Standardized reporting of spine and sacroiliac joints in axial spondyloarthritis MRI: from the ESSR-Arthritis Subcommittee.

OBJECTIVES: Apply a modified Delphi-based approach and produce a practical, radiology-specific set of definitions for interpretation and standardization of the multiple MRI findings in axial spondyloarthritis (ax-SpA), specifically to aid the general radiologist with a musculoskeletal interest, working with gold standard basic MRI protocols. MATERIALS AND METHODS: We report the results of a modified Delphi-based consensus of 35 experts from 13 countries in the Arthritis Subcommittee of the European Society of Musculoskeletal Radiology (ESSR). Seventeen definitions were created (i.e., nine for the spine and eight for the sacroiliac joint) and two Delphi rounds were conducted on an electronic database, collated and revised by the project leader with agreement. Group leads were appointed for each definition following the first round. Final definitions included only those that reached a consensus > 80%; if > 50% agreed on exclusion consensus, definitions were excluded. Final results have been shared during the Arthritis meeting at the Annual ESSR Congress. RESULTS: Fourteen definitions, eight for the spine and six for the sacroiliac joint were agreed for standardized reporting. Andersson's, anterior corner sclerotic and costovertebral joint inflammatory lesions of the spine, with active and non-active erosions, and fat metaplasia of the sacroiliac joint reaching the highest consensus (≥ 95%). More than 50% of the experts agreed to exclude joint space inflammation in the sacroiliac joint and tissue backfill. Syndesmophytes reached 76% agreement. CONCLUSIONS: Agreed definitions by expert radiologists using a modified Delphi process, should allow standardized actionable radiology reports and clarity in reporting terminology of ax-SpA. CLINICAL RELEVANCE STATEMENT: The proposed definitions will support reporting from musculoskeletal and general radiologists working with gold-standard basic MRI, improve confidence in lesion assessment, and standardize terminology to provide actionable reports on MRI in patients with ax-SpA. KEY POINTS: Experts applied a modified Delphi method to optimize the definitions of MRI findings of ax-SpA. After two Delphi rounds and one in-person meeting, fourteen definitions reached the agreement threshold. These consensus-based definitions will aid in actionable reporting specifically for the general radiologist with a musculoskeletal interest.

Using de novo transcriptomes to decipher the relationships in cutthroat trout subspecies (Oncorhynchus clarkii).

For almost 200 years, the taxonomy of cutthroat trout (Oncorhynchus clarkii), a salmonid native to Western North America, has been in flux as ichthyologists and fisheries biologists have tried to describe the diversity within these fishes. Starting in the 1950s, Robert Behnke reexamined the cutthroat trout and identified 14 subspecies based on morphological traits, Pleistocene events, and modern geographic ranges. His designations became instrumental in recognizing and preserving the remaining diversity of cutthroat trout. Over time, molecular techniques (i.e. karyotypes, allozymes, mitochondrial DNA, SNPs, and microsatellite arrays) have largely reinforced Behnke's phylogenies, but have also revealed that some relationships are consistently weakly supported. To further resolve these relationships, we generated de novo transcriptomes for nine cutthroat subspecies, as well as a Bear River Bonneville form and two Colorado River lineages (blue and green). We present phylogenies of these subspecies generated from multiple sets of orthologous genes extracted from our transcriptomes. We confirm many of the relationships identified in previous morphological and molecular studies, as well as discuss the importance of significant differences apparent in our phylogenies from these studies within a geological perspective. Specific findings include three distinct clades: (1) Bear River Bonneville form and Yellowstone cutthroat trout; (2) Bonneville cutthroat trout (n = 2); and (3) Greenback and Rio Grande cutthroat trout. We also identify potential gene transfer between Bonneville cutthroat trout and a population of Colorado River green lineage cutthroat trout. Using these findings, it appears that additional groups warrant species-level consideration if other recent species elevations are retained.

Angle Dependence of Electrode Lead-Related Artifacts in Single- and Dual-Energy Cardiac ECG-Gated CT Scanning-A Phantom Study.

Background: The electrodes of implantable cardiac devices (ICDs) may cause significant problems in cardiac computed tomography (CT) because they are a source of artifacts that obscure surrounding structures and possible pathology. There are a few million patients currently with ICDs, and some of these patients will require cardiac imaging due to coronary artery disease or problems with ICDs. Modern CT scanners can reduce some of the metal artifacts because of MAR software, but in some vendors, it does not work with ECG gating. Introduced in 2008, dual-energy CT scanners can generate virtual monoenergetic images (VMIs), which are much less susceptible to metal artifacts than standard CT images. Objective: This study aimed to evaluate if dual-energy CT can reduce metal artifacts caused by ICD leads by using VMIs. The second objective was to determine how the angle between the electrode and the plane of imaging affects the severity of the artifacts in three planes of imaging. Methods: A 3D-printed model was constructed to obtain a 0-90-degree field at 5-degree intervals between the electrode and each of the planes: axial, coronal, and sagittal. This electrode was scanned in dual-energy and single-energy protocols. VMIs with an energy of 40-140 keV with 10 keV intervals were reconstructed. The length of the two most extended artifacts originating from the tip of the electrode and 2 cm above it-at the point where the thick metallic defibrillating portion of the electrode begins-was measured. Results: For the sagittal plane, these observations were similar for both points of the ICDs that were used as the reference location. VMIs with an energy over 80 keV produce images with fewer artifacts than similar images obtained in the single-energy scanning mode. Conclusions: Virtual monoenergetic imaging techniques may reduce streak artifacts arising from ICD electrodes and improve the quality of the image. Increasing the angle of the electrode as well as the imaging plane can reduce artifacts. The angle between the electrode and the beam of X-rays can be increased by tilting the gantry of the scanner or lifting the upper body of the patient.

Trace Detection of Adulterants in Illicit Opioid Samples Using Surface-Enhanced Raman Scattering and Random Forest Classification.

The detection of trace adulterants in opioid samples is an important aspect of drug checking, a harm reduction measure that is required as a result of the variability and unpredictability of the illicit drug supply. While many analytical methods are suitable for such analysis, community-based approaches require techniques that are amenable to point-of-care applications with minimal sample preparation and automated analysis. We demonstrate that surface-enhanced Raman spectroscopy (SERS), combined with a random forest classifier, is able to detect the presence of two common sedatives, bromazolam (0.32-36% w/w) and xylazine (0.15-15% w/w), found in street opioid samples collected as a part of a community drug checking service. The Raman predictions, benchmarked against mass spectrometry results, exhibited high specificity (88% for bromazolam, 96% for xylazine) and sensitivity (88% for bromazolam, 92% for xylazine) for the compounds of interest. We additionally provide evidence that this exceeds the performance of a more conventional approach using infrared spectral data acquired on the same samples. This demonstrates the feasibility of SERS for point-of-care analysis of challenging multicomponent samples containing trace adulterants.

ß-Galactosidase-Triggered Photodynamic Elimination of Senescent Cells with a Boron Dipyrromethene-Based Photosensitizer.

Senescence is a cellular response having physiological and reparative functions to preserve tissue homeostasis and suppress tumor growth. However, the accumulation of senescent cells would cause deleterious effects that lead to age-related dysfunctions and cancer progression. Hence, selective detection and elimination of senescent cells are crucial yet remain a challenge. A ß-galactosidase (ß-gal)-activated boron dipyrromethene (BODIPY)-based photosensitizer (compound 1) is reported here that can selectively detect and eradicate senescent cells. It contains a galactose moiety connected to a pyridinium BODIPY via a self-immolative nitrophenylene linker, of which the photoactivity is effectively quenched. Upon interactions with the senescence-associated ß-gal, it undergoes enzymatic hydrolysis followed by self-immolation, leading to the release of an activated BODIPY moiety by which the fluorescence emission and singlet oxygen generation are restored. The ability of 1 to detect and eliminate senescent cells is demonstrated in vitro and in vivo, using SK-Mel-103 tumor-bearing mice treated with senescence-inducing therapy. The results demonstrate that 1 can be selectively activated in senescent cells to trigger a robust senolytic effect upon irradiation. This study breaks new ground in the design and application of new senolytic agents based on photodynamic therapy.

