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BACKGROUND: One-fifth of the global population is infected with soil-transmitted helminths (STH). Mass drug administration (MDA) with deworming medication is widely implemented to control morbidity associated with STH infections. However, surveillance of human infection prevalence by collecting individual stool samples is time-consuming, costly, often stigmatized, and logistically challenging. Current methods of STH detection are poorly sensitive, particularly in low-intensity and low-prevalence populations. METHODOLOGY/PRINCIPAL FINDINGS: We aimed to develop a sensitive and specific molecular method for detecting STH DNA in large volumes of soil (20 g) by conducting laboratory and proof of concept studies across field sites in Kenya, Benin, and India. We collected human stool (n = 669) and soil (n = 478) from 322 households across the three study sites. We developed protocols for DNA extraction from 20 g of soil and qPCR to detect Ascaris lumbricoides, Trichuris trichiura, Necator americanus, and Ancylostoma duodenale. Agreement between detection of STH via qPCR, digital droplet PCR (ddPCR), and microscopy-based methods was assessed using the Cohens Kappa statistic. Finally, we estimated associations between soil characteristics and detection of STH in soil by qPCR, as well as between STH detected in soil and STH detected in stool from matched households, adjusting for soil characteristics. The overall prevalence of STH in soil by qPCR was 31% for A. lumbricoides, 3% for T. trichiura, and 13% for any hookworm species. ddPCR and qPCR performed similarly. However, there was poor agreement between STH detected in soil by qPCR versus light microscopy. Microscopy underestimated the prevalence of A. lumbricoides and N. americanus and overestimated T. trichiura. Detection of an STH species in household soil was strongly associated with increased odds of a household member being infected with that same species. CONCLUSIONS/SIGNIFICANCE: Soil surveillance for STH has several benefits over stool-based surveillance, including lower cost and higher success rates for sample collection. Considering that delivery of MDA occurs at the community level, environmental surveillance using molecular methods could be a cost-effective alternate strategy for monitoring STH in these populations.

The Trillat procedure, initially described by Albert Trillat, is historically one of the first techniques for addressing recurrent anterior shoulder instability, incorporating fascinating biomechanical mechanisms. After lowering, medializing, and fixing the coracoid process to the glenoid neck, the subcoracoid space is reduced, the subscapularis lowered, and its line of pull changed, accentuating the function of the subscapularis as a humeral head depressor centering the glenohumeral joint. Furthermore, the conjoint tendon creates a ‘seatbelt’ effect, preventing anteroinferior humeral head dislocation. Even though contemporary preferences lean towards arthroscopic Bankart repair with optional remplissage, bone augmentation, and the Latarjet procedure, enduring surgical indications remain valid for the Trillat procedure, which offers joint preservation and superior outcomes in two distinct scenarios: (i) older patients with massive irreparable cuff tears and anterior recurrent instability with an intact subscapularis tendon regardless of the extent of glenoid bone loss; (ii) younger patients with instability associated shoulder joint capsule hyperlaxity without concomitant injuries (glenoid bone loss, large Hill–Sachs lesion). Complications associated with the Trillat procedure include recurrent anterior instability, potential overtightening of the coracoid, leading to pain and a significant reduction in range of motion, risk of subcoracoid impingement, and restriction of external rotation by up to 10°, a limitation that is generally well-tolerated. The Trillat procedure may be an effective alternative technique for specific indications and should remain part of the surgical armamentarium for addressing anterior shoulder instability.

This paper explores the use of linguistic strategies, specifically discourse markers like 'but', to express contrasts between expectations and reality when faced with unexpected events. The study concentrates on Denial of Expectation (DofE), themost powerful form of contrast, which arises when the expected value based on background assumptions is not met. The main focus of this paper is to model DofE as a weighted homogeneous relationship between object properties. The aim is to predict DofE for numerical properties in specific contexts. I aim to address a gap in previous models by considering the role of context. This is achieved by analyzing contrastive sentences from German car and motorcycle reviews. The research presents the concept of expectation intervals for scalar properties. These intervals align with expectations and exceeding them triggers a potential contrast. The study incorporates causality, expected behavior, and a shift function in selecting contrastive pairs, transforming the conditions into an algorithm.Keywords: contrast; computational and cognitive modeling; discourse analysis

This study investigated modulation of risky-choice framing (RCF) and attribute framing (AF) effects by numeral modi-fication. In Experiment 1, in which the numerals were mod-ified with (the German equivalent of) exactly to enforce a precise reading, there were significant RCF and AF effects. Experiment 2 and 3 addressed the effects of (the German equivalents of) at most and up to. Both modifiers set an upper bound. Yet, they exhibit a sharp contrast in evalua-tive contexts. In Experiment 2, there was a significant inter-action of modifier and frame for RCF, with a reversed framing effect for at most and a standard framing effect for up to. The modifier-by-frame interaction effect was repli-cated in Experiment 3 for AF. To explain framing effects with bare and modified numerals, we propose a semantic-pragmatic account in terms of salience and valence.

Calcium carbonate (CaCO3) is abundant on Earth, is a major component of marine biominerals and thus of sedimentary and metamorphic rocks and it plays a major role in the global carbon cycle by storing atmospheric CO2 into solid biominerals. Six crystalline polymorphs of CaCO3 are known-3 anhydrous: calcite, aragonite, vaterite, and 3 hydrated: ikaite (CaCO3·6H2O), monohydrocalcite (CaCO3·1H2O, MHC), and calcium carbonate hemihydrate (CaCO3·½H2O, CCHH). CCHH was recently discovered and characterized, but exclusively as a synthetic material, not as a naturally occurring mineral. Here, analyzing 200 million spectra with Myriad Mapping (MM) of nanoscale mineral phases, we find CCHH and MHC, along with amorphous precursors, on freshly deposited coral skeleton and nacre surfaces, but not on sea urchin spines. Thus, biomineralization pathways are more complex and diverse than previously understood, opening new questions on isotopes and climate. Crystalline precursors are more accessible than amorphous ones to other spectroscopies and diffraction, in natural and bio-inspired materials.

Abstract The growing number of connected vehicles has led to an increased focus on Vehicle-to-Everything (V2X) communication in the field of transport research. This communication paradigm facilitates cooperation between vehicles and infrastructure to address traffic challenges such as efficiency, sustainability and safety. The development and standardisation of such Cooperative Intelligent Transport Systems (C-ITS) has been pursued in several projects. Beyond technical considerations, assessing the effect of these applications in terms of various impact categories is of paramount importance. However, existing research tends to examine impact categories such as efficiency, sustainability, safety, psychological or socioeconomic impacts separately, often overlooking potential interactions and interdependencies. This approach is inadequate as impacts on one category can have both cascading effects on others and rebound effects. To address this gap, this paper proposes a system dynamics approach using Causal Loop Diagrams (CLD) to illustrate the interconnectedness of impact categories and the potential impacts of C-ITS services. By depicting general relationships, interdependencies and feedback loops between impact category elements, the model accommodates the introduction of single or multiple C-ITS services as separate modules, allowing an analysis of their combined effects on the overall system. To this end, two use cases demonstrate the applicability of the developed CLD and illustrate some of the multiple interrelations between the effects of C-ITS services. The results of this paper support road operators and researchers when setting up the impact assessment of C-ITS services by revealing the dynamic and intertwined nature of different impact categories.

Abstract The broadening of accessible methodologies has enabled mechanistic insights into single-pathogen infections, yet the molecular mechanisms underlying co-infections remain largely elusive, despite their clinical frequency and relevance, generally exacerbating symptom severity and fatality. Here, we describe an unbiased in vitro screening of pairwise co-infections in a murine macrophage model, quantifying pathogen proliferation and host cell death in parallel over time. The screen revealed that the majority of interactions are antagonistic for both metrics, highlighting general patterns depending on the pathogen virulence strategy. We subsequently decipher two distinct molecular interaction points: Firstly, murine Adenovirus 3 modifies ASC-dependent inflammasome responses in murine macrophages, altering host cell death and cytokine production, thereby impacting secondary Salmonella infection. Secondly, murine Adenovirus 2 infection triggers upregulation of Mprip, a crucial mediator of phagocytosis, which in turn causes increased Yersinia uptake, specifically in virus pre-infected bone-marrow-derived macrophages. This work therefore encompasses both a first-of-its-kind systematic assessment of host-pathogen-pathogen interactions, and mechanistic insight into molecular mediators during co-infection.

During cervical carcinogenesis, T‐helper (Th)‐17 cells accumulate in the peripheral blood and tumor tissues of cancer patients. We previously demonstrated that Th17 cells are associated with therapy resistance as well as cervical cancer metastases and relapse; however, the underlying Th17‐driven mechanisms are not fully understood. Here, using microarrays, we found that Th17 cells induced an epithelial‐to‐mesenchymal transition (EMT) phenotype of cervical cancer cells and promoted migration and invasion of 2D cultures and 3D spheroids via induction of microRNA miR‐142‐5p. As the responsible mechanism, we identified the subunits C and D of the succinate dehydrogenase (SDH) complex as new targets of miR‐142‐5p and provided evidence that Th17–miR‐142‐5p‐dependent reduced expression of SDHC and SDHD mediated enhanced migration and invasion of cancer cells using small interfering RNAs (siRNAs) for SDHC and SDHD, and miR‐142‐5p inhibitors. Consistently, patients exhibited high levels of succinate in their serum associated with lymph node metastases and diminished expression of SDHD in patient biopsies correlated with increased numbers of Th17 cells. Correspondingly, a combination of weak or negative SDHD expression and a ratio of Th17/CD4+ T cells > 43.90% in situ was associated with reduced recurrence‐free survival. In summary, we unraveled a previously unknown molecular mechanism by which Th17 cells promote cervical cancer progression and suggest evaluation of Th17 cells as a potential target for immunotherapy in cervical cancer.

Abstract The decrease in sperm count and infertility is a global issue that remains unresolved. By screening environmental bacterial isolates, we have found that a novel lactic acid bacterium, Lactiplantibacillus plantarum SNI3, increased testis size, testosterone levels, sperm count, sexual activity and fertility in mice that have consumed the bacteria for four weeks. The abundance of L. plantarum in the colon microbiome was positively associated with sperm count. Fecal microbiota transplantation (FMT) from L. plantarum SNI3-dosed mice improved testicular functions in microbiome-attenuated recipient animals. To identify mediators that confer pro-reproductive effects on the host, untargeted in situ mass spectrometry metabolomics was performed on testis samples of L. plantarum SNI3-treated and control mice. Enrichment pathway analysis revealed several perturbed metabolic pathways in the testis of treated mice. Within the testis, a dipeptide, glutamyl-glutamate (GluGlu) was the most upregulated metabolite following L. plantarum SNI3 administration. To validate the pro-reproductive feature of GluGlu, systemic and local injections of the dipeptide have been performed. γ-GluGlu increased sperm count but had no effect on testosterone. These findings highlight the role of γ-GluGlu in mediating spermatogenetic effects of L. plantarum on the male mouse host and –following relevant human clinical trials- may provide future tools for treating certain forms of male infertility.

Abstract Background Vaccination is one of the greatest tools for individuals to stay healthy. Individuals are, however, often exposed to misinformation via digital and social media, and thus, may miss the opportunity to develop scientific knowledge about vaccines and trust in relevant stakeholders. This has a damaging impact on vaccine confidence. Understanding vaccine confidence is particularly important in North Dakota, where vaccination rates are lower than national averages. Objectives The objectives of this research are to examine the association between vaccine confidence and three potential sources of it, namely, trust, vaccine knowledge, and vaccine information sources and to investigate the relative strength of three vaccine confidence sources, while accounting for covariates. Methods Students (n = 517, 56.6%) and staff and faculty (n = 397, 43.4%) at the University of North Dakota (n = 914) completed an online survey. Logistic regressions estimated odds ratios (OR) and 95% confidence intervals (CI) for associations among trust in doctors, family/friends, government health agencies, charitable organizations, and religious organizations, vaccine knowledge, vaccine information sources as well as vaccine confidence, accounting for gender, race, marital status, age, religion, political ideology, education, and health status. Results The mean age of participants was 29.43 years (SD = 13.48). Most were females (71.6%) and white (91.5%). Great trust in doctors (OR = 3.29, p

