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Adaptive immune responses are induced by vaccination and infection, yet little is known about how CD4+ T cell memory differs between these two contexts. Notable differences in humoral and cellular immune responses to primary mRNA vaccination were observed and associated with prior COVID-19 history, including in the establishment and recall of Spike-specific CD4+ T cells. It was unclear whether CD4+ T cell memory established by infection or mRNA vaccination as the first exposure to Spike was qualitatively similar. To assess whether the mechanism of initial memory T cell priming affected subsequent responses to Spike protein, 14 people who were receiving a third mRNA vaccination, referenced here as the booster, were stratified based on whether the first exposure to Spike protein was by viral infection or immunization (infection-primed or vaccine-primed). Using multimodal scRNA-seq of activation-induced marker (AIM)-reactive Spike-specific CD4+ T cells, we identified 220 differentially expressed genes between infection- and vaccine-primed patients at the post-booster time point. Infection-primed participants had greater expression of genes related to cytotoxicity and interferon signaling. Gene set enrichment analysis (GSEA) revealed enrichment for Interferon Alpha, Interferon Gamma, and Inflammatory response gene sets in Spike-specific CD4+ T cells from infection-primed individuals, whereas Spike-specific CD4+ T cells from vaccine-primed individuals had strong enrichment for proliferative pathways by GSEA. Finally, SARS-CoV-2 breakthrough infection in vaccine-primed participants resulted in subtle changes in the transcriptional landscape of Spike-specific memory CD4+ T cells relative to pre-breakthrough samples but did not recapitulate the transcriptional profile of infection-primed Spike-specific CD4+ T cells. Together, these data suggest that CD4+ T cell memory is durably imprinted by the inflammatory context of SARS-CoV-2 infection, which has implications for personalization of vaccination based on prior infection history.SARS-CoV-2 infection and mRNA vaccination prime transcriptionally distinct CD4+ T cell memory landscapes which are sustained with subsequent doses of vaccine.

SummaryAdaptive immune responses are induced by vaccination and infection, yet little is known about how CD4+ T cell memory differs when primed in these two contexts. Notably, viral infection is generally associated with higher levels of systemic inflammation than is vaccination. To assess whether the inflammatory milieu at the time of CD4+ T cell priming has long-term effects on memory, we compared Spike-specific memory CD4+ T cells in 22 individuals around the time of the participants’ third SARS-CoV-2 mRNA vaccination, with stratification by whether the participants’ first exposure to Spike was via virus or mRNA vaccine. Multimodal single-cell profiling of Spike-specific CD4+ T cells revealed 755 differentially expressed genes that distinguished infection- and vaccine-primed memory CD4+ T cells. Spike-specific CD4+ T cells from infection-primed individuals had strong enrichment for cytotoxicity and interferon signaling genes, whereas Spike-specific CD4+ T cells from vaccine-primed individuals were enriched for proliferative pathways by gene set enrichment analysis. Moreover, Spike-specific memory CD4+ T cells established by infection had distinct epigenetic landscapes driven by enrichment of IRF-family transcription factors, relative to T cells established by mRNA vaccination. This transcriptional imprint was minimally altered following subsequent mRNA vaccination or breakthrough infection, reflecting the strong bias induced by the inflammatory environment during initial memory differentiation. Together, these data suggest that the inflammatory context during CD4+ T cell priming is durably imprinted in the memory state at transcriptional and epigenetic levels, which has implications for personalization of vaccination based on prior infection history.One Sentence SummarySARS-CoV-2 infection versus SARS-CoV-2 mRNA vaccination prime durable transcriptionally and epigenetically distinct Spike-specific CD4+ T cell memory landscapes.

