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Abstract The latest Triassic was characterised by protracted biotic extinctions concluding in the End-Triassic Extinction (~ 200 Ma) and a global carbon cycle perturbation. The onset of declining diversity is closely related to reducing conditions that spread globally from upper Sevatian (uppermost Norian) to across the Norian-Rhaetian boundary, likely triggered by unusually high volcanic activity. We correlate significant organic carbon cycle perturbations to an increase of CO2 in the ocean–atmosphere system, likely outgassed by the Angayucham igneous province, the onset of which is indicated by the initiation of a rapid decline in 87Sr/86Sr and 188Os/187Os seawater values. A possible causal mechanism involves elevated CO2 levels causing global warming and accelerating chemical weathering, which increased nutrient discharge to the oceans and greatly increased biological productivity. Higher export production and oxidation of organic matter led to a global O2 decrease in marine water across the Norian/Rhaetian boundary (NRB). Biotic consequences of dysoxia/anoxia include worldwide extinctions in some fossil groups, such as bivalves, ammonoids, conodonts, radiolarians.

ABSTRACT Pseudomonas alloputida KT2440 is a ubiquitous, soil-dwelling bacterium that metabolizes recalcitrant and volatile carbon sources. The latter is utilized by two redundant, Ca- and lanthanide (Ln)-dependent, pyrroloquinoline quinone-dependent alcohol dehydrogenases (PQQ ADH), PedE and PedH, whose expression is regulated by Ln availability. P. alloputida KT2440 is the best-studied non-methylotroph in the context of Ln-utilization. Combined with microfluidic cultivation and single-cell elemental analysis, we studied the impact of light and heavy Ln on transcriptome-wide gene expression when growing P. alloputida KT2440 with 2-phenylethanol as the carbon and energy source. Light Ln (La, Ce, and Nd) and a mixture of light and heavy Ln (La, Ce, Nd, Dy, Ho, Er, and Yb) had a positive effect on growth, whereas supplementation with heavy Ln (Dy, Ho, Er, and Yb) exerted fitness costs. These were likely a consequence of mismetallation and non-utilizable Ln interfering with Ln sensing and signaling. The measured amounts of cell-associated Ln varied between elements. Gene expression analysis suggested that the Ln sensing and signaling machinery, the two-component system PedS2R2 and PedH, responds differently to (non-)utilizable Ln. We expanded our understanding of the lanthanide (Ln) switch in P. alloputida KT2440, demonstrating that it adjusts the levels of pedE and pedH transcripts based on the availability of Ln. We propose that the usability of Ln influences the bacterium’s response to different Ln elements.IMPORTANCEThe Ln switch, the inverse regulation of Ca- and Ln-dependent PQQ ADH in response to Ln availability in organisms featuring both, is central to our understanding of Ln utilization. Although the preference of bacteria for light Ln is well known, the effect of different Ln, light and heavy, on growth and gene expression has rarely been studied. We provide evidence for a fine-tuning mechanism of Ca- and Ln-dependent PQQ ADH in P. alloputida KT2440 on the transcriptome level. The response to (non-)utilizable Ln differs depending on the element. Ln commonly co-occur in nature. Our findings underline that Ln-utilizing microbes must be able to discriminate between Ln to use them effectively. Considering the prevalence of Ln-dependent proteins in many microbial taxa, more work addressing Ln sensing and signaling is needed. Ln availability likely necessitates different adaptations regarding Ln utilization.

Abstract Casitas B‐cell lineage (CBL) syndrome is a rare RASopathy known to predispose to CBL‐mutated juvenile myelomonocytic leukemia (JMML) in childhood. Adulthood acute myeloid leukemia arising out of a genetic aberrancies consistent with prior CBL‐mutated JMML has been twice previously described, but chronic myeloproliferative neoplasia has not. We present a case of progressive myeloproliferative neoplasm in adulthood in the context of CBL syndrome alongside a novel CSF3R variant. We also review pathogenic splice‐site mutations in CBL‐mutated JMML.

Published Sn isotope data along with 150 new analyses of cassiterite and four granite analyses constrain two major tin isotope fractionation steps associated with (1) separation of tin from the magma/orthomagmatic transitional environment and (2) hydrothermal activity. A distinct Sn isotope difference across deposit type, geological host rocks, and time of ore deposit formation demonstrates that the difference in the mean δ124Sn value represents the operation of a unified process. The lower Sn isotope values present in both residual igneous rocks and pegmatite suggest that heavier Sn isotopes were extracted from the system during orthomagmatic fluid separation, likely by F ligands with Sn. Rayleigh distillation models this first F ligand-induced fractionation. The subsequent development of the hydrothermal system is characterized by heavier Sn isotope composition proximal to the intrusion, which persists in spite of Sn isotope fractionating towards isotopically lighter Sn during hydrothermal evolution.

Lactococcus garviae (L. garviae) is a gram-positive coccus belonging to the Streptococcaceae family. While primarily a pathogen in fish farms causing hemorrhagic sepsis, it can act as a rare opportunistic pathogen in humans. A 2021 case report by Bravo et al. documented less than 30 cases of infective endocarditis caused by L. garviae worldwide at that time [1]. This case report describes the 27th documented case globally and 7th documented case in the USA of L. garviae causing infective endocarditis of a prosthetic valve [1].L. garviae is found in unpasteurized dairy products, raw fish, and meat (pork, beef, and poultry), but the route of human transmission remains unclear [3]. It seems to have a predilection for individuals with prosthetic valves, immunocompromised states, prior gastrointestinal surgery, gastrointestinal disorders (colon polyps and diverticulosis), and the use of acid-reducing medications [1-3]. Infective endocarditis is the most common systemic disease caused by L. garviae [1-4].This report details the case of a 75-year-old male, with multiple comorbidities and risk factors for L. garviae infection who was admitted for “symptomatic anemia”. High clinical suspicion, coupled with an inadequate hemoglobin response to transfusion, a normal anemia workup, and blood cultures positive for L. garviae, promoted a transesophageal echocardiogram (TEE). However, the results were negative. Consequently, an 18F-fluorodeoxyglucose positron emission tomography/computed tomography scan (18FDG PET/CT) was performed. The scan revealed increased uptake in the aortic valve replacement consistent with prosthetic valve endocarditis in the setting of Lactococcus garviae bacteremia.

Abstract Copper (Cu) is a cofactor in numerous key proteins and, thus, an essential element for life. In biological systems, Cu isotope abundances shift with metabolic and homeostatic state. However, the mechanisms underpinning these isotopic shifts remain poorly understood, hampering use of Cu isotopes as biomarkers. Computational predictions suggest that isotope fractionation occurs when proteins bind Cu, with the magnitude of this effect dependent on the identity and arrangement of the coordinating amino acids. This study sought to constrain equilibrium isotope fractionation values for Cu bound by common amino acids at protein metal-binding sites. Free and bound metal ions were separated via Donnan dialysis using a cation-permeable membrane. Isotope ratios of pre- and post-dialysis solutions were measured by MC-ICP-MS following purification. Sulfur ligands (cysteine) preferentially bound the light isotope (63Cu) relative to water (Δ65Cucomplex-free = − 0.48 ± 0.18‰) while oxygen ligands favored the heavy isotope (65Cu; + 0.26 ± 0.04‰ for glutamate and + 0.16 ± 0.10‰ for aspartate). Binding by nitrogen ligands (histidine) imparted no isotope effect (− 0.01 ± 0.04‰). This experimental work unequivocally demonstrates that amino acids differentially fractionate Cu isotopes and supports the hypothesis that metalloprotein biosynthesis affects the distribution of transition metal isotopes in biological systems.

Abstract Introduction Immunocompromised patients are at increased risk for herpes zoster (HZ)-associated complications. Despite standard therapy with systemic antiviral drugs and analgesics, complications are frequently encountered, including generalization of lesions or persistent neuropathic pain, so-called post-herpetic neuralgia (PHN). Given the scarcity of literature and awareness of therapeutic options to improve patient outcomes, especially for vulnerable patient groups, here we describe a strategy based on early intensification of treatment with a varicella zoster virus-specific hyperimmunoglobulin (VZV-IgG), which is approved in the adjuvant treatment of HZ. Methods For this case series, we selected four cases of HZ in patients with impaired immunity due to hemato-oncologic disease or immunosuppressive treatment who presented with either existing generalized lesions and/or severe pain or with other risk factors for a complicated HZ course such as PHN. They were considered to be representative examples of different patient profiles eligible for intensification of treatment by the addition of VZV-IgG to virostatic therapy. Case Report All patients showed a rapid response to combined treatment with VZV-IgG and a virostatic agent. In two patients who had generalized lesions, the formation of new lesions ceased 1 day after VZV-IgG infusion. One patient, with mantle cell lymphoma, achieved complete healing of the lesions 9 days after diagnosis of HZ, a rare occurrence compared to similar cases or cohorts. A patient with HZ in the cervical region showed a good response after a single dose of VZV-IgG. None of the patients developed post-zoster-related complications. Combination therapy of a virostatic agent and VZV-IgG was well tolerated in these four cases. Conclusion This case series demonstrates highly satisfactory treatment effectiveness and tolerability for VZV-IgG in the adjuvant treatment of immunocompromised HZ patients and supports early intensification of HZ therapy in patients at high risk of severe disease progression.

La producción de semilla de calidad constituye uno de los retos principales para la seguridad y la soberanía alimentaria tanto de poblaciones urbanas como rurales, requiriendo procesos que reconozcan no solo el potencial de los territorios sino la diversidad asociada a las comunidades campesinas y sus formas de producción, de modo que permitan reducir las brechas producto del uso de semilla de baja o nula calidad física, genética, fisiológica y sanitaria que disminuya la afectación en los rendimientos de los cultivos de plátano, piña y yuca. Para ello, se llevó a cabo un proceso de investigación participativa para atender a la demanda de proyectos que mejoren la seguridad alimentaria y nutricional de la población del departamento del Casanare - Colombia. Como resultado, se implementó la metodología basada en encuentros con productores de los sistemas productivos para la construcción de conocimiento a partir de cartografía social, la elaboración de calendarios económicos y mapeos de actores y necesidades. Esta lectura de los entornos permitió el desarrollo de actividades para la selección participativa de materiales de siembra, procesos de multiplicación intensiva de materiales, así como la transformación y producción de derivados del plátano, piña y yuca. Las conclusiones tienen que ver con la importancia de dimensionar al productor como un participante activo en los procesos de investigación en la construcción de conocimiento que aporte en la generación y apropiación de soluciones sustentadas en ciencia, tecnología e innovación en favor de la seguridad alimentaria y con ello la reducción de la pobreza. Se proyecta en un futuro cercano llevar a cabo un proceso de formación de formadores con universidades aliadas para dejar capacidades instaladas y para promover el acceso y disponibilidad de semilla de calidad.

Abstract Background In randomized trials in women with breast cancer, exercise has been shown to have beneficial effects on cancer‐related circulating biomarkers that may impact survival. Such studies are lacking for ovarian cancer. Methods This secondary analysis of a published randomized controlled trial examined the impact of a 6‐month exercise intervention versus attention‐control on change in prespecified circulating biomarkers (cancer antigen 125 (CA‐125), C‐reactive protein (CRP), insulin‐like growth factor‐1(IGF‐1), insulin and leptin) in a subset of participants who provided a fasting blood draw (N = 104/144) at enrollment and at 6 months. Change in biomarkers between study arms was compared using a linear mixed effects model analysis. An exploratory analysis of the exercise intervention versus attention‐control on all‐cause mortality included all (N = 144) participants. All statistical tests were two‐sided. Results Participants included in the biomarker analysis were 57.0 ± 8.8 (mean ± SD) years old and 1.6 ± 0.9 years post‐diagnosis. Adherence to the exercise intervention was 176.4 ± 63.5 min/week. Post intervention IGF‐1 (group difference in change: −14.2 (−26.1 to −2.3) ng/mL (least squared means (95% CI))) and leptin (−8.9 (−16.5 to −1.4) ng/mL) were significantly reduced in the exercise group (N = 53) compared to those in attention‐control (N = 51). No group difference in change was seen for CA‐125 (p = 0.54), CRP (p = 0.95), or insulin (p = 0.37). With median follow‐up of 70 months [range 6.6–105.4 months], 50/144 (34.7%) (exercise group; 24/74 (32.4%) versus attention‐control group; 26/70 (37.1%)) participants died with no between group difference in overall survival (p = 0.99). Conclusions Further studies are needed to determine the clinical significance of exercise‐induced changes in cancer‐related circulating biomarkers in women with ovarian cancer.

The cut flower sector is an area of horticulture that generates great economic and academic interest worldwide, the production of flowers represents a market segment that has aesthetic and sentimental purposes in many regions of the world. In recent years, a large amount of research has been generated that has promoted this sector, therefore, in this work we have proposed to develop a systematic review in this field of knowledge, with the objective of consolidating knowledge, guiding future research, and supporting informed decisions, thus contributing to the efficient use of resources and the continuous advancement of the cut flower industry. The systematic review process was divided into six stages, starting with the definition of the search equation and the collection of information from the prestigious Scopus database. Subsequently, a detailed quality and technical analysis of the 532 documents collected was conducted. These documents were grouped into 13 topics that are related to the production system, ranging from propagation techniques, genome study, genetic improvement to topics of current interest such as sustainability. Each of these topics was examined and the results of this analysis led to the preparation of this technical document, which includes relevant aspects that have contributed to the improvement of productivity and productive diversity in species and under different climatic conditions.

ABSTRACT Lanthanides (Ln) are the most recently described life metals and are central to methylotrophy (type of metabolism in which organic substrates without carbon-carbon bonds serve as carbon and energy source) in diverse taxa. We recently characterized a novel, Ln-dependent, and Ln-accumulating methylotroph, Beijerinckiaceae bacterium RH AL1, which requires lighter Ln (La, Ce, Nd) for methanol oxidation. Starting from two sets of incubations, one with different La concentrations (50 nM and 1 µM) and one with different Ln elements [La, Nd, or an Ln cocktail (containing Ce, Nd, Dy, Ho, Er, Yb)], we could show that La concentration and different Ln elements strongly affect gene expression and intracellular Ln accumulation. Differential gene expression analysis revealed that up to 41% of the encoded genes were differentially expressed. The effects of La concentration and Ln elements were not limited to Ln-dependent methanol oxidation but reached into many aspects of metabolism. We observed that Ln influence the flagellar and chemotactic machinery and that they affect polyhydroxyalkanoate biosynthesis. The most differentially expressed genes included lanM, coding for the well-characterized lanthanide-binding protein lanmodulin, and a glucose dehydrogenase gene linked to the conversion of β-D-glucose to D-glucono-1,5-lactone, a known potential metal chelator. Electron microscopy, together with RNAseq, suggested that Beijerinckiaceae bacterium RH AL1 can discriminate between Ln elements and that they are differently taken up and accumulated. The discrimination of Ln and links between Ln and various aspects of metabolism underline a broader physiological role for Ln in Beijerinckiaceae bacterium RH AL1. IMPORTANCE Since its discovery, Ln-dependent metabolism in bacteria attracted a lot of attention due to its bio-metallurgical application potential regarding Ln recycling and circular economy. The physiological role of Ln is mostly studied dependent on presence and absence. Comparisons of how different (utilizable) Ln affect metabolism have rarely been done. We noticed unexpectedly pronounced changes in gene expression caused by different Ln supplementation. Our research suggests that strain RH AL1 distinguishes different Ln elements and that the effect of Ln reaches into many aspects of metabolism, for instance, chemotaxis, motility, and polyhydroxyalkanoate metabolism. Our findings regarding Ln accumulation suggest a distinction between individual Ln elements and provide insights relating to intracellular Ln homeostasis. Understanding comprehensively how microbes distinguish and handle different Ln elements is key for turning knowledge into application regarding Ln-centered biometallurgy.

Abstract Exceptionally well‐preserved tufas located west of Calama, Atacama Desert, Chile, designated Santa Juana tufas, record episodic wetter conditions, relative to today, over the past 500,000 years. Globally, tufa architecture and depositional details are poorly understood as most described tufas have been degraded by weathering and erosion. In the hyperarid Atacama, post‐depositional alteration is negligible, therefore, the exceptional preservation of Santa Juana tufas documented in this study provides new information about tufa facies and their complex interactions. Santa Juana facies include microbial stromatolites, phytoherms, cascadestone, flowstone and porous limestone. Phytoherms, consisting of former plant stems coated with calcite, developed in channels, within pools, and along spring discharge aprons. Cascadestone, representing former waterfalls, preserves microbial filaments and delicate V‐shaped calcite crystals. Flowstone lines shallow subvertical to subhorizontal channels, representing sites of rapidly sluicing water flow. Porous limestone, containing sparse calcite and/or gypsum and anhydrite cement crystals, represents detrital accumulations. Stable isotope results, coupled with U/Th ages, show that by the Quaternary, relative to the Neogene, groundwater was less supercharged with volcanogenic CO2 so degassing was moderated. The δ18O ratios from Miocene–Pliocene palustrine and lacustrine freshwater carbonates that underlie Santa Juana tufas indicate significant evaporation, but the tufa δ18O signal indicates a less evaporative trend due to shorter atmosphere exposure time. Biological fractionation in δ13C is largely masked by the region's volcanogenic carbon footprint, although tufa petrography shows well‐preserved microbial filaments and laminations. The range of tufa ages in this study shows that there were wetter time periods within the drainage basin headwater area in the Quaternary, but that by the late Pleistocene to early Holocene, aridity to hyperaridity became established. The lack of diagenesis or alteration within the Santa Juana tufas indicates that there has been minimal rainfall since their deposition.

Ornamental plants play a fundamental role in diverse applications, from cut flower production to landscape design and space decoration. The ornamental industry, which is part of horticulture, has experienced significant advances and mobilizes billions of dollars in the global economy, being also a totally globalized market. In recent years, this industry has implemented advanced production strategies, from genetic improvement to sustainability and supply chain, promoting scientific research in various areas. However, the dispersion of knowledge has hindered the integration of the various research networks. Therefore, this article seeks to provide an overview of the scientific production in the cut flower sector, establishing a reference line for researchers, using bibliometrics as a tool to identify trends and the scientific structure of this area of knowledge. The results revealed that worldwide since 1983 there have been 975 articles focused on this productive system, gene rated in more than 69 countries by 2750 authors who published their research in 160 academic journals. Relevant research topics that are already developed and those that need a more intense and integrated research focus on the knowledge already generated were also identified.

Digitale Kompetenzen nehmen infolge einer voranschreitenden Mediatisierung aller Alters- und Lebensbereiche eine zunehmend wichtige Rolle für die soziale und gesellschaftliche Teilhabe ein. Besonders ältere Generationen stehen hier vor grossen Herausforderungen, da sie durch ihre Medienbiografie andere Voraussetzungen für die kompetente Nutzung mit sich bringen. Unterstützung wird mittlerweile durch eine Vielzahl von formellen und informellen Bildungsangeboten für ältere Erwachsene geboten, die auf eine Stärkung digitaler Kompetenzen abzielen. Um die Wirksamkeit dieser Bildungsformate zu prüfen, bedarf es einer Messung digitaler Kompetenzen, die allerdings vielerorts nicht hinreichend evaluiert wird. Mitunter fehlt es für diese Personengruppe an theoretisch-konzeptionell abgeleiteten und empirisch-methodisch validen Messinstrumenten. Die Autor:innengruppe des Beitrags hat sich deshalb seit März 2022 zusammengefunden und aktuelle Modelle digitaler Kompetenz sowie darauf aufbauende Messinstrumente diskutiert. Eine Übersicht hierüber soll in diesem Beitrag vorgestellt werden. Aus forschungsprojektbedingtem Evaluationsbedarf wurde im Verlauf ein bereits bestehendes Messinstrument (DigCompSAT auf Grundlage des Digital Competence Framework for Citizens, DigComp) so überarbeitet, dass ein erster Versuch für reduziertes und reliables Messinstrument zur Evaluation digitaler Kompetenzen älterer Erwachsener vorgeschlagen werden kann, welches weiterer Prüfung und Verbesserung bedarf.

Background Locally advanced/recurrent head and neck squamous cell carcinoma (HNSCC) is associated with significant morbidity and mortality. To target upregulated ErbB dimer expression in this cancer, we developed an autologous CD28-based chimeric antigen receptor T-cell (CAR-T) approach named T4 immunotherapy. Patient-derived T-cells are engineered by retroviral transduction to coexpress a panErbB-specific CAR called T1E28ζ and an IL-4-responsive chimeric cytokine receptor, 4αβ, which allows IL-4-mediated enrichment of transduced cells during manufacture. These cells elicit preclinical antitumor activity against HNSCC and other carcinomas. In this trial, we used intratumoral delivery to mitigate significant clinical risk of on-target off-tumor toxicity owing to low-level ErbB expression in healthy tissues.Methods We undertook a phase 1 dose-escalation 3+3 trial of intratumoral T4 immunotherapy in HNSCC (NCT01818323). CAR T-cell batches were manufactured from 40 to 130 mL of whole blood using a 2-week semiclosed process. A single CAR T-cell treatment, formulated as a fresh product in 1–4 mL of medium, was injected into one or more target lesions. Dose of CAR T-cells was escalated in 5 cohorts from 1×107−1×109 T4+ T-cells, administered without prior lymphodepletion.Results Despite baseline lymphopenia in most enrolled subjects, the target cell dose was successfully manufactured in all cases, yielding up to 7.5 billion T-cells (67.5±11.8% transduced), without any batch failures. Treatment-related adverse events were all grade 2 or less, with no dose-limiting toxicities (Common Terminology Criteria for Adverse Events V.4.0). Frequent treatment-related adverse events were tumor swelling, pain, pyrexias, chills, and fatigue. There was no evidence of leakage of T4+ T-cells into the circulation following intratumoral delivery, and injection of radiolabeled cells demonstrated intratumoral persistence. Despite rapid progression at trial entry, stabilization of disease (Response Evaluation Criteria in Solid Tumors V.1.1) was observed in 9 of 15 subjects (60%) at 6 weeks post-CAR T-cell administration. Subsequent treatment with pembrolizumab and T-VEC oncolytic virus achieved a rapid complete clinical response in one subject, which was durable for over 3 years. Median overall survival was greater than for historical controls. Disease stabilization was associated with the administration of an immunophenotypically fitter, less exhausted, T4 CAR T-cell product.Conclusions These data demonstrate the safe intratumoral administration of T4 immunotherapy in advanced HNSCC.

Impaired awareness of hypoglycaemia (IAH) is a risk for severe hypoglycaemia in insulin treatment of type 1 diabetes (T1D). Here the authors report that a group programme focussing on changing cognitive barriers to avoiding hypoglycaemia (HARPdoc) does not reduce severe hypoglycaemia more than a programme focussing on behaviours (BGAT) in a randomized control trial in adults with T1D and treatment-resistant IAH and severe hypoglycaemia.

Angola suffers from a high child mortality rate and a prevalence of anemia due to malnutrition. The aim of this study is to provide a comprehensive overview of the mineral content of 43 wild edible plants. A total of 24 different elements (aluminum, antimony, arsenic, cadmium, calcium, chromium, cobalt, copper, iron, lead, lithium, magnesium, manganese, molybdenum, nickel, potassium, selenium, silicon, sodium, strontium, titanium, thallium, vanadium, zinc) were analyzed by inductively coupled plasma atomic emission spectroscopy to identify nutritional beneficial and hazardous plants. For the majority of studied species (31 of 43) data lack completely. For the remaining, only macronutrient contents are published yet, determining their (ultra)trace element and heavy metal contents for the first time. None of the examined plants pose a risk to human health due to low heavy metal contents, seasonality, and low amounts of consumed plant parts. Iron and zinc rich plant parts, such as fruits of Canarium schweinfurthii, or leaves of Crassocephalum rubens, Solanum americanum, and Piper umbellatum could help combating deficiency syndromes. The genus Landolphia shows to be an aluminum hyperaccumulator with aluminum contents >1000 mg/kg. Results of this study serve as a database for upcoming research. The nutritional value of edible plants is evaluated.

Immune complex (IC) vasculitides present inflammations of vessel walls associated with perivascular deposition of immunoglobulins (Igs), mostly ICs. They encompass systemic and skin-limited variants of IgA vasculitis (IgAV), cryoglobulinemic vasculitis (CV), rheumatoid, lupus, and hypocomplementemic vasculitides, serum sickness cutaneous IgM/IgG (non-IgA) vasculitis, and recurrent macular (hypergammaglobulinemic or exertion-induced) vasculitis. Serum sickness and CV fulfill the criteria of a type III hypersensitivity immune reaction as large lattices of the IC precipitate at vessel walls and activate polymorphonuclear neutrophils (PMNs). Immunoglobulin-A vasculitis differs with regard to the causes of perivascular deposition of ICs since here many IgA1 molecules are hypoglycosylated (Gd-IgA1), which appears to facilitate their perivascular deposition in skin and mesangium (via e.g. CD71). The reasons for increased generation of immunoglobulins or formation of IC and their perivascular deposition in either skin or systemic organs are different and not fully explored. A common denominator of OC vasculitides is the activation of PMNs near the vessel wall via Fcy or Fcα receptors. Acute episodes of IgAV additionally require PMNs to become preactivated by IgA1 or by IC already in circulation. This intravascular priming results in increased adherence and subsequently vessel-destructive NETosis when they encounter IgA deposited at the vessel walls. Binding of IgA1 to PMNs in blood stream is associated with increased serum levels of hypogalactosidated IgA1. The characteristic clinical picture of IgAV (and also of so-called IgG/IgM vasculitis) comprises palpable or retiform purpura with a clear predilection for lower legs, probably due to stasis-related reduction in blood velocity, while in other IC vasculitides, additional factors influence the sites of vasculitides. Our knowledge of distinct forms and different pathophysiological pathways of IC vasculitides may lead to in efficacious or targeted therapies. Antibodies to complement components or intestinal budesonide for IgAV are promising agents (the latter suppresses the pathophysiologically related IgA nephropathy by reducing the generation of mucosal IgA.

Abstract Background Increasing participation in the Australian National Bowel Cancer Screening Program (NBCSP) is the most efficient and cost-effective way of reducing mortality associated with colorectal cancer by detecting and treating early-stage disease. Currently, only 44% of Australians aged 50–74 years complete the NBCSP. This efficacy trial aims to test whether this SMS intervention is an effective method for increasing participation in the NBCSP. Furthermore, a process evaluation will explore the barriers and facilitators to sending the SMS from general practice. Methods We will recruit 20 general practices in the western region of Victoria, Australia to participate in a cluster randomised controlled trial. General practices will be randomly allocated with a 1:1 ratio to either a control or intervention group. Established general practice software will be used to identify patients aged 50 to 60 years old who are due to receive a NBCSP kit in the next month. The SMS intervention includes GP endorsement and links to narrative messages about the benefits of and instructions on how to complete the NBCSP kit. It will be sent from intervention general practices to eligible patients prior to receiving the NBCSP kit. We require 1400 eligible patients to provide 80% power with a two-sided 5% significance level to detect a 10% increase in CRC screening participation in the intervention group compared to the control group. Our primary outcome is the difference in the proportion of eligible patients who completed a faecal occult blood test (FOBT) between the intervention and control group for up to 12 months after the SMS was sent, as recorded in their electronic medical record (EMR). A process evaluation using interview data collected from general practice staff (GP, practice managers, nurses) and patients will explore the feasibility and acceptability of sending and receiving a SMS to prompt completing a NBCSP kit. Discussion This efficacy trial will provide initial trial evidence of the utility of an SMS narrative intervention to increase participation in the NBCSP. The results will inform decisions about the need for and design of a larger, multi-state trial of this SMS intervention to determine its cost-effectiveness and future implementation. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12620001020976 . Registered on 17 October 2020.

Carnivores are currently colonizing cities where they were previously absent. These urban environments are novel ecosystems characterized by habitat degradation and fragmentation, availability of human food, and different prey assemblages than surrounding areas. Coyotes (Canis latrans) established a breeding population in New York City (NYC) over the last few decades, but their ecology within NYC is poorly understood. In this study, we used non-invasive scat sampling and DNA metabarcoding to profile vertebrate, invertebrate, and plant dietary items with the goal to compare the diets of urban coyotes to those inhabiting non-urban areas. We found that both urban and non-urban coyotes consumed a variety of plants and animals as well as human food. Raccoons (Procyon lotor) were an important food item for coyotes within and outside NYC. In contrast, white-tailed deer (Odocoileus virginianus) were mainly eaten by coyotes inhabiting non-urban areas. Domestic chicken (Gallus gallus) was the human food item found in most scats from both urban and non-urban coyotes. Domestic cats (Felis catus) were consumed by urban coyotes but were detected in only a small proportion of the scats (

Elevated Zn isotope compositions occur in K-Pg sedimentary layers of three different depositional environments across North America and the Caribbean. The data indicate a volatilization event, and act as a robust mechanistic indicator of the meteorite impact at the end of the Cretaceous.

The present study attempted to translate and culturally adapt an established research instrument, the Hypoglycemia Fear Survey (HFS) questionnaire, to the Greek population and evaluate its validity and internal consistency so that it can be used for the assessment of hypoglycemia fear in Greek children and adolescents with T1DM and their parents. One hundred Greek children and adolescents with T1DM, 54 males, 6–18 years old, and one of their parents participated in this validation study. The participants completed the translated Greek HFS, which includes one version for children (CHFS) and one for parents (PHFS). Exploratory Factor Analysis (EFA) was used to assess construct validity. Internal consistency was assessed using Cronbach’s alpha, and convergent validity was established by estimating the correlation coefficients between the scores of the HFS scales/subscales and the different constructs of the Pediatric Quality of Life Inventory. The CHFS and PHFS exhibited adequate internal consistency for the total score and the Worry subscale, but lower consistency for the Behavior subscale. High test–retest reliability was also shown. We conclude that the Greek version of the HFS is a valid and reliable instrument to assess the fear of hypoglycemia in Greek children and adolescents with T1DM and their parents.

BackgroundMuseums can be instrumental in fostering social inclusion and may improve the overall health of the older population. Over the course of the 2019 coronavirus pandemic, many older adults suffered as a result of confinement measures, which may have accelerated the processes that lead to physical frailty and increased mental health risks. This study aims to examine whether a 3-month cycle of weekly virtual tours of the Montreal Museum of Fine Arts (MMFA) may have improved feelings of social inclusion, wellbeing and quality of life, and reduced physical frailty in older adults living within the community of Montreal.Methods and designA total of 106 older adults, who were community-dwellers living in Montreal (Quebec, Canada), were recruited for a randomized controlled trial in two parallel groups (intervention with n = 53 vs control with n = 53) between January and April 2022. The intervention consisted of a 3-month cycle of weekly virtual museum tours of the MMFA. Social isolation, wellbeing, quality of life and frailty were evaluated using validated scales that were assessed on a web platform at baseline (M0) and after 3 months (M3) in the intervention group. The control group completed the same assessment according to the same schedule. The outcomes were the mean scores at M0 and M3, and changes in mean scores between M0 and M3.ResultsThe intervention group showed significant improvements in their social isolation, wellbeing, quality of life and frailty scores when compared to the control group, the highest benefits being observed with frailty.ConclusionThe results suggest that the 3-month cycle of weekly virtual MMFA tours may improve social inclusion, physical and mental health in community-dwelling older adults living in Montreal.Trial registrationhttps://clinicaltrials.gov/ct2/show/NCT05046288, identifier NCT05046288.

BackgroundMobile health (mHealth) interventions for self-management are a promising way to meet the needs of patients with chronic diseases in primary care practices. Therefore, an mHealth intervention, TelePraCMan, was developed and evaluated for patients with type 2 diabetes mellitus, chronic obstructive pulmonary disease, high blood pressure, or heart failure in a German primary care setting. TelePraCMan entails a symptom diary, an appointment manager, a manager to document goals, and a warning system. The app should foster the self-management of participating patients. ObjectiveWe aimed to examine the effects of TelePraCMan on patient activation and quality of life and explored the underlying contextual factors, impacts, and degree of implementation. MethodsIn a prospective observational study design, we collected data by using interviews and written questionnaires from participating patients (intervention and control groups) and primary care workers (physicians and practice assistants). The primary outcomes of interest were patient-reported quality of life (12-Item Short Form Survey) and patient activation (patient activation measure). The quantitative analysis focused on differences between patients in the intervention and control groups, as well as before (T0) and after (T1) the intervention. Interviews were analyzed by using qualitative content analysis via MAXQDA (VERBI GmbH). ResultsAt baseline, 25 patients and 24 primary care workers completed the questionnaire, and 18 patients and 21 primary care workers completed the follow-up survey. The patients were predominantly male and, on average, aged 64 (SD 11) years (T0). The primary care workers were mostly female (62%) and, on average, aged 47 (SD 10) years (T0). No differences were observed in the outcomes before and after the intervention or between the intervention and control groups. In the additional interviews, 4 patients and 11 primary care workers were included. The interviewees perceived that the intervention was useful for some patients. However, contextual factors and problems with implementation activities negatively affected the use of the app with patients. The main reasons for the low participation were the COVID-19 pandemic and the target group, which seemed to have less interest in mHealth; the interviewees attributed this to the older age of patients. However, the respondents felt that the app would be better accepted in 5 or 10 years. ConclusionsAlthough the TelePraCMan app was rated as very good and important by the participants, few patients used it. The digital intervention was hardly implemented and had limited impact in the current setting of German primary care. Trial RegistrationGerman Clinical Trials Register DRKS00017320; https://tinyurl.com/4uwrzu85

Extracellular vesicles (EVs) are important mediators in the intercellular communication, influencing the function and phenotype of different cell types within the tumor micro-milieu and thus promote tumor progression. Since EVs safely transport packages of proteins, lipids and also nucleic acids such as miRNAs, EVs and their cargo can serve as diagnostic and prognostic markers. Therefore, the aim of this study was to investigate EV embedded miRNAs specific for melanoma, which could serve as potential biomarkers. In contrast to previous studies, we not only analysed miRNAs from EVs, but also included the miRNA profiles from the EV-secreting cells to identify candidates as suitable biomarkers. While the characterization of EVs derived from normal melanocytes and melanoma cells showed largely comparable properties with regard to size distribution and expression of protein markers, the NGS analyses yielded marked differences for several miRNAs. While miRNA load of EVs derived from normal human epidermal melanocytes (NHEMs) and melanoma cells were very similar, they were highly different from their secreting cells. By comprehensive analyses, six miRNAs were identified to be enriched in both melanoma cells and melanoma cell-derived EVs. Of those, the accumulation of miR-92b-3p, miR-182-5p and miR-183-5p in EVs could be validated in vitro. By functional network generation and pathway enrichment analysis we revealed an association with different tumor entities and signaling pathways contributing melanoma progression. Furthermore, we found that miR-92b-3p, miR-182-5p and miR-183-5p were also enriched in EVs derived from serum of melanoma patients. Our results support the hypothesis that miRNAs derived from EVs can serve as prognostic or diagnostic liquid biopsy markers in melanoma. We identified EV-derived miRNAs and showed that those miRNAs, which were enriched in melanoma cells and EVs, are also found elevated in serum-derived EVs of patients with metastatic melanoma, but not in healthy subjects.

The phyllosphere, the aboveground part of a plant, is a harsh environment with diverse abiotic and biotic stresses, including oscillating nutrient availability and temperature as well as exposure to UV radiation. Microbial colonization of this dynamic environment requires specific adaptive traits, including tolerance to fluctuating temperatures, the production of secondary metabolites and pigments to successfully compete with other microorganisms and to withstand abiotic stresses. Here, we isolated 175 yeasts, comprising 15 different genera, from the wheat flag leaf and characterized a selection of these for various adaptive traits such as substrate utilization, tolerance to different temperatures, biofilm formation, and antagonism toward the fungal leaf pathogen Fusarium graminearum. Collectively our results revealed that the wheat flag leaf is a rich resource of taxonomically and phenotypically diverse yeast genera that exhibit various traits that can contribute to survival in the harsh phyllosphere environment.

Background: Pyothorax in cats is routinely managed, at least initially, with thoracic tube placement associated with systemic antimicrobial administration. Traditionally, large-bore trocar-type thoracostomy tubes have preferentially been used for the drainage of thick material from the pleural space. In recent years, the use of small-bore wire-guided thoracic drains has increased in both small animals and in humans. Few studies have highlighted the efficacy of small-bore wire-guided thoracostomy tubes. Aim: The purpose of this study was to describe the use of small-bore wire-guided thoracostomy tubes in feline pyothorax in terms of efficacy, safety and outcome. Methods: Cats with pyothorax managed with small-bore thoracostomy tubes (2015-2018) were retrospectively studied. The number of drains inserted, the need for anesthesia and analgesia for chest tube placement and maintenance, and related major and minor complications were reviewed. Clinical data, diagnostic results, treatment and outcome were recorded. Results: Ten cats were enrolled. Thoracostomy tube placement was unilateral in 7/10 cats despite the presence of bilateral effusion in 9/10 cats, and required sedation (8/10) or anesthesia (2/10). Three cats experienced minor complications during the chest tube insertion, including self-limiting pneumothorax (1/3) and malpositioning (2/3). One cat had a major complication (non functional malposition) requiring reposition of the drain. Pain management was adequately achieved using opioids (8/10) or opioids plus nonsteroidal anti-inflammatory drugs (NSAIDs) (2/10). Partial chest tube occlusion occurred in 3 cases and it was resolved with lavage. In one case, the occlusion was complete, requiring drain removal. Three/10 cats were treated medically, combining thoracostomy tubes and antibiotics while 7/10 cats underwent surgery. All the cats survived. Conclusion: Small-bore thoracostomy tubes represent a safe and effective option for the initial management of feline pyothorax. In fact, mainly minor complications were reported during insertion and usage. The small-bore thoracostomy tubes were well tolerated by the cats with a satisfactory performance in terms of exudate drainage in most cases. The combined use of a small-bore thoracostomy drain together with the common practice of surgical treatment might have resulted in the successful management of the cases presented.

Measles is a viral infection that has a characteristic pattern of prodromal symptoms followed by a rash. Previously considered an inevitable childhood condition, measles is known as the “first” classic childhood exanthem. For most children, measles was a one-time, short-term illness; however, some children developed complications that led to severe sequelae and death. The introduction of the measles vaccine dramatically decreased the number of cases, but the current trend against vaccination has caused outbreaks of the condition. We propose the implementation of the AAA approach (assume, advise, and answer) as a way for providers to directly encourage the administration of the vaccine and prevent future cases of measles. Keywords: Measles, vaccination

Background: Bulimia nervosa is a disabling psychiatric disorder that considerably impairs physical health, disrupts psychosocial functioning, and reduces overall quality of life. Despite available treatment, less than half of sufferers achieve recovery and approximately a third become chronically ill. Extreme and enduring cases are particularly resistant to first-line treatment, namely antidepressants and cognitive behavioral therapy, and have the highest rate of premature mortality. Here, we demonstrate that in such cases, repeated sessions of ketamine assisted psychotherapy (KAP) is an effective treatment alternative for improving symptoms.Case Presentation: A 21-year-old woman presented with extreme and enduring bulimia nervosa. She reported recurrent binge-eating and purging by self-induced vomiting 40 episodes per day, which proved refractory to both pharmacological and behavioral treatment at the outpatient, residential, and inpatient level. Provided this, her physician recommended repeated KAP as an exploratory and off-label intervention for her eating disorder. The patient underwent three courses of KAP over 3 months, with each course consisting of six sessions scheduled twice weekly. She showed dramatic reductions in binge-eating and purging following the first course of treatment that continued with the second and third. Complete cessation of behavioral symptoms was achieved 3 months post-treatment. Her remission has sustained for over 1 year to date.Conclusions: To our knowledge, this is the first report of repeated KAP used to treat bulimia nervosa that led to complete and sustained remission, a rare outcome for severe and enduring cases, let alone extreme ones. Additionally, it highlights the degree to which KAP can be tailored at the individual level based on symptom severity and treatment response. While its mechanism of action is unclear, repeated KAP is a promising intervention for bulimia nervosa that warrants future research and clinical practice consideration.

Informal waste reclaimers are a key part of South Africa’s recycling economy, being responsible for around 51% of all paper and packaging waste collected in South Africa in 2017. Active in the waste and recycling landscape for more than three decades, their activity predates the earliest voluntary paper and packaging Extended Producer Responsibility schemes. However, these voluntary schemes have been instrumental in scaling South Africa’s recycling economy. Investment by brand owners, retailers, converters and recyclers has helped develop local end-use markets, creating a demand for paper and packaging recyclables and a resultant increase in their collection. An analysis of tonnage and price data shows that the mean estimate of money paid by the private sector to the informal waste sector through the purchase of recyclables at intermediaries such as buy-back centres, was ZAR625 million in 2012, increasing to ZAR872 million in 2017. This private sector ‘investment’ in the local recycling economy has led to direct and indirect job creation and improved livelihoods, particularly for a large, well-established and effective informal waste sector, and has indirectly funded municipal waste diversion strategies, saving municipalities in both the collection and disposal of waste. Significance: • Informal waste reclaimers make a significant contribution to the diversion of paper and packaging recyclables from landfill to recycling in South Africa. • Limited information exists on the earnings of informal reclaimers. • This paper provides new insights on the annual financial payments made by the private sector to informal reclaimers for the collection of recyclables.

Abstract Background The circular economy framework for human production and consumption is an alternative to the traditional, linear concept of ‘take, make, and dispose’. Circular economy (CE) principles comprise of ‘design out waste and pollution’, ‘retain products and materials in use’, and ‘regenerate natural systems’. This commentary considers the risks and opportunities of the CE for low- and middle-income countries (LMICs) in the context of the Sustainable Development Goals (SDGs), acknowledging that LMICs must identify their own opportunities, while recognising the potential positive and negative environmental health impacts. Main body The implementation of the CE in LMICs is mostly undertaken informally, driven by poverty and unemployment. Activities being employed towards extracting value from waste in LMICs are imposing environmental health risks including exposure to hazardous and toxic working environments, emissions and materials, and infectious diseases. The CE has the potential to aid towards the achievement of the SDGs, in particular SDG 12 (Responsible Consumption and Production) and SDG 11 (Sustainable Cities and Communities). However, since SDG 3 (Good Health and Well-Being) is critical in the pursuit of all SDGs, the negative implications of the CE should be well understood and addressed. We call on policy makers, industry, the health sector, and health-determining sectors to address these issues by defining mechanisms to protect vulnerable populations from the negative health impacts that may arise in LMICs as these countries domesticate the CE. Conclusion Striving towards a better understanding of risks should not undermine support for the CE, which requires the full agency of the public and policy communities to realise the potential to accelerate LMICs towards sustainable production and consumption, with positive synergies for several SDGs.

Abstract: Chromosomal rearrangements involving the mixed lineage leukemia (MLL) gene, also known as KMT2A, are often observed in human leukemias and are generally associated with a poor prognosis. To model these leukemias, we applied clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 gene editing to induce MLL chromosomal rearrangements in human hematopoietic stem and progenitor cells purified from umbilical cord blood. Electroporation of ribonucleoprotein complexes containing chemically modified synthetic single guide RNAs and purified Cas9 protein induced translocations between chromosomes 9 and 11 [t(9;11)] at an efficiency >1%. Transplantation of gene-edited cells into immune-compromised mice rapidly induced acute leukemias of different lineages and often with multiclonal origins dictated by the duration of in vitro culture prior to transplantation. Breakpoint junction sequences served as biomarkers to monitor clonal selection and progression in culture and in vivo. High-dimensional cell surface and intracellular protein analysis by mass cytometry (CyTOF) revealed that gene-edited leukemias recapitulated disease-specific protein expression observed in human patients and showed that MLL-rearranged (MLLr) mixed phenotype acute leukemias (MPALs) were more similar to acute myeloid leukemias (AMLs) than to acute lymphoblastic leukemias (ALLs). Therefore, highly efficient generation of MLL chromosomal translocations in primary human blood stem cells using CRISPR/Cas9 reliably models human acute MLLr leukemia and provides an experimental platform for basic and translational studies of leukemia biology and therapeutics.

ABSTRACT Host-adapted microorganisms are generally assumed to have evolved from free-living, environmental microorganisms, as examples of the reverse process are rare. In the phylum Gammaproteobacteria, family Moraxellaceae, the genus Psychrobacter includes strains from a broad ecological distribution including animal bodies as well as sea ice and other nonhost environments. To elucidate the relationship between these ecological niches and Psychrobacter’s evolutionary history, we performed tandem genomic analyses with phenotyping of 85 Psychrobacter accessions. Phylogenomic analysis of the family Moraxellaceae reveals that basal members of the Psychrobacter clade are Moraxella spp., a group of often-pathogenic organisms. Psychrobacter exhibited two broad growth patterns in our phenotypic screen: one group that we called the “flexible ecotype” (FE) had the ability to grow between 4 and 37°C, and the other, which we called the “restricted ecotype” (RE), could grow between 4 and 25°C. The FE group includes phylogenetically basal strains, and FE strains exhibit increased transposon copy numbers, smaller genomes, and a higher likelihood to be bile salt resistant. The RE group contains only phylogenetically derived strains and has increased proportions of lipid metabolism and biofilm formation genes, functions that are adaptive to cold stress. In a 16S rRNA gene survey of polar bear fecal samples, we detect both FE and RE strains, but in in vivo colonizations of gnotobiotic mice, only FE strains persist. Our results indicate the ability to grow at 37°C, seemingly necessary for mammalian gut colonization, is an ancestral trait for Psychrobacter, which likely evolved from a pathobiont. IMPORTANCE Host-associated microbes are generally assumed to have evolved from free-living ones. The evolutionary transition of microbes in the opposite direction, from host associated toward free living, has been predicted based on phylogenetic data but not studied in depth. Here, we provide evidence that the genus Psychrobacter, particularly well known for inhabiting low-temperature, high-salt environments such as sea ice, permafrost soils, and frozen foodstuffs, has evolved from a mammalian-associated ancestor. We show that some Psychrobacter strains retain seemingly ancestral genomic and phenotypic traits that correspond with host association while others have diverged to psychrotrophic or psychrophilic lifestyles.