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Implant-associated infections remain a grand unmet medical need because they involve biofilms that protect bacteria from the immune system and harbour antibiotic-tolerant persister cells. There is an urgent need for new biofilm-targeting therapies with antimicrobials, to treat these infections via a non-surgical way. In this work, we address this urgent medical need and engineer antibody-drug conjugates (ADC) that kill bacteria in suspension and in biofilms,in vitroandin vivo. The ADC contains an anti-neoplastic drug mitomycin C, which is also a potent antimicrobial against biofilms. While most ADCs are clinically validated as anti-cancer therapeutics where the drug is released after internalisation of the ADC in the target cell, the ADCs designed herein release the conjugated drug without cell entry. This is achieved with a novel mechanism of drug, which likely involves an interaction of ADC with thiols on the bacterial cell surface. ADC targeted towards bacteria were superior by the afforded antimicrobial effects compared to the non-specific counterpart, in suspension and within biofilms,in vitroandin vivo. An implant-associated murine osteomyelitis model was then used to demonstrate the ability of the antibody to reach the infection, and the superior antimicrobial efficacy compared to standard antibiotic treatmentin vivo. Our results illustrate the development of ADCs into a new area of application with a significant translational potential.

Seaweed farming is a growing industry worldwide, and its sustainable management requires detailed knowledge about the environmental implications of detrital release. This study investigates benthic degradation of kelp detritus in defaunated mesocosms. The degradation dynamics were investigated over several weeks by resolving O2 and dissolved inorganic carbon (DIC) fluxes as a function of detritus amendments (0.15 g wet weight [WW] m-2 to 1 kg WW m-2), temperature (8 and 15°C), and presence of O2 for 2 commercially important kelp species: Saccharina latissima and Alaria esculenta. Kelp fragments were deposited in 2 different ways to simulate oxic and anoxic degradation: on the sediment surface (surface amendments) and just below the oxic surface sediment layer (subsurface amendments). All amendments resulted in high initial O2 consumption followed by an exponential decrease in O2 uptake over time. The degradation rates increased linearly with the amount of kelp added for both species and for both types of amendments. S. latissima expressed higher decay constants across all experiments and had a higher percentage turnover of carbon. In some instances, microbial priming apparently enabled enhanced degradation of pre-existing resilient sedimentary carbon. The absolute degradation rates of kelp were reduced in the absence of O2, and sulfate reduction resulted in gradual accumulation of iron sulfide. Lower ambient temperature reduced the benthic mineralization rate of both kelp species, particularly during the initial incubation stages. The current study demonstrates the importance of key variables for microbial kelp degradation in marine sediments and their dynamics—variables that should be carefully considered when assessing environmental implications of seaweed farming.

BackgroundEvaluation of effectiveness and safety of new systemic treatments for atopic dermatitis (AD) after approval is important. There are few published data exceeding 52-week therapy with dupilumab.ObjectivesTo examine the safety, effectiveness and drug survival of dupilumab in a Danish nationwide cohort with moderate-to-severe AD up to 104 weeks exposure.MethodsWe included 347 adult patients with AD who were treated with dupilumab and registered in the SCRATCH registry during 2017–2022.ResultsAt all visits, we observed improvement in AD severity measured by Eczema Area and Severity Index (EASI) [median (IQR)]. EASI score at baseline was 18.0 (10.6–25.2), at week 4: 6.5 (3.5–11.6), at week 16: 3.7 (1.2–6.2), at week 52: 2.0 (0.8–3.6), at week 104: 1.7 (0.8–3.8). While drug survival was high (week 52: 90%; week 104: 86%), AD in the head-and-neck area remained present in most patients at high levels; proportion with head-and-neck AD at baseline was 76% and 68% at week 104. 35% of patients reported any AE. Conjunctivitis was the most frequent (25% of all patients) and median time to first registration of conjunctivitis was 201 days.ConclusionsWhile 2-year drug survival was 86%, dupilumab was unable to effectively treat AD in the head-and-neck area, and conjunctivitis was found in 25% of patients.

Er løftearbejde, langvarig gående stående arbejde, knæliggende arbejde eller en kombination af disse risikofaktorer for at udvikle slidgigt (artrose) i hofte og/eller knæ? Er tidligere ledskader i hofte eller knæ risikofaktorer for artrose i hofte eller knæ? Er BMI>25 tidligt i livet en risikofaktor for at udvikle artrose i hofte eller knæ? Projektets formal er at undersøge relationerne mellem miljø- og arbejdsmæssige risikofaktorer og risiko for kunstig hofteled (Total Hofte Alloplastik (THA)) og kunstig knæled (Total Knæ Alloplastik (TKA)) på grund af slidgigt i henholdsvis hofte og knæ, samt at undersøge, om disse risikofaktor-slidgigt relationer er underlagt genetisk effekt modifikation

Humans and pigs share a close contact relationship, similar biological traits, and one of the highest estimated number of viruses compared to other mammalian species. The contribution and directionality of viral exchange between humans and pigs remain unclear for some of these viruses, but their transmission routes are important to characterize in order to prevent outbreaks of disease in both host species. This review collects and assesses the evidence to determine the likely transmission route of 27 viruses between humans and pigs.

Snailfishes are among the most rapidly radiating families of marine fishes, resulting in a global distribution from the coastal intertidal to deep subduction trenches. The true diversity and distribution of deep-water snailfishes, particularly at hadal depths (>6000 m) and in the Southern Hemisphere, remain uncertain due to the rarity of samples. Here, we present the snailfish diversity at near-hadal and hadal depths in the Atacama Trench, which runs along the southwest coast of South America. Using free-fall baited cameras and traps, we documented at least three species of hadal snailfishes between 5920 and 7608 m based on distinct morphologies. One snailfish specimen was recovered from 6714 m, which we describe herein as Paraliparis selti sp. nov., based on a combined morphological and molecular taxonomic approach (16S, COI, and Cyt-b). Paraliparis selti sp. nov. is morphologically distinct from described snailfishes due to a combination of high number of; vertebrae (65) particularly the abdominal vertebrae (12), dorsal fin rays (60), anal fin rays (52), and caudal fin rays (8); comparatively low number of pectoral fin rays (18) which forms a deep notch with two widely spaced non-rudimentary rays. Micro-CT was used to minimise dissection of the specimen and to provide a digital holotype. Paraliparis selti sp. nov. highlights the importance of the Liparidae at hadal depths and provides evidence for at least two independent radiations of snailfishes into the hadal zone.

PUVA is a treatment that combines oral methoxypsoralen (8-MOP) with ultraviolet radiation A (UVA). It is used for severe psoriasis and the early stages of T-cell lymphoma. X-rays are an effective treatment for skin cancers. Both treatments are in higher doses used to treat skin malignancies and simultaneously increase the risk of keratinocyte cancer. The main objective of this study was to test whether a few PUVA or X-ray treatments could delay the development of ultraviolet radiation (UVR)-induced skin tumors in a well-established hairless mouse model. Three groups of immunocompetent mice (total, N = 75) were included in the study. All groups were UVR-exposed during the study period. In addition, one group was treated with PUVA and another group was treated with X-rays at days 45, 52, 90 and 97. A control group was treated with UVR only. We recorded when the first, second and third skin tumors were induced in each mouse. Skin tumors developed significantly earlier in both the PUVA and X-ray groups (median, 188 days) than in the control mice (median, 215 days; p

International audience; The biology and ecology of benthic fauna from extreme environments, such as the hadal zone (> 6,000 m depth), is scarce due to the difficulties of access, exploration, and work logistics. The few exploration cruises of bottom settings have shown that benthic foraminifera, and meiofauna in general, display high abundances in the sediments, indicating that these organisms present unique adaptations and interactions to extreme conditions (e. g. high hydrostatic pressure, limitation of calcite and organic matter, etc.). As such, new species to science have also been reported. The Peru-Chile trench represents the deepest ecosystem in the South Pacific. It has been explored only on three occasions describing it as a eutrophic environment with high biomass of meiofauna. For foraminifera, only species reports have been published, being the ecology neglected. In this study, we aimed to determine the community structure (abundance, diversity, spatial and vertical distribution) of the foraminifera collected from 6 stations in the Atacama trench in the SONNE Cruise during 2018. We compared the taxa features to granulometry and proxies of food, organic matter source, and oxygenation. Dissolved oxygen at all trench stations penetrated 3-5 cm into the sediments and TOC was 0.5-1.3 %. The grain size was mainly silt-rich. The presence of 120 morphospecies, many of them soft-walled, is reported. The community was dominated by large specimens (>500 µm), and small specimens (63-150 µm) were rare. The bulk of the community concentrated in the first centimeter of sediment despite all the trench stations were fully oxygenated. However, different assemblages were found in the 6 analyzed stations. We argue if these community differences are generated by the gradient of organic matter nature or the presence/abundance of meiofaunal/macrofaunal predators. Our results contribute to the knowledge of ecology and diversity of foraminifera from the Atacama Trench and give insight to the role of this group in the benthic food webs in hadal settings.

