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Elimination of chronic hepatitis C (HCV) will require scaling up treatment, including possible HCV treatment by primary care providers. The District of Columbia (DC) has a substantial population living with untreated hepatitis C, and treatment expansion would benefit the resident population. The aim of this study was to assess the knowledge, attitudes, and behaviors of primary care providers and specialists related to hepatitis C screening and treatment. We conducted a prospective, online survey of physicians and nurse practitioners (n = 153) in DC on their knowledge, attitudes, and behaviors related to hepatitis C screening and treatment, as well as referral patterns, interest in learning, and preferred learning modalities. We compared responses by provider type. Key findings indicated that HCV screening and treatment knowledge was higher among specialty physicians as compared to primary care providers. The most common reported facilitators of HCV screening included a prompt in the electronic medical record (63%), patient education (57%), and support staff (41%). While 71% reported that HCV treatment was important in the community they serve, only 26% indicated that access to HCV specialist expertise and consultation was a major area of need. Additionally, 59% reported that they refer all HCV patients to specialists for treatment. Primary care providers in DC had moderate interest in learning how to treat chronic hepatitis C, but they need additional training. Patients are typically referred to gastroenterology, infectious diseases, and hepatology specialists who may have limited capacity to expand treatment.

The dynamics of energetic particle (EP) species, born from fusion reactions or plasma heating schemes, are critical for predicting the behavior of magnetic confinement fusion experiments and future fusion reactors. Because energetic particles are largely collisionless, the orbits of Monte Carlo samples drawn from a given distribution function can be efficiently integrated in prescribed electromagnetic fields. In addition to the static magneto-hydrodynamic (MHD) equilibrium fields produced by the electromagnetic coils of a fusion device, MHD waves can be excited by -- and resonantly transport -- energetic particle populations. FIRM3D is an open-source Python/C++/CUDA software suite for modeling energetic particle dynamics in 3D magnetic fields, available at https://github.com/ColumbiaStellaratorTheory/firm3d. The core guiding-center integration routines grew out of SIMSOPT (Landreman et al., 2021), but have been extended to include additional physics and diagnostics not typically required in the stellarator optimization context. This standalone framework enables focused development of energetic particle physics capabilities with minimal dependencies, making it accessible to the broader stellarator and plasma physics community. Components of FIRM3D include interfaces with MHD equilibrium and wave stability software (BOOZ_XFORM, AE3D, FAR3D); CPU and GPU parallelized integration of the guiding center orbit equation, with symplectic and Runge-Kutta integrator options; and orbit visualization and transport diagnostics, including Poincare maps, orbit classification, and weighted Birkhoff averaging.

This work presents the compact experimental negative triangularity reactor (CENTAUR), a low overnight cost, high-field tokamak, breakeven reactor design, achieving a predicted total fusion power of 40MW and scientific energy gain of 1.3. Ballooning stability calculations confirm that the device's pedestal is within the first stability regime, which is consistent with the expected ELM-free operation associated with negative triangularity (NT) plasmas. The geometry of the NT divertor allows for high fraction of radiated power (13.5\\(\\%\\)) between the separatrix and plasma facing components. Heat transport modeling based on simulations of the edge region show heat loads into plasma facing components well below material limits. The magnet system employs rare-earth barium copper oxide (REBCO) high-temperature superconductors in 18 toroidal field coils, an hourglass-shaped central solenoid, and six poloidal field coils to support high-field (\\(B_0=10.9\\) T) plasma confinement, shaping, and current drive. Neutronics analysis shows that a 12 cm \\(B_4C\\) shield keeps superconducting magnet heating below the 33~K quench limit during 10 s, 40 MW DT pulses. With this shielding, the modeled fluence indicates HTS components can survive more than ten times the 3000-pulse design lifetime. Iteration of economic analysis in tandem with the technical design process allows CENTAUR to achieve its overnight cost goal of$\\$ $2B determined using a custom costing model that predicts a total overnight cost of \\(1.6\\)B\\(0.2\\)B.

