 min was 3.106 times of those with each exercise time <30 min (OR=3.106, P=0009). CONCLUSIONS: Doing aerobic exercise or each exercise time >60 min helps to delay the progress of AGA and improve the symptom of AGA.

Suppression of miR-143 contributes to overexpression of IL-6, HIF-1α and NF-κB p65 in Cr(VI)-induced human exposure and tumor growth.

Hexavalent chromium [Cr(VI)] is a known occupational and environmental contaminant and carcinogen, but new mechanisms of Cr(VI)-induced carcinogenesis remain to be elucidated. In this study, we found that expression of miR-143 is decreased, whereas that of Interleukin 6 (IL-6) is increased in blood samples of Cr(VI)-exposing workers compared with corresponding unexposed workers. In addition, IL-6 was increased in human bronchial epithelial cells (BEAS-Cr) exposed to Cr(VI) compared with unexposed BEAS-2B cells. To further investigate the mechanisms by which Cr(VI) promotes these changes, we assessed the effects of miR-143 on gene expression and found that miR-143 suppressed expression of IL-6, HIF-1α and NF-κB p65, and that inhibiting miR-143 promoted expression of IL-6, HIF-1α and NF-κB p65. Interestingly, IL-6 regulated expression of HIF-1α, and HIF-1α transcriptionally regulated expression of IL-6. Experiments in animals showed that miR-143 inhibited tumor growth and angiogenesis by regulating IL-6/HIF-1α and downstream signaling pathways in vivo. These outcomes support the hypothesis that the miR-143/IL-6/HIF-1α pathway functions to regulate Cr(VI)-induced carcinogenesis.

Developmental exposure of decabromodiphenyl ether impairs subventricular zone neurogenesis and morphology of granule cells in mouse olfactory bulb.

Polybrominated diphenyl ethers (PBDEs) are additive flame retardants widely used in various products (e.g., textiles, consumer electronics, and plastics). Strong evidence indicates that PBDEs are developmental neurotoxicants that can cause neurodevelopmental disabilities and cognitive defects. Currently, decabromodiphenyl ether (BDE 209) is the only PBDE permitted for production in most countries. This study investigated the impact of BDE 209 on postnatal neurogenesis in the subventricular zone (SVZ) of ICR mice. For this purpose, pregnant ICR mice were orally administrated a daily dose of 0, 20 or 100 mg/kg BDE 209 from gestation day 6 to postnatal day 16. Bromodeoxyuridine (BrdU) incorporation and in vivo postnatal electroporation were performed to label the newly generated cells in the SVZ. On PND 16, a reduction of type-B stem cells was found in the 100 mg/kg group. BDE 209 also decreased the number of newborn cells and Calretinin+ interneurons in granule cell layer at the dose of 100 mg/kg. In addition, we observed impaired neuronal migration and dendritic development of newborn olfactory granule cells in both 20 and 100 mg/kg groups. In conclusion, developmental exposure to BDE 209 produces adverse effects on SVZ neurogenesis and dendritic growth of mouse offspring. These findings suggest a potential risk of BDE 209 in human neurodevelopment.

Association Between Endometrial/Subendometrial Vasculature and Embryo Transfer Outcome: A Meta-analysis and Subgroup Analysis.

OBJECTIVES: To examine the association between endometrial/subendometrial vasculature and in vitro fertilization-embryo transfer (IVF-ET) and frozen embryo transfer (FET) outcomes. METHODS: A meta-analysis of studies using endometrial/subendometrial 3-dimensional ultrasound and power Doppler angiography was performed to examine the vascularization index (VI), flow index (FI), and vascularization-flow index (VFI) in pregnant and nonpregnant women. Ten articles were analyzed, including 895 pregnant women and 882 nonpregnant women. RESULTS: A subgroup analysis of the measuring time showed that the endometrial VI (standardized mean difference [SMD], 0.57; 95% confidence interval [CI], 0.40, 0.74; P < .00001), FI (SMD, 0.56; 95% CI, 0.33, 0.78; P < .00001), and VFI (SMD, 0.45; 95% CI, 0.28, 0.61; P < .00001) measured on the ET day, but not on the human chorionic gonadotropin (hCG) trigger day, were significantly higher in pregnant than nonpregnant women. Additionally, the subendometrial FI was significantly increased in pregnant women on the both hCG day (SMD, 0.68; 95% CI, 0.31, 1.06; P = .004) and ET day (SMD, 0.30; 95% CI, 0.08, 0.52; P = .007). A subgroup analysis of cycle type showed that the endometrial VI (SMD, 0.52; 95% CI, 0.30, 0.74; P < .00001), FI (SMD, 0.44; 95% CI, 0.22, 0.66; P = .0001), and VFI (SMD, 0.45; 95% CI, 0.23, 0.67; P = .03) on the ET day were significantly increased in pregnant women in the FET subgroup. CONCLUSIONS: The subendometrial FI on the hCG day and endometrial VI, FI, and VFI on the ET day are potentially associated with pregnancy occurrence during IVF-ET. The endometrial VI, FI, and VFI could help identify appropriate timing for FET. However, the accuracy of these indices in predicting pregnancy occurrence must be further evaluated in additional large-scale studies.

Aberrant expression of LIMK1 impairs neuronal migration during neocortex development.

Neuronal migration is essential for the formation of cortical layers, and proper neuronal migration requires the coordination of cytoskeletal regulation. LIMK1 is a serine/threonine protein kinase that mediates actin dynamics by regulating actin depolymerization factor/cofilin. However, the role of LIMK1 in neuronal migration and its potential mechanism remains elusive. Here, we found that using the in utero electroporation to overexpress LIMK1 and its mutants, constitutively active LIMK1 (LIMK1-CA) and dominant-negative LIMK1 (LIMK1-DN), impaired neuronal migration in the embryonic mouse brain. In addition, the aberrant expression of LIMK1-WT and LIMK1-CA induced abnormal branching and increased the length of the leading process, while LIMK1-DN-transfected neurons gave rise to two leading processes. Furthermore, the co-transfection of LIMK1-CA and cofilin-S3A partially rescued the migration deficiency and fully rescued the morphological changes in migrating neurons induced by LIMK1-CA. Our results indicated that LIMK1 negatively regulated neuronal migration by affecting the neuronal cytoskeleton and that its effects were partly mediated by cofilin phosphorylation.

Graphene-coated nanowires with a drop-shaped cross section for 10 nm confinement and 1 mm propagation.

Strong confinement and long-range propagation of electromagnetic energy are longed for when designing efficient miniaturized photonic devices. Here, a graphene-coated nanowire with a drop-shaped cross section is proposed for guiding graphene surface plasmon polaritons to demonstrate an extremely long propagation length (1 mm) with ultra-strong mode confinement (10 nm), which results from the distinctive mode field distribution caused by both the top and bottom arcs of the waveguide. The combination of nanoconcentration and long-range propagation makes the waveguide very useful in nanophotonics, bio-photonics, and highly integrated photonic circuits.

Thin-wall tubes for coupling terahertz waves to metal wires.

Bare metal wires are among the most promising waveguides for guiding terahertz (THz) surface plasmon polaritons. In this study, a thin-wall tube is proposed for coupling THz waves to a metal wire with ultrahigh efficiency, which results from three high mode matchings for the two waveguides: field distributions, polarization directions, and wave vectors. According to the mode-overlap calculation, the coupling efficiency can be always between 84% and 94% when the frequency of THz waves is in the range of 0.2-3 THz and the metal wire radius is 0.5 mm. The maximum efficiency is as high as 94% at 0.5 THz, which is much higher than that obtained by the previous methods. We further conclude that the optimal coupling efficiency can be obtained when the outer tube radius is equal to the wire radius and simultaneously the real propagation constants of modes in the two waveguides are the same.

Hematological parameters as diagnostic biomarkers for patients with rosacea.

Rosacea is a chronic inflammatory skin disease. Systemic inflammation plays a vital role in the pathogenesis of rosacea. Many studies have reported hematological parameters as biomarkers for diseases with inflammatory processes. However, the diagnostic value of hematological parameters in rosacea remains a puzzle. This study involved 462 patients with rosacea, including erythematotelangiectatic rosacea (ETR, n = 179), papulopustular rosacea (PPR, n = 250), and phymatous rosacea (PhR, n = 33), and 924 healthy control subjects. Demographic, clinical, and laboratory information was collected and compared between rosacea subtypes. The hematological parameters of the patients and the healthy controls were compared retrospectively. The platelet volume (MPV) and platelet crit (PCT) were significantly upregulated, and the lower red cell distribution width (RDW) was significantly downregulated in rosacea compared to healthy controls, and they were identified as the diagnostic biomarkers for rosacea with area under the curve values of 0.828, 0.742, and 0.787, respectively. Comparing the hematological parameters among the three rosacea subtypes, we found that platelet-to-lymphocyte ratio and platelet-to-neutrophil ratio values in the ETR group were significantly higher than those in the PPR and PhR groups. The correlation between hematological parameters and clinical scores showed that RDW was negatively correlated with the Clinician Erythema Assessment score. However, there was no significant correlation between the Investigator Global Assessment score and hematological parameters. In conclusion, PCT, MPV, and RDW have diagnostic value for rosacea, and RDW is correlated with the severity of rosacea erythema, implying the potential applications of PCT, MPV, and RDW in the diagnosis and monitoring of rosacea.

Integrated Omics Reveal the Molecular Characterization and Pathogenic Mechanism of Rosacea.

Recent efforts have described the transcriptomic landscape of rosacea. However, little is known about its proteomic characteristics. In this study, the proteome and phosphoproteome of lesional skin, paired nonlesional skin, and healthy skin were analyzed by liquid chromatography coupled with tandem mass spectrometry. The molecular characteristics and potential pathogenic mechanism of rosacea were demonstrated by integrating the proteome, phosphoproteome, and previous transcriptome. The proteomic data revealed a significant upregulation of inflammation- and axon extension-related proteins in lesional skin and nonlesional skin versus in healthy skin, implying an inflammatory and nerve-hypersensitive microenvironment in rosacea skin. Of these, axon-related proteins (DPYSL2 and DBNL) were correlated with the Clinician's Erythema Assessment score, and neutrophil-related proteins (ELANE and S100A family) were correlated with the Investigator's Global Assessment score. Moreover, comorbidity-related proteins were differentially expressed in rosacea; of these, SNCA was positively correlated with Clinician's Erythema Assessment score, implying a potential correlation between rosacea and comorbidities. Subsequently, the integrated proteome and transcriptome demonstrated consistent immune disturbances at both the transcriptional and protein levels. The integrative analysis of the proteome and phosphoproteome revealed the key transcription factor network and kinase network that drive the dysregulation of immunity and vasculature in rosacea. In conclusion, our multiomics analysis enables more comprehensive insight into rosacea and offers an opportunity for, to our knowledge, previously unreported treatment strategies.

Correction: A Novel Convolutional Neural Network for the Diagnosis and Classification of Rosacea: Usability Study.

[This corrects the article DOI: 10.2196/23415.].

Granulomatous rosacea in Chinese patients: Clinical-histopathological analysis and pathogenesis exploration.

The pathogenesis of granulomatous rosacea (GR), the only variant of rosacea, is unclear. To investigate the differences between GR and non-granulomatous rosacea (NGR) in clinical characteristics, histopathological changes and gene expression for the purpose of providing new ideas on the pathogenesis of rosacea. A total of 30 GR and 60 NGR patients were included. Their clinical and histopathological information was collected retrospectively, and the characteristics of immune cell infiltration were investigated by multiple immunohistochemical staining. RNA sequencing and transcriptome analysis were performed on three pairs of skin samples from GR and NGR patients, respectively. Then, the expressions of candidate genes that were potentially associated with granuloma formation were verified by immunohistochemical staining. It was found that GR patients were more prone to the occurrence of rosacea in the forehead, periocular and perioral skin (p = 0.001, p < 0.001, p = 0.001), and presented more severe papules and pustules when compared with NGR patients (p = 0.032). For histopathological features, the inflammatory cells primarily infiltrated around hair follicles in the GR group and around blood vessels in the NGR group. In addition, the neutrophils were richer (p = 0.036) and the expression levels of CD4+ , CD8+ and CD68+ cells were higher (p = 0.047, p < 0.001, p < 0.001) in the GR group than in the NGR group. In addition, the GR group had apparent collagen hyperplasia (p = 0.026). A total of 420 differentially expressed genes (DEGs) were detected, and bioinformatics analysis showed that the DEGs were enriched in neutrophil activation, adaptive immune response and other biological processes. Lastly, the candidate genes related to neutrophil activation and collagen hyperplasia, i.e., Cathepsin S (CTSS), Cathepsin Z (CTSZ) and matrix metalloproteinases 9 (MMP9), were confirmed to be highly expressed in the GR group. The clinical and histopathological features of GR exhibited a very diverse pattern compared with NGR, and the underlying mechanisms may be related to neutrophil activation and collagen hyperplasia.

EGCG identified as an autophagy inducer for rosacea therapy.

Background: Rosacea is a common facial skin inflammatory disease featured by hyperactivation of mTORC1 signaling in the epidermis. Due to unclear pathogenesis, the effective treatment options for rosacea remain limited. Methods: Weighted gene co-expression network analysis (WGCNA) analyzed the relationship between epidermis autophagy and mTOR pathways in rosacea, and further demonstrated it through immunofluorescence and qPCR analysis. A potential therapeutic agent for rosacea was predicted based on the key genes of the WGCNA module. In vivo and in vitro experiments were conducted to verify its therapeutic role. Drug-target prediction (TargetNet, Swiss, and Tcmsp) and molecular docking offered potential pharmacological targets. Results: WGCNA showed that epidermis autophagy was related to the activation of mTOR pathways in rosacea. Next, autophagy was downregulated in the epidermis of rosacea, which was regulated by mTOR. In addition, the in vivo experiment demonstrated that autophagy induction could be an effective treatment strategy for rosacea. Subsequently, based on the key genes of the WGCNA module, epigallocatechin-3-gallate (EGCG) was predicted as a potential therapeutic agent for rosacea. Furthermore, the therapeutic role of EGCG on rosacea was confirmed in vivo and in vitro. Finally, drug-target prediction and molecular docking revealed that AKT1/MAPK1/MMP9 could be the pharmacological targets of EGCG in rosacea. Conclusion: Collectively, our findings revealed the vital role of autophagy in rosacea and identified that EGCG, as a therapeutic agent for rosacea, attenuated rosacea-like inflammation via inducing autophagy in keratinocytes.

Efficacy and safety of antibiotic agents in the treatment of rosacea: a systemic network meta-analysis.

Background: Antibiotics are considered the backbone of rosacea management, especially for controlling inflammatory papules and pustules. We aim to evaluate the efficacy and safety of varied prescriptions and doses of antibiotics in treating rosacea by network meta-analysis. Methods: In this study, we compared all available randomized controlled trials (RCTs) that have studied systemic and topical antibiotics and placebo in rosacea therapy. We searched databases such as the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, PubMed, Web of Science, and LILACS for published and unpublished RCTs on ClinicalTrials.gov before April 2023. The primary outcome was the improvement of the Investigator's Global Assessment (IGA) scores, and the secondary outcomes consisted of the improvement of the Patient's Global Assessment (PaGA) scores, Clinician's Erythema Assessment (CEA) scores, and adverse events (AEs). We used Bayesian random effects models for multiple treatment comparisons. Results: We identified 1,703 results through these databases. Thirty-one randomized trials with 8,226 patients were included. The heterogeneity and inconsistency between the trials were low, with a low risk of bias of all trials. Oral doxycycline 40 mg, minocycline 100 mg, and minocycline 40 mg, as well as topical ivermectin and metronidazole 0.75%, were effective in treating papules and pustules, thereby decreasing IGA in rosacea. Among these, minocycline 100 mg ranked top in efficacy. As for improving the PaGA scores, topical ivermectin, metronidazole 1%, and systemic oxytetracycline were effective, of which oxytetracycline worked the best. Both doxycycline 40 mg and metronidazole 0.75% presented no therapeutic effect for erythema. Considering the safety of the agents, systemic application of azithromycin and doxycycline 100 mg significantly increase the risk of AEs. Conclusion: Our review suggests that a high dosage of systemic minocycline is the most effective in treating rosacea phenotypes with papules and pustules with a low risk of AEs. However, there were no sufficient evidence-based data in exploring the influence of antibiotics on erythema. The phenotype of rosacea should be taken into consideration along with benefit and safety when making prescriptions due to AEs. Clinical Trial Registration: NCT(2016): http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/962/CN-01506962/frame.html NCT(2017): http://cochranelibrary-wiley.com/o/cochrane/clcentral/articles/764/CN-01565764/frame.html.

Whole genome sequencing identifies genetic variants associated with neurogenic inflammation in rosacea.

Rosacea is a chronic inflammatory skin disorder with high incidence rate. Although genetic predisposition to rosacea is suggested by existing evidence, the genetic basis remains largely unknown. Here we present the integrated results of whole genome sequencing (WGS) in 3 large rosacea families and whole exome sequencing (WES) in 49 additional validation families. We identify single rare deleterious variants of LRRC4, SH3PXD2A and SLC26A8 in large families, respectively. The relevance of SH3PXD2A, SLC26A8 and LRR family genes in rosacea predisposition is underscored by presence of additional variants in independent families. Gene ontology analysis suggests that these genes encode proteins taking part in neural synaptic processes and cell adhesion. In vitro functional analysis shows that mutations in LRRC4, SH3PXD2A and SLC26A8 induce the production of vasoactive neuropeptides in human neural cells. In a mouse model recapitulating a recurrent Lrrc4 mutation from human patients, we find rosacea-like skin inflammation, underpinned by excessive vasoactive intestinal peptide (VIP) release by peripheral neurons. These findings strongly support familial inheritance and neurogenic inflammation in rosacea development and provide mechanistic insight into the etiopathogenesis of the condition.