Photo-metallo-immunotherapy: Fabricating Chromium-Based Nanocomposites to Enhance CAR-T Cell Infiltration and Cytotoxicity against Solid Tumors.

The infiltration and cytotoxicity of chimeric antigen receptor (CAR)-T cells are crucial for effective elimination of solid tumors. While metallo-immunotherapy is a promising strategy that can activate the antitumor immunity, its role in promoting CAR-T cell therapy remains elusive. The first single-element nanomaterial based on chromium nanoparticles (Cr NPs) for cancer photo-metallo-immunotherapy has been reported previously. Herein, an extended study using biodegradable polydopamine as a versatile carrier for these nanoparticles, enabling synergistic CAR-T cell therapy, is reported. The results show that these nanocomposites with or without further encapsulation of the anticancer drug alpelisib can promote the CAR-T cell migration and antitumor effect. Upon irradiation with near-infrared light, they caused mild hyperthermia that can "warm" the "cold" tumor microenvironment (TME). The administration of B7-H3 CAR-T cells to NOD severe combined immunodeficiency gamma mice bearing a human hepatoma or PIK3CA-mutated breast tumor can significantly inhibit the tumor growth after the induction of tumor hyperthermia by the nanocomposites and promote the secretion of serum cytokines, including IL-2, IFN-γ, and TNF-α. The trivalent Cr3+ ions, which are the major degradation product of these nanocomposites, can increase the CXCL13 and CCL3 chemokine expressions to generate tertiary lymphoid structures (TLSs) in the tumor tissues, facilitating the CAR-T cell infiltration.

Immobilising an acid-cleavable dimeric phthalocyanine on gold nanobipyramids for intracellular pH detection and photodynamic elimination of cancer cells.

An acetal-linked dimeric phthalocyanine has been synthesised and immobilised on the surface of gold nanobipyramids. The resulting nanocomposite serves as a highly sensitive probe for intracellular pH through its acid-responsive fluorescence and surface-enhanced Raman scattering signals. The phthalocyanine units released in the acidic intracellular environment can also effectively eliminate the cancer cells upon light irradiation, rendering this simple fabricated nanosystem a bimodal and bifunctional theranostic agent.

Promotion and Detection of Cell-Cell Interactions through a Bioorthogonal Approach.

Manipulation of cell-cell interactions via cell surface modification is crucial in tissue engineering and cell-based therapy. To be able to monitor intercellular interactions, it can also provide useful information for understanding how the cells interact and communicate. We report herein a facile bioorthogonal strategy to promote and monitor cell-cell interactions. It involves the use of a maleimide-appended tetrazine-caged boron dipyrromethene (BODIPY)-based fluorescent probe and a maleimide-substituted bicyclo[6.1.0]non-4-yne (BCN) to modify the membrane of macrophage (RAW 264.7) and cancer (HT29, HeLa, and A431) cells, respectively, via maleimide-thiol conjugation. After modification, the two kinds of cells interact strongly through inverse electron-demand Diels-Alder reaction of the surface tetrazine and BCN moieties. The coupling also disrupts the tetrazine quenching unit, restoring the fluorescence emission of the BODIPY core on the cell-cell interface, and promotes phagocytosis. Hence, this approach can promote and facilitate the detection of intercellular interactions, rendering it potentially useful for macrophage-based immunotherapy.

Genotypic analysis of RTS,S/AS01E malaria vaccine efficacy against parasite infection as a function of dosage regimen and baseline malaria infection status in children aged 5-17 months in Ghana and Kenya: a longitudinal phase 2b randomised controlled trial.

BACKGROUND: The first licensed malaria vaccine, RTS,S/AS01E, confers moderate protection against symptomatic disease. Because many malaria infections are asymptomatic, we conducted a large-scale longitudinal parasite genotyping study of samples from a clinical trial exploring how vaccine dosing regimen affects vaccine efficacy. METHODS: Between Sept 28, 2017, and Sept 25, 2018, 1500 children aged 5-17 months were randomly assigned (1:1:1:1:1) to receive four different RTS,S/AS01E regimens or a rabies control vaccine in a phase 2b open-label clinical trial in Ghana and Kenya. Participants in the four RTS,S groups received two full doses at month 0 and month 1 and either full doses at month 2 and month 20 (group R012-20); full doses at month 2, month 14, month 26, and month 38 (group R012-14); fractional doses at month 2, month 14, month 26, and month 38 (group Fx012-14; early fourth dose); or fractional doses at month 7, month 20, and month 32 (group Fx017-20; delayed third dose). We evaluated the time to the first new genotypically detected infection and the total number of new infections during two follow-up periods (12 months and 20 months) in more than 36 000 dried blood spot specimens from 1500 participants. To study vaccine effects on time to the first new infection, we defined vaccine efficacy as one minus the hazard ratio (HR; RTS,S vs control) of the first new infection. We performed a post-hoc analysis of vaccine efficacy based on malaria infection status at first vaccination and force of infection by month 2. This trial (MAL-095) is registered with ClinicalTrials.gov, NCT03281291. FINDINGS: We observed significant and similar vaccine efficacy (25-43%; 95% CI union 9-53) against first new infection for all four RTS,S/AS01E regimens across both follow-up periods (12 months and 20 months). Each RTS,S/AS01E regimen significantly reduced the mean number of new infections in the 20-month follow-up period by 1·1-1·6 infections (95% CI union 0·6-2·1). Vaccine efficacy against first new infection was significantly higher in participants who were infected with malaria (68%; 95% CI 50-80) than in those who were uninfected (37%; 23-48) at the first vaccination (p=0·0053). INTERPRETATION: All tested dosing regimens blocked some infections to a similar degree. Improved vaccine efficacy in participants infected during vaccination could suggest new strategies for highly efficacious malaria vaccine development and implementation. FUNDING: GlaxoSmithKline Biologicals SA, PATH, Bill & Melinda Gates Foundation, and the German Federal Ministry of Education and Research.

Preliminary findings from the Dynamics of the Immune Responses to Repeat Influenza Vaccination Exposures (DRIVE I) Study: a Randomized Controlled Trial.

Background: Studies have reported that repeated annual vaccination may influence the effectiveness of the influenza vaccination in the current season. The mechanisms underlying these differences are unclear but might include "focusing" of the adaptive immune response to older strains. Methods: We established a 5-year randomized placebo-controlled trial of repeated influenza vaccination (Flublok, Sanofi Pasteur) in adults 18-45 years of age. Participants were randomized equally between five groups, with planned annual receipt of vaccination (V) or saline placebo (P) as follows: P-P-P-P-V, P-P-P-V-V, P-P-V-V-V, P-V-V-V-V, or V-V-V-VV. Serum samples were collected each year just before vaccination and after 30 and 182 days. A subset of sera were tested by hemagglutination inhibition assays, focus reduction neutralization tests and enzyme-linked immunosorbent assays against vaccine strains. Results: From 23 October 2020 through 11 March 2021 we enrolled and randomized 447 adults. We selected sera from 95 participants at five timepoints from the first two study years for testing. Among vaccinated individuals, antibody titers increased between days 0 and 30 against each of the vaccine strains, with substantial increases for first-time vaccinees and smaller increases for repeat vaccinees, who had higher pre-vaccination titers in year 2. There were statistically significant reductions in the proportion of participants achieving a four-fold greater rise in antibody titer for the repeat vaccinees for A(H1N1), B/Victoria and B/Yamagata, but not for influenza A(H3N2). There were no statistically significant differences between groups in geometric mean titers at day 30 or the proportions of participants with antibody titers ≥40 at day 30 for any of the vaccine strains. Conclusions: In the first two years, repeat vaccinees and first-time vaccinees had similar post-vaccination geometric mean titers to all four vaccine strains, indicative of similar levels of clinical protection. The vaccine strains of A(H1N1) and A(H3N2) were updated in year 2, providing an opportunity to explore antigenic distances between those strains in humans in subsequent years.

Revisiting the use of the EORTC QLQ-STO22 to assess health-related quality of life of patients with gastric cancer: incorporating updated treatment options and cross-cultural perspectives.

BACKGROUND: The EORTC QLQ-STO22 (QLQ-STO22) is a firmly established and validated measure of health-related quality of life (HRQoL) for people with gastric cancer (GC), developed over two decades ago. Since then there have been dramatic changes in treatment options for GC. Also, East Asian patients were not involved in the development of QLQ-STO22, where GC is most prevalent and the QLQ-STO22 is widely used. A review with appropriate updating of the measure was planned. This study aims to capture HRQoL issues associated with new treatments and the perspectives of patients and health care professionals (HCPs) from different cultural backgrounds, including East Asia. METHODS: A systematic literature review and open-ended interviews were preformed to identify potential new HRQoL issues relating to GC. This was followed by structured interviews where HCPs and patients reviewed the QLQ-STO22 alongside new issues regarding relevance, importance, and acceptability. RESULTS: The review of 267 publications and interviews with 104 patients and 18 HCPs (48 and 9 from East Asia, respectively) generated a list of 58 new issues. Three of these relating to eating small amounts, flatulence, and neuropathy were recommended for inclusion in an updated version of the QLQ-STO22 and covered by five additional questions. CONCLUSIONS: This study supports the content validity of the QLQ-STO22, suggesting its continued relevance to patients with GC, including those from East Asia. The updated version with additional questions and linguistic changes will enhance its specificity, but further testing is required.

An alternative surgical technique for removal of multiple uveal cysts in a dog: A case report.

Uveal cysts have been reported to cause vision changes in dogs. The objective of this article is to report removing multiple uveal cysts from both eyes of a canine patient using a previously unreported methodology. A bimanual irrigation and aspiration procedure is reported here as an alternative method for managing multiple anterior segment iris cysts in the dog. The results of the surgery were mild postoperative inflammation that resolved within 1 week and no other complications were encountered. Overall, the authors conclude that the procedure was a less invasive alternative to the traditional approaches for removal of multiple uveal cysts including laser rupture of cysts, direct aspiration or removal using coaxial irrigation and aspiration through a standard clear corneal approach to the anterior chamber with or without the aid of viscoelastic floatation. The procedure eliminated the need for sutures, marked activity restrictions, or an Elizabethan collar postoperatively. This is the first report of bimanual irrigation and aspiration for multiple uveal cyst removal in dogs.

SARS-CoV-2-infected human airway epithelial cell cultures uniquely lack interferon and immediate early gene responses caused by other coronaviruses.

Objectives: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of a class of highly pathogenic coronaviruses. The large family of coronaviruses, however, also includes members that cause only mild symptoms, like human coronavirus-229E (HCoV-229E) or OC43 (HCoV-OC43). Unravelling how molecular (and cellular) pathophysiology differs between highly and low pathogenic coronaviruses is important for the development of therapeutic strategies. Methods: Here, we analysed the transcriptome of primary human bronchial epithelial cells (PBEC), differentiated at the air-liquid interface (ALI) after infection with SARS-CoV-2, SARS-CoV, Middle East Respiratory Syndrome (MERS)-CoV and HCoV-229E using bulk RNA sequencing. Results: ALI-PBEC were efficiently infected by all viruses, and SARS-CoV, MERS-CoV and HCoV-229E infection resulted in a largely similar transcriptional response. The response to SARS-CoV-2 infection differed markedly as it uniquely lacked the increase in expression of immediate early genes, including FOS, FOSB and NR4A1 that was observed with all other coronaviruses. This finding was further confirmed in publicly available experimental and clinical datasets. Interfering with NR4A1 signalling in Calu-3 lung epithelial cells resulted in a 100-fold reduction in extracellular RNA copies of SARS-CoV-2 and MERS-CoV, suggesting an involvement in virus replication. Furthermore, a lack in induction of interferon-related gene expression characterised the main difference between the highly pathogenic coronaviruses and low pathogenic viruses HCoV-229E and HCoV-OC43. Conclusion: Our results demonstrate a previously unknown suppression of a host response gene set by SARS-CoV-2 and confirm a difference in interferon-related gene expression between highly pathogenic and low pathogenic coronaviruses.

Decreased risk of non-influenza respiratory infection after influenza B virus infection in children.

Previous studies suggest that influenza virus infection may provide temporary non-specific immunity and hence lower the risk of non-influenza respiratory virus infection. In a randomized controlled trial of influenza vaccination, 1 330 children were followed-up in 2009-2011. Respiratory swabs were collected when they reported acute respiratory illness and tested against influenza and other respiratory viruses. We used Poisson regression to compare the incidence of non-influenza respiratory virus infection before and after influenza virus infection. Based on 52 children with influenza B virus infection, the incidence rate ratio (IRR) of non-influenza respiratory virus infection after influenza virus infection was 0.47 (95% confidence interval: 0.27-0.82) compared with before infection. Simulation suggested that this IRR was 0.87 if the temporary protection did not exist. We identified a decreased risk of non-influenza respiratory virus infection after influenza B virus infection in children. Further investigation is needed to determine if this decreased risk could be attributed to temporary non-specific immunity acquired from influenza virus infection.

Variable-Angle Surface Spectroscopy Reveals the Water Structure in the Stern Layer at Charged Aqueous Interfaces.

At charged aqueous interfaces, the second-order nonlinear optical response originates from water molecules within the diffuse part of the electrical double layer, which are ordered by the surface field and from water that additionally experiences chemical and physical interactions with the surface in the Stern layer. These two environments can either reinforce or diminish the overall signal and can be disentangled by varying the coherence length of their interaction with external laser fields. Here, we demonstrate a method in which the angle of incidence is varied to afford a significant change in the coherence length. When this technique was applied to the silica-water interface, it was observed that water molecules in the Stern and diffuse layers direct their hydrogen atoms toward the mineral surface at a low ionic strength and neutral pH. A decrease in the signal with increasing ionic strength is attributed to hydrated cation adsorption that competes with free water for deprotonated silanol sites.

Heterochronic shift in gene expression leads to ontogenetic morphological divergence between two closely related polyploid species.

Heterochrony-alteration to the rate or timing of development-is an important mechanism of trait differentiation associated with speciation. Heterochrony may explain the morphological divergence between two polyploid species, June sucker (Chasmistes liorus) and Utah sucker (Catostomus ardens). The larvae of both species have terminal mouths; however, as adults, June sucker and Utah sucker develop subterminal and ventral mouths, respectively. We document a difference in the timing of shape development and a corresponding change in the timing of gene expression, suggesting the distinctive mouth morphology in June suckers may result from paedomorphosis. Specifically, adult June suckers exhibit an intermediate mouth morphology between the larval (terminal) and ancestral (ventral) states. Endemic and sympatric Chasmistes/Catostomus pairs in two other lakes also are morphologically divergent, but genetically similar. These species pairs could have resulted from the differential expression of genes and corresponding divergence in trait development. Paedomorphosis may lead to adaptive diversification in Catostomids.