A New Technique for Finding Needles in Haystacks: A Geometric Approach to Distinguishing Between a New Source and Random Fluctuations

We propose a new test statistic based on a score process for determining the statistical significance of a putative signal that may be a small perturbation to a noisy experimental background. We derive the reference distribution for this score test statistic; it has an elegant geometrical interpretation as well as broad applicability. We illustrate the technique in the context of a model problem from high-energy particle physics. Monte Carlo experimental results confirm that the score test results in a significantly improved rate of signal detection.Comment: 5 pages, 4 figure

The Role of Zero-Modes in the Canonical Quantization of Heavy-Fermion QED in Light-Cone Coordinates

Four-dimensional heavy-fermion QED is studied in light-cone coordinates with (anti-)periodic field boundary conditions. We carry out a consistent light-cone canonical quantization of this model using the Dirac algorithm for a system with first- and second-class constraints. To examine the role of the zero modes, we consider the quantization procedure in {the }zero-mode {and the non-zero-mode} sectors separately. In both sectors we obtain the physical variables and their canonical commutation relations. The physical Hamiltonian is constructed via a step-by-step exclusion of the unphysical degrees of freedom. An example using this Hamiltonian in which the zero modes play a role is the verification of the correct Coulomb potential between two heavy fermions.Comment: 22 pages, CWRUTH-93-5 (Latex

Anti-Inflammatory Cytokines Predominate in Acute Human Plasmodium knowlesi Infections

Plasmodium knowlesi has entered the human population of Southeast Asia. Naturally acquired knowlesi malaria is newly described with relatively little available data, including data on the host response to infection. Therefore pre-treatment cytokine and chemokine profiles were determined for 94 P. knowlesi, and for comparison, 20, P. vivax and 22 P. falciparum, patients recruited in Malaysian Borneo. Nine, five and one patient with P. knowlesi, P. falciparum and P. vivax respectively had complicated malaria as defined by World Health Organisation. Patients with uncomplicated P. knowlesi had lower levels of the pro-inflammatory cytokines IL-8 and TNFα than those with complicated disease (both p<0.05, Dunn's post test, DPT). The anti-inflammatory cytokines IL-1ra and IL-10 were detected in all patients in the study. IL-1ra, the most abundant cytokine measured, correlated with parasitaemia in P. knowlesi (rs = 0.47, p =  <0.0001), P. vivax (rs = 0.61, p = 0.0042) and P. falciparum (rs = 0.57,p = 0.0054) malaria. IL-10 correlated with parasitaemia in both P. knowlesi (rs = 0.54, p =  <0.0001) and P. vivax (rs = 0.78, p =  <0.0001) infections. There were between group differences in soluble markers of macrophage activation (MIP-1β and MCP-1). P. knowlesi patients had significantly lower levels of MIP-1β than P. falciparum (DPT, p =  <0.01). Uncomplicated P. knowlesi patients had significantly lower levels of MCP-1 than uncomplicated P. falciparum patients (DPT, p =  <0.001). There was no significant difference between complicated and uncomplicated P. knowlesi infections. MCP-1, MIP-1β, IL-8 and TNFα increased in complicated P. knowlesi but decreased in complicated P. falciparum infections. Descriptions of human knowlesi malaria provide a comparative means to discover mediators of pathophysiology in severe P. knowlesi as well as P. falciparum malaria. Crucially, P. knowlesi may be the disease and experimental primate model for severe malaria

Expanding the Whipple Accelerated Recovery Pathway (WARP) To All Patients Undergoing Pancreaticoduodenectomy (PD)

Introduction: Pancreaticoduodenectomy (PD) is a complex abdominal procedure with high rates of perioperative morbidity. The Whipple Accelerated Recovery Pathway (WARP) was developed for highly selected patients undergoing PD to reduce hospital length of stay (LOS) and time to adjuvant therapy (TTAT), without increasing post-operative complications (POC) or readmission rates (RR). The purpose of this study was to determine if WARP could be implemented for all-risk patients undergoing PD. Methods: A single-institution, retrospective analysis of 281 patients implemented on the WARP between 2017-2020 was performed. 119 patients were categorized as WARP-eligible (WEPs) according to original inclusion criteria, and 162 were deemed WARP-ineligible (WIPs). Primary endpoints include LOS, TTAT, RR, and POC. Data was collected from Epic and a multivariate analysis with logistic regression was performed. Results: 28 POC were found in WEPs (23.5%) compared to 73 POC in WIPs (45.1%) (p\u3c0.05). Delayed gastric emptying (DGE) and post-operative pancreatic fistulas (POPF) were higher in WIPs: DGE was found in 10.2% of WEPs vs. 26.2% of WIPs (p\u3c0.05), while POPF was found in 5.1% of WEPs vs. 21% of WIPs (p\u3c0.05). Mean LOS was 5 days for WEPs vs. 6 days for WIPs (p\u3c0.05). TTAT was 55 days for WEPs, compared to 63 days in WIPs (p\u3c0.05). RR was 12.6% for WEPs and 23.5% for WIPs (p\u3c0.05). Discussion: WARP results in lowered POC, TTAT, LOS, and RR, cutting costs to patients. WARP may be expanded to all PD patients; however, WIPs may benefit from additional modifications that are specific for patient risk factor

Southampton PRegnancy Intervention for the Next Generation (SPRING):protocol for a randomised controlled trial

BACKGROUND: The nutritional status and health of mothers influence the growth and development of infants during pregnancy and postnatal life. Interventions that focus on improving the nutritional status and lifestyle of mothers have the potential to optimise the development of the fetus as well as improve the health of mothers themselves. Improving the diets of women of childbearing age is likely to require complex interventions that are delivered in a socially and culturally appropriate context. In this study we aim to test the efficacy of two interventions: behaviour change (Healthy Conversation Skills) and vitamin D supplementation, and to explore the efficacy of an intervention that combines both, in improving the diet quality and nutritional status of pregnant women. METHODS/DESIGN: Women attending the maternity hospital in Southampton are recruited at between 8 and 12 weeks gestation. They are randomised to one of four groups following a factorial design: Healthy Conversation Skills support plus vitamin D supplementation (1000 IU cholecalciferol) (n = 150); Healthy Conversation Skills support plus placebo (n = 150); usual care plus vitamin D supplementation (n = 150); usual care plus placebo (n = 150). Questionnaire data include parity, sunlight exposure, diet assessment allowing assessment of diet quality, cigarette and alcohol consumption, well-being, self-efficacy and food involvement. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH) vitamin D. Maternal diet quality and 25(OH) vitamin D are the primary outcomes. Secondary outcomes are women's level of self-efficacy at 34 weeks, pregnancy weight gain, women's self-efficacy and breastfeeding status at one month after birth and neonatal bone mineral content, assessed by DXA within the first 14 days after birth. DISCUSSION: This trial is evaluating two approaches to improving maternal diet: a behaviour change intervention and vitamin D supplementation. The factorial design of this trial has the advantage of enabling each intervention to be tested separately as well as allowing exploration of the synergistic effect of both interventions on women's diets and vitamin D levels. TRIAL REGISTRATION: ISRCTN07227232 . Registered on 13 September 2013

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin

Pan-cancer Alterations of the MYC Oncogene and Its Proximal Network across the Cancer Genome Atlas

Although theMYConcogene has been implicated incancer, a systematic assessment of alterations ofMYC, related transcription factors, and co-regulatoryproteins, forming the proximal MYC network (PMN),across human cancers is lacking. Using computa-tional approaches, we define genomic and proteo-mic features associated with MYC and the PMNacross the 33 cancers of The Cancer Genome Atlas.Pan-cancer, 28% of all samples had at least one ofthe MYC paralogs amplified. In contrast, the MYCantagonists MGA and MNT were the most frequentlymutated or deleted members, proposing a roleas tumor suppressors.MYCalterations were mutu-ally exclusive withPIK3CA,PTEN,APC,orBRAFalterations, suggesting that MYC is a distinct onco-genic driver. Expression analysis revealed MYC-associated pathways in tumor subtypes, such asimmune response and growth factor signaling; chro-matin, translation, and DNA replication/repair wereconserved pan-cancer. This analysis reveals insightsinto MYC biology and is a reference for biomarkersand therapeutics for cancers with alterations ofMYC or the PMN

Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context

Long noncoding RNAs (lncRNAs) are commonly dys-regulated in tumors, but only a handful are known toplay pathophysiological roles in cancer. We inferredlncRNAs that dysregulate cancer pathways, onco-genes, and tumor suppressors (cancer genes) bymodeling their effects on the activity of transcriptionfactors, RNA-binding proteins, and microRNAs in5,185 TCGA tumors and 1,019 ENCODE assays.Our predictions included hundreds of candidateonco- and tumor-suppressor lncRNAs (cancerlncRNAs) whose somatic alterations account for thedysregulation of dozens of cancer genes and path-ways in each of 14 tumor contexts. To demonstrateproof of concept, we showed that perturbations tar-geting OIP5-AS1 (an inferred tumor suppressor) andTUG1 and WT1-AS (inferred onco-lncRNAs) dysre-gulated cancer genes and altered proliferation ofbreast and gynecologic cancer cells. Our analysis in-dicates that, although most lncRNAs are dysregu-lated in a tumor-specific manner, some, includingOIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergis-tically dysregulate cancer pathways in multiple tumorcontexts

Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images

Beyond sample curation and basic pathologic characterization, the digitized H&E-stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumorinfiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment