A pool of anglepoised light : the legacy of colonialism in three Indian novels written in English

This thesis examines the work of three major Indian novelists belonging to consecutive generations whose responses to the legacy of colonialism emerges from and signals important historical shifts in postcolonial India. Focusing on three novels, the first written in the period immediately preceding independence, the last in the late 1990s, the thesis demonstrates that the colonial legacy is a dynamic force informing and shaping the consciousness of the Indian novelist writing in English. The similarities and differences between Raja Rao's Kanthapura (1938), Salman Rushdie's Midnight's Children (1981), and Arundhati Roy's The God of Small Things (1997) demonstrate that the residual effects of colonialism remain forcefully felt but the responses to those effects are so various as to undermine the notion that there is a single, stable colonial legacy, This thesis, focusing on three novels in particular, is not concerned with postcolonialism as a global condition but with the changes that have occurred within Indian writing in English

Chief Amongst The Angels? International Prosecutors And The Modernist Project

This thesis argues that three successive generations of prosecutors—each of whom at some moment in time belong to a major institution designed specifically to enforce international criminal law—are best understood as agents of the law, politics and war. By examining the relevant institutional arrangements, including formal prosecutorial mandates, the thesis recognises that these prosecutors play vital roles in the enforcement of international criminal law. By critically examining prosecutorial performance during the pre-trial and trial phases this thesis contends, firstly, that these prosecutors are also political actors serving, unwittingly or otherwise, in the interests of economic liberalisation, expressed as neo-capitalism during the middle of the twentieth century or as neoliberalism in the late twentieth century. By foregrounding the material and ideational conditions giving rise to those major enforcement institutions this thesis contends, secondly, that international prosecutors also help wage a mostly silent and largely unacknowledged war fought by proponents of various utopian movements. In order to support these two main contentions the thesis situates the development of international criminal law and its major institutions as a significant temporality of a discourse against politico-cruelty, a term used here to refer to cruel acts committed as a means of achieving some substantive end. It also contextualises the collective prosecutorial efforts within the project of modernity and, more specifically, what is described here as a politico-cultural civil war fought for control over that project. Using international criminal law as a means of confronting humanity’s worst excesses and curbing modernity’s most violent pathologies, international prosecutors of war crimes, crimes against humanity, crimes of genocide and crimes of aggression might represent the vanguard in the quest for international criminal justice and be regarded by many as featuring among humanity’s better angels. Indeed, they might well be characterised in world affairs as chief amongst the angels. But, at the same time, these politico-legal actors, whose mandates are derived from, and re-inscribe, particular configurations of power emerging in the aftermath of global conflict, need to be recognised as the auxiliary combatants of those seeking to maintain their control over the modernist project

The Two-Handed Tile Assembly Model is not Intrinsically Universal

The Two-Handed Tile Assembly Model (2HAM) is a model of algorithmic self-assembly in which large structures, or assemblies of tiles, are grown by the binding of smaller assemblies. In order to bind, two assemblies must have matching glues that can simultaneously touch each other, and stick together with strength that is at least the temperature τ, where τ is some fixed positive integer. We ask whether the 2HAM is intrinsically universal. In other words, we ask: is there a single 2HAM tile set U which can be used to simulate any instance of the model? Our main result is a negative answer to this question. We show that for all τ′ < τ, each temperature-τ′ 2HAM tile system does not simulate at least one temperature-τ 2HAM tile system. This impossibility result proves that the 2HAM is not intrinsically universal and stands in contrast to the fact that the (single-tile addition) abstract Tile Assembly Model is intrinsically universal. On the positive side, we prove that, for every fixed temperature τ ≥ 2, temperature-τ 2HAM tile systems are indeed intrinsically universal. In other words, for each τ there is a single intrinsically universal 2HAM tile set U_τ that, when appropriately initialized, is capable of simulating the behavior of any temperature-τ 2HAM tile system. As a corollary, we find an infinite set of infinite hierarchies of 2HAM systems with strictly increasing simulation power within each hierarchy. Finally, we show that for each τ, there is a temperature-τ 2HAM system that simultaneously simulates all temperature-τ 2HAM systems

The Two-Handed Tile Assembly Model Is Not Intrinsically Universal

In this paper, we study the intrinsic universality of the well-studied Two-Handed Tile Assembly Model (2HAM), in which two “supertile” assemblies, each consisting of one or more unit-square tiles, can fuse together (self-assemble) whenever their total attachment strength is at least the global temperature τ. Our main result is that for all τ′ < τ, each temperature-τ′ 2HAM tile system cannot simulate at least one temperature-τ 2HAM tile system. This impossibility result proves that the 2HAM is not intrinsically universal, in stark contrast to the simpler abstract Tile Assembly Model which was shown to be intrinsically universal (The tile assembly model is intrinsically universal, FOCS 2012). On the positive side, we prove that, for every fixed temperature τ ≥ 2, temperature-τ 2HAM tile systems are intrinsically universal: for each τ there is a single universal 2HAM tile set U that, when appropriately initialized, is capable of simulating the behavior of any temperature τ 2HAM tile system. As a corollary of these results we find an infinite set of infinite hierarchies of 2HAM systems with strictly increasing power within each hierarchy. Finally, we show how to construct, for each τ, a temperature-τ 2HAM system that simultaneously simulates all temperature-τ 2HAM systems

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

The development and validation of a scoring tool to predict the operative duration of elective laparoscopic cholecystectomy

Background: The ability to accurately predict operative duration has the potential to optimise theatre efficiency and utilisation, thus reducing costs and increasing staff and patient satisfaction. With laparoscopic cholecystectomy being one of the most commonly performed procedures worldwide, a tool to predict operative duration could be extremely beneficial to healthcare organisations. Methods: Data collected from the CholeS study on patients undergoing cholecystectomy in UK and Irish hospitals between 04/2014 and 05/2014 were used to study operative duration. A multivariable binary logistic regression model was produced in order to identify significant independent predictors of long (> 90 min) operations. The resulting model was converted to a risk score, which was subsequently validated on second cohort of patients using ROC curves. Results: After exclusions, data were available for 7227 patients in the derivation (CholeS) cohort. The median operative duration was 60 min (interquartile range 45–85), with 17.7% of operations lasting longer than 90 min. Ten factors were found to be significant independent predictors of operative durations > 90 min, including ASA, age, previous surgical admissions, BMI, gallbladder wall thickness and CBD diameter. A risk score was then produced from these factors, and applied to a cohort of 2405 patients from a tertiary centre for external validation. This returned an area under the ROC curve of 0.708 (SE = 0.013, p  90 min increasing more than eightfold from 5.1 to 41.8% in the extremes of the score. Conclusion: The scoring tool produced in this study was found to be significantly predictive of long operative durations on validation in an external cohort. As such, the tool may have the potential to enable organisations to better organise theatre lists and deliver greater efficiencies in care

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

A blood atlas of COVID-19 defines hallmarks of disease severity and specificity.

Treatment of severe COVID-19 is currently limited by clinical heterogeneity and incomplete description of specific immune biomarkers. We present here a comprehensive multi-omic blood atlas for patients with varying COVID-19 severity in an integrated comparison with influenza and sepsis patients versus healthy volunteers. We identify immune signatures and correlates of host response. Hallmarks of disease severity involved cells, their inflammatory mediators and networks, including progenitor cells and specific myeloid and lymphocyte subsets, features of the immune repertoire, acute phase response, metabolism, and coagulation. Persisting immune activation involving AP-1/p38MAPK was a specific feature of COVID-19. The plasma proteome enabled sub-phenotyping into patient clusters, predictive of severity and outcome. Systems-based integrative analyses including tensor and matrix decomposition of all modalities revealed feature groupings linked with severity and specificity compared to influenza and sepsis. Our approach and blood atlas will support future drug development, clinical trial design, and personalized medicine approaches for COVID-19

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival