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Introduction: Left gastric artery embolisation (LGAE) is a well-established treatment for major upper gastrointestinal (GI) bleeding when control is not established via upper GI endoscopy and recently has shown promising results for weight loss in small single arm studies. LGAE could be a treatment option in between our current tier-3 and tier-4 services for obesity. EMBIO is a National Institute for Health Research funded trial, a multicentre double-blinded randomised controlled trial between Imperial College National Health Service Trust and University College London Hospital, comparing LGAE versus Placebo procedure. The key aims of the trial is to evaluate LGAE efficacy on weight loss, its mechanism of action, safety profile and obesity-related comorbidities., Methods and Analysis: 76 participants will be recruited from the existing tier-3 database after providing informed consent. Key inclusion criteria include adults aged 18-70 with a body mass index 35-50 kg/m 2 and appropriate anatomy of the left gastric artery and coeliac plexus on CT Angiogram. Key exclusion criteria included previous major abdominal and bariatric surgery, weight >150 kg, type 2 diabetes on any medications other than metformin and the use of weight modifying medications. Participants will undergo mechanistic visits 1 week prior to the intervention and 3, 6 and 12 months postintervention. Informed consent will be received from each participant and they will be randomised in a 1:1 ratio to left gastric artery embolisation and placebo treatment. Blinding strategies include the use of moderate doses of sedation, visual and auditory isolation. All participants will enter a tier-3 weight management programme postintervention. The primary analysis will estimate the difference between the groups in the mean per cent weight loss at 12 months., Ethics and Dissemination: This trial shall be conducted in full conformity with the 1964 Declaration of Helsinki and all subsequent revisions. Local research ethics approval was granted by London-Central Research Ethics Committee, (Reference 19/LO/0509) on 11 October 2019. The Medicines and Healthcare products Regulatory Agency (MHRA) issued the Letter of No Objection on 8 April 2022 (Reference CI/2022/0008/GB). The trial's development and progress are monitored by an independent trial steering committee and data monitoring and ethics committee. The researchers plan to disseminate results at conferences, in peer- reviewed journals as well as lay media and to patient organisations., Trial Registration Number: ISRCTN16158402., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To evaluate the effect of colchicine and high-intensity rosuvastatin in addition to standard of care on the progression of COVID-19 disease in hospitalised patients., Design: A pragmatic, open-label, multicentre, randomised controlled trial conducted from October 2020 to September 2021. Follow-up was conducted at 30 and 60 days. The electronic medical record was used at all stages of the trial including screening, enrolment, randomisation, event ascertainment and follow-up., Setting: Four centres in the Yale New Haven Health System., Participants: Non-critically ill hospitalised patients with COVID-19., Interventions: Patients were randomised 1:1 to either colchicine plus high-intensity rosuvastatin in addition to standard of care versus standard of care alone. Assigned treatment was continued for the duration of index hospitalisation or 30 days, whichever was shorter., Primary and Secondary Outcome Measures: The prespecified primary endpoint was progression to severe COVID-19 disease (new high-flow or non-invasive ventilation, mechanical ventilation, need for vasopressors, renal replacement therapy or extracorporeal membrane oxygenation, or death) or arterial/venous thromboembolic events (ischaemic stroke, myocardial infarction, deep venous thrombosis or pulmonary embolism) evaluated at 30 days., Results: Among the 250 patients randomised in this trial (125 to each arm), the median age was 61 years, 44% were women, 15% were Black and 26% were Hispanic/Latino. As part of the standard of care, patients received remdesivir (87%), dexamethasone (92%), tocilizumab (18%), baricitinib (2%), prophylactic/therapeutic anticoagulation (98%) and aspirin (91%). The trial was terminated early by the data and safety monitoring board for futility. No patients were lost to follow-up due to electronic medical record follow-up. There was no significant difference in the primary endpoint at 30 days between the active arm and standard of care arm (15.2% vs 8.8%, respectively, p=0.17)., Conclusions: In this small, open-label, randomised trial of non-critically ill hospitalised patients with COVID-19, the combination of colchicine and rosuvastatin in addition to standard of care did not appear to reduce the risk of progression of COVID-19 disease or thromboembolic events, although the trial was underpowered due to a lower-than-expected event rate. The trial leveraged the power of electronic medical records for efficiency and improved follow-up and demonstrates the utility of incorporating electronic medical records into future trials., Trial Registration: NCT04472611., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is an unmet need for an accurate, validated, noninvasive test for diagnosing and monitoring bladder cancer (BC). Detection of BC-associated mutations in urinary DNA via targeted deep sequencing could meet this need., Objective: To test the ability of mutational analysis of urinary DNA to noninvasively detect BC within the context of haematuria investigations and non-muscle-invasive BC (NMIBC) surveillance., Design, Setting, and Participants: Capture-based ultra-deep sequencing was performed for 443 somatic mutations in 23 genes in 591 urine cell-pellet DNAs from haematuria clinic patients and 293 from NMIBC surveillance patients. Variant calling was optimised to minimise false positives using urine samples from 162 haematuria clinic patients without BC., Outcome Measurements and Statistical Analysis: The sensitivity and specificity for BC diagnosis were determined., Results and Limitations: Mutational analysis of urinary DNA detected 144 of the 165 haematuria patients diagnosed with incident BC from two independent cohorts, yielding overall sensitivity of 87.3% (95% confidence interval [CI] 81.2-92.0%) at specificity of 84.8% (95% CI 79.9-89.0%). The sensitivity was 97.4% for grade 3, 86.5% for grade 2, and 70.8% for grade 1 BC. Among NMIBC surveillance patients, 25 out of 29 recurrent BCs were detected, yielding sensitivity of 86.2% (95% CI 70.8-97.7%) at specificity of 62.5% (95% CI 56.1-68.0%); a positive urine mutation test in the absence of clinically detectable disease was associated with a 2.6-fold increase in the risk of future recurrence. The low number of recurrences in the NMIBC surveillance cohort and the lower sensitivity for detecting grade 1 pTa BC are limitations., Conclusions: Detection of mutations in a small panel of BC-associated genes could facilitate noninvasive BC testing and expedite haematuria investigations. Following further validation, the test could also play a role in NMIBC surveillance., Patient Summary: Identification of alterations in genes that are frequently mutated in bladder cancer appears to be a promising strategy for detecting disease from urine samples and reducing reliance on examination of the bladder via a telescopic camera inserted through the urethra., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

CD4 + T cells are essential for protection against viruses, including SARS-CoV-2. The sensitivity of CD4 + T cells to mutations in SARS-CoV-2 variants of concern (VOCs) is poorly understood. Here, we isolated 159 SARS-CoV-2-specific CD4 + T cell clones from healthcare workers previously infected with wild-type SARS-CoV-2 (D614G) and defined 21 epitopes in spike, membrane and nucleoprotein. Lack of CD4 + T cell cross-reactivity between SARS-CoV-2 and endemic beta-coronaviruses suggested these responses arose from naïve rather than pre-existing cross-reactive coronavirus-specific T cells. Of the 17 epitopes located in the spike protein, 10 were mutated in VOCs and CD4 + T cell clone recognition of 7 of them was impaired, including 3 of the 4 epitopes mutated in omicron. Our results indicated that broad targeting of epitopes by CD4 + T cells likely limits evasion by current VOCs. However, continued genomic surveillance is vital to identify new mutations able to evade CD4 + T cell immunity., (© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Men with prostate cancer experience immediate and long-term consequences of the disease and its treatment. They require both long-term monitoring for recurrence or progression and follow-up to identify and help manage psychosocial and physical impacts. Holistic Needs Assessment aims to ensure patient-centered continuing cancer care. However, paper-based generic tools have had limited uptake within cancer services, and there is little evidence of their impact. With the expansion of remote methods of care delivery and to enhance the value of generic tools, we developed a web-based Composite Holistic Needs Assessment Adaptive Tool-Prostate (CHAT-P) specifically for prostate cancer., Objective: This paper described the context, conceptual underpinning, and approach to design that informed the development of CHAT-P, starting from the initial concept to readiness for deployment. Through this narrative, we sought to contribute to the expanding body of knowledge regarding the coproduction process of innovative digital systems with potential for enhanced cancer care delivery., Methods: The development of CHAT-P was guided by the principles of coproduction. Men with prostate cancer and health care professionals contributed to each stage of the process. Testing was conducted iteratively over a 5-year period. An initial rapid review of patient-reported outcome measures identified candidate items for inclusion. These items were categorized and allocated to overarching domains. After the first round of user testing, further items were added, improvements were made to the adaptive branching system, and response categories were refined. A functioning version of CHAT-P was tested with 16 patients recruited from 3 outpatient clinics, with interviewers adopting the think-aloud technique. Interview transcripts were analyzed using a framework approach. Interviews and informal discussions with health care professionals informed the development of a linked care plan and clinician-facing platform, which were incorporated into a separate feasibility study of digitally enhanced integrated cancer care., Results: The findings from the interview study demonstrated the usability, acceptability, and potential value of CHAT-P. Men recognized the benefits of a personalized approach and the importance of a holistic understanding of their needs. Preparation for the consultation by the completion of CHAT-P was also recognized as empowering. The possible limitations identified were related to the importance of care teams responding to the issues selected in the assessment. The subsequent feasibility study highlighted the need for attention to men's psychological concerns and demonstrated the ability of CHAT-P to capture red flag symptoms requiring urgent investigation., Conclusions: CHAT-P offers an innovative means by which men can communicate their concerns to their health care teams before a physical or remote consultation. There is now a need for a full evaluation of the implementation process and outcomes where CHAT-P is introduced into the clinical pathway. There is also scope for adapting the CHAT-P model to other cancers., (©Rebecca Appleton, Veronica Nanton, Nisar Ahmed, Joelle Loew, Julia Roscoe, Radha Muthuswamy, Prashant Patel, Jeremy Dale, Sam H Ahmedzai. Originally published in JMIR Cancer (https://cancer.jmir.org), 19.10.2022.)

Air pollution and its limits are regulated by the environmental protection agency of an individual country according to their National Ambient Air Quality Standards (NAAQS). Particulate matter (e.g., TSP, PM 10 , and PM 2.5 ) is one of the important criteria pollutants of NAAQS. Their measurement methods are specified in NAAQS, and detailed technical descriptions are given in standards. This review focuses on the sampling and analysis techniques and methods in the context of PM samplers' design mentioned in countries specific PM measuring standards (e.g., EPA Part 50, CEN 12341, IS 5182(23), etc.) and their comparison wherever is necessary. It discusses, different designs of PM samplers mentioned in standards and its important components, e.g., size fractionators cutoff efficiency, PM sampler head design, flow measurement, and calibration, and also addresses the important issues that are the limitation of present standards. Our review reveals that most of the country-specific standards show common practice in measuring PM 2.5 using WINS impactor and VSCC cyclone as mentioned in EPA Part 50, except European Union (EU) standards, which has different design and parameters. For PM 10 measurement, sampler design is different in EU and Indian standards than that of U.S. EPA and other countries' standards, which is discussed in length here. All standards lack in pointing some inherent problems like change in D 50 cutoff of size fractionator of sampler under a high particle mass loading condition, which is common in countries like China and India. Other important issues where most of the standards lack include PM head design and specification, a key component of PM sampler on which the mass measurement results are largely dependent. Implications : The review paper discusses the air quality standards compliances of different countries and their comparisons. It focuses on the sampling and analysis techniques in context of PM samplers' design mentioned in countries specific PM measuring standards, and also addresses the important issues that are not mentioned in standards. Therefore, the discussions and findings of the review may be very useful while revising the existing air quality standards of different countries and to fill the research gap in this domain. Further, we have discussed several technical issues described in standards related to PM sampling which may be very helpful for PM sampler designing or modification in current designs as per the prevailing ambient conditions of a country.

Background and study aims  Population-level data on the outcomes of pancreaticobiliary endoscopic ultrasound (PB-EUS) are limited. We examined national PB-EUS and fine-needle aspiration (FNA) activity, its relation to pancreatic cancer therapy, associated mortality and adverse events. Patients and methods  Adults undergoing PB-EUS in England from 2007-2016 were identified in Hospital Episode Statistics. A pancreatic cancer cohort diagnosed within 6 months of PB-EUS were studied separately. Multivariable logistic regression models examined associations with 30-day mortality and therapies for pancreatic cancer. Results  79,269 PB-EUS in 68,908 subjects were identified. Annual numbers increased from 2,874 (28 % FNA) to 12,752 (35 % FNA) from 2007 to 2016. 8,840 subjects (13 %) were diagnosed with pancreatic cancer. Sedation related adverse events were coded in 0.5 % and emergency admission with acute pancreatitis in 0.2 % within 48 hours of PB-EUS. 1.5 % of subjects died within 30 days of PB-EUS. Factors associated with 30-day mortality included increasing age (odds ratio 1.03 [95 % CI 1.03-1.04]); male sex (1.38 [1.24-1.56]); increasing comorbidity (1.49 [1.27-1.74]); EUS-FNA (2.26 [1.98-2.57]); pancreatic cancer (1.39 [1.19-1.62]); increasing deprivation (least deprived quintile 0.76 [0.62-0.93]) and lower provider PB-EUS volume (2.83 [2.15-3.73]). Factors associated with surgical resection in the pancreatic cancer cohort included lower provider PB-EUS volume (0.44 [0.26-0.74]) and the least deprived subjects (1.33 [1.12-1.57]). 33 % of pancreatic cancer subjects who underwent EUS, did not subsequently receive active cancer treatment. Conclusions  Lower provider PB-EUS volume was associated with higher 30-day mortality and reduced rates of both pancreatic cancer surgery and chemotherapy. These results suggest potential issues with case selection in lower-volume EUS providers., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Purpose: Muscle-invasive bladder cancer (MIBC) is an aggressive disease with a complex treatment. In Brazil, as in most developing countries, data are scarce, but mortality seems exceedingly high. We have created a centralization program involving a multidisciplinary clinic in a region comprising seven municipalities. The aim of this study is to evaluate the impact of a multidisciplinary clinic and a centralization-of-care program (CABEM program) on MIBC treatment in Brazil., Patients and Methods: A total of 116 consecutive patients were evaluated. In group 1, 58 patients treated for MIBC before establishing a bladder cancer program from 2011 to 2017 were retrospectively evaluated. Group 2 represented 58 patients treated for MIBC after the implementation of the CABEM centralization program. Age, sex, staging, comorbidity indexes, mortality rates, type of treatment, and perioperative outcomes were compared., Results: Patients from group 2 versus 1 were older (68 v 64.2 years, P = .02) with a higher body mass index (25.5 v 22.6 kg/m 2 , P = .017) and had more comorbidities according to both age-adjusted Charlson Comorbidity Index (4.2 v 2.8, P = .0007) and Isbarn index (60.6 v 43.9, P = .0027). Radical cystectomy (RC) was the only treatment modality for patients in group 1, whereas in group 2, there were 31 (53%) RC; three (5%) partial cystectomies; seven (12%) trimodal therapies; 13 (22%) palliative chemotherapies; and three (5%) exclusive transurethral resections of the bladder tumor. No patient in group 1 received neoadjuvant chemotherapy, whereas it was offered to 69% of patients treated with RC. Ninety-day mortality rates were 34.5% versus 5% for groups 1 versus 2 ( P < .002). One-year mortality was also lower in group 2., Conclusion: Our data support that a centralization program, a structured bladder clinic associated with protocols, a multidisciplinary team, and inclusion of chemotherapy and radiotherapy treatments can pleasingly improve outcomes for patients with MIBC., Competing Interests: Phillipe E. SpiessLeadership: NCCN, Global Society of Rare Genitourinary TumorsHonoraria: UptoDateOther Relationship: NCCNUncompensated Relationships: Moffitt Cancer Center Sidney GlinaHonoraria: PfizerNo other potential conflicts of interest were reported.

Aim: We propose a method for screening full blood count metadata for evidence of communicable and noncommunicable diseases using machine learning (ML)., Materials & Methods: High dimensional hematology metadata was extracted over an 11-month period from Sysmex hematology analyzers from 43,761 patients. Predictive models for age, sex and individuality were developed to demonstrate the personalized nature of hematology data. Both numeric and raw flow cytometry data were used for both supervised and unsupervised ML to predict the presence of pneumonia, urinary tract infection and COVID-19. Heart failure was used as an objective to prove method generalizability., Results: Chronological age was predicted by a deep neural network with R 2 : 0.59; mean absolute error: 12; sex with AUROC: 0.83, phi: 0.47; individuality with 99.7% accuracy, phi: 0.97; pneumonia with AUROC: 0.74, sensitivity 58%, specificity 79%, 95% CI: 0.73-0.75, p < 0.0001; urinary tract infection AUROC: 0.68, sensitivity 52%, specificity 79%, 95% CI: 0.67-0.68, p < 0.0001; COVID-19 AUROC: 0.8, sensitivity 82%, specificity 75%, 95% CI: 0.79-0.8, p = 0.0006; and heart failure area under the receiver operator curve (AUROC): 0.78, sensitivity 72%, specificity 72%, 95% CI: 0.77-0.78; p < 0.0001., Conclusion: ML applied to hematology data could predict communicable and noncommunicable diseases, both at local and global levels., Competing Interests: Financial & competing interests disclosure D Steele and C McKenzie are employees of Sysmex Corporation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript., (© 2021 The authors.)

Flecainide is a class 1C antiarrhythmic, which is known to cause several cardiac and non-cardiac adverse reactions. We report a case of a 62-year-old woman with atrial fibrillation who presented with generalised myalgias and intermittent chest heaviness after being started on flecainide. She had undergone her third cardiac ablation 1 week prior to presentation and was subsequently started on flecainide 150 mg two times per day. On physical examination, she had diminished reflexes and diffuse calf tenderness. Her blood tests demonstrated an increased erythrocyte sedimentation rate and C reactive protein, but otherwise normal infectious and autoimmune labs. Her ECG showed normal sinus rhythm. A Naranjo score of 7 suggested flecainide as a probable cause of her myalgias. The patient's symptoms started to normalise within 24 hours of discontinuation of flecainide. Our case highlights that myalgias are a potential rare adverse effect that should be considered in patients prescribed flecainide., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Angiography is inaccurate in assessing functional significance of coronary lesions, and often stenoses deemed severe on angiographic assessment do not restrict coronary blood flow at rest or with maximal dilatation. Angiography-guided revascularization has not shown improvement in hard clinical outcomes in stable ischemic heart disease (SIHD). Most current guidelines for SIHD recommend invasive functional assessment of lesions to guide revascularization if prior evidence of ischemia is not available. There has been several recent advances and development of novel methods in this arena. Various contemporary clinical trials have been undertaken for validation of these indices. Here we review the physiological basis, tools, techniques, and evidence base for various invasive (resting as well as hyperemic) and noninvasive methods for functional assessment of coronary lesions. Left main stenosis, bifurcation lesions, serial stenosis, and acute coronary syndrome each causes unique disequilibrium that may affect measurements and require special considerations for accurate functional assessment., Competing Interests: Conflict of Interest None declared., (International College of Angiology. This article is published by Thieme.)

Background: High-intensity focused ultrasound (HIFU) is a novel therapy for prostate cancer. Owing to a lack of long-term data, HIFU is recommended for use only in the context of research., Objective: To examine the trend for HIFU use nationally and rates of strictures and fistulae., Design, Setting, and Participants: Patients undergoing HIFU for prostate cancer between April 2007 and March 2018 were studied in an English national database (Hospital Episode Statistics). Data on complications were included for patients with a minimum of 1-yr follow-up. Analysis of complications was controlled for other interventions., Outcome Measures and Statistical Analysis: Descriptive analyses of HIFU rates and the incidence of strictures and fistulae were carried out. Cox and logistic regression models were built for urethral stricture incidence., Results and Limitations: A total of 2320 HIFU treatments among 1990 patients were identified. The median age was 67yr (interquartile range 61-72). Some 1742 patients met the criteria for follow-up analysis. The highest-volume centre performed 1513 HIFU procedures, followed by 194 at the second highest. The number of HIFU procedures increased annually, rising from 196 to 283 per year. There were 208 patients (11.9%) who went on to have radiotherapy and 102 (5.9%) radical prostatectomy after HIFU. Following HIFU, stricture developed in 133/1290 patients (10.3%) and urinary fistula in 16/1240 (1.3%) before any further intervention. More recent years for HIFU were associated with a lower likelihood of stricture formation (2016/2017 vs 2007/2008: hazard ratio 0.30, 95% confidence interval 0.11-0.79; p=0.015). Limitations include the lack of staging information and unknown rates of HIFU outside of publicly funded health care., Conclusions: HIFU is performed at a large number of low-volume centres and complication rates do not differ from those for established therapies., Patient Summary: This report highlights the trend for provision of high-intensity focused ultrasound treatment for prostate cancer in England. The results suggest that the rate of urethral structural complications may not be lower than that for established prostate cancer treatments., (Copyright © 2019. Published by Elsevier B.V.)

Background: Some 1.5 million people in the UK have a learning disability (LD). This vulnerable group derives less benefit from population-based education programs. They are prone to underenrolment in screening programs and may lack the ability to perform self-examination., Objective: To identify patients with LD in England and assess their testicular cancer (TC) survival in comparison to the general population., Design, Setting, and Participants: Patient records were identified from the Hospital Episode Statistics database. All patients resident in England with a diagnosis of mental debility, "developmental disorder of scholastic skills", or attending under the specialty of LD between April 1, 2001 and June 30, 2015 were included., Outcome Measurements and Statistical Analysis: We measured survival outcomes according to the Kaplan-Meier method and used log-rank tests to assess survival difference between demographic groups., Results and Limitations: Of 158138 male patients with LD, 331 had TC and 32 died of cancer. LD patients had a poorer prognosis, with 10-yr TC-specific survival of 88.4% (95% confidence interval [CI] 84.5-92.4%) in the LD group versus 96.8% (95% CI 96.6-97.1%) in the non-LD group. LD patients also had lower all-cause survival rates. The 10-yr survival rate was 77.6% (95% CI 72.2-83.3%) for LD patients versus 89.9% (95% CI 89.4-90.3%) for non-LD patients, while the corresponding 5-yr rates were 84% (95% CI 79.9-88.4%) versus 92.2% (95% CI 91.8-92.5%)., Conclusions: Education regarding self-examination for TC must be provided in a format suitable for those with LD. Carers for male patients with LD should be informed about testicular examination and sinister signs., Patient Summary: Testicular cancer patients who also have a learning disability (LD) have a one in nine chance of dying, compared to a one in 36 chance for testicular cancer patients without LD. This is because patients with LD are less likely to detect the disease at an earlier stage., (Copyright © 2018. Published by Elsevier B.V.)

Biomarkers have a variety of clinical applications in multiple stages of diagnosis and therapy. Troponin T and brain natriuretic peptide are the best-known in the cardiovascular field, but experimental studies have identified new biomarkers with potential clinical value. In this article, novel biomarkers of kidney injury are investigated in the context of their relationship with atherosclerotic coronary disease. This review was carried out through a search in the PubMed database using as keywords each biomarker to be studied with the descriptor (DECS/MeSH) "Myocardial Infarction", and the keywords "coronary" and "cardiovascular", using the Boolean operator "AND". After the selection, 24 articles published between 2003 and 2017 were identified for the review. Eight biomarkers were investigated: neutrophil gelatinase-associated lipocalin (NGAL), fibroblast growth factor 23 (FGF23), tissue inhibitor of metalloproteinase-2 (TIMP-2), syndecan-1, interleukin-6 (IL-6), galectin-3, and the vascular cell adhesion molecules ICAM-1 and VCAM-1. Most identified articles were experimental studies, studies on human subjects having few participants. There are several promising biomarkers in the setting of coronary disease. The main evidence available in the literature suggests that elevated NGAL levels are associated with better prognosis after cardiac arrest and with comorbid kidney injury; elevated FGF23 is associated with coronary artery disease severity; TIMP-2 protects against coronary artery disease; increased expression of syndecan-1 is observed in myocardial infarction (MI) and protects against an exacerbated inflammatory response; IL-6 is associated with atherosclerotic disease and major cardiovascular outcomes; galectin-3 correlates with adverse clinical events post-MI; and elevated ICAM-1/VCAM-1 levels are associated with risk of coronary disease. Further studies are required to better investigate the role of each of these biomarkers in both stable coronary disease and acute coronary syndrome., (Copyright © 2020 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The optimal timing of radiotherapy after radical prostatectomy for prostate cancer is uncertain. We aimed to compare the efficacy and safety of adjuvant radiotherapy versus an observation policy with salvage radiotherapy for prostate-specific antigen (PSA) biochemical progression., Methods: We did a randomised controlled trial enrolling patients with at least one risk factor (pathological T-stage 3 or 4, Gleason score of 7-10, positive margins, or preoperative PSA ≥10 ng/mL) for biochemical progression after radical prostatectomy (RADICALS-RT). The study took place in trial-accredited centres in Canada, Denmark, Ireland, and the UK. Patients were randomly assigned in a 1:1 ratio to adjuvant radiotherapy or an observation policy with salvage radiotherapy for PSA biochemical progression (PSA ≥0·1 ng/mL or three consecutive rises). Masking was not deemed feasible. Stratification factors were Gleason score, margin status, planned radiotherapy schedule (52·5 Gy in 20 fractions or 66 Gy in 33 fractions), and centre. The primary outcome measure was freedom from distant metastases, designed with 80% power to detect an improvement from 90% with salvage radiotherapy (control) to 95% at 10 years with adjuvant radiotherapy. We report on biochemical progression-free survival, freedom from non-protocol hormone therapy, safety, and patient-reported outcomes. Standard survival analysis methods were used. A hazard ratio (HR) of less than 1 favoured adjuvant radiotherapy. This study is registered with ClinicalTrials.gov, NCT00541047., Findings: Between Nov 22, 2007, and Dec 30, 2016, 1396 patients were randomly assigned, 699 (50%) to salvage radiotherapy and 697 (50%) to adjuvant radiotherapy. Allocated groups were balanced with a median age of 65 years (IQR 60-68). Median follow-up was 4·9 years (IQR 3·0-6·1). 649 (93%) of 697 participants in the adjuvant radiotherapy group reported radiotherapy within 6 months; 228 (33%) of 699 in the salvage radiotherapy group reported radiotherapy within 8 years after randomisation. With 169 events, 5-year biochemical progression-free survival was 85% for those in the adjuvant radiotherapy group and 88% for those in the salvage radiotherapy group (HR 1·10, 95% CI 0·81-1·49; p=0·56). Freedom from non-protocol hormone therapy at 5 years was 93% for those in the adjuvant radiotherapy group versus 92% for those in the salvage radiotherapy group (HR 0·88, 95% CI 0·58-1·33; p=0·53). Self-reported urinary incontinence was worse at 1 year for those in the adjuvant radiotherapy group (mean score 4·8 vs 4·0; p=0·0023). Grade 3-4 urethral stricture within 2 years was reported in 6% of individuals in the adjuvant radiotherapy group versus 4% in the salvage radiotherapy group (p=0·020)., Interpretation: These initial results do not support routine administration of adjuvant radiotherapy after radical prostatectomy. Adjuvant radiotherapy increases the risk of urinary morbidity. An observation policy with salvage radiotherapy for PSA biochemical progression should be the current standard after radical prostatectomy., Funding: Cancer Research UK, MRC Clinical Trials Unit, and Canadian Cancer Society., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Acute limb ischemia (ALI) is a vascular emergency associated with a high risk for limb loss and death. Most cases result from in situ thrombosis in patients with preexisting peripheral arterial disease or those who have undergone vascular procedures including stenting and bypass grafts. The other common source is cardioembolic. The incidence has decreased in recent times due to better anticoagulation strategies. Patients with suspected ALI should be evaluated promptly by a vascular specialist and consideration should be given for transfer to a higher level of care if such expertise is not available locally. Initial assessment should focus on staging severity of ischemic injury and potential for limb salvage. Neurological deficits can occur early and are an important poor prognostic sign. Duplex ultrasound and computed tomography angiography help plan intervention in patients with a still-viable limb and prompt catheter-based angiography is mandated in patients with an immediately threatened limb. Further investigations need to be pursued to differentiate embolic from thrombotic cause for acute occlusion as this can change management. Options include intravascular interventions, surgical bypass, or a hybrid approach. In this article, the authors discuss the common etiologies, clinical evaluation, and management of patients presenting with acute limb ischemia., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

Introduction: Relieving obstructive jaundice in inoperable pancreato-biliary cancers improves quality of life and permits chemotherapy. Percutaneous transhepatic cholangiography with drainage and/or stenting relieves jaundice but can be associated with significant morbidity and mortality. Percutaneous transhepatic biliary drainage (PTBD) in malignant biliary obstruction was therefore examined in a national cohort to establish risk factors for poor outcomes., Methods: Retrospective study of adult patients undergoing PTBD for palliation of pancreato-biliary cancer in England between 2001 and 2014 identified from Hospital Episode Statistics. Multivariate logistic regression analysis was used to examine associations with mortality and the need for a repeat PTBD within 2 months., Results: 16 822 patients analysed (median age 72 (range 19-104) years, 50.3% men). 58% pancreatic and 30% biliary tract cancer. In-hospital and 30-day mortality were 15.3% (95% CI 14.7% to 15.9%) and 23.1% (22.4%-23.8%), respectively. 20.2% suffered a coded complication within 3 months. Factors associated with 30-day mortality: age (≥81 years OR 2.68 (95% CI 2.37 to 3.03), p<0.001), increasing comorbidity (Charlson score 20+, 3.10 (2.64-3.65), p<0.001), pre-existing renal dysfunction (2.37 (2.12-2.65), p<0.001) and non-pancreatic cancer (unspecified biliary tract 1.28 (1.08-1.52), p=0.004). Women had lower mortality (0.91 (0.84-0.98), p=0.011), as did patients undergoing PTBD in a 'higher volume' provider (84-180 PTBDs per year 0.68 (0.58-0.79), p<0.001)., Conclusions: In patients undergoing PTBD for the palliation of malignant biliary obstruction, 30-day mortality was high at 23.1%. Mortality was higher in older patients, men, those with increasing comorbidity, a cancer site other than pancreas and at 'lower-volume' PTBD providers., Competing Interests: Competing interests: KSM is the inventor of a biliary biopsy forceps kit that was first licensed in 2013. The rights have been transferred to Cook Medical and he receives minimal royalties for sales of this device., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Relieving malignant biliary obstruction improves quality of life and permits chemotherapy. Outcomes of endoscopic retrograde cholangio-pancratography(ERCP) in inoperable malignant biliary obstruction have been examined in a national cohort to establish factors associated with poor outcomes., Methods: Hospital Episode Statistics include diagnostic and procedural data for all NHS hospital attendances in England. Patients from 2006 to 2017 with a Hepaticopancreaticobiliary (HPB) malignancy who had undergone ERCP were studied. Patients undergoing a potentially curative operation were excluded. Associations between demographics, co-morbidities, unit ERCP volume and mortality were examined by logistic regression., Findings: 39,702 patients were included; 49.4% were male; median age was 75 (IQR 66-88)years. Pancreatic cancer was the most common tumour (63.9%). Mortality was 4.1%, 9.7% and 19.1% for 7-day, in hospital and 30-day respectively. On multivariable analysis: men (OR 1.20(95%CI 1.14-1.26), p < 0.001); increasing age quintile 78-83(1.73(1.59-1.89), p < 0.001), >83(2.70(2.48-2.94), p < 0.001); most deprived quintile (1.21(1.11-1.32), p < 0.001); increasing co-morbidity score >20(3.36(2.94-3.84), p < 0.001); small bowel malignancy (1.45(1.22-1.72), p < 0.001), intrahepatic biliary malignancy(1.10(1.03-1.17), p  = 0.005) and year of ERCP 2006/07 (1.37(1.22-1.55), p < 0.001) were associated with increased 30-day mortality. Extrahepatic biliary tree cancers (0.67(0.61-0.73), p <0.001), high volume providers of ERCP (>318 annually, 0.91(0.84-0.98), p  = 0.01) and high volume of ERCP for malignant obstruction (>40 annually (0.91(0.85-0.98), p  = 0.014) were negatively associated with 30-day mortality. Patients were less likely to require a second ERCP in high volume providers (>318, 8.0%) compared to low volume ((<204, 13.4%), p <0.001)., Interpretation: Short term mortality in patients with malignant biliary obstruction following ERCP was high. 30-day mortality was positively associated with increasing age and co-morbidity, men, deprivation, and earlier year of ERCP and negatively with extrahepatic biliary tree cancer and high volume ERCP providers., Funding: Internal funding only., (© 2019 Published by Elsevier Ltd.)

An estimated half of all heart failure (HF) populations has been categorized to have diastolic HF (DHF), but sparse data are available describing etiologies and predictors of 30-day readmission in DHF population. The study cohort was derived from the National Readmission Database 2013 to 2014, a subset of the Healthcare Cost and Utilization Project sponsored by the Agency for Healthcare Research and Quality. DHF was identified using International Classification of Diseases, 9th Revision code 428.3x in primary diagnosis field. Readmission etiologies were identified by International Classification of Diseases, 9th Revision code in primary diagnosis field. The primary outcome was 30-day readmission. Hierarchical multivariable logistic regression was used to adjust for confounders. In total, 192,394 patients with DHF were included, of which 40,927 (21.27%) patients were readmitted with total readmissions of 47,056 within 30 days. Predictors of increased readmissions were age (odds ratio [OR] 1.002, 95% confidence interval [CI] 1.001 to 1.0003, p <0.001), diabetes (OR 1.08, 95% CI 1.05 to 1.11, p <0.001), chronic pulmonary disease (OR 1.18, 95% CI 1.15 to 1.21, p <0.001), renal failure (OR 1.21, 95% CI 1.17 to 1.25, p <0.001), peripheral vascular disease (OR 1.05, 95% CI 1.02 to 1.09, p = 0.002), anemia (OR 1.12, 95% CI 1.10 to 1.15, p <0.001), transfusion during index admission (OR 1.18, 95% CI 1.13 to 1.23, p <0.001), discharge to the facility (OR 1.13, 95% CI 1.10 to 1.16, p <0.001), length of stay >2 days, and Charlson comorbidity index ≥3, whereas obesity (OR 0.82, 95% CI 0.80 to 0.85, p <0.001), elective admissions (OR 0.88, 95% CI 0.83 to 0.94, p <0.001), and non-Medicare/Medicaid primary payer were predictors of lower readmission rate. Most common etiologies of readmission were acute HF (28.01%), infections (9.54%), acute kidney injury (5.35%), acute respiratory failure (4.86%), and pneumonia (3.92%). In conclusion, DHF population with higher comorbidity burden, longer length of stay, and discharge to facility were prone to increased readmissions, with most common etiologies of readmission being HF, infections, and acute kidney injury., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Cancer/testis antigen (CTAg) expression is restricted to spermatogenic cells in an immune-privileged site within the testis. However, these proteins are expressed aberrantly by malignant cells and T-cell responses against CTAgs develop in many cancer patients. We investigated the prevalence, magnitude and phenotype of CTAg-specific T cells in the blood of patients with testicular germ cell tumors (TGCTs). CD8 + and CD4 + T-cell responses against MAGE-A family antigens were present in 44% (20/45) of patients' samples assayed by ex vivo IFN-γ ELISPOT. The presence of MAGE-specific CD8 + T cells was further determined following short-term in vitro expansion through the use of pMHC-I multimers containing known immunogenic peptides. Longitudinal analysis revealed that the frequency of MAGE-specific T cells decreased by 89% following orchidectomy suggesting that persistence of tumor antigen is required to sustain CTAg-specific T-cell immunity. Notably, this decrease correlated with a decline in the global effector/memory T-cell pool following treatment. Spontaneous T-cell immunity against CTAg proteins therefore develops in many patients with testicular cancer and may play an important role in the excellent clinical outcome of patients with this tumor subtype., (© 2017 The Authors. European Journal of Immunology published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Heart failure (HF) is the most common discharge diagnosis across the United States, and these patients are particularly vulnerable to readmissions, increasing attention to