State enrolment and energy-carbon transitions: syndromic experimentation and atomisation in England

This article analyses how national governments seek to enrol different subjects and objects in energy-carbon restructuring. It takes analysis beyond consideration of particular subjectivities and governmentalities to consider an expanded range of objects and subjects of governing at a distance. Developing an analytical model of ‘modes of enrolment’ focusing on power modalities, forms of policy integration and policy targets, the article explores five broad modes of enrolment employed in England. The article shows how policy across all modes of enrolment in England has increasingly tended towards disordered, syndromic experimentation and government by-project rather than any systematic programme of government

Second echelon node predicts metastatic involvement of additional axillary nodes following sentinel node biopsy in early breast cancer

BACKGROUND : In many patients with early breast cancer, the sentinel lymph node (SLN) is the sole site of regional nodal metastasis. This subgroup of patients may not benefit from completion axillary lymph node dissection (CALND). AIMS: This pilot study evaluates the status of 2nd echelon (station) lymph nodes in the axilla as a predictor of additional positive nodes in the axilla in the presence of sentinel node metastasis. SETTINGS AND DESIGN: Cross-sectional study of 40 breast cancer patients. MATERIALS AND METHODS: Forty patients with invasive breast cancer underwent SLN biopsy followed by 2nd echelon lymph node biopsy in the same sitting. SLN mapping was performed using a combined technique of isosulfan blue and 99 mTc-sulfur colloid. SLNs (Station I) were defined as blue and/or hot nodes. These nodes were then injected with 0.1 ml of blue dye using a fine needle and their efferent lymphatic was traced to identify the Station II nodes. Then a complete ALND was performed. All the specimens were sent separately for histopathological evaluation. RESULTS : SLNs (Station I nodes) were successfully identified in 98% (39/40) patients. Of the 17 patients with a positive SLN, 8 (47%) patients had no further positive nodes in the axilla, 9 (53%) patients had additional metastasis in nonsentinel lymph nodes upon CALND. Station II nodes were identified in 76% (13/17) patients with a positive SLN. Station II nodes accurately predicted the status of the remaining axilla in 92% patients (12/13). STATISTICAL ANALYSIS : We calculated the Sensitivity, Negative predictive value, Positive predictive value, False negative rate and Identification rate. CONCLUSION : Station II nodes may predict metastatic involvement of additional nodes in the axilla

Clinical Efficacy of Organ-Preserving Pancreatectomy for Benign or Low-Grade Malignant Potential Lesion

The clinical usefulness of organ-preserving pancreatectomy is not well established due to technical difficulty and ambiguity of functional merit. The purpose of this study is to evaluate the clinical efficacy of organ-preserving pancreatectomy such as duodenum-preserving resection of the head of the pancreas (DPRHP), pancreatic head resection with segmental duodenectomy (PHRSD), central pancreatectomy (CP) and spleen-preserving distal pancreatectomy (SPDP). Between 1995 and 2007, the DPRHP were performed in 14 patients, the PHRSD in 16 patients, the CP in 13 patients, and the SPDP in 45 patients for preoperatively diagnosed benign lesions or tumors with low-grade malignant potential. The clinical outcomes including surgical details, postoperative complications and long-term functional outcomes were compared between organ-preserving pancreatectomy and conventional pancreatectomy group. Major postoperative complications constituted the following: bile duct stricture (7.1% [1/14]) in DPRHP, delayed gastric emptying (31.2% [5/16]) in PHRSD, pancreatic fistula (21.4% [3/14]) in CP. There were no significant differences in postoperative complications and long-term functional outcomes between two groups. Organ-preserving pancreatectomy is associated with tolerable postoperative complications, and good long-term outcome comparing to conventional pancreatectomy. Organ-preserving pancreatectomy could be alternative treatment for benign or low-grade malignant potential lesion of the pancreas or ampullary/parapapillary duodenum

Cost effectiveness of ulcerative colitis treatment in Germany: a comparison of two oral formulations of mesalazine

