Is open radical cystectomy facing extinction?

Otvorena radikalna cistektomija sa svim pridruženim oblicima derivacije urina je zlatni standard u liječenju invazivnog raka mokraćnog mjehura. Radikalna cistektomija je opsežna operacija sa značajnim poslijeoperacijskim morbiditetom i smrtnošću. Tijekom proteklog desetljeća, laparoskopija i robotika značajno prodiru u svakodnevnu kiruršku praksu. Općenito prihvaćene prednosti minimalno invazivne kirurgije uključuju smanjeni operativni gubitak krvi i tjelesnih tekućina, slabiju poslijeoperacijsku bol, kraći bolnički boravak, brži povratak radnim aktivnostima, estetski ugodne rezultate i zadovoljavajuću kontrolu maligne bolesti. Poteškoće u širem prihvaćanju minimalno invazivnih operacija jesu strma krivulja učenja, ograničen broj centara za edukaciju, a u slućaju robotski potpomognute kirurgije veliki početni trošak i trošak potrošnih materijala. Za sada u našoj svakodnevnici ima mjesta za otvorenu, laparaskopsku i robotski potpomognutu radikalnu cistektomiju, sve dok se ne učini temeljita procjena i usporedba novih minimalno invazivnih kirurških opcija. Prikazat ćemo pregled naših iskustava u minimalno invazivnoj radikalnoj cistektomiji.Open radical cystectomy with variety of urinary diversions has remained the gold standard for the treatment of muscle invasive bladder cancer. This is a major surgical procedure with significant post-operative morbidity and mortality. Over the last decade laparoscopy and robotics have made significant inroads into our surgical practice. The well known attractions of minimally invasive surgery include reduced blood and tissue fluid loss during surgery, less post-operative pain, shorter hospital stay, quicker return to work, cosmetically pleasing results and equivalent cancer control. The difficulty in widespread adoption of these minimally invasive options are steep learning curves, limited facilities for training, in the case of robotics formidable initial capital costs and cost of disposables. At present it may be fair to say that there is still a place for open, laparoscopic and robotic radical cystectomy until we have made rigorous evaluation of the new minimally invasive surgical options. A review of our experience of minimally invasive radical cystectomy will be presented

Delayed bowel perforation following suprapubic catheter insertion

BACKGROUND: Complications of suprapubic catheter insertion are rare but can be significant. We describe an unusual complication of a delayed bowel perforation following suprapubic catheter insertion. CASE PRESENTATION: A gentleman presented with features of peritonitis and feculent discharge along a suprapubic catheter two months after insertion of the catheter. CONCLUSION: Bowel perforation is the most feared complication of suprapubic catheter insertion especially in patients with lower abdominal scar. The risk may be reduced with the use of ultrasound scan guidance

The Ser82 RAGE variant affects lung function and serum RAGE in smokers and sRAGE production in vitro

Introduction: Genome-Wide Association Studies have identified associations between lung function measures and Chronic Obstructive Pulmonary Disease (COPD) and chromosome region 6p21 containing the gene for the Advanced Glycation End Product Receptor (AGER, encoding RAGE). We aimed to (i) characterise RAGE expression in the lung, (ii) identify AGER transcripts, (iii) ascertain if SNP rs2070600 (Gly82Ser C/T) is associated with lung function and serum sRAGE levels and (iv) identify whether the Gly82Ser variant is functionally important in altering sRAGE levels in an airway epithelial cell model. Methods: Immunohistochemistry was used to identify RAGE protein expression in 26 human tissues and qPCR was used to quantify AGER mRNA in lung cells. Gene expression array data was used to identify AGER expression during lung development in 38 fetal lung samples. RNA-Seq was used to identify AGER transcripts in lung cells. sRAGE levels were assessed in cells and patient serum by ELISA. BEAS2B-R1 cells were transfected to overexpress RAGE protein with either the Gly82 or Ser82 variant and sRAGE levels identified. Results: Immunohistochemical assessment of 6 adult lung samples identified high RAGE expression in the alveoli of healthy adults and individuals with COPD. AGER/RAGE expression increased across developmental stages in human fetal lung at both the mRNA (38 samples) and protein levels (20 samples). Extensive AGER splicing was identified. The rs2070600T (Ser82) allele is associated with higher FEV1, FEV1/FVC and lower serum sRAGE levels in UK smokers. Using an airway epithelium model overexpressing the Gly82 or Ser82 variants we found that HMGB1 activation of the RAGE-Ser82 receptor results in lower sRAGE production. Conclusions: This study provides new information regarding the expression profile and potential role of RAGE in the human lung and shows a functional role of the Gly82Ser variant. These findings advance our understanding of the potential mechanisms underlying COPD particularly for carriers of this AGER polymorphism

“Crocodiles in the corridors” : security vetting, race and Whitehall, 1945 – 1968

In July 2018, the UK’s Intelligence & Security Committee issued a report into diversity and inclusion across the intelligence and security community. The picture the report painted was far from satisfactory; in short, Britain’s intelligence agencies did not ‘fully reflect the ethnic make-up of modern Britain’. The report argued that Britain’s spy agencies – MI5, SIS (or MI6) and GCHQ – should improve black, Asian and ethnic minority recruitment, highlighting areas for improvement, especially around the vetting of recruits. This problem stems from the post-war Cold War 'security state' and the development of security-vetting programmes from the 1940s, aiming to protect Whitehall from Soviet spies and 'fellow travellers' to those with so-called 'character defects' - drink, drugs and homosexuality. But this 'security state' also saw the newly emerging multicultural Britain as a major threat. The so-called 'Windrush Generation' of migrants from the Caribbean, and migration from the Indian subcontinent and Africa, forever changed the social complexion of Britain, but posed significant questions for security officials. What was Britishness? With first or second generation migrants entering the civil service, who was a 'UK eye' and what access to secret information should they have? To what extent was discrimination justifiable to protect state secrets, and how should officials respond to new legislation such as the Race Discrimination Act? As this article shows, new entrants to the civil service faced deeply engrained prejudices, and questions over their loyalty to Britain. As late as the 1960s (and beyond), 'coloured' members of the civil service were rejected from secret posts across government, including the Ministry of Defence and intelligence and security services, especially MI5 and GCHQ, with discrimination on ‘security’ grounds justified by the landmark 1968 Race Relations Act, which barred race discrimination for housing and employment elsewhere

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

Systematic review with meta-analysis of the epidemiological evidence relating smoking to COPD, chronic bronchitis and emphysema

<p>Abstract</p> <p>Background</p> <p>Smoking is a known cause of the outcomes COPD, chronic bronchitis (CB) and emphysema, but no previous systematic review exists. We summarize evidence for various smoking indices.</p> <p>Methods</p> <p>Based on MEDLINE searches and other sources we obtained papers published to 2006 describing epidemiological studies relating incidence or prevalence of these outcomes to smoking. Studies in children or adolescents, or in populations at high respiratory disease risk or with co-existing diseases were excluded. Study-specific data were extracted on design, exposures and outcomes considered, and confounder adjustment. For each outcome RRs/ORs and 95% CIs were extracted for ever, current and ex smoking and various dose response indices, and meta-analyses and meta-regressions conducted to determine how relationships were modified by various study and RR characteristics.</p> <p>Results</p> <p>Of 218 studies identified, 133 provide data for COPD, 101 for CB and 28 for emphysema. RR estimates are markedly heterogeneous. Based on random-effects meta-analyses of most-adjusted RR/ORs, estimates are elevated for ever smoking (COPD 2.89, CI 2.63-3.17, n = 129 RRs; CB 2.69, 2.50-2.90, n = 114; emphysema 4.51, 3.38-6.02, n = 28), current smoking (COPD 3.51, 3.08-3.99; CB 3.41, 3.13-3.72; emphysema 4.87, 2.83-8.41) and ex smoking (COPD 2.35, 2.11-2.63; CB 1.63, 1.50-1.78; emphysema 3.52, 2.51-4.94). For COPD, RRs are higher for males, for studies conducted in North America, for cigarette smoking rather than any product smoking, and where the unexposed base is never smoking any product, and are markedly lower when asthma is included in the COPD definition. Variations by sex, continent, smoking product and unexposed group are in the same direction for CB, but less clearly demonstrated. For all outcomes RRs are higher when based on mortality, and for COPD are markedly lower when based on lung function. For all outcomes, risk increases with amount smoked and pack-years. Limited data show risk decreases with increasing starting age for COPD and CB and with increasing quitting duration for COPD. No clear relationship is seen with duration of smoking.</p> <p>Conclusions</p> <p>The results confirm and quantify the causal relationships with smoking.</p

Genome-wide association analyses for lung function and chronic obstructive pulmonary disease identify new loci and potential druggable targets

Chronic obstructive pulmonary disease (COPD) is characterized by reduced lung function and is the third leading cause of death globally. Through genome-wide association discovery in 48,943 individuals, selected from extremes of the lung function distribution in UK Biobank, and follow-up in 95,375 individuals, we increased the yield of independent signals for lung function from 54 to 97. A genetic risk score was associated with COPD susceptibility (odds ratio per 1 s.d. of the risk score (∼6 alleles) (95% confidence interval) = 1.24 (1.20-1.27), P = 5.05 × 10‾⁴⁹), and we observed a 3.7-fold difference in COPD risk between individuals in the highest and lowest genetic risk score deciles in UK Biobank. The 97 signals show enrichment in genes for development, elastic fibers and epigenetic regulation pathways. We highlight targets for drugs and compounds in development for COPD and asthma (genes in the inositol phosphate metabolism pathway and CHRM3) and describe targets for potential drug repositioning from other clinical indications.This work was funded by a Medical Research Council (MRC) strategic award to M.D.T., I.P.H., D.S. and L.V.W. (MC_PC_12010). This research has been conducted using the UK Biobank Resource under application 648. This article presents independent research funded partially by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the UK Department of Health. This research used the ALICE and SPECTRE High-Performance Computing Facilities at the University of Leicester. Additional acknowledgments and funding details can be found in the Supplementary Note