potential ways to address the problem. The study cohort was derived from the Healthcare Cost and Utilization Project's National Readmission Data 2013, sponsored by the Agency for Healthcare Research and Quality. HF was identified using appropriate International Classification of Diseases, Ninth Revision, Clinical Modification codes. Readmission was defined as a subsequent hospital admission within 30 days after discharge day of index admission. Readmission causes were identified using International Classification of Diseases, Ninth Revision, codes in primary diagnosis filed. The primary outcome was 30-day readmission. Hierarchical 2-level logistic models were used to evaluate study outcomes. From a total 301,892 principal admissions (73.4% age ≥65 years and 50.6% men), 55,857 (18.5%) patients were readmitted with a total of 64,264 readmissions during the study year. Among the etiologies of readmission, cardiac causes (49.8%) were most common (HF being most common followed by coronary artery disease and arrhythmias), whereas pulmonary causes were responsible for 13.1% and renal causes for 8.9% of the readmissions. Significant predictors of increased 30-day readmission included diabetes (odds ratio, 95% confidence interval, p value: 1.06, 1.03 to 1.08, p <0.001), chronic lung disease (1.13, 1.11 to 1.16, p <0.001), renal failure/electrolyte imbalance (1.12, 1.10 to 1.15, p <0.001), discharge to facilities (1.07, 1.04 to 1.09, p <0.001), lengthier hospital stay, and transfusion during index admission. In conclusion, readmission after a hospitalization for HF is common. Although it may be necessary to readmit some patients, the striking rate of readmission demands efforts to further clarify the determinants of readmission and develop strategies in terms of quality of care and care transitions to prevent this adverse outcome., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: We aim to present transperineal template-guided prostate biopsy (template biopsy) outcomes at a tertiary referral centre. Furthermore, to identify the detection rate of prostate cancer in those with a previous negative transrectal ultrasound guided prostate biopsy and the upgrade rate of those on active surveillance for Gleason 3 + 3 = 6 prostate adenocarcinoma., Material and Methods: We conducted a prospective study of 200 consecutive men who underwent template biopsy over a 22-month period in a tertiary referral centre, using a standard 24 region template prostate biopsy technique. Indications and histology results, as well as complications, were recorded., Results: Median age was 67 years and median PSA was 10 ng/mL. Overall detection rate was 47%. 39.5% of cases with previous negative transrectal biopsies were found to have prostate adenocarcinoma. 47.5% of cases on active surveillance for Gleason 3 + 3 = 6 prostate adenocarcinoma were upgraded. The most frequent complication was acute urinary retention at a rate of 12.5%, however, the use of a single prophylactic dose of tamsulosin was found to be beneficial, with 13 cases needed to treat to prevent one episode., Conclusions: Template biopsies are safe and efficacious with an overall detection rate of 47% in the present series. Due to the high detection rate, one must consider template biopsy following one negative transrectal biopsy where there is persistent clinical suspicion. Furthermore, those considering active surveillance for Gleason 3 + 3 = 6 disease should be offered template biopsy to confirm the grade of their disease.

A rapid, specific and reliable isocratic high-performance liquid chromatography combined with quadrupole time-of-flight electrospray ionization tandem mass spectrometry (LC/Q-TOF-ESI-MS/MS) method has been developed and validated for the identification and characterization of stressed degradation products of metoprolol. Metoprolol, an anti-hypertensive drug, was subjected to hydrolysis (acidic, alkaline and neutral), oxidation, photolysis and thermal stress, as per ICH-specified conditions. The drug showed extensive degradation under oxidative and hydrolysis (acid and base) stress conditions. However, it was stable to thermal, neutral and photolysis stress conditions. A total of 14 degradation products were observed and the chromatographic separation of the drug and its degradation products was achieved on a C(18) column (4.6 × 250 mm, 5 µm). To characterize degradation products, initially the mass spectral fragmentation pathway of the drug was established with the help of MS/MS, MS(n) and accurate mass measurements. Similarly, fragmentation pattern and accurate masses of the degradation products were established by subjecting them to LC-MS/QTOF analysis. Structure elucidation of degradation products was achieved by comparing their fragmentation pattern with that of the drug. The degradation products DP(2) (m/z 153) and DP(14) (m/z 236) were matched with impurity B, listed in European Pharmacopoeia and British Pharmacopoeia, and impurity I, respectively. The LC-MS method was validated with respect to specificity, linearity, accuracy and precision., (Copyright © 2011 John Wiley & Sons, Ltd.)

This review provides an overview of emerging techniques, namely, photodynamic diagnosis (PDD), narrow band imaging (NBI), Raman spectroscopy, optical coherence tomography, virtual cystoscopy, and endoscopic microscopy for its use in the diagnosis and surveillance of bladder cancer. The technology, clinical evidence and future applications of these approaches are discussed with particular emphasis on PDD and NBI. These approaches show promise to optimise cystoscopy and transurethral resection of bladder tumours.