IntroductionGait difficulties are common in Parkinson’s disease (PD) and cause significant disability. These symptoms are often resistant to treatment. Spinal cord stimulation (SCS) has been found to improve gait, including freezing of gait, in a small number of patients with PD. The mechanism of action is unclear, and some patients are non-responders. With this double-blind, placebo-controlled efficacy and feasibility clinical and imaging study, we aim to shed light on the mechanism of action of SCS and collect data to inform development of a scientifically sound clinical trial protocol. We also aim to identify clinical and imaging biomarkers at baseline that could be predictive of a favourable or a negative outcome of SCS and improve patient selection.Methods and analysisA total of 14 patients will be assessed with clinical rating scales and gait evaluations at baseline, and at 6 and 12 months after SCS implantation. They will also receive serial18F-deoxyglucose and18FEOBV PET scans to assess the effects of SCS on cortical/subcortical activity and brain cholinergic function. The first two patients will be included in an open pilot study while the rest will be randomised to receive active treatment or placebo (no stimulation) for 6 months. From this point, the entire cohort will enter an open label active treatment phase for a subsequent 6 months.Ethics and disseminationThis study was reviewed and approved by the Committee on Health Research Ethics, Central Denmark RM. It is funded by the Danish Council for Independent Research. Independent of outcome, the results will be published in peer-reviewed journals and presented at national and international conferences.Trial registration numberNCT05110053; ClinicalTrials.gov Identifier.

Chronic neuropathic pain is often very difficult to treat effectively and constitutes a significant burden on both the affected patients and society. Invasive neuromodulation, electrical stimulation of specific nerve structures with implanted electrodes, can be a viable treatment option for patients suffering from severe, chronic neuropathic pain where conventional treatment has not provided sufficient pain relief. Careful patient selection is vital. This paper provides an overview of the treatment field in Denmark.

Small headwater streams are recognized for intense outgassing to the atmosphere of climate‐relevant carbon dioxide (CO2) and methane (CH4). Though these headwaters are markedly oversaturated for both CO2 and CH4, the origins and controls over the fate of these two carbon‐gases are still poorly constrained, especially for the stronger greenhouse gas CH4. Here, by measuring stream‐based production of CO2 and CH4, concurrently with their rates of outgassing to the atmosphere, we identify distinct biophysical control mechanisms for each gas. We show that while CO2 is largely imported from the catchment in proportion to discharge, CO2 outgassing can be modulated by in‐stream metabolism to offset outgassing by up to 30% in spring and summer. In contrast, CH4 shows a non‐linear response to seasonal changes in discharge and is predominantly produced in the streambed in relation to sediment type. Further, once released from the streambed, outgassing of CH4 at the surface and flow‐driven dilution occur far more rapidly than biological methane oxidation and CH4 leaves the water largely unaltered by biology. Incorporating the intense carbon cycling of headwater streams into the global carbon cycle will require distinct parameterizations for each carbon gas in Earth system models., Plain Language Summary: There is growing interest in the global carbon cycle and how carbon is transformed in the landscape into the greenhouse gases carbon dioxide (CO2) and methane–with methane being by far the more potent than CO2. Streams and rivers are recognized hotspots of carbon cycling in the landscape, commonly harboring large amounts of CO2 and methane–yet what controls either gas in streams is not fully understood. Without that understanding, we cannot predict how carbon cycling will respond to climate change or to other human alteration of the landscape. Here we researched different components of the carbon cycle in streams to show that each gas is influenced by quite distinct “biophysical” control mechanisms. While CO2 in streams results largely from physical run‐off from the land, once in a stream it can be changed by the stream biology that ebbs and flows with the seasons. Contrastingly, methane is largely created by biology within the streambed itself but once released into the wider stream that methane is then dispersed by the physical forces of stream flow. Put more simply, CO2 is physically carried to the stream to then be altered by biology, whereas as methane is borne from biology in the stream, to then be physically carried away., Key Points: There are different controls on the outgassing of the greenhouse gases carbon dioxide and methane in streams. Carbon dioxide results largely from physical run‐off from the land and is then altered in stream by biology depending on season. In contrast, methane is created in the streambed but once released to the stream is then dispersed by the physical forces of stream flow., Natural Environment Research Council (NERC) http://dx.doi.org/10.13039/501100000270, Deutsche Forschungsgemeinschaft (DFG) http://dx.doi.org/10.13039/501100001659, EC | H2020 | H2020 Priority Excellent Science | H2020 European Research Council (ERC) http://dx.doi.org/10.13039/100010663, FNU, Danish National Research Foundation