Anxious Records: Race, Imperial Belonging, and the Black Literary Imagination, 1900 - 1946

This dissertation excavates the print and archive culture of diasporic and continental Africans who forged a community in Cape Town between 1900 and 1946. Although the writers I consider write after the Victorian era, I use the term "black Victorian" to preserve their own political investments in a late nineteenth-century understanding of liberal empire. With the abolition of slavery in 1834 across the British Empire and the Cape Colony's qualified nonracial franchise of 1853, Cape Town, and District Six in particular, took on new significance in black radicalism. By writing periodicals, pamphlets and autobiographies, black Victorians hoped to write themselves into the culture of empire. These recovered texts read uncannily, unsettling the construction of official archives as well as contemporary canons of South African, African and diasporic African literatures. By turning to the traffic of ideas between Africa and its diaspora in Cape Town, this dissertation recovers a vision of (black) modernity that had not yet succumbed to the formulations of anti-imperial nationalisms

Anxious Records: Race, Imperial Belonging, and the Black Literary Imagination, 1900 - 1946

This dissertation excavates the print and archive culture of diasporic and continental Africans who forged a community in Cape Town between 1900 and 1946. Although the writers I consider write after the Victorian era, I use the term "black Victorian" to preserve their own political investments in a late nineteenth-century understanding of liberal empire. With the abolition of slavery in 1834 across the British Empire and the Cape Colony's qualified nonracial franchise of 1853, Cape Town, and District Six in particular, took on new significance in black radicalism. By writing periodicals, pamphlets and autobiographies, black Victorians hoped to write themselves into the culture of empire. These recovered texts read uncannily, unsettling the construction of official archives as well as contemporary canons of South African, African and diasporic African literatures. By turning to the traffic of ideas between Africa and its diaspora in Cape Town, this dissertation recovers a vision of (black) modernity that had not yet succumbed to the formulations of anti-imperial nationalisms

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Acute obstetric coagulopathy during postpartum hemorrhage is caused by hyperfibrinolysis and dysfibrinogenemia: an observational cohort study

Background Postpartum hemorrhage (PPH) may be exacerbated by hemostatic impairment. Information about PPH-associated coagulopathy is limited, often resulting in treatment strategies based on data derived from trauma studies. Objectives To investigate hemostatic changes associated with PPH. Patients/Methods From a population of 11 279 maternities, 518 (4.6%) women were recruited with PPH ≥ 1000 mL or placental abruption, amniotic fluid embolism, or concealed bleeding. Routine coagulation and viscoelastometric results were collated. Stored plasma samples were used to investigate women with bleeds > 2000 mL or those at increased risk of coagulopathy defined as placenta abruption, amniotic fluid embolism, or need for blood components. Procoagulant factors were assayed and global hemostasis was assessed using thrombin generation. Fibrinolysis was investigated with D-dimer and plasmin/antiplasmin complexes. Dysfibrinogenemia was assessed using the Clauss/antigen ratio. Results At 1000 mL blood loss, Clauss fibrinogen was ≤2 g/L in 2.4% of women and 6/27 (22.2%) cases of abruption. Women with very large bleeds (>3000 mL) had evidence of a dilutional coagulopathy, although hemostatic impairment was uncommon. A subgroup of 12 women (1.06/1000 maternities) had a distinct coagulopathy characterized by massive fibrinolysis (plasmin/antiplasmin > 40 000 ng/mL), increased D-dimer, hypofibrinogenemia, dysfibrinogenemia, reduced factor V and factor VIII, and increased activated protein C, termed acute obstetric coagulopathy. It was associated with fetal or neonatal death in 50% of cases and increased maternal morbidity. Conclusions Clinically significant hemostatic impairment is uncommon during PPH, but a subgroup of women have a distinct and severe coagulopathy characterized by hyperfibrinolysis, low fibrinogen, and dysfibrinogenemia associated with poor fetal outcomes

Whole-genome sequencing reveals host factors underlying critical COVID-19

Altres ajuts: Department of Health and Social Care (DHSC); Illumina; LifeArc; Medical Research Council (MRC); UKRI; Sepsis Research (the Fiona Elizabeth Agnew Trust); the Intensive Care Society, Wellcome Trust Senior Research Fellowship (223164/Z/21/Z); BBSRC Institute Program Support Grant to the Roslin Institute (BBS/E/D/20002172, BBS/E/D/10002070, BBS/E/D/30002275); UKRI grants (MC_PC_20004, MC_PC_19025, MC_PC_1905, MRNO2995X/1); UK Research and Innovation (MC_PC_20029); the Wellcome PhD training fellowship for clinicians (204979/Z/16/Z); the Edinburgh Clinical Academic Track (ECAT) programme; the National Institute for Health Research, the Wellcome Trust; the MRC; Cancer Research UK; the DHSC; NHS England; the Smilow family; the National Center for Advancing Translational Sciences of the National Institutes of Health (CTSA award number UL1TR001878); the Perelman School of Medicine at the University of Pennsylvania; National Institute on Aging (NIA U01AG009740); the National Institute on Aging (RC2 AG036495, RC4 AG039029); the Common Fund of the Office of the Director of the National Institutes of Health; NCI; NHGRI; NHLBI; NIDA; NIMH; NINDS.Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care or hospitalization after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes-including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)-in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Summary: Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n = 378), compared to 0.24% of controls (odds ratio [OR] = 12.3, p = 1.27 × 10−10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax = 46.5, p = 1.74 × 10−15). Association signals for the X-chromosomal gene TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1, and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19 and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway