Successful treatment of recalcitrant generalized pustular psoriasis of pregnancy with spesolimab.

Generalized pustular psoriasis (GPP) in pregnancy can lead to severe complications for both mother and fetus. The treatment of this disease is challenging, especially in recalcitrant and severe cases. Until present, there are no evidence-based guidelines for the treatment of GPP in pregnancy. Spesolimab, a human monoclonal antibody against the IL-36 receptor, has recently attracted attention as a new therapy for GPP flare. This biologic provides rapid and sustained control of symptoms of GPP flare, although its use in pregnant women has not been reported to date. Here, we report a pregnant woman with refractory GPP who did not respond well to systemic steroids. Administration of spesolimab resulted in complete control of the disease and the birth of a healthy baby. Our case demonstrates that IL-36RN inhibitors are a potentially effective and safe treatment option for GPP in pregnancy.

The facial microbiome and metabolome across different geographic regions.

IMPORTANCE: Characterization of the skin microbiome and metabolome across geography will help uncover the climate factors behind the prevalence of skin disorders and provide suggestions for skincare products for people living in different geographic regions.

Brain glucose metabolism on [18F]-FDG PET/CT: a dynamic biomarker predicting depression and anxiety in cancer patients.

Objectives: To explore the correlation between the incidence rates of depression and anxiety and cerebral glucose metabolism in cancer patients. Methods: The experiment subjects consisted of patients with lung cancer, head and neck tumor, stomach cancer, intestinal cancer, breast cancer and healthy individuals. A total of 240 tumor patients and 39 healthy individuals were included. All subjects were evaluated by the Hamilton depression scale (HAMD) and Manifest anxiety scale (MAS), and were examined by whole body Positron Emission Tomography/Computed Tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG). Demographic, baseline clinical characteristics, brain glucose metabolic changes, emotional disorder scores and their relations were statistically analyzed. Results: The incidence rates of depression and anxiety in patients with lung cancer were higher than those in patients with other tumors, and Standard uptake values (SUVs) and metabolic volume in bilateral frontal lobe, bilateral temporal lobe, bilateral caudate nucleus, bilateral hippocampus, left cingulate gyrus were lower than those in patients with other tumors. We also found that poor pathological differentiation, and advanced TNM stage independently associated with depression and anxiety risk. SUVs in the bilateral frontal lobe, bilateral temporal lobe, bilateral caudate nucleus, bilateral hippocampus, left cingulate gyrus were negatively correlated with HAMD and MAS scores. Conclusion: This study revealed the correlation between brain glucose metabolism and emotional disorders in cancer patients. The changes in brain glucose metabolism were expected to play a major role in emotional disorders in cancer patients as psychobiological markers. These findings indicated that functional imaging can be applied for psychological assessment of cancer patients as an innovative method.

Comparative analysis of whole genomes and transcriptomes of Microsporum canis from invasive dermatophytosis and tinea capitis.

ABSTRACTGenomes of strains of the zoophilic dermatophyte Microsporum canis from invasive (disseminated and subcutaneous) and noninvasive (tinea capitis) infections were compared. Especially the disseminated strain showed significant syntenic rearrangements, including multiple translocations and inversions, and numerous SNPs and Indels in comparison to the noninvasive strain. In transcriptome analysis, both invasive strains were enriched for GO pathways related to components of the membrane, iron binding and heme binding, which possibly enables them to invade deeper into dermis and blood vessels. At 37 °C, invasive strains showed gene expression enriched for DNA replication, mismatch repair, N-glycan biosynthesis and ribosome biogenesis. The invasive strains were slightly less susceptible to multiple antifungal agents suggesting that acquired elevated drug resistance might be involved in the refractory disease courses. Patient with disseminated infection failed to respond to a combined antifungal treatment with itraconazole, terbinafine, fluconazole and posaconazole.

Clostridioides difficile infection: microbe-microbe interactions and live biotherapeutics.

Clostridioides difficile is a gram-positive, spore-forming, obligate anaerobe that infects the colon. C. difficile is estimated to cause nearly half a million cases in the United States annually, with about 29,000 associated deaths. Unfortunately, the current antibiotic treatment is not ideal. While antibiotics can treat the infections, they also disrupt the gut microbiota that mediates colonization resistance against enteric pathogens, including C. difficile; disrupted gut microbiota provides a window of opportunity for recurrent infections. Therefore, therapeutics that restore the gut microbiota and suppress C. difficile are being evaluated for safety and efficacy. This review will start with mechanisms by which gut bacteria affect C. difficile pathogenesis, followed by a discussion on biotherapeutics for recurrent C. difficile infections.

Mode of action of elasnin as biofilm formation eradicator of methicillin-resistant Staphylococcus aureus.

Biofilm is made up of microbes and their extracellular matrix, making microorganisms highly tolerant, resistant, and resilient to a wide range of antimicrobials. Biofilm treatment with conventional antimicrobial agents can accelerate the evolution and spread of resistance due to the reduced efficacy and increased gene transfer and differentiation within biofilms. Therefore, effective biofilm-targeting compounds are currently highly sought after. In the present study, we identified elasnin as a potent biofilm-targeting compound against methicillin-resistant Staphylococcus aureus (MRSA). Elasnin effectively inhibited biofilm formation and especially eradicated the pre-formed biofilms of MRSA with low cytotoxicity and low risk of resistance development and retains its activity in a chronic wound biofilms model. A comprehensive mechanistic study using multi-omics and confocal and scanning electron microscopy revealed that elasnin induced the biofilm matrix destruction in a time-dependent manner and interfered with the cell division during the exponential phase, primarily by repressing the expression of virulence factors. Cells released from the elasnin-treated biofilms exhibited a defective appearance and became more sensitive to beta-lactam antibiotic penicillin G. Through gene overexpression and deletion assay, we discovered the key role of sarZ during elasnin-induced biofilm eradication. Overall, the present study identified elasnin as a potent biofilm eradicator against MRSA that harbors potential to be developed for biofilm removal and chronic wound treatment, and provided new insights into the molecular targets for biofilm eradication in MRSA.

Discovery, Yield Improvement, and Application in Marine Coatings of Potent Antifouling Compounds Albofungins Targeting Multiple Fouling Organisms.

Marine biofouling caused huge economic losses of maritime industries. We aim to develop high-efficient, less-toxic, and cost-effective antifoulants to solve the problems of biofouling. In this study, we described the antifouling compounds albofungin and its derivatives (albofungin A, chrestoxanthone A, and chloroalbofungin) isolated from the metabolites of bacterium Streptomyces chrestomyceticus BCC 24770, the construction of high-yield strains for albofungin production, and application of albofungin-based antifouling coatings. Results showed that these albofungins have potent antibiofilm activities against Gram-positive and Gram-negative bacteria and anti-macrofouling activities against larval settlement of major fouling organisms with low cytotoxicity. With the best antifouling activity and highest yield in bacterial culture, albofungin was subsequently incorporated with hydrolyzable and degradable copolymer to form antifouling coatings, which altered biofilm structures and prevented the settlement of macrofouling organisms in marine environments. Our results suggested that albofungins were promising antifouling compounds with potential application in marine environments.

Altered skin fungal and bacterial community compositions in tinea capitis.

BACKGROUND: Tinea capitis is an infection of the scalp and hair shaft caused by dermatophytes that predominantly occurs in children. Skin fungal infections have been found to be associated with alterations in the overall bacterial and fungal communities. However, the scalp microbiome in tinea capitis have not been fully investigated. OBJECTIVES: To investigate and compare the scalp bacterial and fungal microbiomes between children with tinea capitis and healthy children and between children and adults. METHODS: Skin samples were collected from the scalp. Bacterial and fungal community compositions were analysed by amplification sequencing of the V3-V4 of 16S rDNA and ITS1-5F, respectively. RESULTS: The predominant fungi detected using amplicon sequencing were consistent with the culture- or real-time PCR-positive pathogens in most samples. Children with tinea capitis had lower fungal and higher bacterial Shannon diversity than healthy children. A higher relative abundance of pathogenic fungi and significant alterations in the bacterial community in the lesional sites of tinea capitis than healthy scalps. Compared with adults, healthy children were characterised by higher Shannon diversities with significantly lower relative abundances of Malassezia and Cutibacterium and higher relative abundances of Candida and Streptococcus. CONCLUSIONS: We demonstrated that tinea capitis was characterised by significant alterations in both fungal and bacterial communities and amplicon sequencing could be a complementary method for pathogen identification.

Bathiapeptides: Polythiazole-Containing Peptides from a Marine Biofilm-Derived Bacillus sp.

Bacteria in marine biofilms are a rich reservoir of natural products. To facilitate novel secondary metabolite discovery, we investigated the metabolic profile of a marine biofilm-derived Bacillus sp. B19-2 by combining bioinformatics and LC-UV-MS analyses. After dereplication and purification of putatively unknown compounds, a new family of compounds 1-8 was uncovered and named bathiapeptides. Structural elucidation using NMR, HRESIMS, ozonolysis, advanced Marfey's analysis, and X-ray diffraction revealed that bathiapeptides are polypeptides that contain a rare polythiazole moiety. These compounds exhibited strong cytotoxicity against Hep G2, HeLa, MCF-7, and MGC-803 cell lines, and the lowest IC50 value was 0.5 µM. An iterative biosynthesis logic in bathiapeptides' biosynthesis was proposed based on the identified chemical structures and putative gene cluster analysis.

Marine biofilms: diversity, interactions and biofouling.

Marine biofilms are ubiquitous in the marine environment. These complex microbial communities rapidly respond to environmental changes and encompass hugely diverse microbial structures, functions and metabolisms. Nevertheless, knowledge is limited on the microbial community structures and functions of natural marine biofilms and their influence on global geochemical cycles. Microbial cues, including secondary metabolites and microbial structures, regulate interactions between microorganisms, with their environment and with other benthic organisms, which affects their community succession and metamorphosis. Furthermore, marine biofilms are key mediators of marine biofouling, which greatly affect marine industries. In this Review, we discuss marine biofilm dynamics, including their diversity, abundance and functions. We also highlight knowledge gaps, areas for future research and potential biotechnological applications of marine biofilms.

CinA mediates multidrug tolerance in Mycobacterium tuberculosis.

The ability of Mycobacterium tuberculosis (Mtb) to resist and tolerate antibiotics complicates the development of improved tuberculosis (TB) chemotherapies. Here we define the Mtb protein CinA as a major determinant of drug tolerance and as a potential target to shorten TB chemotherapy. By reducing the fraction of drug-tolerant persisters, genetic inactivation of cinA accelerated killing of Mtb by four antibiotics in clinical use: isoniazid, ethionamide, delamanid and pretomanid. Mtb ΔcinA was killed rapidly in conditions known to impede the efficacy of isoniazid, such as during nutrient starvation, during persistence in a caseum mimetic, in activated macrophages and during chronic mouse infection. Deletion of CinA also increased in vivo killing of Mtb by BPaL, a combination of pretomanid, bedaquiline and linezolid that is used to treat highly drug-resistant TB. Genetic and drug metabolism studies suggest that CinA mediates drug tolerance via cleavage of NAD-drug adducts.

Ketoconazole 2% cream alters the skin fungal microbiome in seborrhoeic dermatitis: a cohort study.

BACKGROUND: Seborrhoeic dermatitis (SD) is a common chronic inflammatory dermatosis. Current theories on the pathogenesis of SD highlight the role of microbes on the skin surface. Ketoconazole is commonly used for the treatment of SD; however, there are limited data focusing on the effects of ketoconazole in shaping the skin microbiome in patients with SD. AIM: In this prospective cohort study, we used a high-throughput DNA sequencing method to characterize the cutaneous microbial communities of patients with SD before and after topical ketoconazole treatment. METHODS: In total, 30 patients with facial SD and 15 age- and sex-matched healthy controls (HCs) were enrolled in this study. Skin swabs were collected from SD lesional sites of the cheek at baseline, after ketoconazole treatment and 2 weeks post-treatment. DNA was extracted from skin samples. The bacterial 16S V3V4 rRNA and fungal internal transcribed spacer 1-5F regions were sequenced, and the microbial community compositions were analysed. RESULTS: Significantly lower bacterial and fungal diversities were detected at the lesional sites of facial SD compared with HCs. A decreased relative abundance of Cutibacterium and increased abundances of Malassezia and Staphylococcus were found in facial SD. Disease diversity was positively correlated with the relative abundances of Malassezia, Staphylococcus and Corynebacterium, while transepidermal water loss was negatively associated with the relative abundance of Cutibacterium. After ketoconazole treatment, fungal Shannon diversity and the relative abundances of Candida and Aspergillus were significantly increased at the lesional sites, and the relative abundance of Malassezia showed a decreasing trend. These changing trends were maintained until 2 weeks post-treatment. CONCLUSION: Facial SD showed lower fungal diversity accompanied by increased relative abundances of Malassezia and Staphylococcus and decreased relative abundance of Cutibacterium. Ketoconazole treatment reduced Malassezia and increased fungal diversity to restore skin microbial communities.

Dysbiosis of nail microbiome in patients with psoriasis.

Shifts in skin microbiome are considered to be involved in the pathogenesis of psoriasis. However, data on the microbial dysbiosis of nail psoriasis are scarce. In this study, we aim to investigate and characterize the nail bacterial and fungal microbiome in patients with psoriasis. Nail samples were collected prospectively from 36 subjects with nail psoriasis, 24 psoriatic subjects without nail involvement and 32 healthy controls. Amplicon sequencing was performed to evaluate the bacterial and fungal community compositions. Significant alterations in the bacterial microbiome were found in the nail samples of psoriatic patients. The unaffected nails in psoriatic patients were associated with higher bacterial diversity, and a higher relative abundance of Enhydrobacter, whereas nail psoriasis was correlated with a decreased relative abundance of Anaerococcus. Shifts in fungal community composition were reflected by a higher proportion of Malassezia in the unaffected nails of psoriatic patients and an increased proportion of Candida in psoriatic nails. Shifts in the nail microbiome in psoriasis suggest a potential role of microbes in the development of nail psoriasis. Future researches focusing on these microorganisms may help to explain the pathogenesis of psoriasis.

Dysbiosis of skin mycobiome in atopic dermatitis.

Atopic dermatitis (AD) is a chronic and relapsing inflammatory skin disease with an increasing prevalence worldwide. The aetiology and pathogenesis of AD have not been fully elucidated. Previous studies have suggested the role of fungi as a triggering factor in the development AD. Here we conducted a systematic review to investigate the skin mycobiome profiles in AD and to address whether there is an association between fungal dysbiosis and AD. We searched Medline/PubMed, Embase and Web of Science for research studies published in English between January 1st, 2010 and April 21st, 2021. A total of 11 human studies and 3 animal studies were included in this analysis. Fungal dysbiosis was observed in AD lesions with a depleted amount of Malassezia and a higher abundance of filamentous fungi. A positive correlation between Candida and Staphylococcus was also demonstrated in AD. We supposed that specific species of Malassezia spp. and Candida spp. may play a role in the pathogenesis of AD by interacting with the pathogenic bacteria. Topical application of emollients could improve the skin barrier function and restore the skin fungal flora by increasing the amount of Malassezia. Further studies focusing on the complex interplay between specific skin fungi and the host can provide better insight into the role of microorganisms in the pathogenesis of AD.

Free thyroxine, brain frailty and clock drawing test performance in patients with acute minor stroke or transient ischaemic attack.

OBJECTIVE: Thyroid dysfunction is associated with an elevated risk of cognitive decline, but the mechanism underlying this relationship is elusive. In this study, we investigate the relationships between free thyroxine (FT4), brain frailty and clock drawing test (CDT) performance in patients with acute minor stroke or transient ischaemic attack (TIA). DESIGN, PATIENTS AND MEASUREMENTS: A total of 204 consecutive patients admitted to our hospital within 72 h after the onset of acute minor stroke or TIA were prospectively enroled and categorized in terms of quartiles of FT4 between March 2018 and August 2019. Brain frailty on magnetic resonance imaging was rated according to previously published criteria. Cognitive performance was assessed with the CDT. RESULTS: Generalized linear analysis revealed that FT4 was independently associated with higher brain frailty score after adjusting potential confounders (ß, 0.03; 95% confidence interval [CI], 0.00-0.06; p = 0.0205), which is consistent with the result of FT4 (quartile) as a categorical variable (ß, 0.34; 95% CI, 0.01-0.68; p = 0.0059; ptrend = 0.0807). A nonlinear relationship was detected between FT4 and brain frailty score, which had an inflection point of 1.19. FT4 was also associated with poor CDT performance (odds ratio, 1.15; 95% CI, 1.04-1.26; p = 0.0051). And mediation analysis found that brain frailty partially mediated the positive relationship between FT4 and poor CDT performance (indirect effect = 0.0024; 95% CI, 0.0003-0.01, p = 0.04). CONCLUSIONS: Our findings suggested that a higher FT4 level was associated with a higher brain frailty score and poorer CDT performance, and brain frailty might play an important effect on the association between FT4 and cognitive decline.

Characterisation of the nail microbiome in psoriatic and nonpsoriatic patients with onychomycosis.

BACKGROUND: Onychomycosis (OM) is the most common infectious nail disease, and it occurs frequently in patients with psoriasis. Microbial community shifts have been suggested to play a role in psoriasis and fungal infection occurrence. OBJECTIVES: To investigate and compare nail microbial community compositions in psoriatic and nonpsoriatic patients with OM. METHODS: Toenail samples were collected from nonpsoriatic patients with OM, psoriatic patients with nail psoriasis (NP) and OM, patients with only NP and healthy controls. Bacterial and fungal community compositions were analysed by amplicon sequencing of the V3-V4 regions of the 16S rDNA gene and the ITS1 region, respectively. RESULTS: Psoriatic OM patients had higher bacterial and fungal alpha diversities. Taxonomic analysis revealed a significantly lower relative abundance of Trichophyton rubrum (32.88% vs 82.18%, p < .001) and an increased trend of the abundance of Candida in psoriatic patients with OM than in nonpsoriatic patients. Nonpsoriatic patients with OM had a higher abundance of Staphylococcus than healthy controls (59.66% vs 45.76%, p < .05). Trichophyton, Alternaria and Malassezia could accurately differentiate psoriatic and nonpsoriatic patients with OM, with an area under the curve (AUC) of 0.86. The severity of OM was positively correlated with the relative abundance of Trichophyton rubrum. Further, Trichophyton was positively correlated with Staphylococcus and negatively correlated with Corynebacterium, Anaerococcus, Malassezia and Alternaria. CONCLUSIONS: The nail microbiome in psoriatic patients with OM has distinct bacterial and fungal signatures, suggesting that different dysbiosis is associated with the pathogenesis of OM in psoriatic and nonpsoriatic patients.

Multiple acyl-CoA dehydrogenase deficiency kills Mycobacterium tuberculosis in vitro and during infection.

The human pathogen Mycobacterium tuberculosis depends on host fatty acids as a carbon source. However, fatty acid ß-oxidation is mediated by redundant enzymes, which hampers the development of antitubercular drugs targeting this pathway. Here, we show that rv0338c, which we refer to as etfD, encodes a membrane oxidoreductase essential for ß-oxidation in M. tuberculosis. An etfD deletion mutant is incapable of growing on fatty acids or cholesterol, with long-chain fatty acids being bactericidal, and fails to grow and survive in mice. Analysis of the mutant's metabolome reveals a block in ß-oxidation at the step catalyzed by acyl-CoA dehydrogenases (ACADs), which in other organisms are functionally dependent on an electron transfer flavoprotein (ETF) and its cognate oxidoreductase. We use immunoprecipitation to show that M. tuberculosis EtfD interacts with FixA (EtfB), a protein that is homologous to the human ETF subunit ß and is encoded in an operon with fixB, encoding a homologue of human ETF subunit α. We thus refer to FixA and FixB as EtfB and EtfA, respectively. Our results indicate that EtfBA and EtfD (which is not homologous to human EtfD) function as the ETF and oxidoreductase for ß-oxidation in M. tuberculosis and support this pathway as a potential target for tuberculosis drug development.

Skin microbiome alterations in seborrheic dermatitis and dandruff: A systematic review.

Seborrheic dermatitis (SD) and dandruff (DF) are common chronic inflammatory skin diseases characterized by recurrent greasy scales, sometimes with erythema and itchiness. Although the exact pathophysiology of the disease is still unclear, current theories highlight the role of microbes on the skin surface in the pathogenesis of SD. Here, we conducted a systematic review to investigate the skin microbiome alterations in patients with SD/DF. We searched Medline/PubMed, Embase and Web of Science for research studies published in English between 1 January 2000 and 31 December 2020. A total of 12 studies with 706 SD/DF samples and 379 healthy samples were included in this study. The scalp and face were predominated by the fungi of Ascomycota and Basidiomycota and the bacteria of Actinobacteria and Firmicutes. In general, the included studies demonstrated an increased Malassezia restricta/Malassezia globosa ratio and a reduction in the Cutibaterium/Staphylococcus ratio in the setting of SD/DF. Staphylococcus was associated with epidermal barrier damage, including elevated levels of trans-epidermal water loss and pH, while Cutibacterium had a positive correlation with water content. Malassezia was also found to be related to an increased itching score and disease severity. Further studies focusing on the interactions between various microbes and the host and microbes can help us to better understand the pathogenesis of SD/DF.