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Abstract Catheter-associated urinary tract infections (CAUTIs) are amongst the most common nosocomial infections worldwide and are difficult to treat partly due to development of multidrug-resistance from CAUTI-related pathogens. Importantly, CAUTI often leads to secondary bloodstream infections and death. A major challenge is to predict when patients will develop CAUTIs and which populations are at-risk for bloodstream infections. Catheter-induced inflammation promotes fibrinogen (Fg) and fibrin accumulation in the bladder which are exploited as a biofilm formation platform by CAUTI pathogens. Using our established mouse model of CAUTI, here we identified that host populations exhibiting either genetic or acquired fibrinolytic-deficiencies, inducing fibrin deposition in the catheterized bladder, are predisposed to severe CAUTI and septicemia by diverse uropathogens in mono- and poly-microbial infections. Furthermore, here we found that Enterococcus faecalis, a prevalent CAUTI pathogen, uses the secreted protease, SprE, to induce fibrin accumulation and create a niche ideal for growth, biofilm formation, and persistence during CAUTI.

IntroductionSoft tissue sarcomas (STS) are highly metastatic, connective-tissue lineage solid cancers. Immunologically, sarcomas are frequently characterized by a paucity of tumor infiltrating lymphocytes and an immune suppressive microenvironment. Activation of the STING pathway can induce potent immune-driven anti-tumor responses within immunogenic solid tumors; however, this strategy has not been evaluated in immunologically cold sarcomas. Herein, we assessed the therapeutic response of intratumoral STING activation in an immunologically cold murine model of undifferentiated pleomorphic sarcoma (UPS).Materials and ResultsA single intratumoral injection of the murine STING agonist, DMXAA resulted in durable cure in up to 60% of UPS-bearing mice. In mice with synchronous lung metastases, STING activation within hindlimb tumors resulted in 50% cure in both anatomic sites. Surviving mice all rejected UPS re-challenge in the hindlimb and lung. Therapeutic efficacy of STING was inhibited by lymphocyte deficiency but unaffected by macrophage deficiency. Immune phenotyping demonstrated enrichment of lymphocytic responses in tumors at multiple timepoints following treatment. Immune checkpoint blockade enhanced survival following STING activation.DiscussionThese data suggest intratumoral activation of the STING pathway elicits local and systemic anti-tumor immune responses in a lymphocyte poor sarcoma model and deserves further evaluation as an adjunctive local and systemic treatment for sarcomas.

Sarcomas are rare, difficult to treat, mesenchymal lineage tumours that affect children and adults. Immunologically-based therapies have improved outcomes for numerous adult cancers, however, these therapeutic strategies have been minimally effective in sarcoma so far. Clinically relevant, immunologically-competent, and transplantable pre-clinical sarcoma models are essential to advance sarcoma immunology research. Herein we show that Cre-mediated activation of KrasG12D, and deletion of Trp53, in the hindlimb muscles of C57Bl/6 mice results in the highly penetrant, rapid onset undifferentiated pleomorphic sarcomas (UPS), one of the most common human sarcoma subtypes. Cell lines derived from spontaneous UPS tumours can be reproducibly transplanted into the hindlimbs or lungs of naïve, immune competent syngeneic mice. Immunological characterization of both spontaneous and transplanted UPS tumours demonstrates an immunologically-'quiescent' microenvironment, characterized by a paucity of lymphocytes, limited spontaneous adaptive immune pathways, and dense macrophage infiltrates. Macrophages are the dominant immune population in both spontaneous and transplanted UPS tumours, although compared to spontaneous tumours, transplanted tumours demonstrate increased spontaneous lymphocytic infiltrates. The growth of transplanted UPS tumours is unaffected by host lymphocyte deficiency, and despite strong expression of PD-1 on tumour infiltrating lymphocytes, tumours are resistant to immunological checkpoint blockade. This spontaneous and transplantable immune competent UPS model will be an important experimental tool in the pre-clinical development and evaluation of novel immunotherapeutic approaches for immunologically cold soft tissue sarcomas.

Recent technological advancements have permitted high-throughput measurement of the human genome, epigenome, metabolome, transcriptome, and proteome at the population level. We hypothesized that subsets of genes identified from omic studies might have closely related biological functions and thus might interact directly at the network level. Therefore, we conducted an integrative analysis of multi-omic datasets of non-small cell lung cancer (NSCLC) to search for association patterns beyond the genome and transcriptome. A large, complex, and robust gene network containing well-known lung cancer-related genes, including EGFR and TERT, was identified from combined gene lists for lung adenocarcinoma. Members of the hypoxia-inducible factor (HIF) gene family were at the center of this network. Subsequent sequencing of network hub genes within a subset of samples from the Transdisciplinary Research in Cancer of the Lung-International Lung Cancer Consortium (TRICL-ILCCO) consortium revealed a SNP (rs12614710) in EPAS1 associated with NSCLC that reached genome-wide significance (OR = 1.50; 95% CI: 1.31–1.72; p = 7.75 × 10−9). Using imputed data, we found that this SNP remained significant in the entire TRICL-ILCCO consortium (p = .03). Additional functional studies are warranted to better understand interrelationships among genetic polymorphisms, DNA methylation status, and EPAS1 expression. Keywords: Non-small cell lung cancer, Lung adenocarcinoma, Integrated analysis, Network analysis, Hypoxia-inducible factor

