A tetravalent bispecific antibody outperforms the combination of its parental antibodies and neutralizes diverse SARS-CoV-2 variants.

The devastating impact of COVID-19 on global health shows the need to increase our pandemic preparedness. Recombinant therapeutic antibodies were successfully used to treat and protect at-risk patients from COVID-19. However, the currently circulating Omicron subvariants of SARS-CoV-2 are largely resistant to therapeutic antibodies, and novel approaches to generate broadly neutralizing antibodies are urgently needed. Here, we describe a tetravalent bispecific antibody, A7A9 TVB, which actively neutralized many SARS-CoV-2 variants of concern, including early Omicron subvariants. Interestingly, A7A9 TVB neutralized more variants at lower concentration as compared to the combination of its parental monoclonal antibodies, A7K and A9L. A7A9 also reduced the viral load of authentic Omicron BA.1 virus in infected pseudostratified primary human nasal epithelial cells. Overall, A7A9 displayed the characteristics of a potent broadly neutralizing antibody, which may be suitable for prophylactic and therapeutic applications in the clinics, thus highlighting the usefulness of an effective antibody-designing approach.

Use of mesna prophylaxis in patients with cyclophosphamide-treated ANCA-associated vasculitis: cross-sectional survey of practitioners.

BACKGROUND: There may be some diversity in the practice of co-prescribing 2-mercaptoethane sodium sulfonate (mesna) with cyclophosphamide (CYC) for ANCA-associated vasculitis (AAV). OBJECTIVES: To assess the practice of prescribing mesna prophylaxis for CYC-treated patients with AAV. METHODS: We invited authors of publications on AAV referenced in MEDLINE over the previous 10 years to participate in an anonymous online survey. Respondents were eligible if they were involved in CYC treatments for AAV. The survey asked about the characteristics of the respondents and their practice in using CYC and mesna to treat AAV and the underlying rationale. We compared 18 variables between mesna prescribers and their counterparts to identify factors associated with mesna use. RESULTS: In total, 139 eligible individuals completed the survey. The participants were from 34 countries and were essentially physicians (98%). Overall, 68%, 19% and 13% of respondents prescribed mesna systematically, never, or on a selective basis. As compared with never/selective-prescribers, systematic-prescribers were more often ≤ 39 years old (P = 0.008), more often used intermittent pulse therapy as the exclusive/predominant CYC administration scheme (P < 0.001), were more frequently based in France/Germany/Italy than in England/United States (P < 0.001), and more often indicated adherence to local standards (P = 0.003) or (inter)national guidelines for AAV (P < 0.001) as a rationale for their mesna practice. Never/selective-prescribers more commonly reported that their mesna prescription pattern had changed as compared with their former practice (P < 0.001). CONCLUSIONS: Systematic co-prescription of mesna is the prevailing practice for CYC treatments for AAV. The practice seems to involve practicability considerations and differs between generations.

Three-dimensional electron diffraction on clinkers: the belite α'H incommensurate modulated structure.

Traditional X-ray methods are extensively applied to commercial cement samples in order to determine their physical and chemical properties. Powder patterns are routinely used to quantify the composition of these phase mixtures, but structure determination becomes difficult because of reflection overlapping caused by the high number of different crystal structures. The fast-growing 3D electron diffraction technique and its related automated acquisition protocols arise as a potentially very interesting tool for the cement industry, since they enable the fast and systematic acquisition of diffraction data from individual particles. In this context, electron diffraction has been used in the investigation of the different crystalline phases present in various commercial clinkers for cement. Automated data collection procedures and subsequent data processing have enabled the structural characterization of the different crystal structures from which the α'H polymorph of Ca2SiO4 (belite) exhibited satellite reflections. Its average crystal structure has been known since 1971 and satellite reflections have been reported previously, yet the modulation was never fully described by means of the superspace formalism. Here, the incommensurately modulated structure is solved and refined using harmonic and crenel functions in the superspace group Pnma(α00)0ss, showing the potential of 3D electron diffraction for systematic crystallographic characterizations of cement. A full description of the different belite polymorphs is provided considering this modulated structure.

Enforcement of Fairness Norms by Punishment: A Comparison of Gains and Losses.

Although in everyday life decisions about losses are prevalent (e.g., the climate crisis and the COVID-19 crisis), there is hardly any research on decisions in the loss domain. Therefore, we conducted online experiments with a sample of 672 participants (mostly students), using third-party punishment dictator games (DGs) in the loss domain to explore the impact of losses and punishment threats on the conformity to the fairness norm. Subjects in the treatment condition have to divide a loss of -10 € with the threat of a third-party punishment with different strengths (control: gains, no punishment). Overall, the statistical evidence seems rather weak, but when it comes to losses, subjects are more rational and straightforward with their words and deeds than with gains. Therefore, in the loss domain, subjects are more likely to believe that the fairness norm should be followed, and they subjectively perceive that the others do as well. Furthermore, although dictators' decisions are more selfish in the loss domain, dictators there react more strongly to the punishment threat by reducing their demands than in the gains domain. This holds as long as the punishment threat is strong enough, as judged from a rational perspective.

Pulmonary Vein Isolation Followed by Biatrial Ablation of Rotational Activity in Patients with Persistent Atrial Fibrillation: Results of the Cryo-Vest Study.

Background and Aims: Noninvasive mapping allows the identification of patient-specific atrial rotational activity (RA) that might play a key role in the perpetuation of persistent atrial fibrillation (PsAF). So far, the impact of pulmonary vein isolation by cryoballoon (Cryo-PVI) on RA is unclear. Moreover, the long-term effect of periprocedural termination of AF during the ablation procedure is controversial. Methods: Noninvasive electrocardiographic mapping with a 252-electrode vest was performed in 42 patients with PsAF. After the first analysis, Cryo-PVI was performed. The RA was analyzed again and then targeted by radiofrequency catheter ablation. The primary clinical endpoint was periprocedural termination of AF. The secondary endpoint was freedom from any atrial arrhythmia >30 s during a 12-month follow-up. Results: In 33 patients (79%), right atrial RA was identified leading to biatrial ablation, and nine patients (21%) had left atrial RA only. Twelve patients (28.6%) converted from AF to sinus rhythm (SR) (Group A). Thirteen patients (30.9%) converted to atrial tachycardia (AT) (Group B). In 17 patients (40.5%), AF was not terminated by ablation (Group C). After a mean follow-up time of 13.8 months, 26 patients were free from AF and AT (61.9%). In terms of rhythm, control Group A (75%) and B (83.3%) showed higher success rates than Group C (33.3%) (p < 0.01). Cryo-PVI had no substantial impact on RA. Conclusions: The RA-based ablation approach showed acceptable success rates. Periprocedural termination of AF had a positive predictive impact on the outcome. No difference was observed between conversion to SR or to AT. Cryo-PVI had no impact on RA.

Risk loci involved in giant cell arteritis susceptibility: a genome-wide association study.

BACKGROUND: Giant cell arteritis is an age-related vasculitis that mainly affects the aorta and its branches in individuals aged 50 years and older. Current options for diagnosis and treatment are scarce, highlighting the need to better understand its underlying pathogenesis. Genome-wide association studies (GWAS) have emerged as a powerful tool for unravelling the pathogenic mechanisms involved in complex diseases. We aimed to characterise the genetic basis of giant cell arteritis by performing the largest GWAS of this vasculitis to date and to assess the functional consequences and clinical implications of identified risk loci. METHODS: We collected and meta-analysed genomic data from patients with giant cell arteritis and healthy controls of European ancestry from ten cohorts across Europe and North America. Eligible patients required confirmation of giant cell arteritis diagnosis by positive temporal artery biopsy, positive temporal artery doppler ultrasonography, or imaging techniques confirming large-vessel vasculitis. We assessed the functional consequences of loci associated with giant cell arteritis using cell enrichment analysis, fine-mapping, and causal gene prioritisation. We also performed a drug repurposing analysis and developed a polygenic risk score to explore the clinical implications of our findings. FINDINGS: We included a total of 3498 patients with giant cell arteritis and 15 550 controls. We identified three novel loci associated with risk of giant cell arteritis. Two loci, MFGE8 (rs8029053; p=4·96 × 10-8; OR 1·19 [95% CI 1·12-1·26]) and VTN (rs704; p=2·75 × 10-9; OR 0·84 [0·79-0·89]), were related to angiogenesis pathways and the third locus, CCDC25 (rs11782624; p=1·28 × 10-8; OR 1·18 [1·12-1·25]), was related to neutrophil extracellular traps (NETs). We also found an association between this vasculitis and HLA region and PLG. Variants associated with giant cell arteritis seemed to fulfil a specific regulatory role in crucial immune cell types. Furthermore, we identified several drugs that could represent promising candidates for treatment of this disease. The polygenic risk score model was able to identify individuals at increased risk of developing giant cell arteritis (90th percentile OR 2·87 [95% CI 2·15-3·82]; p=1·73 × 10-13). INTERPRETATION: We have found several additional loci associated with giant cell arteritis, highlighting the crucial role of angiogenesis in disease susceptibility. Our study represents a step forward in the translation of genomic findings to clinical practice in giant cell arteritis, proposing new treatments and a method to measure genetic predisposition to this vasculitis. FUNDING: Institute of Health Carlos III, Spanish Ministry of Science and Innovation, UK Medical Research Council, and National Institute for Health and Care Research.