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Khalid Al-Kofahi,1,* Peter Korsten,2,* Christian Ascoli,3 Shanti Virupannavar,4 Mehdi Mirsaeidi,5 Ian Chang,6 Naim Qaqish,7 Lesley A Saketkoo,8 Robert P Baughman,9 Nadera J Sweiss3,4 1Department of Molecular Biosciences, University of Kansas, Lawrence, KS, USA; 2Department of Nephrology and Rheumatology, University Medical Center Göttingen, Göttingen, Germany; 3Division of Pulmonary, Critical Care, Sleep and Allergy, University of Illinois at Chicago, Chicago, IL, 4Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 5Division of Pulmonary, Allergy, Critical Care and Sleep Medicine, University of Miami Miller School of Medicine, Miami, FL, 6Department of Medicine, Michigan State University College of Osteopathic Medicine, East Lansing, MI, 7Department of Gastroenterology, Hepatology and Nutrition, University of Buffalo, Buffalo, NY, 8New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, Louisiana State University Health Sciences Center, New Orleans, LA, 9Department of Medicine, University Medical Center of Cincinnati, Cincinnati, OH, USA *These authors contributed equally to this work Background: Sarcoidosis is a chronic multisystem disease of unknown etiology characterized by noncaseating granulomas that most often involves the lungs, but frequently has extrapulmonary manifestations, which might be difficult to treat in individual patients. Objective: To review different disease manifestations, focusing on extrapulmonary organ systems, and to provide treatment options for refractory cases. Materials and methods: We performed a literature search using Medline and Google Scholar for individual or combined keywords of “sarcoidosis, extrapulmonary, treatment, kidney, neurosarcoidosis, cardiovascular, gastrointestinal, transplantation, musculoskeletal, rheumatology, arthritis, and skin”. Peer-reviewed articles, including review articles, clinical trials, observational trials, and case reports that were published in English were included. References from retrieved articles were also manually searched for relevant articles.Results and conclusion: Isolated involvement of a single organ or organ system is rare in sarcoidosis, and thus all patients must be thoroughly evaluated for additional disease manifestations. Cardiac sarcoidosis and neurosarcoidosis may be life-threatening. Clinicians need to assess patients comprehensively using clinical, laboratory, imaging, and histopathological data to recommend competently the best and least toxic treatment option for the individual patient. Keywords: sarcoidosis, immunosuppressive agents, chronic granulomatous diseases, diagnostic tests

Abstract Intermediate-length repeat expansions in ATAXIN-2 (ATXN2) are the strongest genetic risk factor for amyotrophic lateral sclerosis (ALS). At the molecular level, ATXN2 intermediate expansions enhance TDP-43 toxicity and pathology. However, whether this triggers ALS pathogenesis at the cellular and functional level remains unknown. Here, we combine patient-derived and mouse models to dissect the effects of ATXN2 intermediate expansions in an ALS background. iPSC-derived motor neurons from ATXN2-ALS patients show altered stress granules, neurite damage and abnormal electrophysiological properties compared to healthy control and other familial ALS mutations. In TDP-43 Tg -ALS mice, ATXN2-Q33 causes reduced motor function, NMJ alterations, neuron degeneration and altered in vitro stress granule dynamics. Furthermore, gene expression changes related to mitochondrial function and inflammatory response are detected and confirmed at the cellular level in mice and human neuron and organoid models. Together, these results define pathogenic defects underlying ATXN2-ALS and provide a framework for future research into ATXN2-dependent pathogenesis and therapy.

Abstract Animals plastically adjust their physiological and behavioural phenotypes to conform to their social environment—social niche conformance. The degree of sexual competition is a critical part of the social environment to which animals adjust their phenotypes, but the underlying genetic mechanisms are poorly understood. We conducted a study to investigate how differences in sperm competition risk affect the gene expression profiles of the testes and two brain areas (posterior pallium and optic tectum) in breeding male zebra finches (Taeniopygia castanotis). In this pre-registered study, we investigated a large sample of 59 individual transcriptomes. We compared two experimental groups: males held in single breeding pairs (low sexual competition) versus those held in two pairs (elevated sexual competition) per breeding cage. Using weighted gene co-expression network analysis (WGCNA), we observed significant effects of the social treatment in all three tissues. However, only the treatment effects found in the pallium were confirmed by an additional randomisation test for statistical robustness. Likewise, the differential gene expression analysis revealed treatment effects only in the posterior pallium (ten genes) and optic tectum (six genes). No treatment effects were found in the testis at the single gene level. Thus, our experiments do not provide strong evidence for transcriptomic adjustment specific to manipulated sperm competition risk. However, we did observe transcriptomic adjustments to the manipulated social environment in the posterior pallium. These effects were polygenic rather than based on few individual genes with strong effects. Our findings are discussed in relation to an accompanying paper using the same animals, which reports behavioural results consistent with the results presented here.

Anjali Shetty,1 Rebekah Hanson,1 Peter Korsten,2 Munir Shawagfeh,3 Shiva Arami,1 Suncica Volkov,1 Olga Vila1 William Swedler,1 Abdel Naser Shunaigat,4 Sameer Smadi,4 Ray Sawaqed,5 David Perkins,1 Shiva Shahrara,1 Nadera J Sweiss11Department of Rheumatology, Pharmacy, Transplant, University of Illinois at Chicago, Chicago, IL, USA; 2Department of Nephrology and Rheumatology, University Medicine Göttingen, Göttingen, Germany; 3Anesthesia and Pain Management, King Hussein Cancer Center, Amman, Jordan; 4Liver Transplant, Kidney Transplant Royal Medical Services, Jordan; 5Cardiac Surgery Methodist Hospitals, Merrillville, IN, USAAbstract: Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by joint pain, swelling, stiffness, and progressive destruction of the small joints of the hands and feet. Treatment of RA has improved over the past decade. With multiple cytokines well-known now to play a role in the pathogenesis of RA, including tumor necrosis factor alpha, interleukin (IL)-1β, and IL-6, many targeted biological treatments against these cytokines have emerged, changing the treatment of this disease. Tocilizumab (TCZ) is a recombinant humanized monoclonal antibody against the IL-6 receptor and has been approved in many countries, including the United States, for the treatment of moderate to severe RA in patients who have not adequately responded to one or more disease-modifying antirheumatic drugs (DMARDs) or cannot tolerate other approved drug classes for RA. The aim of this review is to discuss the role of IL-6 in RA, and to provide an overview of the mode of action, pharmacokinetics, and safety of TCZ. Furthermore, efficacy studies of TCZ as both monotherapy and combination therapy will be evaluated. There have been several important clinical trials evaluating the efficacy and safety of TCZ in RA patients; this review summarizes this data from 14 key trials with emphasis on Phase III trials. Review of these trials provides strong evidence that its use, both as monotherapy and in combination with methotrexate or other DMARDs, is an effective treatment in reducing the signs and symptoms of RA. TCZ showed tolerable safety but care is required for its use since there are some important safety concerns including elevated liver enzymes, elevated low-density lipoprotein, infections, and gastrointestinal perforations. Additionally, given the efficacy of TCZ in the treatment of RA, this review discusses how TCZ may be beneficial in the treatment of other autoimmune diseases, spinal disease, cardiovascular disease, organ transplantation, and malignancies where elevated levels of IL-6 may play a role in the pathogenesis of these diseases.Keywords: tocilizumab, IL-6, rheumatoid arthritis, biologics

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Fruit- and vegetable-processing facilities may contaminate wastewater via contaminants found in the produce and disinfecting chemicals used. These contaminants may include agrochemicals, pesticides, and disinfectants such as chlorine and quaternary ammonium compounds (QACs). Some compounds may exhibit harmful endocrine-disrupting activity. This study investigated the impact of a minimally processed vegetable facility on wastewater quality via in vitro bioassays and chemical screening. Estrogen activity was assessed via a yeast estrogen screen (YES), and (anti-)androgenic and glucocorticoid activities were evaluated via an MDA-kb2 reporter gene assay. The samples were screened via gas and liquid chromatography–tandem mass spectrometry (GC-MS/MS and LC-MS/MS) to identify target compounds, and GC coupled with time-of-flight mass spectrometry (GC-TOFMS) was used for non-targeted screening. Sample complexity and chemical profiles were assessed using GC-TOFMS. Estrogenic activity was detected in 16 samples (n = 24) with an upper limit of 595 ± 37 ng/L estradiol equivalents (EEqs). The final wastewater before discharge had an EEq of 0.23 ng/L, which is within the ecological effect-based trigger value range for the estrogenic activity of wastewater (0.2–0.4 ng/L EEq). Androgenic activity was detected in one sample with a dihydrotestosterone equivalent (DHTEq) value of 10 ± 2.7 ng/L. No antiandrogenic activity was detected. The GC-MS/MS and LC-MS/MS results indicated the presence of multiple pesticides, nonylphenols, triclocarban, and triclosan. Many of these compounds exhibit estrogenic activity, which may explain the positive YES assay findings. These findings showed that wastewater from the facility contained detergents, disinfectants, and pesticides and displayed hormonal activity. Food-processing facilities release large volumes of wastewater, which may affect the quality of the water eventually being discharged into the environment. We recommend expanding conventional water quality monitoring efforts to include additional factors like endocrine activity and disinfectant byproducts.

Various aspects of sociality in mammals (e.g., dyadic connectedness) are linked with measures of biological fitness (e.g., longevity). How within- and between-individual variation in relevant social traits arises in uncontrolled wild populations is challenging to determine but is crucial for understanding constraints on the evolution of sociality. We use an advanced statistical method, known as the 'animal model', which incorporates pedigree information, to look at social, genetic, and environmental influences on sociality in a long-lived wild primate. We leverage a longitudinal database spanning 20 years of observation on individually recognized white-faced capuchin monkeys (Cebus capucinus imitator), with a multi-generational pedigree. We analyze two measures of spatial association, using repeat sampling of 376 individuals (mean: 53.5 months per subject, range: 6-185 months per subject). Conditioned on the effects of age, sex, group size, seasonality, and El Niño-Southern Oscillation phases, we show low to moderate long-term repeatability (across years) of the proportion of time spent social (posterior mode [95% Highest Posterior Density interval]: 0.207 [0.169, 0.265]) and of average number of partners (0.144 [0.113, 0.181]) (latent scale). Most of this long-term repeatability could be explained by modest heritability (h2social: 0.152 [0.094, 0.207]; h2partners: 0.113 [0.076, 0.149]) with small long-term maternal effects (m2social: 0.000 [0.000, 0.045]; m2partners: 0.000 [0.000, 0.041]). Our models capture the majority of variance in our behavioral traits, with much of the variance explained by temporally changing factors, such as group of residence, highlighting potential limits to the evolvability of our trait due to social and environmental constraints.

In 2021, one in five people in Africa was affected by hunger, and the continent had the highest prevalence of undernourished people globally. We argue that food systems in Africa can be more resilient if their development includes climate adaptation.

After having traveled to California in 2017, a 26-year old Dutch man presented in 2020 with persisting cough and shortness of breath. Radiology showed cystic bronchiectasis with peri-bronchial consolidation in his right upper lobe. Laboratory studies in August 2021 showed an increased total IgE, specific Aspergillus IgE, eosinophilia and positive BAL culture for Coccidioides immitis/posadasii. After 6 weeks of itraconazole treatment for suspected allergic bronchopulmonary aspergillosis, symptoms persisted and respiratory cultures remained positive. The infection was cleared after a 6-month course of fluconazole. (max 75 words)

IntroductionRapidly progressive glomerulonephritis (RPGN) is characterized by a rapid loss of kidney function, affecting both renal and overall patient survival. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small vessel vasculitis affecting multiple organ systems including the kidney, and among most frequent causes of RPGN. We here aimed to validate a recently described scoring system for short-term treatment response to therapeutic plasma exchange (PLEX) in a well-characterized and independent cohort of severe renal AAV presenting with RPGN. Furthermore, we compared this scoring with established classification systems in renal AAV including histopathological findings.MethodsWe here directly compare the scoring system with retrospective data about PLEX treatment in our own clinical practice and according to current recommendations in a cohort of 53 patients with severe AAV presenting with RPGN confirmed by kidney biopsy.ResultsWe here confirm that PLEX scoring is capable to identify patients at risk for short-term poor outcome in severe AAV presenting with RPGN (p

Salmonella have been implicated in foodborne disease outbreaks globally and is a pressing concern in the South African small-scale sector due to inadequate hygiene standards and limited regulatory oversight, leading to a higher risk of foodborne diseases. By investigating irrigation water and leafy green vegetables produced by small-scale growers and sold through unregulated supply chains, this study was able to determine the presence, serotype distribution, virulence gene profiles, antibiotic resistance, and genetic diversity of Salmonella isolated from these sources. From 426 samples, 21 Salmonella-positive samples were identified, providing 53 Salmonella isolates. Of these, six different Salmonella serotypes and sequence types (STs) were identified, including Salmonella II 42:r: ST1208 (33.96%; n = 18), Salmonella Enteritidis: ST11 (22.64%; n = 12), Salmonella II 42:z29: ST4395 (16.98%; n = 9), Salmonella Havana: ST1524 (15.09%; n = 8), Salmonella Typhimurium: ST19 (9.43%; n = 5), and Salmonella IIIb 47:i:z: ST7890 (1.89%; n = 1). A total of 92.45% of the isolates were found to be multidrug-resistant, showing high rates of resistance to aztreonam (88.68%; n = 47), ceftazidime (86.79%; n = 46), nalidixic acid (77.36%; n = 41), cefotaxime (75.47%; n = 40), cefepime (71.70%; n = 38), and streptomycin (69.81%; n = 37). All isolates possessed the aac(6')-Iaa antimicrobial resistance gene, with a range of between 9 and 256 virulence genes. Eleven cluster patterns were observed from Enterobacterial Repetitive Intergenic Consensus sequence analyses, demonstrating high diversity among the Salmonella spp., with water and fresh produce isolates clustering, suggesting water as a potential contamination source. Plasmid replicon types were identified in 41.51% (n = 22) of the isolates, including Col(pHAD28) in Salmonella Havana (5.66%; n = 3), Col156 in Salmonella II 42:z29:- (1.89%; n = 1) and both IncFIB(S) and IncFII(S) in Salmonella Enteritidis (22.64; n = 12), Salmonella Typhimurium (9.43%; n = 5), and Salmonella Havana (1.89%; n = 1). This study highlights the presence of multidrug-resistant and multivirulent Salmonella spp. in the small-scale leafy green vegetable supply chains, underscoring the need for the development of a “fit-for-purpose” food safety management system within this system.

Abstract Morogo is an African indigenous term used for leafy green vegetables harvested in the wild or cultivated in small-scale farms and consumed by the local populations of the region. Small-scale farmers have gained recognition as important suppliers of morogo to informal settlements. In commercial production systems, leafy green vegetables have increasingly been reported as associated with foodborne pathogens and disease outbreaks. Little is known of the presence of these organisms on leafy green vegetables in the informal unregulated food systems. This study aimed to profile bacterial communities in irrigation water (flooding and overhead irrigation water) and leafy green vegetables (Brassica rapa L. chinensis and Brassica rapa varieties of morogo) to establish the natural bacterial flora at the water-fresh produce interface from five small-scale farms in two provinces in South Africa. Illumina MiSeq high-throughput sequencing showed that each farm exhibited a unique bacterial community composition, with an overall high relative abundance of Proteobacteria, Firmicutes and Actinobacteria, including prominent families such as Burkholderiaceae (48%), Enterobacteriaceae (34%), Bacillales Family XII (8%), Rhodobacteraceae (3%), Micrococcaceae (1.98%) and Pseudomonadaceae (1.79%). Specific Enterobacteriaceae Serratia, Enterobacter, Salmonella, Shigella, Escherichia coli, Buchnera, Citrobacter, Klebsiella and Proteus were identified, in addition to unique communities associated with plant or irrigation water source. These findings suggest that the edible plant microbiome can play an important role as transient contributor to the human gut and has the potential to affect overall health.

Abstract About 388 million school‐going children worldwide benefit from school feeding schemes, which make use of fresh produce to prepare meals. Fresh produce including leafy greens and other vegetables were served at 37% and 31% of school feeding programs, respectively, in Africa. This study aimed at assessing the microbiological quality of fresh produce grown onsite or supplied to South African schools that are part of the national school feeding programs that benefit over 9 million school‐going children. Coliforms, Escherichia coli, Enterobacteriaceae, and Staphylococcus aureus were enumerated from fresh produce (n = 321) samples. The occurrence of E. coli, Listeria monocytogenes, Salmonella spp., and extended‐spectrum β‐lactamase (ESBL)‐producing Enterobacteriaceae was determined. Presumptive pathogens were tested for antimicrobial resistance. E. coli was further tested for diarrheagenic virulence genes. Enterobacteriaceae on 62.5% of fresh produce samples (200/321) exceeded previous microbiological guidelines for ready‐to‐eat food, while 86% (276/321 samples) and 31.6% (101/321 samples) exceeded coliform and E. coli criteria, respectively. A total of 76 Enterobacteriaceae were isolated from fresh produce including E. coli (n = 43), Enterobacter spp. (n = 15), and Klebsiella spp. (n = 18). Extended‐spectrum β‐lactamase production was confirmed in 11 E. coli, 13 Enterobacter spp., and 17 Klebsiella spp. isolates. No diarrheagenic virulence genes were detected in E. coli isolates. However, multidrug resistance (MDR) was found in 60.5% (26/43) of the E. coli isolates, while all (100%; n = 41) of the confirmed ESBL and AmpC Enterobacteriaceae showed MDR. Our study indicates the reality of the potential health risk that contaminated fresh produce may pose to school‐going children, especially with the growing food safety challenges and antimicrobial resistance crisis globally. This also shows that improved food safety approaches to prevent foodborne illness and the spread of foodborne pathogens through the food served by school feeding schemes are necessary.

BackgroundThe impact and consequences of the COVID-19 pandemic on people with rheumatic disease are unclear. We developed the COVID-19 Global Rheumatology Alliance Patient Experience Survey to assess the effects of the COVID-19 pandemic on people with rheumatic disease worldwide.MethodsSurvey questions were developed by key stakeholder groups and disseminated worldwide through social media, websites, and patient support organisations. Questions included demographics, rheumatic disease diagnosis, COVID-19 diagnosis, adoption of protective behaviours to mitigate COVID-19 exposure, medication access and changes, health-care access and communication with rheumatologists, and changes in employment or schooling. Adults age 18 years and older with inflammatory or autoimmune rheumatic diseases were eligible for inclusion. We included participants with and without a COVID-19 diagnosis. We excluded participants reporting only non-inflammatory rheumatic diseases such as fibromyalgia or osteoarthritis.Findings12 117 responses to the survey were received between April 3 and May 8, 2020, and of these, 10 407 respondents had included appropriate age data. We included complete responses from 9300 adults with rheumatic disease (mean age 46·1 years; 8375 [90·1%] women, 893 [9·6%] men, and 32 [0·3%] participants who identified as non-binary). 6273 (67·5%) of respondents identified as White, 1565 (16·8%) as Latin American, 198 (2·1%) as Black, 190 (2·0%) as Asian, and 42 (0·5%) as Native American or Aboriginal or First Nation. The most common rheumatic disease diagnoses included rheumatoid arthritis (3636 [39·1%] of 9300), systemic lupus erythematosus (2882 [31·0%]), and Sjögren's syndrome (1290 [13·9%]). Most respondents (6921 [82·0%] of 8441) continued their antirheumatic medications as prescribed. Almost all (9266 [99·7%] of 9297) respondents adopted protective behaviours to limit SARS-CoV-2 exposure. A change in employment status occurred in 2524 (27·1%) of 9300) of respondents, with a 13·6% decrease in the number in full-time employment (from 4066 to 3514).InterpretationPeople with rheumatic disease maintained therapy and followed public health advice to mitigate the risks of COVID-19. Substantial employment status changes occurred, with potential implications for health-care access, medication affordability, mental health, and rheumatic disease activity.FundingAmerican College of Rheumatology.

Background: Handheld ultrasound devices are increasingly used by medical professionals for bedside ultrasound-guided interventions. Especially for vascular access procedures, the width of the imaging plane, known as the slice thickness or elevational beam width is a prominent source for misinterpretation. A wide slice thickness can lead to the interpretation that 2 objects (i.e. needle and vessel) are on the same plane while in fact they are not and thereby negatively influencing the performance of in-plane ultrasound-guided interventions. Therefore, the beam profiles of three popular handheld US devices are tested and compared to a conventional US device. Methods: The GE VScan, Philips Lumify and Butterfly IQ ​+ ​are tested using a slice phantom to determine the slice thickness. For comparison, a Philips Affiniti machine was investigated. Both linear and curved array settings were analyzed. In a slice phantom, a diffuse scattering plane at an angle of exactly 45° is scanned. For each imaging depth, the vertical height of the imaged rectangle corresponds to the slice thickness at that depth. Main results: For the linear array transducers, the focus depth ranges from 1.5 to 3.5 cm. At the focus depth, all transducers have a reasonable slice thickness of approximately 1 mm. More superficially, the slice thickness varies between 1 and 4 mm. The curved array probes have larger focus depths, ranging from 2.7 to 7.3 cm. The slice thickness at focus depth varies between 1.4 and 3.8 mm, but at 2 cm depth is even more than 5 mm. Conclusions: The slice thickness of handheld ultrasound transducers varies between the different devices, and can be suboptimal for superficial in-plane ultrasound-guided interventions. The larger slice thickness of the curved array settings may complicate in-plane guidance. Handheld ultrasound users should be aware of the beam characteristics of their devices to optimize guidance for interventions.

Recent publications have argued that there are potentially serious consequences for researchers in recognising distinct genera in the terminal fusarioid clade of the family Nectriaceae. Thus, an alternate hypothesis, namely a very broad concept of the genus Fusarium was proposed. In doing so, however, a significant body of data that supports distinct genera in Nectriaceae based on morphology, biology, and phylogeny is disregarded. A DNA phylogeny based on 19 orthologous protein-coding genes was presented to support a very broad concept of Fusarium at the F1 node in Nectriaceae. Here, we demonstrate that re-analyses of this dataset show that all 19 genes support the F3 node that represents Fusarium sensu stricto as defined by F. sambucinum (sexual morph synonym Gibberella pulicaris). The backbone of the phylogeny is resolved by the concatenated alignment, but only six of the 19 genes fully support the F1 node, representing the broad circumscription of Fusarium. Furthermore, a re-analysis of the concatenated dataset revealed alternate topologies in different phylogenetic algorithms, highlighting the deep divergence and unresolved placement of various Nectriaceae lineages proposed as members of Fusarium. Species of Fusarium s. str. are characterised by Gibberella sexual morphs, asexual morphs with thin- or thick-walled macroconidia that have variously shaped apical and basal cells, and trichothecene mycotoxin production, which separates them from other fusarioid genera. Here we show that the Wollenweber concept of Fusarium presently accounts for 20 segregate genera with clear-cut synapomorphic traits, and that fusarioid macroconidia represent a character that has been gained or lost multiple times throughout Nectriaceae. Thus, the very broad circumscription of Fusarium is blurry and without apparent synapomorphies, and does not include all genera with fusarium-like macroconidia, which are spread throughout Nectriaceae (e.g., Cosmosporella, Macroconia, Microcera). In this study four new genera are introduced, along with 18 new species and 16 new combinations. These names convey information about relationships, morphology, and ecological preference that would otherwise be lost in a broader definition of Fusarium. To assist users to correctly identify fusarioid genera and species, we introduce a new online identification database, Fusarioid-ID, accessible at www.fusarium.org. The database comprises partial sequences from multiple genes commonly used to identify fusarioid taxa (act1, CaM, his3, rpb1, rpb2, tef1, tub2, ITS, and LSU). In this paper, we also present a nomenclator of names that have been introduced in Fusarium up to January 2021 as well as their current status, types, and diagnostic DNA barcode data. In this study, researchers from 46 countries, representing taxonomists, plant pathologists, medical mycologists, quarantine officials, regulatory agencies, and students, strongly support the application and use of a more precisely delimited Fusarium (= Gibberella) concept to accommodate taxa from the robust monophyletic node F3 on the basis of a well-defined and unique combination of morphological and biochemical features. This F3 node includes, among others, species of the F. fujikuroi, F. incarnatum-equiseti, F. oxysporum, and F. sambucinum species complexes, but not species of Bisifusarium [F. dimerum species complex (SC)], Cyanonectria (F. buxicola SC), Geejayessia (F. staphyleae SC), Neocosmospora (F. solani SC) or Rectifusarium (F. ventricosum SC). The present study represents the first step to generating a new online monograph of Fusarium and allied fusarioid genera (www.fusarium.org).

Abstract Introduction Thrombotic thrombocytopenic purpura-hemolytic uremic syndrome is a life-threatening condition with various etiopathogeneses. Without therapy approximately 90% of all patients die from the disease. Case presentation We report the case of a 17-year-old Caucasian woman with widespread hematomas and headache. Due to hemolytic anemia, thrombocytopenia, and schistocytosis, thrombotic thrombocytopenic purpura-hemolytic uremic syndrome was suspected and plasma exchange therapy was initiated immediately. Since her thrombocyte level did not increase during the first week of therapy, plasma treatment had to be intensified to a twice-daily schedule. Further diagnostics showed markedly reduced activities of both ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 - also known as von Willebrand factor-cleaving protease) and factor H. Test results for antibodies against both proteins were positive. While plasma exchange therapy was continued, rituximab was given once weekly for four consecutive weeks. After the last dose, thrombocytes and activities of ADAMTS-13 and factor H increased into the normal range. Our patient improved and was discharged from the hospital. Conclusions Since no clinical symptoms/laboratory findings indicated a malignant or specific autoimmune-mediated disorder, the diagnosis made was thrombotic thrombocytopenic purpura-hemolytic uremic syndrome due to idiopathic combined, autoantibody-mediated ADAMTS-13/factor H deficiency.

Abstract Objective Social functioning is an important factor in the evaluation of postoperative health‐related quality of life (HRQoL) for pituitary adenoma patients. In a prospective cohort study multidimensional HRQoL of non‐functioning (NFA) and functioning (FA) pituitary adenoma patients were evaluated following endoscopic endonasal surgery using the endoscopic endonasal sinus and skull base surgery questionnaire (EES‐Q). Methods Prospectively, 101 patients were included. The EES‐Q was completed preoperatively and postoperatively (2 weeks, 3 months, 1 year). Sinonasal complaints were completed daily during the first week postoperatively. Preoperative and postoperative scores were compared. A generalized estimating equation (uni‐ and multivariate) analysis was performed to identify significant HRQoL changes related to selected covariates. Results Two weeks postoperatively, physical (p

Involvement of the complement system is key to the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis, but immunometabolic implications, especially on serum uric acid (UA) levels, still need to be elucidated. A total of 34 patients with biopsy-proven ANCA-associated renal vasculitis between 2015 and 2020 were retrospectively enrolled. Serum UA levels were correlated with clinical and histopathological characteristics, separated for critically ill (CI, n = 19), myeloperoxidase (MPO)-ANCA (n = 21) and proteinase 3 (PR3)-ANCA (n = 13) subgroups. We here identified inverse correlations of serum UA levels and complement C3 levels in the total cohort (p = 0.005) and the CI subgroup (p < 0.001). Intrarenal complement C4d deposition in venules correlated with serum UA levels in the total cohort (p = 0.007) and in the CI subgroup (p = 0.016). Significant associations of serum UA levels and tubulitis in areas of scarred cortex (t-IFTA) were identified in the total cohort (p = 0.008), and both subgroups of CI (p = 0.034) and MPO-ANCA (p = 0.029). In PR3-ANCA, interstitial fibrosis (ci) was observed as the strongest association with serum UA levels (p = 0.022). Our observations broaden our current understanding of contributory metabolic factors that influence the initial disease course in ANCA-associated renal vasculitis.

In 1647, one year ahead of the official celebrations of the Peace of Westphalia, the Dutch poet and playwright Joost van den Vondel published a long panegyric called De getemde Mars (‘Mars Tamed’), a poem fully translated into English for the first time in this article. Despite celebrating the Peace, Vondel did not refrain from presenting extremely violent scenes of war in the middle part of the poem. Surprisingly, however, the war scene shifts from the wars that devastated Europe to a war which Mars wages against Jupiter and his circle of gods. Unable to control Mars, and on the verge of seeing his rule collapse, Jupiter looks for support and finds it in an allegorical maiden representing the Dutch Republic and its main hub Amsterdam. This article argues that the allegory employed by Vondel is set up against itself. The familiar allegorisation of classical material for Christian purposes turns into a baroque allegory that works against principles of theologically underpinned political sovereignty. Here, the poem testifies to a distinct civil pride, with Vondel considering the burgomasters of Amsterdam, which he takes as embodying civil government, as a prominent source of international peace. By 1648, however, the Dutch Republic had also become an imperial and global power that confronted other sovereign states in violent actions. In this context, the poem’s baroque contradictions multiply.

Plasma exchange rapidly depletes pathogenic anti-neutrophil cytoplasmic autoantibodies (ANCAs) and is considered for induction therapy in severe ANCA-associated vasculitis. The aim of plasma exchange is to remove putative disease mediators from the circulation, such as toxic macromolecules and pathogenic ANCAs. To our knowledge, we here provide the first report of applying high-dose IVIGs prior to plasma exchange and assessment of ANCA autoantibody elimination in a patient with severe pulmonary renal syndrome due to ANCA-associated vasculitis. After high-dose application of intravenous immunoglobulins (IVIGs) prior to plasma exchange treatment, efficacy of myeloperoxidase (MPO)-ANCA autoantibody elimination was substantially increased, associated with rapid clearance of MPO-ANCA autoantibodies. High-dose IVIGs resulted in marked reduction of MPO-ANCA autoantibody levels and did not directly affect autoantibody clearance by plasma exchange itself, as also confirmed by comparable MPO-ANCAs in the exchange fluid relative to serum levels. Moreover, measurements of serum creatinine and albuminuria confirmed that high-dose IVIGs were well tolerated and did not exacerbate kidney injury.

BackgroundThe advent of immune checkpoint inhibitors (ICIs) has powerfully broadened the scope of treatment options for malignancies with an ongoing increase of indications, but immune-related adverse events (irAEs) represent a serious threat to treatment success. Agents directed against programmed cell death protein 1 (PD-1) or its ligand 1 (PD-L1) are known to cause renal complications with an incidence of 3%. In contrast, subclinical renal involvement is estimated to be much higher, up to 29%. We recently reported about urinary flow cytometry-based detection of urinary PD-L1-positive (PD-L1+) kidney cells correlating with tubular PD-L1-positivity that reflected susceptibility to develop ICI-related nephrotoxicity as an irAE attending ICI treatment. Therefore, we designed a study protocol to evaluate urinary detection of PD-L1+ kidney cells as a tool for non-invasive biomonitoring of renal complications in cancer patients treated with ICIs.MethodsA prospective, controlled, non-interventional, longitudinal, single-center observational study will be conducted at the Department of Nephrology and Rheumatology of the University Medical Center Göttingen, Germany. We intend to enroll approximately 200 patients treated with immunotherapy from the Departments of Urology, Dermatology, and Hematology and Medical Oncology of the University Medical Center Göttingen, Germany. First, we will assess clinical, laboratory, histopathological, and urinary parameters in addition to urinary cell collection. Then, we will perform a correlative analysis between urinary flow cytometry of different PD-L1+ cell of renal origin with the onset of ICI-related nephrotoxicity.DiscussionBecause of growing ICI-treatment applicability with an expectable incidence of renal complications, providing cost-efficient and easily performable diagnostic tools for treatment-attendant and non-invasive biomonitoring becomes vital to improve both renal and overall survival rates in cancer patients receiving immunotherapy.Trial registrationhttps://www.drks.de, DRKS-ID DRKS00030999.

Diabetic nephropathy is a common microvascular complication of diabetes mellitus. It is characterized by progressive chronic kidney disease (CKD) with decline of kidney function by hyperfiltration. On a mechanistic level, activation of the complement system has been implicated in the pathogenesis of diabetic nephropathy. Therefore, here we pursued a transcriptome array-based approach to link intrarenal SGLT-2 and the synthesis of distinct complement components in diabetic nephropathy. Publicly available datasets for SLC5A2 (encoding SGLT-2) and complement system components were extracted specifically from microdissected tubulointerstitial (healthy controls: n = 31, diabetic nephropathy: n = 17) and glomerular compartments (healthy controls: n = 21, diabetic nephropathy: n = 12). First, we compared tubulointerstitial and glomerular log2 SLC5A2 mRNA expression levels and confirmed a predominant synthesis within the tubulointerstitial compartment. Among various complement components and receptors, the only significant finding was a positive association between SLC5A2 and the tubulointerstitial synthesis of the complement component C5 in diabetic nephropathy (p = 0.0109). Finally, intrarenal expression of SLC5A2 was associated predominantly with pathways involved in metabolic processes. Interestingly, intrarenal complement C5 synthesis was also associated with enrichment of metabolic signaling pathways, overlapping with SLC5A2 for “metabolism” and “biological oxidations”. These observations could be of relevance in the pathogenesis of diabetic nephropathy and implicate a mechanistic link between SGLT-2 and intrarenal complement synthesis.

BackgroundMultidrug-resistant extended-spectrum β-lactamase (ESBL)-producing Enterobacterales is regarded as a critical health issue, yet, surveillance in the water-plant-food interface remains low, especially in Africa.ObjectivesThe objective of the study was to elucidate the distribution and prevalence of antimicrobial resistance in clinically significant members of the Enterobacterales order isolated from the water-plant-food interface in Africa.MethodsA literature search was conducted using six online databases according to the PRISMA guidelines. All available published studies involving phenotypic and genotypic characterization of ESBL-producing Enterobacterales from water, fresh produce or soil in Africa were considered eligible. Identification and characterization methods used as well as a network analysis according to the isolation source and publication year were summarized. Analysis of Escherichia coli, Salmonella spp. and Klebsiella pneumoniae included the calculation of the multiple antibiotic resistance (MAR) index according to isolation sources and statistical analysis was performed using RStudio.ResultsOverall, 51 studies were included for further investigation. Twelve African countries were represented, with environmental AMR surveillance studies predominantly conducted in South Africa. In 76.47% of the studies, occurrence of antimicrobial resistant bacteria was investigated in irrigation water samples, while 50.98% of the studies included fresh produce samples. Analysis of bacterial phenotypic antimicrobial resistance profiles were reported in 94.12% of the studies, with the disk diffusion method predominantly used. When investigating the MAR indexes of the characterized Escherichia coli, Klebsiella pneumoniae and Salmonella spp., from different sources (water, fresh produce or soil), no significant differences were seen across the countries. The only genetic determinant identified using PCR detection in all the studies was the blaCTX − M resistance gene. Only four studies used whole genome sequence analysis for molecular isolate characterization.DiscussionGlobally, AMR surveillance programmes recognize ESBL- and carbapenemase-producing Enterobacterales as vectors of great importance in AMR gene dissemination. However, in low- and middle-income countries, such as those in Africa, challenges to implementing effective and sustainable AMR surveillance programmes remain. This review emphasizes the need for improved surveillance, standardized methods and documentation of resistance gene dissemination across the farm-to-fork continuum in Africa.

Background: Ultrasound guidance increases first-pass success rates and decreases the number of cannulation attempts and complications during radial artery catheterisation but it is debatable whether short-, long-, or oblique-axis imaging is superior for obtaining access. Three-dimensional (3D) biplanar ultrasound combines both short- and long-axis views with their respective benefits. This study aimed to determine whether biplanar imaging would improve the accuracy of radial artery catheterisation compared with conventional 2D imaging. Methods: This before-and-after trial included adult patients who required radial artery catheterisation for elective cardiothoracic surgery. The participating anaesthesiologists were experienced in 2D and biplanar ultrasound-guided vascular access. The primary endpoint was successful catheterisation in one skin break without withdrawals. Secondary endpoints were the numbers of punctures and withdrawals, scanning and procedure times, needle visibility, perceived mental effort of the operator, and posterior wall puncture or other mechanical complications. Results: From November 2021 until April 2022, 158 patients were included and analysed (2D=75, biplanar=83), with two failures to catheterise in each group. First-pass success without needle redirections was 58.7% in the 2D group and 60.2% in the biplanar group (difference=1.6%; 95% confidence interval [CI], –14.0%–17.1%; P=0.84), and first-pass success within one skin break was 77.3% in the 2D group vs 81.9% in the biplanar group (difference=4.6%; 95% CI, 8.1%–17.3%; P=0.473). None of the secondary endpoints differed significantly. Conclusions: Biplanar ultrasound guidance did not improve success rates nor other performance measures of radial artery catheterisation. The additional visual information acquired with biplanar imaging did not offer any benefit. Clinical trial registration: N9687 (Dutch Trial Register).

Freshwater sources, often used for domestic and agricultural purposes in low- and middle-income countries are repositories of clinically significant bacterial pathogens. These pathogens are usually diversified in their antibiogram profiles posing public health threats. This study evaluated the spatial diarrhoeal disease risk and antibiogram diversity of diarrheagenic Escherichia coli (DEC) in four access points of the Buffalo River, Eastern Cape Province, South Africa using standard epidemiological, culture, and molecular methods. The diarrhoeal disease risk was characterised using the Monte Carlo simulation, while the antibiogram diversity was assessed using the species observed Whittaker's single alpha-diversity modelling. E. coli mean count was highest in King William's Town dam [16.0 × 102 CFU/100ml (SD: 100.0, 95% CI: 13.5 × 102 to 18.5 × 102)]. Enterohemorrhagic E. coli (stx1/stx2) was the most prevalent DEC pathotype across the study sites. A high diarrhoeal disease risk of 25.0 ×10-2 exceeding the World Health Organization's standard was recorded across the study sites. The average single and multiple antimicrobial resistance indices of the DEC to test antimicrobials were highest in the Eluxolzweni dam [0.52 (SD: 0.25, 95% CI: 0.37 to 0.67)] and King William's Town dam [0.42 (SD: 0.25, 95% CI: 0.27 to 0.57)] respectively. The prevalent antibiotic resistance genes detected were tetA, blaFOX and blaMOX plasmid-mediated AmpC, blaTEM and blaSHV extended-spectrum β-lactamases, which co-occurred across the study sites on network analysis. The phenotypic and genotypic resistance characteristics of the DEC in Maden dam (r = 0.93, p

The pillars of scientific progress in rheumatology are experimentation and observation, followed by the publication of reliable and credible results. These data must then be independently verified, validated, and replicated. Peer and journal-specific technical and statistical reviews are paramount to improving rigor and reproducibility. In addition, research integrity, ethics, and responsible conduct training can help to reduce research misconduct and improve scientific evidence. As the number of published articles in rheumatology grows, the field has become critical for determining reproducibility. Prospective, longitudinal, randomized controlled clinical trials are the gold standard for evaluating clinical intervention efficacy and safety in this space. However, their applicability to larger, more representative patient populations with rheumatological disorders worldwide could be limited due to time, technical, and cost constraints involved with large-scale clinical trials. Accordingly, analysis of real-world, patient-centered clinical data retrieved from established healthcare inventories, such as electronic health records, medical billing reports, and disease registries, are increasingly used to report patient outcomes. Unfortunately, it is unknown whether this clinical research paradigm in rheumatology could be deployed in medically underserved regions.