The lacustrine oil shales of the Coal Creek Member of the Kishenehn Formation in northwestern Montana comprise a relatively unstudied middle Eocene fossil insect locality. Herein, we detail the stratigraphic position of the fossiliferous unit, describe the insect fauna of the Coal Creek locality and document its bias towards very small but remarkably pre-served insects. In addition, the depositional environment is examined and the mineral constituents of the laminations that comprise the varves of the Kishenehn oil shale are defined. Fifteen orders of insects have been recorded with the majority of all insects identified as aquatic with the families Chironomidae (Diptera) and Corixidae (Hemiptera) dominant. The presence of small aquatic insects, many of which are immature, the intact nature of >90% of the fossil insects and the presence of Daphnia ephippia, all indicate that the depositional environment was the shallow margin of a large freshwater lake. The fossil insects occur within fossilized microbial mat layers that comprise the bedding planes of the oil shale. Unlike the fossiliferous shales of the Florissant and Okanagan Highlands, the mats are not a product of diatomaceous algae nor are diatom frustules a component of the sediments or the varve structure. Instead, the varves are composed of very fine eolian siliciclastic silt grains overlaid with non-diatomaceous, possibly cyanobacteria-derived microbial mats which contain distinct traces of polyaromatic hydrocarbons. A distinct third layer composed of essentially pure calcite is present in the shale of some exposures and is presumably derived from the seasonal warming-induced precipitation of carbonate from the lake’s waters. The Coal Creek locality presents a unique opportunity to study both very small middle Eocene insects not often preserved as compression fossils in most Konservat-Lagerstätte and the processes that led to their preservation.

Caddisfly larvae construct underwater protective cases using surrounding materials, thus providing information on environmental conditions in both modern and ancient systems. Microbial bioherms associated with caddisfly cases are found in the Berriassian-Hauterivian (~140-130 Ma) Shinekhudag Formation of Mongolia, and yield new insights into aspects of lacustrine paleoecosystems and paleoenvironments. This formation contains the earliest record of plant-armored caddisfly cases and a rare occurrence of microbial-caddisfly association from the Mesozoic. The bioherms are investigated within the context of stratigraphic correlations, depositional environment interpretations, and basin-evolution models of the sedimentary fill. The bioherms form 0.5-2.0 m diameter mound-shaped bodies and are concentrated within a single, oil shale-bound stratigraphic interval. Each bioherm is composed of up to 40% caddisfly cases along with stromatolites of millimeter-scale, micritic laminations. Petrographic analyses reveal these bioherms are composed of non-systematic associations of columnar and oncoidal microbialites, constructed around colonies of caddisfly cases. The cases are straight to curved, slightly tapered, and tube-shaped, with a progressively increasing length and width trend (7-21 mm by 1.5-2.5 mm). Despite these variations, the case architectures reveal similar construction materials; the particles used for cases are dominated by plant fragments, ostracod valves, carbonate rocks, and rare mica and feldspar grains. Allochems within the bioherms include ooids, ostracods, plant fragments, rare gastropods, feldspar grains bound in micritic matrices, and are consolidated by carbonate dominated cements. The combination of microbial-caddisfly association, plant fragment case particles, and ooids/oncoids are indicative of a shallow, littoral lake setting. Stratigraphic juxtaposition of nearshore bioherms and the bounding distal oil-shale facies suggests that the bioherms developed in an underfilled lake basin, resulting from an abrupt and short-lived lake desiccation event. Lake chemistry is believed to have been relatively alkaline, saline to hypersaline, and rich in Ca, Mg, and HCO3 ions. Through analyzing bioherm characteristics, caddisfly case architecture, carbonate microfacies, and stratigraphic variability, we infer larger-scale processes that controlled basin development during their formation.

Copy number variants (CNVs) are known to cause Mendelian forms of Parkinson disease (PD), most notably in SNCA and PARK2. PARK2 has a recessive mode of inheritance; however, recent evidence demonstrates that a single CNV in PARK2 (but not a single missense mutation) may increase risk for PD. We recently performed a genome-wide association study for PD that excluded individuals known to have either a LRRK2 mutation or two PARK2 mutations. Data from the Illumina370Duo arrays were re-clustered using only white individuals with high quality intensity data, and CNV calls were made using two algorithms, PennCNV and QuantiSNP. After quality assessment, the final sample included 816 cases and 856 controls. Results varied between the two CNV calling algorithms for many regions, including the PARK2 locus (genome-wide p = 0.04 for PennCNV and p = 0.13 for QuantiSNP). However, there was consistent evidence with both algorithms for two novel genes, USP32 and DOCK5 (empirical, genome-wide p-values

The Mesoproterozoic Belt Basin of the northwestern United States and southwestern Canada contains a 5-20-km-thick metasedimentary succession deposited during an important transition in the Precambrian development of North America. Key unresolved issues for the Belt Basin include the chronology of deposition, sources of siliciclastic sediment, and regional paleogeography during Laurentian orogenesis. To address these topics, we acquired detrital zircon U-Pb geochronologic data for eastern exposures of the Belt-Purcell Supergroup in the Lewis thrust salient along the USA-Canada border. To define an integrated chronostratigraphic and provenance framework for the Belt Basin, we calculated maximum depositional ages and qualitatively and quantitatively compared our geochronologic data set to a compilation of Laurentian igneous and metamorphic zircon U-Pb ages using multidimensional scaling and an inverse Monte Carlo model. The results suggest a stratigraphic age range of ca. 1495-1380 Ma, constituting a depositional duration of ~115 m.y. with an average sediment accumulation rate of ~40 m/m.y. for the studied locality (extrapolated to ~155 m/m.y. for the basin depocenter). Variations in sediment provenance are expressed by three distinct intervals within the Belt-Purcell Supergroup. The lower Belt Supergroup succession (Waterton to lower Helena Formations; ca. 1495-1440 Ma) is dominated by Paleoproterozoic and Archean grains derived from the northeastern Canadian Shield. The middle Belt Supergroup succession (upper Helena to Sheppard Formations; ca. 1440-1420 Ma) displays mixed early Mesoproterozoic, late Paleoproterozoic, and Archean zircon age groups. The upper Belt Supergroup succession (Gateway to Roosville Formations; ca. 1420-1380 Ma) contains almost entirely late Paleoproterozoic zircons sourced from the south (Yavapai-Mazatzal and Mojave crustal provinces). We interpret sediment provenance to reflect a continental-scale, fluvial drainage reorganization during middle Belt Supergroup deposition that can be linked to the recently recognized Picuris orogeny. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Anaphylaxis is a severe hypersensitivity reaction with a rapid onset and is potentially life-threatening if not treated promptly. This study aimed to determine the level of knowledge of pediatricians in Turkey in recognizing and treating the clinical symptoms of anaphylaxis, compare the previous studies conducted in Turkey chronologically, and show the current trends on awareness of anaphylaxis in developed and developing countries in the world. SUBJECTS AND METHODS: Pediatric residents and specialists from all over Turkey were included in the study. A questionnaire was prepared by compiling the current literature. Questions were sent to pediatricians via online applications. Statistical tests were used to analyze the data. RESULTS: A total of 524 pediatricians participated in the study. All participants accepted that anaphylaxis was a life-threatening condition. Al-most all suggested epinephrine as the primary drug used in anaphylaxis. The proportion of pediatricians who knew the appropriate dose, route of administration, and place of administration of epinephrine was 82.8%, 88.9%, and 89.7%, respectively. The rate of pediatricians who recognized the clinical features of anaphylaxis was over 90%. The proportion of pediatricians who knew the epinephrine auto-injector and dose was 74.4% and 53.1%, respectively. Pediatricians with less than 10 years of experience and those working in public hospitals had better knowledge about atypical symptoms of anaphylaxis. CONCLUSIONS: Although there are still inadequacies in identifying atypical symptoms and treating anaphylaxis, our study revealed that the level of awareness of anaphylaxis had shown an increasing trend in Turkey over time. On the other hand, the knowledge on diagnosing and treating anaphylaxis still needs to be improved, especially for physicians working in rural areas of developing countries. [ABSTRACT FROM AUTHOR]

Abstract Background Urinary tract infections are common affections, especially for women. Difficult access to a general practitioner to obtain a prescription has led France to offer dispensing under protocol by community pharmacists. The primary objective of this study is to evaluate the effectiveness of a pharmacist care protocol provided to manage women with urinary tract infection symptoms. This objective will be assessed using the Acute Cystitis Symptom Score. Methods PharmaCyst’ is an open-label, multicenter, controlled, cluster-randomized study conducted in the Loire region, France. Women aged between 18 and 65 years presenting to a pharmacy complaining of at least one symptom of an uncomplicated urinary tract infection present over the last 3 days (including burning pain during micturition, dysuria, pollakiuria, urgent urination) will be considered for inclusion. All patients will be contacted on day 3, 10, and month 3. A total of 480 patients need to be recruited for the 24 clusters participating in the research. The quantitative data will be described using means and standard deviations and compared using Student’s t-test. The qualitative data will be described using numbers and percentages and compared using chi2 test (or Fisher’s exact test if necessary). The primary and secondary outcomes analyses will consider the intention-to-treat population. Discussion PharmaCyst’ is the first clinical trial conducted in France only by community pharmacists. Its results could lead to an extension of the protocol. Trial registration The protocol has been approved by the French ethics committee on 2022/12/02 and is registered under the number 49RC22_0240 on ClinicalTrials.gov.

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Presents three mathematical models for the evolution over time of the proportion of minorities in an academic department or similarly selected group of constant size. Analyzes both the steady-state and time-dependent behavior of the proportion of minorities and suggests a method of evaluating the fairness of a department's hiring history. (Author/DB)