Hospital transmission of borderline oxacillin-resistant Staphylococcus aureus evaluated by whole-genome sequencing.

Introduction. Staphylococcus aureus is a major cause of hospital infections worldwide. Awareness towards methicillin-resistant S. aureus (MRSA) infections is high but attention towards borderline oxacillin-resistant S. aureus (BORSA) is limited, possibly due to an underestimated clinical relevance, presumption of low incidence and diagnostic limitations.Gap statement. BORSA surveillance has not been routinely implemented, and thus consensus with regard to a definition and infection control measures is lacking.Aim. Our goals were to investigate the occurrence, molecular characteristics and clinical manifestations of BORSA infections in the hospital setting.Methodology. Following an increased incidence in 2016, BORSA cases in 2014/2016 (in our institution) were more specifically evaluated. Medical records were reviewed to investigate epidemiological links, clinical characteristics and outcomes. Resistance and virulence markers were assessed by whole genome sequencing (WGS). Conventional methods: amplified fragment length polymorphism (AFLP) ; multilocus sequence typing (MLST) and multiple locus variable-number tandem repeat analysis (MLVA) were compared with core genome MLST (cgMLST) and whole-genome single nucleotide polymorphism (wgSNP) analysis to confirm genetic clusters.Results. From 2009 to 2013, BORSA comprised 0.1 % of all clinical S. aureus strains. In 2016, the incidence was six-fold higher in comparison to the baseline. Whole-genome SNP and cgMLST confirmed two BORSA clusters among patients with dermatological conditions. Patients with BORSA presented with skin infections, and one case developed a severe invasive infection with a fatal outcome. Infection control measures successfully prevented further transmission in both clusters. WGS findings showed that BORSA strains carried multiple resistance and virulence genes with increased pathogenic potential.Conclusion. WGS and cgMLST effectively characterized and confirmed BORSA clusters among at-risk patients with clinical manifestations ranging from mild skin infections to life-threatening bacteraemia. Clinical awareness and active monitoring are therefore warranted for the timely implementation of infection control measures to prevent BORSA transmission in high-risk patients.

Open- and Closed-Label Placebo and Nocebo Suggestions About a Sham Transdermal Patch.

OBJECTIVE: Placebo effects may occur when it is known that an inert substance is given (i.e., open-label placebo). It is not yet clear whether these effects are similar to concealed (i.e., closed-label) placebo effects for itch or whether nocebo effects can be induced under open-label conditions. METHODS: Healthy volunteers (n = 112) were randomized to an open-label (I) or closed-label (II) positive suggestions group, or an open-label (III) or closed-label (IV) negative suggestions group. Participants were told, as cover story, that a transdermal caffeine patch would be applied that positively influences cognitive abilities and, as a side effect, positively or negatively (depending on group allocation) influences itch. Participants in the open-label groups were given a rationale explaining placebo and nocebo effect mechanisms. Itch (the primary outcome) was induced at baseline and postsuggestions by histamine iontophoresis. RESULTS: Analyses of variance revealed significantly lower itch in the positive compared with the negative suggestions groups for both open- and closed-label contexts (all, p ≤ .008, Cohen d ≥ 0.47). Self-rated skin response was less severe after positive versus negative suggestions (all, p ≤ .017, Cohen d ≥ 0.33), but no effects on physical skin response were found (all, p ≥ .23, Cohen d ≤ 0.30). CONCLUSIONS: Itch can be reduced by positive compared with negative suggestions under both open- and closed-label conditions. These findings indicate that open-label suggestions may potentially be a tool to use placebo effects for self-reported outcomes in clinical practice, for example, by explaining the role of expectancy in treatment. It needs to be investigated further under which circumstances an open-label rationale may impact placebo and nocebo effects.Trial Registration:www.trialregister.nl; NTR7174.

Skin disorders indicating peripheral arterial occlusive disease and chronic venous insufficiency in organ transplant recipients.

BACKGROUND: Peripheral arterial occlusive disease (PAOD) and chronic venous insufficiency (CVI) in organ transplant recipients (OTR) can lead to harmful outcomes. We made an inventory of cutaneous manifestations of PAOD and CVI in OTR in relation with diabetes and other potential risk factors. METHODS: A prospective study in a single center was performed. OTR (n = 112) were included at the outpatient clinic to investigate clinical signs of PAOD and CVI. The most commonly associated risk factors were determined. RESULTS: PAOD had been diagnosed in 15.6% and CVI in 30.0% of the patients. Diabetes was the cause of organ failure in 9.8% of the patients. Type 1 diabetes had been diagnosed in 8.9% and type 2 diabetes in 21.4% (59.1% new-onset diabetes after transplantation). Type 1 diabetes showed an increased risk for PAOD and limb amputation with hazard ratios of 11.0 (95%CI 3.0-40.2) and 9.1 (95%CI 1.4-58.6). Type 2 diabetes showed no increased risk. CONCLUSIONS: Patients with a history of type 1 diabetes were at high risk for PAOD even years after a simultaneous pancreas kidney transplantation and they should remain under close observation for PAOD even though they are supposedly "cured" from their diabetes to prevent a harmful outcome.

Placebo and nocebo effects for itch and itch-related immune outcomes: A systematic review of animal and human studies.

Placebo and nocebo effects can influence somatic symptoms such as pain. For itch and other dermatological symptoms these effects have been far less investigated. This review systematically integrates evidence from both animal (mainly rodents) and human trials on placebo and nocebo effects in itch, itch-related symptoms and conditions of the skin and mucous membranes, and related immune outcomes (e.g., histamine). Thirty-one animal studies, and fifty-five human studies (k = 21 healthy participants, k = 34 patients) were included. Overall, studies consistently show that placebo and nocebo effects can be induced by various methods (e.g., suggestions, conditioning and social cues), despite high heterogeneity across studies. Effects of suggestions were found consistently across subjective and behavioral parameters (e.g., itch and scratching in humans), whereas conditioning was likely to impact physiological parameters under certain conditions (e.g., conditioning of histamine levels in stressed rodents). Brain areas responsible for itch processing were associated with nocebo effects. Future research may investigate how variations in methods impact placebo and nocebo effects, and whether all symptoms and conditions can be influenced equally.

Skin of atopic dermatitis patients shows disturbed ß-glucocerebrosidase and acid sphingomyelinase activity that relates to changes in stratum corneum lipid composition.

Patients with Atopic Dermatitis (AD) suffer from inflamed skin and skin barrier defects. Proper formation of the outermost part of the skin, the stratum corneum (SC), is crucial for the skin barrier function. In this study we analyzed the localization and activity of lipid enzymes ß-glucocerebrosidase (GBA) and acid sphingomyelinase (ASM) in the skin of AD patients and controls. Localization of both the expression and activity of GBA and ASM in the epidermis of AD patients was altered, particularly at lesional skin sites. These changes aligned with the altered SC lipid composition. More specifically, abnormal localization of GBA and ASM related to an increase in specific ceramide subclasses [AS] and [NS]. Moreover we related the localization of the enzymes to the amounts of SC ceramide subclasses and free fatty acids (FFAs). We report a correlation between altered localization of active GBA and ASM and a disturbed SC lipid composition. Localization of antimicrobial peptide beta-defensin-3 (HBD-3) and AD biomarker Thymus and Activation Regulated Chemokine (TARC) also appeared to be diverging in AD skin compared to control. This research highlights the relation between correct localization of expressed and active lipid enzymes and a normal SC lipid composition for a proper skin barrier.

Antipruritic Placebo Effects by Conditioning H1-antihistamine.

OBJECTIVE: Allergic rhinitis symptoms can be reduced by behaviorally conditioning antihistamine. It is unclear whether these findings extend to histamine-induced itch or work when participants are informed about the conditioning procedure (open-label conditioning). The current study aims to investigate the efficacy of (open-label) antipruritic behavioral conditioning for histamine-induced itch. METHODS: Healthy participants (n = 92; 84% female) were randomized to I) an open-label conditioned, II) closed-label conditioned, III) conditioned-not-evoked control, or IV) nonconditioned control group. A two-phase conditioning paradigm was used. During acquisition, a conditioned stimulus (CS; distinctively tasting beverage) was repeatedly paired with the H1-antihistamine levocetirizine (groups I-III). During evocation, the CS was paired with placebo (I, II), or instead of the CS, water was paired with placebo (III). The nonconditioned control group (IV) received CS with placebo in both phases. Itch after histamine iontophoresis and physiological data (i.e., spirometry, heart rate, skin conductance) were assessed. Combined conditioned and combined control groups were first compared, and analyses were repeated for separate groups. RESULTS: Marginally lower itch was reported in the combined conditioned compared with the control groups (F(1,88) = 2.10, p = .076, ηpartial = 0.02); no differences between separate groups were found. No effects on physiological data were found, except for heart rate, which reduced significantly and consistently for control groups, and less consistently for conditioned groups (group by time interaction: F(7,80) = 2.35, p = .031, ηpartial = 0.17). CONCLUSION: Limited support was found for the efficacy of antipruritic behavioral conditioning, regardless of whether participants were informed about the conditioning procedure. The application of open-label conditioning in patient populations should be further researched. TRIAL REGISTRATION: www.trialregister.nl; ID NTR5544.

Effects of Open- and Closed-Label Nocebo and Placebo Suggestions on Itch and Itch Expectations.

Placebo and nocebo effects have been shown to influence subjective symptoms such as itch. These effects can be induced by influencing outcome expectations through, for example, combining the application of an inert substance (e.g., a cream) with verbal suggestions on the anticipated effects of this substance. Interestingly, placebo effects also occur when it is known that a treatment is inert (i.e., open-label placebo). However, no study to date has examined the efficacy of negative and positive verbal suggestions under similar open-label and closed-label (i.e., concealed placebo/nocebo) conditions in itch. A randomized controlled between-subjects study design was applied in which healthy volunteers (n = 92) were randomized to 1) an open-label positive verbal suggestion group, 2) a closed-label positive verbal suggestion group, 3) an open-label negative verbal suggestion group, or 4) a closed-label negative verbal suggestion group. Verbal suggestions were made regarding the topical application of an inert substance. Itch was evoked experimentally by histamine iontophoresis at baseline and again following suggestions. Itch expectations, self-reported itch during and following iontophoresis, and skin response parameters were measured. Positive suggestions were found to result in significantly lower expected itch than were negative suggestions in both open- and closed-label conditions. No effects of the suggestions on itch during iontophoresis were found, but significantly lower itch was reported in the 4 min following iontophoresis in the (combined open- and closed-label) positive compared with negative verbal suggestion groups. In addition, a smaller increase in skin temperature was found in the positive compared with negative suggestion groups. The findings illustrate a potential role of (open- and closed-label) placebo for optimizing expectations and treatment effects for itch in clinical practice. Clinical Trial Registration: Netherlands Trial Register, trial number: NTR6530.

Placebo Effects of Open-label Verbal Suggestions on Itch.

Placebo effects are positive outcomes that are not due to active treatment components, which may be elicited even when patients are aware of receiving an inert substance (open-label). This proof-of-principle study investigated for the first time whether open-label placebo effects on itch can be induced by verbal suggestions alone. Ninety-two healthy volunteers were randomized to experimental (open-label suggestions) or control (no suggestions) groups. Self-reported itch evoked by histamine iontophoresis was the primary study outcome. In addition, itch expectations, skin condition and affect were assessed. The experimental group expected lower itch than the control group, which was, in turn, related to less experienced itch in this group only, although no significantly different itch levels were reported between groups. The results illustrate a potential role for open-label placebo effects in itch, and suggest that further study of verbal suggestions through an extensive explanation of placebo effects might be promising for clinical practice.

Applying a vernix caseosa based formulation accelerates skin barrier repair by modulating lipid biosynthesis.

Restoring the lipid homeostasis of the stratum corneum (SC) is a common strategy to enhance skin barrier function. Here, we used a ceramide containing vernix caseosa (VC)-based formulation and were able to accelerate barrier recovery in healthy volunteers. The recovery was examined over 16 days by monitoring trans-epidermal water loss (TEWL) after barrier disruption by tape-stripping. Four skin sites were used to examine the effects of both treatment and barrier recovery. After 16 days, samples were harvested at these sites to examine the SC ceramide composition and lipid organization. Changes in ceramide profiles were identified using principal component analysis. After barrier recovery, the untreated sites showed increased levels of ceramide subclass AS and ceramides with a 34 total carbon-atom chain length, while the mean ceramide chain length was reduced. These changes were diminished by treatment with the studied formulation, which concurrently increased the formulated ceramides. Correlations were observed between SC lipid composition, lipid organization, and TEWL, and changes in the ceramide subclass composition suggest changes in the ceramide biosynthesis. These results suggest that VC-based formulations enhance skin barrier recovery and are attractive candidates to treat skin disorders with impaired barrier properties.

Explant cultures of atopic dermatitis biopsies maintain their epidermal characteristics in vitro.

Atopic dermatitis (AD) is a common inflammatory skin disorder characterised by various epidermal alterations. Filaggrin (FLG) mutations are a major predisposing factor for AD and much research has been focused on the FLG protein. Human skin equivalents (HSEs) might be useful tools for increasing our understanding of FLG in AD and to provide a tool for the screening of new therapies aimed at FLG replacement. Our aim is to establish an explant HSE (Ex-HSE) for AD by using non-lesional skin from AD patients wildtype for FLG or harbouring homozygous FLG mutations. These Ex-HSEs were evaluated as to whether they maintained their in vivo characteristics in vitro and whether FLG mutations affected the expression of various differentiation markers. FLG mutations did not affect the outgrowth from the biopsy for the establishment of Ex-HSEs. FLG expression was present in healthy skin and that of AD patients without FLG mutations and in their Ex-HSEs but was barely present in biopsies from patients with FLG mutations and their corresponding Ex-HSEs. AD Ex-HSEs and AD biopsies shared many similarities, i.e., proliferation and the expression of keratin 10 and loricrin, irrespective of FLG mutations. Neither KLK5 nor Lekti expression was affected by FLG mutations but was altered in the respective Ex-HSEs. Thus, Ex-HSEs established from biopsies taken from AD patients maintain their FLG genotype-phenotype in vitro and the expression of most proteins in vivo and in vitro remains similar. Our method is therefore promising as an alternative to genetic engineering approaches in the study of the role of FLG in AD.