<p>Abstract</p> <p>Background</p> <p>The treatment of ulcerative colitis (UC) can place a substantial financial burden on healthcare systems. The anti-inflammatory compound 5-aminosalicylic acid (5-ASA; mesalazine) is the recommended first-line treatment for patients with UC. In this analysis, the incremental cost effectiveness ratio (ICER) of two oral formulations of 5-ASA (Mezavant^®and Asacol^®) is examined in the treatment of patients with mild-to-moderate, active UC in Germany.</p> <p>Methods</p> <p>A Markov cohort model was developed to assess the cost effectiveness of Mezavant compared with Asacol over a 5-year period in the German Statutory Health Insurance (SHI). Drug pricing details for 2009 were applied throughout the model, and overall resource use was determined and also fitted to 2009 from published results of a large cross sectional study of German SHI patients. Cost per quality adjusted life year (QALY) was the primary endpoint for this study. Remission rates were obtained using data from a randomised, phase III trial of Mezavant with an active Asacol reference arm and a long-term, open label, safety and tolerability trial of Mezavant. Uncertainty in the study model was assessed using one-way and probabilistic sensitivity analyses applying a Monte Carlo simulation.</p> <p>Results</p> <p>Over a 5-year period, healthcare costs for patients receiving Mezavant were 624 Euro lower than for patients receiving Asacol. Additionally, patients receiving Mezavant gained 0.011 QALYs or 18 more days in remission compared with Asacol. One-way sensitivity analyses suggest that these results are driven by both differences in the acquisition cost between mesalazine formulations and differences in treatment efficacy. Furthermore, sensitivity analyses suggest a probability of 76% for cost savings and higher QALYs with Mezavant compared with Asacol. If adherence and its influence on the remission rates and the risk of developing colorectal cancer were included in the model, the results might have even been more favorable to Mezavant due to its once daily dosing regimen.</p> <p>Conclusions</p> <p>This model suggests that patients treated with Mezavant may achieve increased time in remission and higher QALYs, with lower direct costs to the SHI when compared with Asacol. Mezavant may therefore be a suitable first-line option for the induction and maintenance of remission in UC.</p

Identification and Characterization of the Lamprey High-Mobility Group Box 1 Gene

High-mobility group box 1 (HMGB1), a highly conserved DNA-binding protein, plays an important role in maintaining nucleosome structures, transcription, and inflammation. We identified a homolog of HMGB1 in the Japanese lamprey (Lampetra japonica). The Lampetra japonica HMGB1 gene (Lj-HMGB1) has over 70% sequence identity with its homologs in jawed vertebrates. Despite the reasonably high sequence identity with other HMGB1 proteins, Lj-HMGB1 did not group together with these proteins in a phylogenetic analysis. We examined Lj-HMGB1 expression in lymphocyte-like cells, and the kidneys, heart, gills, and intestines of lampreys before and after the animals were challenged with lipopolysaccharide (LPS) and concanavalin A (ConA). Lj-HMGB1 was initially expressed at a higher level in the heart, but after treatment with LPS and ConA only the gills demonstrated a significant up-regulation of expression. The recombinant Lj-HMGB1 (rLj-HMGB1) protein bound double-stranded DNA and induced the proliferation of human adenocarcinoma cells to a similar extent as human HMGB1. We further revealed that Lj-HMGB1 was able to induce the production of tumor necrosis factor-α (TNF-α), a pro-inflammatory mediator, in activated human acute monocytic leukemia cells. These results suggest that lampreys use HMGB1 to activate their innate immunity for the purpose of pathogen defense

Sensitivity of SARS-CoV-2 B.1.1.7 to mRNA vaccine-elicited antibodies

SARS-CoV-2 transmission is uncontrolled in many parts of the world, compounded in some areas by higher transmission potential of the B1.1.7 variant1 now reported in 94 countries. It is unclear whether responses to SARS-CoV-2 vaccines based on the prototypic strain will be impacted by mutations found in B.1.1.7. Here we assessed immune responses following vaccination with mRNA-based vaccine BNT162b22. We measured neutralising antibody responses following first and second immunisations using pseudoviruses expressing the wild-type Spike protein or the 8 amino acid mutations found in the B.1.1.7 spike protein. The vaccine sera exhibited a broad range of neutralising titres against the wild-type pseudoviruses that were modestly reduced against B.1.1.7 variant. This reduction was also evident in sera from some convalescent patients. Decreased B.1.1.7 neutralisation was also observed with monoclonal antibodies targeting the N-terminal domain (9 out of 10), the RBM (5 out of 31), but not in RBD neutralising mAbs binding outside the RBM. Introduction of the E484K mutation in a B.1.1.7 background to reflect a newly emergent Variant of Concern (VOC 202102/02) led to a more substantial loss of neutralising activity by vaccine-elicited antibodies and mAbs (19 out of 31) over that conferred by the B.1.1.7 mutations alone. E484K emergence on a B.1.1.7 background represents a threat to the vaccine BNT162b

The circulating SARS-CoV-2 spike variant N439K maintains fitness while evading antibody-mediated immunity

SARS-CoV-2 can mutate to evade immunity, with consequences for the efficacy of emerging vaccines and antibody therapeutics. Herein we demonstrate that the immunodominant SARS-CoV-2 spike (S) receptor binding motif (RBM) is the most divergent region of S, and provide epidemiological, clinical, and molecular characterization of a prevalent RBM variant, N439K. We demonstrate that N439K S protein has enhanced binding affinity to the hACE2 receptor, and that N439K virus has similar clinical outcomes and in vitro replication fitness as compared to wild- type. We observed that the N439K mutation resulted in immune escape from a panel of neutralizing monoclonal antibodies, including one in clinical trials, as well as from polyclonal sera from a sizeable fraction of persons recovered from infection. Immune evasion mutations that maintain virulence and fitness such as N439K can emerge within SARS-CoV-2 S, highlighting the need for ongoing molecular surveillance to guide development and usage of vaccines and therapeutics

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe