BackgroundEpidemic outbreaks of multi-drug resistant (MDR) Acinetobacter baumannii (AB) in intensive care units (ICUs) are increasing. The incidence of MDR AB bacteremia, which develops as a result of colonization, is increasing through widespread dissemination of the pathogen, and further colonization. We sought to determine risk factors for MDR AB bacteremia in patients colonized with MDR AB in the ICU.MethodsWe conducted a retrospective, observational study of 200 patients colonized with MDR AB in the ICU at Severance Hospital, South Korea during the outbreak period between January 2008 and December 2009.ResultsOf the 200 patients colonized with MDR AB, 108 developed MDR AB bacteremia, and 92 did not. APACHE II scores were higher in bacteremic than non-bacteremic patients at the time of ICU admission and colonization (24.0 vs. 21.6; P = 0.035, 22.9 vs. 16.8; P < 0.001, respectively). There was no difference between the two groups in the duration of time from ICU admission to colonization (7.1 vs. 7.2 days; P = 0.923), but the duration of time at risk was shorter in bacteremic patients (12.1 vs. 6.0 days; P = 0.016). A recent invasive procedure was a significant risk factor for development of bacteremia (odds ratio = 3.85; 95% CI 1.45-10.24; P = 0.007). Multivariate analysis indicated infection and respiratory failure at the time of ICU admission, maintenance of mechanical ventilation, maintenance of endotracheal tube instead of switching to a tracheostomy, recent central venous catheter insertion, bacteremia caused by other microorganism after colonization by MDR AB, and prior antimicrobial therapy, were significant risk factors for MDR AB bacteremia.ConclusionsPatients in the ICU, colonized with MDR AB, should be considered for minimizing invasive procedures and early removal of the invasive devices to prevent development of MDR AB bacteremia.

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Purpose We aimed to investigate the effects of dupilumab on 1) the permeability and antimicrobial barrier, 2) the composition of the skin microbiome, and 3) the correlation between changes in skin barrier properties and microbiota in atopic dermatitis (AD) patients. Methods Ten patients with severe AD were treated with dupilumab for 12 weeks. Disease severity was assessed using the Eczema Area and Severity Index (EASI). Skin barrier function was evaluated by measuring transepidermal water loss, stratum corneum (SC) hydration, and pH. The following parameters were analyzed in the pre- and post-treatment SC samples; 1) skin microbiota using 16S rRNA gene sequencing, 2) lipid composition using mass spectrometry, and 3) human β-defensin 2 (hBD-2) expression using quantitative reverse transcription polymerase chain reaction. Results SC hydration levels in the lesional and non-lesional skin increased after 12-week dupilumab therapy (24.2%, P < 0.001 and 59.9%, P < 0.001, respectively, vs. baseline) and correlated with EASI improvement ( r = 0.90, P < 0.001 and r = 0.85, P = 0.003, respectively). Dupilumab increased the long-chain ceramide levels in atopic skin (118.4%, P = 0.028 vs. baseline) that correlated with changes in SC hydration ( r = 0.81, P = 0.007) and reduced the elevated hBD-2 messenger RNA levels (−15.4%, P = 0.005 vs. baseline) in the lesional skin. Dupilumab decreased the abundance of Staphylococcus aureus. In contrast, the microbial diversity and the abundance of Cutibacterium and Corynebacterium species increased, which were correlated with an increase in SC hydration levels (Shannon diversity, r = 0.71, P = 0.027; Cutibacterium , r = 0.73, P = 0.017; Corynebacterium , r = 0.75, P = 0.012). Increased abundance of Cutibacterium species was also correlated with EASI improvement ( r = 0.68, P = 0.032). Conclusions Th2 blockade-induced normalization of skin microbiome in AD patients is associated with increased SC hydration.

BACKGROUND Recessive dystrophic epidermolysis bullosa (RDEB) is an incurable disease that causes severe mucocutaneous fragility due to mutations in COL7A1 (encoding type VII collagen [C7]). In this phase I/IIa trial, we evaluated the safety and possible clinical efficacy of intravenous infusion of allogeneic human umbilical cord blood–derived mesenchymal stem cells (hUCB-MSCs) in patients with RDEB. METHODS Four adult and two pediatric patients with RDEB were treated with 3 intravenous injections of hUCB-MSCs (1 × 10 6 to 3 × 10 6 cells/kg) every 2 weeks and followed up for 8–24 months after treatment. The primary endpoint was safety. Secondary endpoints related to efficacy included clinical parameters, such as disease severity score, wound assessment, itch and pain score, and quality of life. C7 expression levels and inflammatory infiltrates in the skin, as well as serum levels of inflammatory markers and neuropeptides, were also assessed. RESULTS Intravenous hUCB-MSC infusions were well tolerated, without serious adverse events. Improvements in the Birmingham Epidermolysis Bullosa Severity Score, body surface area involvement, blister counts, pain, pruritus, and quality of life were observed with maximal effects at 56–112 days after treatment. hUCB-MSC administration induced M2 macrophage polarization and reduced mast cell infiltration in RDEB skin. Serum levels of substance P were decreased after therapy. Increased C7 expression was observed at the dermoepidermal junction in 1 of 6 patients at day 56. CONCLUSION To the best of our knowledge, this is the first clinical trial of systemic administration of allogeneic hUCB-MSCs in patients with RDEB, demonstrating safety and transient clinical benefits. TRIAL REGISTRATION ClinicalTrials.gov NCT04520022. FUNDING This work was supported by Daewoong Pharmaceutical Co. Ltd. and Kangstem Biotech Co. Ltd.

protein, or isotretinoin-induced TUNEL-positive signals are detectable in sebocytes in the basal and suprabasal layers, but not so or less so in fully differentiated sebocytes in humans in vitro and in vivo (18,19).In conclusion, we put forward novel evidence that DHS exhibit apoptosis resistance by the intracellular increase in store-operated Ca 2+ release, which causes the loss of Ca 2+ influx. Finally, these findings should accelerate the understanding of the mechanisms of sebogenesis and/or sebum production and secretion under physiological conditions. AcknowledgementsThis work was supported in part by a Grant-in-Aid for Scientific Research (C) (#22590506) (To T. S.) and by a grant to private universities provided by The Promotion and Mutual Aid Corporation for Private Schools of Japan. T. S. and A. I. designed the research study and reviewed the data. H. K. and N. A. performed the research and analysed the data. T. S. wrote the study. All authors read and approved the final manuscript. Conflict of interestsThe authors have declared no conflicting interests. Supporting InformationAdditional Supporting Information may be found in the online version of this article: Figure S1. Increase of intracellular Ca 2+ in differentiated hamster sebocytes. Figure S2. Abstract: Tight junction (TJ) is one of the functional barriers present in the skin. Although topical corticosteroids and calcineurin inhibitors are used widely for atopic dermatitis, the effect of these agents on TJs has not been reported. We investigated the structural changes of TJs in mice skin after application of 0.05% clobetasol propionate or 0.1% tacrolimus ointment for 10 days. Clobetasol caused epidermal thinning and decreased collagen density. Basal transepidermal water loss was significantly increased in clobetasoltreated versus vehicle-or tacrolimus-treated skin. Confocal immunofluorescence showed that clobetasol altered the structure of claudin-1,-4 and occludin. Tacrolimus also caused morphological alteration of occludin. Western blot and real-time PCR revealed that clobetasol significantly decreased claudin-1,-4 and occludin, whereas tacrolimus did not significantly affect claudin-1 and -4 but downregulated occludin to a lesser extent compared to clobetasol. In conclusion, we suggest that downregulation of TJ proteins expression is another pathomechanism of corticosteroid-induced permeability barrier disruption.

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