Cannabidiol (CBD)-containing products are widely marketed as over the counter products. Adverse effects reported in anecdotal consumer reports or during clinical studies were first assumed to be due to acid-catalysed cyclization of CBD to psychotropic Δ 9-tetrahydrocannabinol (Δ 9-THC) in the stomach after oral consumption. However, research of pure CBD solutions stored in simulated gastric juice or subjected to various storage conditions such as heat and light with specific liquid chromatographic/tandem mass spectrometric (LC/MS/MS) and ultra-high pressure liquid chromatographic/quadrupole time-of-flight mass spectrometric (UPLC-QTOF) analyses was unable to confirm THC formation. Another hypothesis for the adverse effects of CBD products may be residual Δ 9-THC concentrations in the products as contamination, because most of them are based on hemp extracts containing the full spectrum of cannabinoids besides CBD. Analyses of 413 hemp-based products of the German market (mostly CBD oils) confirmed this hypothesis: 48 products (12%) contained Δ 9-THC above the lowest observed adverse effect level (2.5 mg/day). Hence, it may be assumed that the adverse effects of some commercial CBD products are based on a low-dose effect of Δ 9-THC, with the safety of CBD itself currently being unclear with significant uncertainties regarding possible liver and reproductive toxicity. The safety, efficacy and purity of commercial CBD products is highly questionable, and all of the products in our sample collection showed various non-conformities to European food law such as unsafe Δ 9-THC levels, hemp extracts or CBD isolates as non-approved novel food ingredients, non-approved health claims, and deficits in mandatory food labelling requirements. In view of the growing market for such lifestyle products, the effectiveness of the instrument of food business operators' own responsibility for product safety and regulatory compliance must obviously be challenged, and a strong regulatory framework for hemp products needs to be devised.

PURPOSEGallbladder cancer (GBC) is a biliary tract malignancy characterized by its high lethality. Although the incidence of GBC is low in most countries, specific areas such as Chile display a high incidence. Our collaborative study sought to compare clinical and molecular features of GBC cohorts from Chile and the United States with a focus on ERBB2 alterations.METHODSPatients were accrued at Memorial Sloan Kettering Cancer Center (MSK) or the Pontificia Universidad Católica de Chile (PUC). Clinical information was retrieved from medical records. Genomic analysis was performed by the next-generation sequencing platform MSK-Integrated Mutation Profiling of Actionable Cancer Targets.RESULTSA total of 260 patients with GBC were included, 237 from MSK and 23 from PUC. There were no significant differences in the clinical characteristics between the patients identified at MSK and at PUC except in terms of lithiasis prevalence which was significantly higher in the PUC cohort (85% v 44%; P = .0003). The prevalence of ERBB2 alterations was comparable between the two cohorts (15% v 9%; P = .42). Overall, ERBB2 alterations were present in 14% of patients (8% with ERBB2 amplification, 4% ERBB2 mutation, 1.5% concurrent amplification and mutation, and 0.4% ERBB2 fusion). Notably, patients with GBC that harbored ERBB2 alterations had better overall survival (OS) versus their ERBB2-wild type counterparts (22.3 months v 11.8 months; P = .024).CONCLUSIONThe prevalence of lithiasis seems to be higher in Chilean versus US patients with GBC. A similar prevalence of ERBB2 alterations of overall 14% and better OS suggests that a proportion of them could benefit from human epidermal growth factor receptor type 2–targeted therapies. The smaller cohort of Chile, where the disease prevalence is higher, is a reminder and invitation for the need of more robust next-generation sequencing analyses globally.

IntroductionPancreatic ductal adenocarcinoma (PDAC) remains a leading cause of cancer-related deaths worldwide with limited treatment options due to extensive radiation and chemotherapy resistance. Monotherapy with immune checkpoint blockade showed no survival benefit. A combination of immunomodulation and radiotherapy may offer new treatment strategies, as demonstrated for non-small cell lung cancer. Radiation-induced anti-tumour immunity is mediated through cytosolic nucleic acid sensing pathways that drive the expression of interferon beta-1 (IFNB1) and proinflammatory cytokines.MethodsHuman PDAC cell lines (PANC-1, MIA PaCa-2, BxPC-3) were treated with X-rays and protons. Immunogenic cell death was measured based on HMGB1 release. Cytosolic dsDNA and dsRNA were analysed by immunofluorescence microscopy. Cell cycle progression, MHC-I and PD-L1 expression were determined by flow cytometry. Galectin-1 and IFNB1 were measured by ELISA. The expression levels and the phosphorylation status of the cGAS/STING and RIG-I/MAVS signalling pathways were analysed by western blotting, the expression of IFNB1 and proinflammatory cytokines was determined by RT-qPCR and genome-wide by RNA-seq. CRISPR-Cas9 knock-outs and inhibitors were used to elucidate the relevance of STING, MAVS and NF-κB for radiation-induced IFNB1 activation.ResultsWe demonstrate that a clinically relevant X-ray hypofractionation regimen (3x8 Gy) induces immunogenic cell death and activates IFNB1 and proinflammatory cytokines. Fractionated radiation induces G2/M arrest and accumulation of cytosolic DNA in PDAC cells, which partly originates from mitochondria. RNA-seq analysis shows a global upregulation of type I interferon response and NF-κB signalling in PDAC cells following 3x8 Gy. Radiation-induced immunogenic response is regulated by STING, MAVS and NF-κB. In addition to immunostimulation, radiation also induces immunosuppressive galectin-1. No significant changes in MHC-I or PD-L1 expression were observed. Moreover, PDAC cell lines show similar radiation-induced immune effects when exposed to single-dose protons or photons.ConclusionOur findings provide a rationale for combinatorial radiation-immunomodulatory treatment approaches in PDAC using conventional photon-based or proton beam radiotherapy.

Cannabidiol (CBD)-containing products are widely marketed as over the counter products. Adverse effects reported in anecdotal consumer reports or during clinical studies were first assumed to be due to acid-catalysed cyclization of CBD to psychotropic Δ9-tetrahydrocannabinol (Δ9-THC) in the stomach after oral consumption. However, research of pure CBD solutions stored in simulated gastric juice or subjected to various storage conditions such as heat and light with specific liquid chromatographic/tandem mass spectrometric (LC/MS/MS) and ultra-high pressure liquid chromatographic/quadrupole time-of-flight mass spectrometric (UPLC-QTOF) analyses was unable to confirm THC formation. Another hypothesis for the adverse effects of CBD products may be residual Δ9-THC concentrations in the products as contamination, because most of them are based on hemp extracts containing the full spectrum of cannabinoids besides CBD. Analyses of 413 hemp-based products of the German market (mostly CBD oils) confirmed this hypothesis: 48 products (12%) contained Δ9-THC above the lowest observed adverse effect level (2.5 mg/day). Hence, it may be assumed that the adverse effects of some commercial CBD products are based on a low-dose effect of Δ9-THC, with the safety of CBD itself currently being unclear with significant uncertainties regarding possible liver and reproductive toxicity. The safety, efficacy and purity of commercial CBD products is highly questionable, and all of the products in our sample collection showed various non-conformities to European food law such as unsafe Δ9-THC levels, hemp extracts or CBD isolates as non-approved novel food ingredients, non-approved health claims, and deficits in mandatory food labelling requirements. In view of the growing market for such lifestyle products, the effectiveness of the instrument of food business operators' own responsibility for product safety and regulatory compliance must obviously be challenged, and a strong regulatory framework for hemp products needs to be devised.

Hash functions are a crucial component in incrementally verifiable computation (IVC) protocols and applications. Among those, recursive SNARKs and folding schemes require hash functions to be both fast in native CPU computations and compact in algebraic descriptions (constraints). However, neither SHA-2/3 nor newer algebraic constructions, such as Poseidon, achieve both requirements. In this work we overcome this problem in several steps. First, for certain prime field domains we propose a new design strategy called Kintsugi, which explains how to construct nonlinear layers of high algebraic degree which allow fast native implementations and at the same time also an efficient circuit description for zeroknowledge applications. Then we suggest another layer, based on the Feistel Type-3 scheme, and prove wide trail bounds for its combination with an MDS matrix. We propose a new permutation design named Monolith to be used as a sponge or compression function. It is the first arithmetization-oriented function with a native performance comparable to SHA3-256. At the same time, it outperforms Poseidon in a circuit using the Merkle tree prover in the Plonky2 framework. Contrary to previously proposed designs, Monolith also allows for efficient constant-time native implementations which mitigates the risk of side-channel attacks.