RNA sequencing (RNA-seq) is the leading technology for genome-wide transcript quantification. However, publicly available RNA-seq data is currently provided mostly in raw form, a significant barrier for global and integrative retrospective analyses. ARCHS4 is a web resource that makes the majority of published RNA-seq data from human and mouse available at the gene and transcript levels. For developing ARCHS4, available FASTQ files from RNA-seq experiments from the Gene Expression Omnibus (GEO) were aligned using a cloud-based infrastructure. In total 187,946 samples are accessible through ARCHS4 with 103,083 mouse and 84,863 human. Additionally, the ARCHS4 web interface provides intuitive exploration of the processed data through querying tools, interactive visualization, and gene pages that provide average expression across cell lines and tissues, top co-expressed genes for each gene, and predicted biological functions and protein–protein interactions for each gene based on prior knowledge combined with co-expression. Publicly available RNA-seq data is provided mostly in raw form, resulting in a barrier for integrative analyses. Here, Lachmann et al. develop a high-throughput processing infrastructure and search database (ARCHS4) that provides processed RNA-seq data for 187,946 publicly available mouse and human samples to support exploration and reuse.

We used 10 years of surveillance data to describe listeriosis frequency in Germany. Altogether, 5,576 cases were reported, 91% not pregnancy associated; case counts increased over time. Case-fatality rate was 13% in non–pregnancy-associated cases, most in adults ≥65 years of age. Detecting, investigating, and ending outbreaks might have the greatest effect on incidence

Invasive listeriosis is a severe foodborne infection in humans and is difficult to control. Listeriosis incidence is increasing worldwide, but some countries have implemented molecular surveillance programs to improve recognition and management of listeriosis outbreaks. In Germany, routine whole-genome sequencing, core genome multilocus sequence typing, and single nucleotide polymorphism calling are used for subtyping of Listeria monocytogenes isolates from listeriosis cases and suspected foods. During 2018-2019, an unusually large cluster of L. monocytogenes isolates was identified, including 134 highly clonal, benzalkonium-resistant sequence type 6 isolates collected from 112 notified listeriosis cases. The outbreak was one of the largest reported in Europe during the past 25 years. Epidemiologic investigations identified blood sausage contaminated with L. monocytogenes highly related to clinical isolates; withdrawal of the product from the market ended the outbreak. We describe how epidemiologic investigations and complementary molecular typing of food isolates helped identify the outbreak vehicle.

Background Foodborne infections such as listeriosis caused by the bacterium Listeria monocytogenes represent a significant public health concern, particularly when outbreaks affect many individuals over prolonged time. Systematic collection of pathogen isolates from infected patients, whole genome sequencing (WGS) and phylogenetic analyses allow recognition and termination of outbreaks after source identification and risk profiling of abundant lineages. Methods We here present a multi-dimensional analysis of > 1800 genome sequences from clinical L. monocytogenes isolates collected in Germany between 2018 and 2021. Different WGS-based subtyping methods were used to determine the population structure with its main phylogenetic sublineages as well as for identification of disease clusters. Clinical frequencies of materno-foetal and brain infections and in vitro infection experiments were used for risk profiling of the most abundant sublineages. These sublineages and large disease clusters were further characterised in terms of their genetic and epidemiological properties. Results The collected isolates covered 62% of all notified cases and belonged to 188 infection clusters. Forty-two percent of these clusters were active for > 12 months, 60% generated cases cross-regionally, including 11 multinational clusters. Thirty-seven percent of the clusters were caused by sequence type (ST) ST6, ST8 and ST1 clones. ST1 was identified as hyper- and ST8, ST14, ST29 as well as ST155 as hypovirulent, while ST6 had average virulence potential. Inactivating mutations were found in several virulence and house-keeping genes, particularly in hypovirulent STs. Conclusions Our work presents an in-depth analysis of the genomic characteristics of L. monocytogenes isolates that cause disease in Germany. It supports prioritisation of disease clusters for epidemiological investigations and reinforces the need to analyse the mechanisms underlying hyper- and hypovirulence.

Invasive listeriosis, caused by Listeria (L.) monocytogenes, is a severe foodborne infection, especially for immunocompromised individuals. The aim of our investigation was the identification and analysis of listeriosis outbreaks in Germany with smoked and graved salmon products as the most likely source of infection using whole-genome sequencing (WGS) and patient interviews. In a national surveillance programme, WGS was used for subtyping and core genome multi locus sequence typing (cgMLST) for cluster detection of L. monocytogenes isolates from listeriosis cases as well as food and environmental samples in Germany. Patient interviews were conducted to complement the molecular typing. We identified 22 independent listeriosis outbreaks occurring between 2010 and 2021 that were most likely associated with the consumption of smoked and graved salmon products. In Germany, 228 cases were identified, of 50 deaths (22%) reported 17 were confirmed to have died from listeriosis. Many of these 22 outbreaks were cross-border outbreaks with further cases in other countries. This report shows that smoked and graved salmon products contaminated with L. monocytogenes pose a serious risk for listeriosis infection in Germany. Interdisciplinary efforts including WGS and epidemiological investigations were essential to identifying the source of infection. Uncooked salmon products are high-risk foods frequently contaminated with L. monocytogenes. In order to minimize the risk of infection for consumers, food producers need to improve hygiene measures and reduce the entry of pathogens into food processing. Furthermore, susceptible individuals should be better informed of the risk of acquiring listeriosis from consuming smoked and graved salmon products.

Hereditary pulmonary alveolar proteinosis (herPAP) constitutes a rare, life threatening lung disease characterized by the inability of alveolar macrophages to clear the alveolar airspaces from surfactant phospholipids. On a molecular level, the disorder is defined by a defect in the CSF2RA gene coding for the GM-CSF receptor alpha-chain (CD116). As therapeutic options are limited, we currently pursue a cell and gene therapy approach aiming for the intrapulmonary transplantation of gene-corrected macrophages derived from herPAP-specific induced pluripotent stem cells (herPAP-iPSC) employing transcriptional activator-like effector nucleases (TALENs). Targeted insertion of a codon-optimized CSF2RA -cDNA driven by the hybrid cytomegalovirus (CMV) early enhancer/chicken beta actin (CAG) promoter into the AAVS1 locus resulted in robust expression of the CSF2RA gene in gene-edited herPAP-iPSCs as well as thereof derived macrophages. These macrophages displayed typical morphology, surface phenotype, phagocytic and secretory activity, as well as functional CSF2RA expression verified by STAT5 phosphorylation and GM-CSF uptake studies. Thus, our study provides a proof-of-concept, that TALEN-mediated integration of the CSF2RA gene into the AAVS1 safe harbor locus in patient-specific iPSCs represents an efficient strategy to generate functionally corrected monocytes/macrophages, which in the future may serve as a source for an autologous cell-based gene therapy for the treatment of herPAP.

Induced pluripotent stem cells (iPSCs) offer great promise for the field of regenerative medicine, and iPSC-derived cells have already been applied in clinical practice. However, potential contamination of effector cells with residual pluripotent cells (e.g., teratoma-initiating cells) or effector cell-associated side effects may limit this approach. This also holds true for iPSC-derived hematopoietic cells. Given the therapeutic benefit of macrophages in different disease entities and the feasibility to derive macrophages from human iPSCs, we established human iPSCs harboring the inducible Caspase-9 (iCasp9) suicide safety switch utilizing transcription activator-like effector nuclease (TALEN)-based designer nuclease technology. Mono- or bi-allelic integration of the iCasp9 gene cassette into the AAVS1 locus showed no effect on the pluripotency of human iPSCs and did not interfere with their differentiation towards macrophages. In both, iCasp9-mono and iCasp9-bi-allelic clones, concentrations of 0.1 nM AP20187 were sufficient to induce apoptosis in more than 98% of iPSCs and their progeny—macrophages. Thus, here we provide evidence that the introduction of the iCasp9 suicide gene into the AAVS1 locus enables the effective clearance of human iPSCs and thereof derived macrophages.