Synthesis of bicyclic tripeptides inspired by the ABC-ring system of vancomycin through ruthenium-based cyclization chemistries

The synthesis of a bicyclic tripeptide that mimics the ABC ring system of vancomycin is described by using a ring closing metathesis (RCM) – peptide coupling – ruthenium-catalyzed azide-alkyne cycloaddition (RuAAC) strategy

Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2)

BACKGROUND: Worldwide data for cancer survival are scarce. We aimed to initiate worldwide surveillance of cancer survival by central analysis of population-based registry data, as a metric of the effectiveness of health systems, and to inform global policy on cancer control. METHODS: Individual tumour records were submitted by 279 population-based cancer registries in 67 countries for 25·7 million adults (age 15-99 years) and 75,000 children (age 0-14 years) diagnosed with cancer during 1995-2009 and followed up to Dec 31, 2009, or later. We looked at cancers of the stomach, colon, rectum, liver, lung, breast (women), cervix, ovary, and prostate in adults, and adult and childhood leukaemia. Standardised quality control procedures were applied; errors were corrected by the registry concerned. We estimated 5-year net survival, adjusted for background mortality in every country or region by age (single year), sex, and calendar year, and by race or ethnic origin in some countries. Estimates were age-standardised with the International Cancer Survival Standard weights. FINDINGS: 5-year survival from colon, rectal, and breast cancers has increased steadily in most developed countries. For patients diagnosed during 2005-09, survival for colon and rectal cancer reached 60% or more in 22 countries around the world; for breast cancer, 5-year survival rose to 85% or higher in 17 countries worldwide. Liver and lung cancer remain lethal in all nations: for both cancers, 5-year survival is below 20% everywhere in Europe, in the range 15-19% in North America, and as low as 7-9% in Mongolia and Thailand. Striking rises in 5-year survival from prostate cancer have occurred in many countries: survival rose by 10-20% between 1995-99 and 2005-09 in 22 countries in South America, Asia, and Europe, but survival still varies widely around the world, from less than 60% in Bulgaria and Thailand to 95% or more in Brazil, Puerto Rico, and the USA. For cervical cancer, national estimates of 5-year survival range from less than 50% to more than 70%; regional variations are much wider, and improvements between 1995-99 and 2005-09 have generally been slight. For women diagnosed with ovarian cancer in 2005-09, 5-year survival was 40% or higher only in Ecuador, the USA, and 17 countries in Asia and Europe. 5-year survival for stomach cancer in 2005-09 was high (54-58%) in Japan and South Korea, compared with less than 40% in other countries. By contrast, 5-year survival from adult leukaemia in Japan and South Korea (18-23%) is lower than in most other countries. 5-year survival from childhood acute lymphoblastic leukaemia is less than 60% in several countries, but as high as 90% in Canada and four European countries, which suggests major deficiencies in the management of a largely curable disease. INTERPRETATION: International comparison of survival trends reveals very wide differences that are likely to be attributable to differences in access to early diagnosis and optimum treatment. Continuous worldwide surveillance of cancer survival should become an indispensable source of information for cancer patients and researchers and a stimulus for politicians to improve health policy and health-care systems

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

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 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

MULPEX: A compact multi-layered polymer foil collector for micrometeoroids and orbital debris

Detailed studies of preserved hypervelocity impact residues on spacecraft multi-layer insulation foils have yielded important information about the flux of small particles from different sources in low-Earth orbit (LEO). We have extended our earlier research on impacts occurring in LEO to design and testing of a compact capture device. MUlti-Layer Polymer EXperiment (MULPEX) is simple, cheap to build, lightweight, of no power demand, easy to deploy, and optimised for the efficient collection of impact residue for analysis on return to Earth. The capture medium is a stack of very thin (8 and 40 mu m) polyimide foils, supported on polytetrafluoroethylene sheet frames, surrounded by a protective aluminium casing. The uppermost foil has a very thin metallic coating for thermal protection and resistance to atomic oxygen and ultra-violet exposure. The casing provides a simple detachable interface for deployment on the spacecraft, facing into the desired direction for particle collection. On return to the laboratory, the stacked foils are separated for examination in a variable pressure scanning electron microscope, without need for surface coating. Analysis of impact residue is performed using energy dispersive X-ray spectrometers. Our laboratory experiments, utilising buck-shot firings of analogues to micrometeoroids (35-38 mu m olivine) and space debris (4 mu m alumina and 1 mm stainless steel) in a light gas gun, have shown that impact residue is abundant within the foil layers, and preserves a record of the impacting particle, whether of micrometer or millimetre dimensions. Penetrations of the top foil are easily recognised, and act as a proxy for dimensions of the penetrating particle. Impact may cause disruption and melting, but some residue retains sufficient crystallographic structure to show clear Raman lines, diagnostic of the original mineral. (c) 2005 Published by Elsevier Ltd on behalf of COSPAR

Development of a valid and reliable test to assess trauma radiograph interpretation performance

Objectives\ud \ud The purpose of this investigation was to develop and examine the preliminary validity and reliability among radiographers of a test to assess trauma radiograph interpretation performance suitable for use among health professionals.\ud \ud Methods\ud \ud Stage 1 examined 14,159 consecutive appendicular and axial examinations from a hospital emergency department over a 12 month period to quantify a typical anatomical region case-mix of trauma radiographs. A sample of radiographic cases representative of affected anatomical regions was then developed into the Image Interpretation Test (IIT). Stage 2 involved prospective investigations of the IIT's reliability (inter-rater, intra-rater, internal consistency) and validity (concurrent) among 41 radiographers.\ud \ud Results\ud \ud The IIT included 60 cases. The median (interquartile range) clinical experience of participants was 5 (2–10) years. Case scores were internally consistent (Cronbach's alpha = 0.90). Favourable inter-rater reliability (kappa > 0.70 for 58/60 cases, Intra-class correlation coefficient (ICC) > 0.99 for total score) and intra-rater reliability (kappa > 0.90 for 60/60 cases, ICC > 0.99 for total score) was observed. There was a positive association between radiographers' confidence in image interpretation and IIT score (coefficient = 1.52, r-squared = 0.60, p < 0.001).\ud \ud Conclusions\ud \ud The IIT developed during this investigation included a selection of radiographic cases consistent with anatomical regions represented in an adult trauma case-mix. This study has also provided foundational preliminary evidence to support the reliability and validity of the IIT among radiographers. The findings suggest that it is possible to assess image interpretation performance of adult trauma radiographs with this test

Laparoscopic versus open left lateral hepatic sectionectomy: a comparative study

Background: laparoscopic liver surgery has been difficult to popularize. High volume liver centres have identified left lateral sectionectomy (LLS) as a procedure with potential for transformation into a primarily laparoscopic procedure where surgeons can safely gain proficiency. Methods: forty-four patients underwent either laparoscopic (LLLS) or open (OLLS) left lateral sectionectomy (of segments II/III) for focal lesions at Southampton General Hospital. Results: OLLS and LLLS groups were matched for age, sex and tumour types resected. Median operative time in the LLLS group was 180 (40-340) min and 155 (110-330) min in the OLLS group (p=0.885) with median intra-operative blood loss in the LLLS group 80 (25-800) ml versus a larger 470 (100-3000) ml; p=0.002 for patients receiving OLLS. Post-operative stay was also shorter in the LLLS group (3.5 (1-6) days) compared to the OLLS group (7 (3-12) days; p&lt;0.001). Resection margin was not different in the two groups (11 (1.5-30) mm (LLLS) versus 12 (4-40) mm (OLLS); p=1) and neither was the complication rate (13% for LLLS versus 25% for OLLS; p=0.541). There were no conversions to open in the LLLS group and no deaths in either group at 90 days. Between the first and second 12 LLLS the median operative time fell from 240 (70-340) min to 120 (40-120) min; p=0.005 as well as median post-operative hospital stay from 4.5 (2-6) days to 2 (1-4) days, p=0.001. Conclusion: LLLS is a viable alternative to OLLS with potential improvements in intra-operative blood loss and shorter hospital stay without adversely affecting successful resection or complication rates. Larger prospective studies are required to explore this new avenue in laparoscopic liver surgery