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Although critical for host defense, innate immune cells are also pathologic drivers of acute respiratory distress syndrome (ARDS). Innate immune dynamics during Coronavirus Disease 2019 (COVID-19) ARDS, compared to ARDS from other respiratory pathogens, is unclear. Moreover, mechanisms underlying the beneficial effects of dexamethasone during severe COVID-19 remain elusive. Using single-cell RNA sequencing and plasma proteomics, we discovered that, compared to bacterial ARDS, COVID-19 was associated with expansion of distinct neutrophil states characterized by interferon (IFN) and prostaglandin signaling. Dexamethasone during severe COVID-19 affected circulating neutrophils, altered IFN active neutrophils, downregulated interferon-stimulated genes and activated IL-1R2 + neutrophils. Dexamethasone also expanded immunosuppressive immature neutrophils and remodeled cellular interactions by changing neutrophils from information receivers into information providers. Male patients had higher proportions of IFN active neutrophils and preferential steroid-induced immature neutrophil expansion, potentially affecting outcomes. Our single-cell atlas (see ‘Data availability’ section) defines COVID-19-enriched neutrophil states and molecular mechanisms of dexamethasone action to develop targeted immunotherapies for severe COVID-19. New results shed light on the molecular mechanisms of dexamethasone action, underlying its therapeutic benefit in patients with severe COVID-19.

Several studies have demonstrated a potential interaction between mesenchymal stem cells (MSCs) and saccular aneurysms. In this study, we sought to determine whether allogenic bone marrow-derived MSCs had the ability to prevent aneurysm formation in a known rabbit elastase aneurysm model. MSCs were injected intravenously in experimental rabbits at the time of surgical creation and two weeks postcreation and compared with control rabbits receiving vehicle injection. Angiography was used to compare aneurysm measurements four weeks postcreation, and aneurysms were harvested for histological properties. Serum was collected longitudinally to evaluate cytokine alterations. Serum from control animals was also utilized to perform in vitro tests with MSCs to compare the effect of the serologic environment in animals with and without aneurysms on MSC proliferation and cytokine production. While aneurysm morphometric comparisons revealed no differences, significant cytokine alterations were observed in vitro and in vivo, suggesting both anti-inflammatory and proinflammatory processes were occurring in the presence of MSCs. Histological analyses suggested that tunica intima hyperplasia was inhibited in the presence of MSCs.

The current clinical guidelines for the management of aortic abdominal aneurysms (AAAs) overlook the structural and mechanical heterogeneity of the aortic tissue and its role in the regional weakening that drives disease progression. This study is a comprehensive investigation of the structural and biomechanical heterogeneity of AAA tissue along the length and circumference of the aorta, by means of regional ex vivo and in vivo properties. Biaxial testing and histological analysis were performed on ex vivo human aortic specimens systematically collected during open repair surgery. Wall-shear stress and three-dimensional principal strain analysis were performed to allow for in vivo regional characterization of individual aortas. A marked effect of position along the aortic length was observed in both ex vivo and in vivo properties, with the central regions corresponding to the aneurysmal sac being significantly different from the adjacent regions. The heterogeneity along the circumference of the aorta was reflected in the ex vivo biaxial response at low strains and histological properties. Present findings uniquely show the importance of regional characterization for aortic assessment and the need to correlate heterogeneity at the tissue level with non-invasive measurements aimed at improving clinical outcomes.

A 69-year-old female with antisynthetase syndrome, a history of multiple recurrent infections, and documented previous negative titres for anti-neutrophil cystoplasmic antibody (ANCA) suddenly developed a de novo MPO-ANCA-associated glomerulonephritis three weeks after a fecal microbiota transplantation (FMT) for recurrent Clostridium difficile infections. Six months following her FMT and less than two weeks following treatment for urosepsis, she developed severe cholestasis, a markedly elevated ferritin and hypertriglyceridemia. An initial liver biopsy was suggestive of drug-induced liver injury and thus she was treated with supportive care. After she failed to improve, a second liver biopsy supported the diagnosis of hemophagocytic lymphohistiocytosis (HLH). This case highlights difficulties surrounding the early diagnosis of HLH and also questions the role of FMT and/or recurrent infections as a trigger for ANCA-associated vasculitis.

The indeterminacy of the object (its description always qualified by \"perhaps\") and the changes of scale create a dizzying effect and, moreover, a double image: we are told from the certainty of the mother's perspective that it is in fact a sheep's jaw, and the reader's memoryimage of the object might therefore enact a surreal \"marriage\" of the two.10 In this misrecognition and doubling of the animal skull, there is a connection with To the Lighthouse, where Cam and James have conflicting feelings about the boar's skull nailed to the wall of their bedroom: [...]I would like to speculate on an encounter in Woolf's work with the material visibility of words, at the moment where the optical and the auditory collide in the indeterminate synesthetic space between dream and reality, interior and exterior. While Surrealism manifests a visual hallucinatory imagination, the poet is never posited as a visionary: the freeing of the imagination is dialectical with the presence of the material world. [...]the image and any meaning it might hold is an after-effect of an auditory hallucination, of the condensation and displacement of a non-verbal phenomenon into human language. Enunciating a literary work, the materiality of language (as text itself) merges the auditory and the visual and can be read in terms of the Surrealist situation of the object: it contains latent possibilities, an ephemeral multiplicity of meanings and usages in its tangible manifest surface, and our encounter with its potential surreality (as reader or writer) is a matter of alternative perspectives and visions. 1 See Humm. 2 As well as scientific and technological innovations which offered new perspectives in relation to time and space, Freudian psychoanalysis posited a latent content in manifest appearances: a layered reality in which surface appearances might signify a distorted unconscious desire. 3 I am indebted to Vassiliki Kolocotroni for the suggestion of this term and for much support and inspiration besides. 4 The Surrealist movement referred to here is principally focused on the Parisian group around André Breton.

This thesis foregrounds Virginia Woolf’s 1921 volume of short fiction, Monday or Tuesday, examining its aesthetic qualities and formal strategies through the lens of the literary sketch. ‘Sketch’ is a term that has been invoked in criticism of Monday or Tuesday since its publication, but the provenance of the sketch as a literary genre and its centrality to Woolf’s aesthetic practices have not yet been fully examined in Woolf studies. The idea of the sketch is most often raised in analysis of her unfinished memoir, ‘A Sketch of the Past’, and as a descriptor for the general plotlessness of her short fiction; yet, the historical specificity and formal strategies of the sketch as an established literary genre have largely been elided in such discussions. Attending to the frequency and precision of Woolf’s own use of the term ‘sketch’, and particularly to her declared intention to ‘keep the quality of the sketch in the finished and composed work’ (D II 312), this thesis elucidates the sketch as a key mode of writing for Woolf. It argues that she achieved her desired combination of the sketch and the finished work most fully in the first Hogarth edition of Monday or Tuesday. A set of texts more usually encountered in anthologies or integrated with Woolf’s other short fiction, Monday or Tuesday has itself occupied a relatively marginal place in the critical construction of Woolf’s oeuvre. Although there has been a recent surge of work on the short fiction, Monday or Tuesday has yet to be foregrounded as the sole object of a monograph, or to appear as a scholarly edition. This thesis reads Monday or Tuesday in its entirety, in the specificity of its original publication by Woolf’s Hogarth Press, and considers what is at stake in reading this work as a collection of literary sketches. The analysis performed is grounded in the material qualities of the first UK edition, where the woodcuts by Vanessa Bell and the uncorrected mistakes made in the hand-printing of the book contribute to the effects of the sketch as it appears in print. In these aspects, the thesis builds on the substantial body of scholarship on the Hogarth Press and Bloomsbury aesthetics to discuss Monday or Tuesday as a printed sketchbook. It shows how the sketch manifests in Monday or Tuesday’s material appearance, where it combines the ‘evanescent’ and ‘engraved’ qualities later formulated alongside ‘the life of Monday or Tuesday’ in Woolf’s manifesto for ‘Modern Fiction’ (1925). Utilising Woolf’s own terminology throughout, the thesis explores the simultaneous ephemerality and permanence of the sketch, as something which can project into a future moment of writing, and whose significance can be realised belatedly; as something which works explicitly with the surface impression but which also layers moments of making. The thesis begins by drawing on recent scholarship to outline a history of the sketch as a literary genre which was popular throughout the eighteenth and nineteenth centuries in Europe and America, and identifies examples of this tradition with which Woolf was familiar. Woolf’s deployment of the term ‘sketch’ is discussed in detail, from her early journals and juvenilia to her memoir, and the thesis proceeds to study the ways in which the sketch is at work in Monday or Tuesday. It examines the book’s contents under some conventional categories of the sketch: the scene, the character, and the political sketch. The central chapter of the thesis discusses the poetics and narrative strategies of scene-making and character-sketching, and Chapter Four highlights the feminist political inflections of Woolf’s use of the sketch. These readings show how the literary sketch is not defined simply by its fragmentary, ekphrastic or unfinished qualities, but also utilises narrative strategies of suggestion, deferral and interruption. The thesis reaches for finish in the final chapter by examining the material qualities of the book, including an examination of key variants between the first British and first American editions. While it makes serious strategic claims for the sketch as one possible genre through which to approach Monday or Tuesday, the thesis does not claim to definitively categorise these texts as sketches once and for all. Rather, in the attempt to treat these texts in broad-stroke but incisive detail, it acknowledges the procedures of the sketch itself – its representative provisionality, its potential to function as a detailed study, and its creation of a basis for re-working. It takes the idea of the sketch as a critical apparatus by which to perform the experimental reading that Monday or Tuesday’s own narrative strategies invite. The thesis ultimately seeks to foreground the work of both Monday or Tuesday and the literary sketch in Woolf’s modernist aesthetics, and to prepare the ground for future study of their significance for modernism more generally.

SARS-CoV-2 is a novel coronavirus that causes acute respiratory distress syndrome (ARDS), death and long-term sequelae. Innate immune cells are critical for host defense but are also the primary drivers of ARDS. The relationships between innate cellular responses in ARDS resulting from COVID-19 compared to other causes of ARDS, such as bacterial sepsis is unclear. Moreover, the beneficial effects of dexamethasone therapy during severe COVID-19 remain speculative, but understanding the mechanistic effects could improve evidence-based therapeutic interventions. To interrogate these relationships, we developed an scRNA-Seq and plasma proteomics atlas (biernaskielab.ca/COVID_neutrophil). We discovered that compared to bacterial ARDS, COVID-19 was associated with distinct neutrophil polarization characterized by either interferon (IFN) or prostaglandin (PG) active states. Neutrophils from bacterial ARDS had higher expression of antibacterial molecules such as PLAC8 and CD83. Dexamethasone therapy in COVID patients rapidly altered the IFNactive state, downregulated interferon responsive genes, and activated IL1R2+ve neutrophils. Dexamethasone also induced the emergence of immature neutrophils expressing immunosuppressive molecules ARG1 and ANXA1, which were not present in healthy controls. Moreover, dexamethasone remodeled global cellular interactions by changing neutrophils from information receivers into information providers. Importantly, male patients had higher proportions of IFNactive neutrophils, a greater degree of steroid-induced immature neutrophil expansion, and increased mortality benefit compared to females in the dexamethasone era. Indeed, the highest proportion of IFNactive neutrophils was associated with mortality. These results define neutrophil states unique to COVID-19 when contextualized to other life-threatening infections, thereby enhancing the relevance of our findings at the bedside. Furthermore, the molecular benefits of dexamethasone therapy are also defined, and the identified pathways and plasma proteins can now be targeted to develop improved therapeutics. Competing Interest Statement The authors have declared no competing interest. Footnotes * 1. Validation, using immunofluorescence staining for immature and polarization state proteins, to confirm neutrophil states previously identified in silico. 2. New evidence that the novel neutrophil polarization signatures revealed in our COVID-19 group accurately predict outcomes when applied to a validation cohort of 103 bulk RNA-Seq samples (where 17 cases were fatal). Here we demonstrate that our neutrophil polarization states are a superior predictor of 28-day mortality compared to clinical severity scales such as sequential organ failure assessment (SOFA) across all classification thresholds. Moreover, these signatures are specifically suppressed in the dexamethasone group supporting our evidence of the beneficial mechanisms underpinning this therapy. 3. Evidence at the level of the lung tissue, supporting our studies using blood, of an expansion of IFNactive neutrophils in severe COVID-19 relative to mild/moderate disease (1.5 FC) and in COVID-19 patients relative to those with bacterial pneumonia (4.7 FC). Here, we used inferred neutrophil composition in bronchoalveolar microenvironments by projecting two high-quality BALF sc-RNA-Seq datasets onto our peripheral blood reference. 4. Serum proteomics screen for SARS-CoV-2 viral proteins from COVID-19 patients captured in our study. A proteomic screen for SARS-CoV-2 specific viral proteins in COVID-19 patient serum revealed robust detection of one or more viral proteins in COVID-19. 5. Serum shotgun proteomics using mass spectrometry verified several interferon response elements identified in our scRNAseq analyses. It also revealed dexamethasone-induced alterations in neutrophil antimicrobial proteins and serine proteases, further strengthening our claim that neutrophil-related inflammatory processes are a critical driver of dexamethasone action. In addition, we identify dexamethasone-induced suppression of 10 host plasma proteins that have previously been identified as biomarkers of COVID-19 severity and mortality. Full host proteome (comprising 633 proteins detected) is made queryable through our Online Atlas. 6. New evidence of mortality differences between males and females with life threatening COVID-19 at an epidemiological level. Using a retrospective province-wide (Alberta, Canada) ICU data repository, we compared the mortalities of pre-dexamethasone ICU patients (51 M, 21 F) versus post-dexamethasone (1013 M, 568 F) treated ICU patients. This revealed a statistically significant survival benefit in male COVID-19 patients treated with dexamethasone. We stratified all COVID-19 ICU patients by sex and separated them by the dates when dexamethasone became standard of care and further observed that males had reduced mortalities since dexamethasone became standard of care, but females did not derive any benefit in terms of mortality. * http://www.biernaskielab.ca/COVID_neutrophil

