Nlrp6- and ASC-Dependent Inflammasomes Do Not Shape the Commensal Gut Microbiota Composition.

The gut microbiota regulate susceptibility to multiple human diseases. The Nlrp6-ASC inflammasome is widely regarded as a hallmark host innate immune axis that shapes the gut microbiota composition. This notion stems from studies reporting dysbiosis in mice lacking these inflammasome components when compared with non-littermate wild-type animals. Here, we describe microbial analyses in inflammasome-deficient mice while minimizing non-genetic confounders using littermate-controlled Nlrp6-deficient mice and ex-germ-free littermate-controlled ASC-deficient mice that were all allowed to shape their gut microbiota naturally after birth. Careful microbial phylogenetic analyses of these cohorts failed to reveal regulation of the gut microbiota composition by the Nlrp6- and ASC-dependent inflammasomes. Our results obtained in two geographically separated animal facilities dismiss a generalizable impact of Nlrp6- and ASC-dependent inflammasomes on the composition of the commensal gut microbiota and highlight the necessity for littermate-controlled experimental design in assessing the influence of host immunity on gut microbial ecology.

Safety and Immunogenicity of an Anti-Zika Virus DNA Vaccine.

BACKGROUND: Although Zika virus (ZIKV) infection is typically self-limiting, other associated complications such as congenital birth defects and the Guillain-Barré syndrome are well described. There are no approved vaccines against ZIKV infection. METHODS: In this phase 1, open-label clinical trial, we evaluated the safety and immunogenicity of a synthetic, consensus DNA vaccine (GLS-5700) encoding the ZIKV premembrane and envelope proteins in two groups of 20 participants each. The participants received either 1 mg or 2 mg of vaccine intradermally, with each injection followed by electroporation (the use of a pulsed electric field to introduce the DNA sequence into cells) at baseline, 4 weeks, and 12 weeks. RESULTS: The median age of the participants was 38 years, and 60% were women; 78% were White and 22% Black; in addition, 30% were Hispanic. At the interim analysis at 14 weeks (i.e., after the third dose of vaccine), no serious adverse events were reported. Local reactions at the vaccination site (e.g., injection-site pain, redness, swelling, and itching) occurred in approximately 50% of the participants. After the third dose of vaccine, binding antibodies (as measured on enzyme-linked immunosorbent assay) were detected in all the participants, with geometric mean titers of 1642 and 2871 in recipients of 1 mg and 2 mg of vaccine, respectively. Neutralizing antibodies developed in 62% of the samples on Vero-cell assay. On neuronal-cell assay, there was 90% inhibition of ZIKV infection in 70% of the serum samples and 50% inhibition in 95% of the samples. The intraperitoneal injection of postvaccination serum protected 103 of 112 IFNAR knockout mice (bred with deletion of genes encoding interferon-α and interferon-ß receptors) (92%) that were challenged with a lethal dose of ZIKV-PR209 strain; none of the mice receiving baseline serum survived the challenge. Survival was independent of the neutralization titer. CONCLUSIONS: In this phase 1, open-label clinical trial, a DNA vaccine elicited anti-ZIKV immune responses. Further studies are needed to better evaluate the safety and efficacy of the vaccine. (Funded by GeneOne Life Science and others; ZIKA-001 ClinicalTrials.gov number, NCT02809443.).

Histopathologic regression in patients with primary cutaneous melanoma undergoing sentinel lymph node biopsy is associated with favorable survival and, after metastasis, with improved progression-free survival on immune checkpoint inhibitor therapy: A single-institutional cohort study.

BACKGROUND: Histopathologic regression of cutaneous melanoma is considered a favorable prognostic factor, but its significance in clinical practice remains controversial. OBJECTIVE: To investigate the prognostic importance of regression in patients with primary cutaneous melanoma undergoing sentinel lymph node (SLN) biopsy and to assess its significance in patients progressing to an unresectable stage requiring systemic therapy. METHODS: We retrospectively reviewed patients with newly diagnosed melanoma undergoing SLN biopsy between 2010 and 2015 and available information on histopathologic regression (n = 1179). Survival data and associations of clinical variables with SLN status were assessed. RESULTS: Patients with regressive melanoma showed favorable relapse-free (hazard ratio [HR], 0.52; P = .00013), distant metastasis-free (HR, 0.56; P = .0020), and melanoma-specific survival (HR, 0.35; P = .00053). Regression was associated with negative SLN (odds ratio, 0.48; P = .0077). In patients who progressed to an unresectable stage, regression was associated with favorable progression-free survival under immune checkpoint inhibition (HR, 0.43; P = .031) but not under targeted therapy (HR, 1.14; P = .73) or chemotherapy (HR, 3.65; P = .0095). LIMITATIONS: Retrospective, single-institutional design. CONCLUSIONS: Regression of cutaneous melanoma is associated with improved prognosis in patients eligible for SLN biopsy as well as in patients with unresectable disease receiving systemic therapy with immune checkpoint inhibitors.

Transcriptional Profiling of Staphylococcus aureus during the Transition from Asymptomatic Nasal Colonization to Skin Colonization/Infection in Patients with Atopic Dermatitis.

Staphylococcus aureus acts both as a colonizing commensal bacterium and invasive pathogen. Nasal colonization is associated with an increased risk of infection caused by the identical strain. In patients with atopic dermatitis (AD), the degree of S. aureus colonization is associated with the severity of the disease. Here, we comparatively analyzed the in vivo transcriptional profile of S. aureus colonizing the nose and non-diseased skin (non-lesional skin) as opposed to the diseased skin (lesional skin-defined here as infection) of 12 patients with AD. The transcriptional profile during the asymptomatic colonization of the nose closely resembled that of the lesional skin samples for many of the genes studied, with an elevated expression of the genes encoding adhesion-related proteins and proteases. In addition, the genes that modify and remodel the cell wall and encode proteins that facilitate immune evasion showed increased transcriptional activity. Notably, in a subgroup of patients, the global virulence regulator Agr (accessory gene regulator) and downstream target genes were inactive during nasal colonization but upregulated in the lesional and non-lesional skin samples. Taken together, our results demonstrate a colonization-like transcriptional profile on diseased skin and suggest a role for the peptide quorum sensing system Agr during the transition from asymptomatic nasal colonization to skin colonization/infection.

Pathogenic relevance of antibodies against desmoglein 3 in patients with oral lichen planus.

BACKGROUND AND OBJECTIVES: Oral lichen planus (OLP) is a T cell driven disorder that significantly impairs patients' quality of life. Previous reports suggest that both cellular and humoral activities against desmoglein (dsg) 1 and 3 may be involved in OLP pathogenesis. Here, we aim to analyze the frequency of occurrence and pathological significance of anti-dsg antibodies in a large cohort of OLP patients. MATERIALS AND METHODS: OLP patients were screened for anti-dsg antibodies by enzyme-linked immunosorbent assay in three tertiary referral centers. OLP sera with anti-dsg antibodies were further analyzed by Western blot and dispase-based keratinocyte dissociation assay (DDA) to identify the targeted dsg ectodomains and to assess their pathogenicity. RESULTS: Of 151-screened individuals with OLP, only four patients (2.6%) with erosive OLP showed serum IgG against dsg1/3. Western blot analysis with recombinant dsg3 ectodomains revealed preferential recognition of the extracellular domain 5. By DDA with spontaneously immortalized human keratinocytes, none of the sera from these four patients induced acantholysis. CONCLUSIONS: Activation of humoral immunity occurs prevalently in patients with erosive OLP, probably due to epitope spreading. OLP serum antibodies are unable to induce loss of intercellular adhesion in vitro, strongly suggesting that they are not disease causing but rather an epiphenomenon.

Human sleep consolidates allergic responses conditioned to the environmental context of an allergen exposure.

Allergies are highly prevalent, and allergic responses can be triggered even in the absence of allergens due to Pavlovian conditioning to a specific cue. Here we show in humans suffering from allergic rhinitis that merely reencountering the environmental context in which an allergen was administered a week earlier is sufficient to trigger an allergic response-but only if participants had slept after allergen exposure. This context-conditioning effect was entirely absent when participants stayed awake the night after allergen exposure or were tested in a different context. Unlike in context conditioning, cue conditioning (to an odor stimulus) occurred independently of sleep, a differential pattern that is likewise observed for conditioning in the behavioral domain. Our findings provide evidence that allergic responses can be conditioned to contextual information alone, even after only a single-trial conditioning procedure, and that sleep is necessary to consolidate this rapidly acquired maladaptive response. The results unravel a mechanism that could explain part of the strong psychological impact on allergic responses.

Non invasive in vivo monitoring of dimethyl fumarate treatment in EAE by assessing the glucose metabolism in secondary lymphoid organs.

[18 F]FDG-PET/CT is a high sensitive functional diagnostic imaging modality to monitor tumor but also immune cell activation by determination of the glucose metabolism. Our results show that the anti-inflammatory effects of immunotherapeutics like DMF can be assessed non invasively in vivo during Th1/Th17 cell-mediated encephalomyelitis (EAE) by [18 F]FDG-PET/CT imaging of the draining lymph nodes.

Projecting vaccine demand and impact for emerging zoonotic pathogens.

BACKGROUND: Despite large outbreaks in humans seeming improbable for a number of zoonotic pathogens, several pose a concern due to their epidemiological characteristics and evolutionary potential. To enable effective responses to these pathogens in the event that they undergo future emergence, the Coalition for Epidemic Preparedness Innovations is advancing the development of vaccines for several pathogens prioritized by the World Health Organization. A major challenge in this pursuit is anticipating demand for a vaccine stockpile to support outbreak response. METHODS: We developed a modeling framework for outbreak response for emerging zoonoses under three reactive vaccination strategies to assess sustainable vaccine manufacturing needs, vaccine stockpile requirements, and the potential impact of the outbreak response. This framework incorporates geographically variable zoonotic spillover rates, human-to-human transmission, and the implementation of reactive vaccination campaigns in response to disease outbreaks. As proof of concept, we applied the framework to four priority pathogens: Lassa virus, Nipah virus, MERS coronavirus, and Rift Valley virus. RESULTS: Annual vaccine regimen requirements for a population-wide strategy ranged from > 670,000 (95% prediction interval 0-3,630,000) regimens for Lassa virus to 1,190,000 (95% PrI 0-8,480,000) regimens for Rift Valley fever virus, while the regimens required for ring vaccination or targeting healthcare workers (HCWs) were several orders of magnitude lower (between 1/25 and 1/700) than those required by a population-wide strategy. For each pathogen and vaccination strategy, reactive vaccination typically prevented fewer than 10% of cases, because of their presently low R0 values. Targeting HCWs had a higher per-regimen impact than population-wide vaccination. CONCLUSIONS: Our framework provides a flexible methodology for estimating vaccine stockpile needs and the geographic distribution of demand under a range of outbreak response scenarios. Uncertainties in our model estimates highlight several knowledge gaps that need to be addressed to target vulnerable populations more accurately. These include surveillance gaps that mask the true geographic distribution of each pathogen, details of key routes of spillover from animal reservoirs to humans, and the role of human-to-human transmission outside of healthcare settings. In addition, our estimates are based on the current epidemiology of each pathogen, but pathogen evolution could alter vaccine stockpile requirements.

Out of the mouths of Peer Leaders: Perspectives on how to improve a telephone-based peer support intervention in type 2 diabetes.

OBJECTIVE: To explore the experiences of peer leaders with respect to delivering core components of a 12-month, telephone-based peer support intervention in type 2 diabetes within a tertiary-care setting. METHODS: Seventeen peer leaders were recruited and interviewed. Interviews lasted approximately 20 to 45 min, were audio-taped, and transcribed verbatim. The transcripts were analysed by two team members using the qualitative descriptive approach. FINDINGS: Peer leaders reported mutually beneficial and reciprocal relationships with participants. They encountered challenges in maintaining regular contact with participants and in motivating them to make lifestyle changes. To improve the programme, peer leaders suggested having more frequent - but shorter - training sessions and reducing the diabetes education component of the training programme. To enhance the intervention fidelity and retention rate, they recommended matching peer leaders to participants on more meaningful variables (e.g. diabetes-related commonalities, personality, life experiences, etc.) beyond just gender, geographic proximity and availability. They also requested more frequent face-to-face contacts with participants (Modality of Contact), and additional ongoing support from the research team. CONCLUSION: Peer leaders were satisfied with the intervention design. However, future studies may consider more comprehensive peer leader-matching algorithms and increased opportunities for in-person communication modalities. CLINICALTRIALS: gov Identifier: NCT02804620.

Closed Isolated Zygomatic Arch Fracture Management Made Easy.

BACKGROUND: Zygomatic arch fractures can occur either as isolated fractures or as a part of multiple facial fractures. There are several techniques available for reduction of zygomatic arch fractures, which include closed reduction and open reduction with fixation using metallic splints, closed reduction via Gillies or a gingivobuccal approach is preferred for minimal invasiveness, short operative time, and low complication rate. The aim of the present study is to present a simple, easy, and reliable method for closed reduction of isolated zygomatic arch fractures. PATIENTS AND METHODS: This study included twenty patients presented with isolated zygomatic arch fractures between January of 2017 and December of 2018. All patients were evaluated based on the clinical and radiographic findings. Closed reduction of the zygomatic arches was carried on by a stainless steel wire. Surgical outcomes were subjected for objective assessment based on the postoperative alignment of the zygomatic arch in the computed tomography (CT scan) immediately after surgery and after 3 months. Subjective evaluation was carried out comparing preoperative, 1 and 3 months photographs assessing facial symmetry, as well as the patients' satisfaction. RESULTS: After a period of 3 to 6 months follow-up between January 2017 and December 2019, all patients were satisfied by the overall results, no major complications were recorded and no additional surgery needed for them. CONCLUSIONS: The suture wire method is quick, simple, easy, and effective for the reduction of isolated, depressed fractures of the zygomatic arch.

Immunophenotyping in pemphigus reveals a TH17/TFH17 cell-dominated immune response promoting desmoglein1/3-specific autoantibody production.

BACKGROUND: TH2 cells were thought to be a pivotal factor for initiation of the autoimmune blistering disease pemphigus. However, the role of other T-cell subsets in pemphigus pathogenesis remained unclear. OBJECTIVE: We aimed to characterize the exact phenotype of T cells responsible for the development of pemphigus. METHODS: Whole transcriptome shotgun sequencing was performed to determine differential gene expression in pemphigus lesions and skin of healthy individuals. The cutaneous cytokine signature was further evaluated by real-time quantitative PCR. In peripheral blood, the distribution of TH cell and folliclular helper (TFH) cell subsets was analyzed by flow cytometry. Finally, the capacity of TH and TFH cell subsets to induce desmoglein (Dsg)-specific autoantibodies by memory B cells was evaluated in coculture experiments. RESULTS: Transcriptome analysis of skin samples identified an IL-17A-dominated immune signature in patients with pemphigus, and Kyoto Encyclopedia of Genes and Genomes pathway analysis confirmed the dominance of the IL-17A signaling pathway. Increased expression of IL17A and associated cytokines was also detected by real-time quantitative PCR comparing lesional with perilesional or healthy skin. Interestingly, utilization of flow cytometry showed that patients with active pemphigus had elevated levels of circulating IL-17+, TH17, TFH17, and TFH17.1 cells. Notably, levels of TH17 and TFH17 cells correlated with levels of Dsg-specific CD19+CD27+ memory B cells, and patients with acute pemphigus showed higher levels of Dsg3-autoreactive TFH17 cells. Coculture experiments revealed TFH17 cells as primarily responsible for inducing Dsg-specific autoantibody production by B cells. CONCLUSION: Our findings show that TFH17 cells are critically involved in the pathogenesis of pemphigus and offer novel targets for therapeutic intervention.

Selective inhibition of matrix metalloproteinase 10 (MMP10) with a single-domain antibody.

Since their discovery, the matrix metalloproteinase (MMP) family proteases have been considered as therapeutic targets in numerous diseases and disorders. Unfortunately, clinical trials with MMP inhibitors have failed to yield any clinical benefits of these inhibitors. These failures were largely due to a lack of MMP-selective agents; accordingly, it has become important to identify a platform with which high selectivity can be achieved. To this end, we propose using MMP-targeting antibodies that can achieve high specificity in interactions with their targets. Using a scaffold of single-domain antibodies, here we raised a panel of MMP10-selective antibodies through immunization of llamas, a member of the camelid family, whose members generate conventional heavy/light-chain antibodies and also smaller antibodies lacking light-chain and CH1 domains. We report the generation of a highly selective and tightly binding MMP10 inhibitor (Ki < 2 nm). Using bio-layer interferometry-based binding assays, we found that this antibody interacts with the MMP10 active site. Activity assays demonstrated that the antibody selectively inhibits MMP10 over its closest relative, MMP3. The ability of a single-domain antibody to discriminate between the most conserved MMP pair via an active site-directed mechanism of inhibition reported here supports the potential of this antibody as a broadly applicable scaffold for the development of selective, tightly binding MMP inhibitors.

HIV Infection Is Associated With Variability in Ventricular Repolarization: The Multicenter AIDS Cohort Study (MACS).

BACKGROUND: People living with human immunodeficiency virus (HIV+) have greater risk for sudden arrhythmic death than HIV-uninfected (HIV-) individuals. HIV-associated abnormal cardiac repolarization may contribute to this risk. We investigated whether HIV serostatus is associated with ventricular repolarization lability by using the QT variability index (QTVI), defined as a log measure of QT-interval variance indexed to heart rate variance. METHODS: We studied 1123 men (589 HIV+ and 534 HIV-) from MACS (Multicenter AIDS Cohort Study), using the ZioXT ambulatory electrocardiography patch. Beat-to-beat analysis of up to 4 full days of electrocardiographic data per participant was performed using an automated algorithm (median analyzed duration [quartile 1-quartile 3]: 78.3 [66.3-83.0] hours/person). QTVI was modeled using linear mixed-effects models adjusted for demographics, cardiac risk factors, and HIV-related and inflammatory biomarkers. RESULTS: Mean (SD) age was 60.1 (11.9) years among HIV- and 54.2 (11.2) years among HIV+ participants (P<0.001), 83% of whom had undetectable (<20 copies/mL) HIV-1 viral load (VL). In comparison with HIV- men, HIV+ men had higher QTVI (adjusted difference of +0.077 [95% CI, +0.032 to +0.123]). The magnitude of this association depended on the degree of viremia, such that in HIV+ men with undetectable VL, adjusted QTVI was +0.064 (95% CI, +0.017 to +0.111) higher than in HIV- men, whereas, in HIV+ men with detectable VL, adjusted QTVI was higher by +0.150 (95% CI, 0.072-0.228) than in HIV- referents. Analysis of QTVI subcomponents showed that HIV+ men had: (1) lower heart rate variability irrespective of VL status, and (2) higher QT variability if they had detectable, but not with undetectable, VL, in comparison with HIV- men. Higher levels of C-reactive protein, interleukin-6, intercellular adhesion molecule-1, soluble tumor necrosis factor receptor 2, and soluble cluster of differentiation-163 (borderline), were associated with higher QTVI and partially attenuated the association with HIV serostatus. CONCLUSIONS: HIV+ men have greater beat-to-beat variability in QT interval (QTVI) than HIV- men, especially in the setting of HIV viremia and heightened inflammation. Among HIV+ men, higher QTVI suggests ventricular repolarization lability, which can increase susceptibility to arrhythmias, whereas lower heart rate variability signals a component of autonomic dysfunction.

Easily available ECG and echocardiographic parameters for prediction of left atrial remodeling and atrial fibrillation recurrence after pulmonary vein isolation: A multicenter study.

BACKGROUND: The assessment of noninvasive markers of left atrial (LA) low-voltage substrate (LVS) enables the identification of atrial fibrillation (AF) patients at risk for arrhythmia recurrence after pulmonary vein isolation (PVI). METHODS: In this prospective multicenter study, 292 consecutive AF patients (72% male, 62 ± 11 years, 65% persistent AF) underwent high-density LA voltage mapping in sinus rhythm. LA-LVS (<0.5 mV) was considered as significant at 2 cm2  or above. Preprocedural clinical electrocardiogram and echocardiographic data were assessed to identify predictors of LA-LVS. The role of the identified LA-LVS markers in predicting 1-year arrhythmia freedom after PVI was assessed in 245 patients. RESULTS: Significant LA-LVS was identified in 123 (42%) patients. The amplified sinus P-wave duration (APWD) best predicted LA-LVS, with a 148-ms value providing the best-balanced sensitivity (0.81) and specificity (0.88). An APWD over 160 ms was associated with LA-LVS in 96% of patients, whereas an APWD under 145 ms in 15%. Remaining gray zones improved their accuracy by introduction of systolic pulmonary artery pressure (sPAP) of 35 mmHg or above, age, and sex. According to COX regression, the risk of arrhythmia recurrence 12 months following PVI was twofold and threefold higher in patients with APWD 145-160 and over 160 ms, compared to APWD under 145 ms. Integration of pulmonary hypertension further improved the outcome prediction in the intermediate APWD group: Patients with APWD 145-160 ms and normal sPAP had similar outcome than patients with APWD under 145 ms (hazard ratio [HR] 1.62, p = .14), whereas high sPAP implied worse outcome (HR 2.56, p < .001). CONCLUSIONS: The APWD identifies LA-LVS and risk for arrhythmia recurrence after PVI. Our prediction model becomes optimized by means of integration of the pulmonary artery pressure.

Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1.

Through their capacity to sense danger signals and to generate active interleukin-1ß (IL-1ß), inflammasomes occupy a central role in the inflammatory response. In contrast to IL-1ß, little is known about how IL-1α is regulated. We found that all inflammasome activators also induced the secretion of IL-1α, leading to the cosecretion of both IL-1 cytokines. Depending on the type of inflammasome activator, release of IL-1α was inflammasome dependent or independent. Calcium influx induced by the opening of cation channels was sufficient for the inflammasome-independent IL-1α secretion. In both cases, IL-1α was released primarily in a processed form, resulting from intracellular cleavage by calpain-like proteases. Inflammasome-caspase-1-dependent release of IL-1α and IL-1ß was independent of caspase-1 catalytic activity, defining a mode of action for caspase-1. Because inflammasomes contribute to the pathology of numerous chronic inflammatory diseases such as gout and diabetes, IL-1α antagonists may be beneficial in the treatment of these disorders.

One-year outcomes of supersaturated oxygen therapy in acute anterior myocardial infarction: The IC-HOT study.

BACKGROUND: Supersaturated oxygen (SSO2 ) has recently been approved by the U.S. Food and Drug Administration for administration after primary percutaneous coronary intervention (pPCI) in patients with anterior ST-segment elevation myocardial infarction (STEMI) based on its demonstration of infarct size reduction in the IC-HOT study. OBJECTIVES: To describe the 1-year clinical outcomes of intracoronary SSO2 treatment after pPCI in patients with anterior STEMI. METHODS: IC-HOT was a prospective, open-label, single-arm study in which 100 patients without cardiogenic shock undergoing successful pPCI of an occluded left anterior descending coronary artery were treated with a 60-min SSO2 infusion. One-year clinical outcomes were compared with a propensity-matched control group of similar patients with anterior STEMI enrolled in the INFUSE-AMI trial. RESULTS: Baseline and postprocedural characteristics were similar in the two groups except for pre-PCI thrombolysis in myocardial infarction 3 flow, which was less prevalent in patients treated with SSO2 (9.6% vs. 22.9%, p = .02). Treatment with SSO2 was associated with a lower 1-year rate of the composite endpoint of all-cause death or new-onset heart failure (HF) or hospitalization for HF (0.0% vs. 12.3%, p = .001). All-cause mortality, driven by cardiovascular mortality, and new-onset HF or HF hospitalization were each individually lower in SSO2 -treated patients. There were no significant differences between groups in the 1-year rates of reinfarction or clinically driven target vessel revascularization. CONCLUSIONS: Infusion of SSO2 following pPCI in patients with anterior STEMI was associated with improved 1-year clinical outcomes including lower rates of death and new-onset HF or HF hospitalizations.

Stevens-Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysis.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare and severe skin and mucosal reactions that are associated with high mortality. Despite the severity, an evidence-based treatment protocol for SJS/TEN is still lacking. METHOD: In this systematic review and meta-analysis, the PubMed database was searched using the following terms: [Stevens-Johnson syndrome] OR [toxic epidermal necrolysis] AND [therapy] OR [treatment] over a 20-year period (1999-2019) in the German and English language. All clinical studies reporting on the treatment of SJS/TEN were included, and epidemiological and diagnostic aspects of treatment were analysed. A meta-analysis was conducted on all comparative clinical studies that met the inclusion criteria. RESULTS: A total of 88 studies met the inclusion criteria, reporting outcomes in 2647 patients. Treatment was either supportive or used systemic corticosteroid, intravenous immunoglobulin, plasmapheresis, cyclosporine, thalidomide or cyclophosphamide therapy. The meta-analysis included 16 (18%) studies, reporting outcomes in 976 (37%) patients. Systemic glucocorticoids showed a survival benefit for SJS/TEN patients in all analyses compared with other forms of treatment. Cyclosporine treatment also showed promising results, despite being used in a small cohort of patients. No beneficial effects on mortality could be demonstrated for intravenous immunoglobulins. CONCLUSION: Glucocorticoids and cyclosporine may be tentatively recommended as the most promising immunomodulatory therapies for SJS/TEN, but these results should be investigated in future prospective controlled trials.

Stevens-Johnson syndrome and toxic epidermal necrolysis: a 10-year experience in a burns unit.

OBJECTIVE: Stevens-Johnson syndrome (SJS) and its more severe counterpart, toxic epidermal necrolysis (TEN), are skin hypersensitivity reactions defined by epidermal blistering and necrosis. The exact pathophysiology of SJS/TEN is yet to be deciphered, but a number of risk factors have been identified including adverse drug reactions. The diagnosis of SJS/TEN is made on a clinical basis, and treatment consists of supportive care and occasionally immunosuppressants, such as cyclosporin, high-dose intravenous immunoglobulins and/or corticosteroids. Mortality rates can reach 20-25% in adults but are reduced with early intervention. To identify optimal treatment regimens, to better understand the patient cohort affected, and to help identify key risk factors for mortality, we report our experience with the treatment and management of SJS/TEN patients. METHODS: A retrospective review of consecutive patients with SJS and/or TEN admitted to a single burns centre in Germany, between 2008 and 2018, was conducted. The primary outcomes of demographics, clinical course, treatment and patient-reported outcomes were recorded and compared with a control group of patients with burns without a diagnosis of SJS/TEN. RESULTS: A total of 23 patients with SJS/TEN met the inclusion criteria: 17 (74%) with TEN; four (17%) with SJS/TEN overlap; and two (9%) with SJS. Of the patients, 14 (61%) were female and nine (39%) were male. Patient age ranged from 32-78 years (mean: 52 years). A matched cohort of 23 patients with burns served as the control group. All patients received standard of care with a multidisciplinary team. Compared with the control group, SJS/TEN patients had higher mortality rates (n=6, 26% versus n=8, 35%, respectively). The average age of death was 69 years in SJS/TEN patients versus 63 years in control group patients. Age and SCORTEN scores were significant predictors of mortality. CONCLUSIONS: SJS and TEN are rare but extreme reactions of the skin and mucosa, associated with high disease mortality rates. This 10-year single-centre retrospective review contributes to the bank of information for reviews evaluating the management of SJS/TEN patients.

RIPK1 and TRADD Regulate TNF-Induced Signaling and Ripoptosome Formation.

TNF is a proinflammatory cytokine that is critical for the coordination of tissue homeostasis. RIPK1 and TRADD are the main participants in the transduction of TNF signaling. However, data on the cell fate-controlling functions of both molecules are quite controversial. Here, we address the functions of RIPK1 and TRADD in TNF signaling by generating RIPK1- or TRADD-deficient human cell lines. We demonstrate that RIPK1 is relevant for TNF-induced apoptosis and necroptosis in conditions with depleted IAPs. In addition, TRADD is dispensable for necroptosis but required for apoptosis. We reveal a new possible function of TRADD as a negative regulator of NIK stabilization and subsequent ripoptosome formation. Furthermore, we show that RIPK1 and TRADD do not appear to be essential for the activation of MAPK signaling. Moreover, partially repressing NF-κB activation in both RIPK1 and TRADD KO cells does not result in sensitization to TNF alone due to the absence of NIK stabilization. Importantly, we demonstrate that RIPK1 is essential for preventing TRADD from undergoing TNF-induced ubiquitination and degradation. Taken together, our findings provide further insights into the specific functions of RIPK1 and TRADD in the regulation of TNF-dependent signaling, which controls the balance between cell death and survival.

Effect of additional pressing on the color and translucency of pressable ceramic materials: An in vitro study.

STATEMENT OF PROBLEM: Whether reusing the buttons of pressable ceramic materials affects their color or translucency is unclear. PURPOSE: The purpose of this in vitro study was to investigate the effect of additional pressing on the color and translucency of 3 different lithium disilicate ceramic brands. MATERIAL AND METHODS: Seventy-two disk-shaped ceramic specimens (Ø14×1.5 mm) were divided into 2 groups: pressed group and additionally pressed group, each containing 36 specimens. These groups were further divided into 3 subgroups: lithium disilicate (LDS), lithium disilicate with high-density micronization technology (LDS-HDM), and zirconia-reinforced lithium silicate (ZLS). Pressing was performed in the press group yielding 36 pressed specimens. Additional pressing was performed by using the buttons resulting from the press group, yielding 36 additionally pressed specimens. Color differences and translucency between pressed and additionally pressed groups were measured with a portable spectrophotometer (VITA Easyshade Compact). The translucency parameter (TP) was measured on black and white backgrounds. Color differences between the 2 groups were analyzed statistically by using the Kruskal-Wallis nonparametric test followed by the Dunn-Sidek method for individual comparison among means of all groups (α=.05). RESULTS: A statistically significant difference was found in color after additional pressing among the 3 tested materials (P=.005). After additional pressing, color difference (ΔE) values were found between the LDS group (3.78 ±1.11) and the ZLS group (3.03 ±1.44). These ΔE values were beyond the selected clinical perceptible threshold (ΔE=2.6). However, the LDS-HDM group had a ΔE value of 1.80 ±1.22, which is considered clinically not perceivable. Furthermore, LDS showed a statistically significant decrease in translucency after additional pressing (P=.002). However, after additional pressing, ZLS and LDS-HDM showed no statistically significant differences in translucency (P>.05). CONCLUSIONS: The colors of the 3 tested materials were affected by additional pressing. Only LDS-HDM showed color changes below the selected clinically perceptible threshold (ΔE=2.6). Furthermore, only LDS showed a significant decrease in translucency.