Funding Information: Publication costs for this article were supported by ecancer (UK Charity number 1176307). Publisher Copyright: © the authors; licensee ecancermedicalscience. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Background: Cervical cancer (CC) is the first cause of cancer-related deaths among Cape Verdean women. The absence of a national screening programme and a lack of dedicated cancer treatment facilities contribute to its high mortality rate. In an effort to improve the prognosis of these women, a health cooperation agreement was established between Portugal and Cape Verde (CV), allowing their evacuation to Portuguese hospitals. Our aim was to characterise CC among CV women, and to assess the response given to these patients in Instituto Português de Oncologia de Lisboa Francisco Gentil (IPOLFG), so that their treatment and follow-up protocols can be optimised and overall prognosis improved. Methods: Retrospective evaluation of women diagnosed with CC in CV that underwent therapy in IPOLFG between 2013 and 2020. Risk factors, demographic and tumour characteristics, treatment and outcomes were reviewed. Results: Fifty-eight patients were included. Squamous cell carcinoma was the most frequent (91.5%) histological type. HPV DNA was present in 25 out of 26 samples.The agreement rate between the pathology analysis performed in CV and in Portugal was high (87.9%); however, the agreement regarding the FIGO stage was low (15.5%). This may be explained by both the time interval between diagnosis and treatment (around 6 months) and by the absence of resources to accurately stage the disease in CV. In IPOLFG, 77.6% of patients received combined chemo-radiotherapy. Post-treatment follow-up varied widely, due to disease-related and bureaucratic issues. Eighteen patients developed cancer-related complications and/or cancer-related death. The survival rate and median overall survival (OS) in our cohort were of 89.7% and 73.2 months, respectively. Conclusions: Although most women had advanced-stage disease, the OS in our cohort was better than what has been reported for other African countries, probably because state-of-the-art treatment, frequently not accessible in those countries, was offered to all patients. publishersversion published

Small animal models have been a challenge for the study of SARS-CoV-2 transmission, with most investigators using golden hamsters or ferrets1, 2. Mice have the advantages of low cost, wide availability, less regulatory and husbandry challenges, and the existence of a versatile reagent and genetic toolbox. However, adult mice do not robustly transmit SARS-CoV-23. Here we establish a model based on neonatal mice that allows for transmission of clinical SARS-CoV-2 isolates. We characterize tropism, respiratory tract replication and transmission of ancestral WA-1 compared to variants Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.617.2), Omicron BA.1 and Omicron BQ.1.1. We identify inter-variant differences in timing and magnitude of infectious particle shedding from index mice, both of which shape transmission to contact mice. Furthermore, we characterize two recombinant SARS-CoV-2 lacking either the ORF6 or ORF8 host antagonists. The removal of ORF8 shifts viral replication towards the lower respiratory tract, resulting in significantly delayed and reduced transmission in our model. Our results demonstrate the potential of our neonatal mouse model to characterize viral and host determinants of SARS-CoV-2 transmission, while revealing for the first time a role for an accessory protein in this context.

Breast cancer is the most common tumor in women and represents the leading cause of cancer death. Radiation therapy plays a key-role in the treatment of all breast cancer stages. Therefore, the adoption of evidence-based treatments is warranted, to ensure equity of access and standardization of care in clinical practice.This national document on the highest evidence-based available data was developed and endorsed by the Italian Association of Radiation and Clinical Oncology (AIRO) Breast Cancer Group.We analyzed literature data regarding breast radiation therapy, using the SIGN (Scottish Intercollegiate Guidelines Network) methodology (www.sign.ac.uk). Updated findings from the literature were examined, including the highest levels of evidence (meta-analyses, randomized trials, and international guidelines) with a significant impact on clinical practice. The document deals with the role of radiation therapy in the treatment of primary breast cancer, local relapse, and metastatic disease, with focus on diagnosis, staging, local and systemic therapies, and follow up. Information is given on indications, techniques, total doses, and fractionations.An extensive literature review from 2013 to 2021 was performed. The work was organized according to a general index of different topics and most chapters included individual questions and, when possible, synoptic and summary tables. Indications for radiation therapy in breast cancer were examined and integrated with other oncological treatments. A total of 50 questions were analyzed and answered.Four large areas of interest were investigated: (1) general strategy (multidisciplinary approach, contraindications, preliminary assessments, staging and management of patients with electronic devices); (2) systemic therapy (primary, adjuvant, in metastatic setting); (3) clinical aspects (invasive, non-invasive and micro-invasive carcinoma; particular situations such as young and elderly patients, breast cancer in males and cancer during pregnancy; follow up with possible acute and late toxicities; loco-regional relapse and metastatic disease); (4) technical aspects (radiation after conservative surgery or mastectomy, indications for boost, lymph node radiotherapy and partial breast irradiation).Appendixes about tumor bed boost and breast and lymph nodes contouring were implemented, including a dedicated web application. The scientific work was reviewed and validated by an expert group of breast cancer key-opinion leaders.Optimal breast cancer management requires a multidisciplinary approach sharing therapeutic strategies with the other involved specialists and the patient, within a coordinated and dedicated clinical path. In recent years, the high-level quality radiation therapy has shown a significant impact on local control and survival of breast cancer patients. Therefore, it is necessary to offer and guarantee accurate treatments according to the best standards of evidence-based medicine.

International audience; Bounded depth refers to a property of Kripke frames that serve as semantics for intuitionistic logic. We introduce nested sequent calculi for the intermediate logics of bounded depth. Our calculi are obtained in a modular way by adding suitable structural rules to a variant of Fitting's calculus for intuitionistic propositional logic, for which we present the first syntactic cut elimination proof. This proof modularly extends to the new nested sequent calculi introduced in this paper.

We establish a novel connection between two research areas in non-classical logics which have been developed independently of each other so far: on the one hand, input/output logic, introduced within a research program developing logical formalizations of normative reasoning in philosophical logic and AI; on the other hand, subordination algebras, investigated in the context of a research program integrating topological, algebraic, and duality-theoretic techniques in the study of the semantics of modal logic. Specifically, we propose that the basic framework of input/output logic, as well as its extensions, can be given formal semantics on (slight generalizations of) subordination algebras. The existence of this interpretation brings benefits to both research areas: on the one hand, this connection allows for a novel conceptual understanding of subordination algebras as mathematical models of the properties and behaviour of norms; on the other hand, thanks to the well developed connection between subordination algebras and modal logic, the output operators in input/output logic can be given a new formal representation as modal operators, whose properties can be explicitly axiomatised in a suitable language, and be systematically studied by means of mathematically established and powerful tools.

An otherwise healthy 72-year-old Chinese patient diagnosed with exudative age-related macular degeneration and decreased vision in left eye was fully investigated. The retrospective analysis of past multimodal imaging revealed bilateral severe choroidal neovascularization and choroiditis associated with a positive tuberculin skin testing and interferon-gamma release assay (QuantiFERON-TB Gold – Cellestis®, Chadstone, VIC, Australia) suggestive of latent ocular tuberculosis. The variable presentation and tests’ results interpretation represent the greatest limitations in understanding and treating intraocular TB (IOTB). This may present without any other systemic symptoms, the intraocular tissues are of limited access to biopsies and other tests, including imaging and immunological tests, are of relative value. This case highlights how variable may be the presentation of IOTB, which can be easily misdiagnosed leading to a delayed treatment and worse prognosis.

The present white paper, referring to the 4th Assisi Think Tank Meeting on breast cancer, reviews state-of-the-art data, on-going studies and research proposals.

Background The ARDS is characterized by different degrees of impairment in oxygenation and distribution of the lung disease. Two radiological patterns have been described: a focal and a diffuse one. These two patterns could present significant differences both in gas exchange and in the response to a recruitment maneuver. At the present time, it is not known if the focal and the diffuse pattern could be characterized by a difference in the lung and chest wall mechanical characteristics. Our aims were to investigate, at two levels of PEEP, if focal vs. diffuse ARDS patterns could be characterized by different lung CT characteristics, partitioned respiratory mechanics and lung recruitability. Methods CT patterns were analyzed by two radiologists and were classified as focal or diffuse. The changes from 5 to 15 cmH2O in blood gas analysis and partitioned respiratory mechanics were analyzed. Lung CT scan was performed at 5 and 45 cmH2O of PEEP to evaluate lung recruitability. Results One-hundred and ten patients showed a diffuse pattern, while 58 showed a focal pattern. At 5 cmH2O of PEEP, the driving pressure and the elastance, both the respiratory system and of the lung, were significantly higher in the diffuse pattern compared to the focal (14 [11–16] vs 11 [9–15 cmH2O; 28 [23–34] vs 21 [17–27] cmH2O/L; 22 [17–28] vs 14 [12–19] cmH2O/L). By increasing PEEP, the driving pressure and the respiratory system elastance significantly decreased in diffuse pattern, while they increased or did not change in the focal pattern (Δ15-5: − 1 [− 2 to 1] vs 0 [− 1 to 2]; − 1 [− 4 to 2] vs 1 [− 2 to 5]). At 5 cmH2O of PEEP, the diffuse pattern had a lower lung gas (743 [537–984] vs 1222 [918–1974] mL) and higher lung weight (1618 [1388–2001] vs 1222 [1059–1394] g) compared to focal pattern. The lung recruitability was significantly higher in diffuse compared to focal pattern 21% [13–29] vs 11% [6–16]. Considering the median of lung recruitability of the whole population (16.1%), the recruiters were 65% and 22% in the diffuse and focal pattern, respectively. Conclusions An early identification of lung morphology can be useful to choose the ventilatory setting. A diffuse pattern has a better response to the increase of PEEP and to the recruitment maneuver.

Introduction: Sentinel lymph node biopsy (SLNB) is the gold standard in invasive breast cancer. Axillary dissection (ALND) is controversial in some presentations.Areas covered: Key questions were f...