To determine the performance of TOTAL30 for Astigmatism (T30fA; Alcon; Fort Worth, TX, USA) contact lenses (CLs) in existing CL wearers who are also frequent digital device users. This 1-month, 3-visit study recruited adult, 18- to 40-year-old subjects who were required to use daily digital devices for at least 8 hours per day. All subjects were refit into T30fA CLs. A text message visual analog scale (VAS) (±50 scale; positive being comfortable) evaluate at-home eye comfort across the day at 1 day, 1 week, and 1 month. Subjects were evaluated at 1 month with the Computer Vision Syndrome Questionnaire (CVS-Q), Impact of Dry Eye on Everyday Life (IDEEL) Quality of Life questionnaire, and a custom questionnaire. A total 48 subjects were analyzed (mean age = 28.8 ± 6.3 years; 75% female). At 1 month, IDEEL daily activities, feelings, and work domains scores were 96.7 ± 6.6, 96.4 ± 6.2, and 94.8 ± 8.6, respectively. CVS-Q scores were 3.48 ± 3.73. Most of the subjects indicated that they were satisfied with the overall performance of the study CLs (81.3%) and with their level of eye strain with the study CLs (87.3%). When evaluating CL comfort with the VAS, comfort did not differ across the month at each time point (all p-value ≥ 0.16), yet CL comfort did decrease minimally across the wear day (all p-value < 0.001). These data suggest that the monthly study CLs can provide an excellent wearing experience for those with frequent digital device use.

Background There are many well-described potential gastrointestinal (GI) side effects of pancreatic resection that can cause patients to suffer from chronic malabsorption, diarrhea, and persistent nausea. These GI symptoms can affect postoperative recovery, initiation of adjuvant therapy, and overall quality of life (QOL). The purpose of this study is to quantify the incidence of post-procedural complications and identify patients at higher risk for experiencing GI dysfunction after pancreatectomy. Methods A retrospective review of patients who underwent pancreatic resection at a single institution between January 2014 and December 2019 was performed. Demographics, operative factors, and postoperative gastrointestinal symptomatology and treatments were obtained by chart review. Significance tests were performed to compare GI dysfunction between patient subgroups. Results A total of 545 patients underwent pancreatic resection; within the cohort 451 patients (83%) underwent a pancreaticoduodenectomy (PD) and the most common indication was pancreatic adenocarcinoma. Two-thirds of patients (67%) reported gastrointestinal symptoms persisting beyond hospitalization. Only 105 patients (20%) were referred to gastroenterology for evaluation with 30 patients (5.5%) receiving a formal diagnosis. Patients who underwent PD were more likely to report GI symptoms and patients who identified as Caucasian were more likely to be referred to gastroenterology for evaluation. Conclusions Gastrointestinal dysfunction after pancreatic resection occurs frequently yet only a small percentage of patients are referred for formal testing and diagnosis. There also appears to be a racial difference in referral patterns. Patients would benefit if earlier attention was dedicated to the diagnosis and corresponding treatment for postoperative digestive health disorders to optimize treatment planning and QOL.