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Limited donor sites and poor long-term outcomes with standard treatment for large skin defects remain a huge problem. An autologous, bilayered, laboratory-grown skin substitute (denovoSkin) was developed to overcome this problem and has shown to be safe in 10 pediatric patients in a Phase I clinical trial after transplantation. The goal of this article was to report on 48-month long-term results. The pediatric participants of the phase I clinical trial were followed up at yearly visits up to 5 years after transplantation. Safety parameters, including the occurrence of adverse events, possible deviations of vital signs, and changes in concomitant therapy as well as additional parameters regarding skin stability, scar quality, and tumor formation, were assessed. Furthermore, scar maturation was photographically documented. Of the 10 patients treated with denovoSkin in this phase I clinical trial, 7 completed the 5-year follow-up period. Skin substitutes continued to be deemed safe, remained stable, and practically unchanged, with no sign of fragility and no tumor formation at clinical examination. Scar quality, captured using the Patient and Observer Scar Assessment Scale, was evaluated as close to normal skin. Transplantation of this laboratory-grown skin substitute in children is to date considered safe and shows encouraging functional and aesthetical long-term results close to normal skin. These results are promising and highlight the potential of a life-saving therapy for large skin defects. A multicentre, prospective, randomized, phase II clinical trial is currently ongoing to further evaluate the safety and efficacy of this novel skin substitute. Clinicaltrials.gov identifier NCT02145130., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Burn Association.) more...

Enterovirus D68 (EV-D68) infections are associated with severe respiratory disease and acute flaccid myelitis (AFM). The European Non-Polio Enterovirus Network (ENPEN) aimed to investigate the epidemiological and genetic characteristics of EV-D68 infections and its clinical impact during the fall-winter season of 2021-2022. From 19 European countries, 58 institutes reported 10 481 (6.8%) EV-positive samples of which 1004 (9.6%) were identified as EV-D68 (including 852 respiratory samples). Clinical data were reported for 969 cases; 78.9% of infections were reported in children (0-5 years); and 37.9% of cases were hospitalized. Acute respiratory distress was commonly noted (93.1%) followed by fever (49.4%). Neurological problems were observed in 6.4% of cases including 6 diagnosed with AFM. Phylodynamic/Nextstrain and phylogenetic analyses based on 694 sequences showed the emergence of 2 novel B3-derived lineages, with no regional clustering. In conclusion, we describe a large-scale European EV-D68 upsurge with severe clinical impact and the emergence of B3-derived lineages., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.) more...

Background: Patients with congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD) and dementia are underrepresented in specialist palliative home care (SPHC). However, the complexity of their conditions requires collaboration between general practitioners (GPs) and SPHC teams and timely integration into SPHC to effectively meet their needs., Objective: To facilitate joint palliative care planning and the timely transfer of patients with advanced chronic non-malignant conditions to SPHC., Methods: A two-arm, unblinded, cluster-randomised controlled trial. 49 GP practices in northern Germany were randomised using web-based block randomisation. We included patients with advanced CHF, COPD and/or dementia. The KOPAL intervention consisted of a SPHC nurse-patient consultation followed by an interprofessional telephone case conference between SPHC team and GP. The primary outcome was the number of hospital admissions 48 weeks after baseline. Secondary analyses examined the effects on health-related quality of life and self-rated health status, as measured by the EuroQol 5D scale., Results: A total of 172 patients were included in the analyses. 80.4% of GP practices had worked with SHPC before, most of them exclusively for cancer patients. At baseline, patients reported a mean EQ-VAS of 48.4, a mean quality of life index (EQ-5D-5L) of 0.63 and an average of 0.80 hospital admissions in the previous year. The intervention did not significantly reduce hospital admissions (incidence rate ratio = 0.79, 95%CI: [0.49, 1.26], P = 0.31) or the number of days spent in hospital (incidence rate ratio = 0.65, 95%CI: [0.28, 1.49], P = 0.29). There was also no significant effect on quality of life (∆ = -0.02, 95%CI: [-0.09, 0.05], P = 0.53) or self-rated health (∆ = -2.48, 95%CI: [-9.95, 4.99], P = 0.51)., Conclusions: The study did not show the hypothesised effect on hospitalisations and health-related quality of life. Future research should focus on refining this approach, with particular emphasis on optimising the timing of case conferences and implementing discussed changes to treatment plans, to improve collaboration between GPs and SPHC teams., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society.) more...

Background: Sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA from wastewater samples has emerged as a valuable tool for detecting the presence and relative abundances of SARS-CoV-2 variants in a community. By analyzing the viral genetic material present in wastewater, researchers and public health authorities can gain early insights into the spread of virus lineages and emerging mutations. Constructing reference datasets from known SARS-CoV-2 lineages and their mutation profiles has become state-of-the-art for assigning viral lineages and their relative abundances from wastewater sequencing data. However, selecting reference sequences or mutations directly affects the predictive power., Results: Here, we show the impact of a mutation- and sequence-based reference reconstruction for SARS-CoV-2 abundance estimation. We benchmark 3 datasets: (i) synthetic "spike-in"' mixtures; (ii) German wastewater samples from early 2021, mainly comprising Alpha; and (iii) samples obtained from wastewater at an international airport in Germany from the end of 2021, including first signals of Omicron. The 2 approaches differ in sublineage detection, with the marker mutation-based method, in particular, being challenged by the increasing number of mutations and lineages. However, the estimations of both approaches depend on selecting representative references and optimized parameter settings. By performing parameter escalation experiments, we demonstrate the effects of reference size and alternative allele frequency cutoffs for abundance estimation. We show how different parameter settings can lead to different results for our test datasets and illustrate the effects of virus lineage composition of wastewater samples and references., Conclusions: Our study highlights current computational challenges, focusing on the general reference design, which directly impacts abundance allocations. We illustrate advantages and disadvantages that may be relevant for further developments in the wastewater community and in the context of defining robust quality metrics., (© The Author(s) 2024. Published by Oxford University Press GigaScience.) more...

Activation of mucosal-associated invariant T cells (MAIT cells) by certain bacteria, viruses, and yeast is well studied, but the activation potential of filamentous moulds from the order Mucorales is not known. Here, we show a rapid response of human MAIT cells against the Mucorales species Mucor circinelloides, Rhizopus arrhizus, and Rhizopus microsporus. This activation included upregulation of CD69 and degranulation marked by increased CD107a expression, while intracellular perforin and granzyme A expression were reduced. Furthermore, blocking of the antigen-presenting molecule major histocompatibility complex class I-related abrogated MAIT cell activation demonstrating a T cell receptor-dependent stimulation by Mucorales., (The Author(s) 2020. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology.) more...

Background: Candida albicans and Candida glabrata are the 2 most prevalent Candida species causing bloodstream infections. Patterns of innate immune activation triggered by the 2 fungi differ considerably., Methods: To analyze human natural killer (NK) cell activation by both species, we performed ex vivo whole-blood infection assays and confrontation assays with primary human NK cells., Results: C. albicans was a stronger activator for isolated human NK cells than C. glabrata. In contrast, activation of blood NK cells, characterized by an upregulated surface exposure of early activation antigen CD69 and death receptor ligand TRAIL, as well as interferon-γ (IFN-γ) secretion, was more pronounced during C. glabrata infection. NK cell activation in blood is mediated by humoral mediators released by other immune cells and does not depend on direct activation by fungal cells. Cross-talk between Candida-confronted monocyte-derived dendritic cells (moDC) and NK cells resulted in the same NK activation phenotype as NK cells in human blood. Blocking experiments and cytokine substitution identified interleukin-12 as a critical mediator in regulation of primary NK cells by moDC., Conclusions: Activation of human NK cells in response to Candida in human blood mainly occurs indirectly by mediators released from monocytic cells., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.) more...

Autologous bio-engineered dermo-epidermal skin substitutes are a promising treatment for large skin defects such as burns. For their successful clinical application, the graft dressing must protect and support the keratinocyte layer and, in many cases, possess antimicrobial properties. However, silver in many antimicrobial dressings may inhibit keratinocyte growth and differentiation. The purpose of our study was to evaluate the effect of various wound dressings on the healing of a human hydrogel-based dermo-epidermal skin substitute in preparation for the first-in-human clinical trials. Human dermo-epidermal skin substitutes approved for clinical trials were produced under good manufacturing practice conditions, transplanted onto immuno-incompetent rats, and dressed with either Vaseline Gauze™ (Kendall Medtronic, Minneapolis, USA), Suprathel (PolyMedics Innovations GmbH, Denkendorf, Germany), Urgotul SSD (Urgo Medical, Shepshed, United Kingdom), Mepilex AG (Mölnlycke Health Care, Gothenburg, Sweden), or Acticoat™ (Smith&Nephew, Baar, Switzerland). Grafts were assessed clinically for take, epithelialization, and infection at 10 and 21 days post-transplantation, and histologically at 21 days. There were three subjects each in the Vaseline Gauze™ and Suprathel groups, and four subjects each in the Urgotul SSD, Mepilex AG, and Acticoat™ groups. For all samples, the take rate was 100% and the expected keratinocyte number, epithelialization and epidermal stratification were observed. All of the dressings in the current study were well tolerated by our human dermo-epidermal skin substitute. The tolerance of the silver-based dressings is particularly relevant given the high risk of bacterial contamination with large skin defects, and provides pivotal information as we embark on clinical trials for this novel skin substitute. more...

In this study, results are presented from the on-board radiation assessment detector (RAD) of Mars Science Laboratory (MSL). RAD is designed to measure the energetic particle radiation environment, which consists of galactic cosmic rays (GCRs) and solar energetic particles (SEPs) as well as secondary particles created by nuclear interactions of primary particles in the shielding (during cruise) or Martian soil and atmosphere (surface measurements). During the cruise, RAD collected data on space radiation from inside the craft, thus allowing for a reasonable estimation of what a human crew travelling to/from Mars might be exposed to. On the surface of Mars, RAD is shielded by the atmosphere (from above) and the planet itself (from below). RAD measures the first detailed radiation data from the surface of another planet, and they are highly relevant for planning future crewed missions. The results for radiation dose and dose equivalent (a quantity most directly related to human health risk) are presented during the cruise phase, as well as on the Martian surface. Dose and dose equivalent are dominated by the continuous GCR radiation, but several SEP events were also detected and are discussed here., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.) more...