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Background: Endovenous laser ablation and ultrasound-guided foam sclerotherapy are recommended alternatives to surgery for the treatment of primary varicose veins, but their long-term comparative effectiveness remains uncertain.Methods: In a randomized, controlled trial involving 798 participants with primary varicose veins at 11 centers in the United Kingdom, we compared the outcomes of laser ablation, foam sclerotherapy, and surgery. Primary outcomes at 5 years were disease-specific quality of life and generic quality of life, as well as cost-effectiveness based on models of expected costs and quality-adjusted life-years (QALYs) gained that used data on participants' treatment costs and scores on the EuroQol EQ-5D questionnaire.Results: Quality-of-life questionnaires were completed by 595 (75%) of the 798 trial participants. After adjustment for baseline scores and other covariates, scores on the Aberdeen Varicose Vein Questionnaire (on which scores range from 0 to 100, with lower scores indicating a better quality of life) were lower among patients who underwent laser ablation or surgery than among those who underwent foam sclerotherapy (effect size [adjusted differences between groups] for laser ablation vs. foam sclerotherapy, -2.86; 95% confidence interval [CI], -4.49 to -1.22; P<0.001; and for surgery vs. foam sclerotherapy, -2.60; 95% CI, -3.99 to -1.22; P<0.001). Generic quality-of-life measures did not differ among treatment groups. At a threshold willingness-to-pay ratio of £20,000 ($28,433 in U.S. dollars) per QALY, 77.2% of the cost-effectiveness model iterations favored laser ablation. In a two-way comparison between foam sclerotherapy and surgery, 54.5% of the model iterations favored surgery.Conclusions: In a randomized trial of treatments for varicose veins, disease-specific quality of life 5 years after treatment was better after laser ablation or surgery than after foam sclerotherapy. The majority of the probabilistic cost-effectiveness model iterations favored laser ablation at a willingness-to-pay ratio of £20,000 ($28,433) per QALY. (Funded by the National Institute for Health Research; CLASS Current Controlled Trials number, ISRCTN51995477.). [ABSTRACT FROM AUTHOR]

Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E 2 (PGE 2 ) production in cancer cells with pre-existing COX-2 activity. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE 2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Our findings suggest COX-2/PGE 2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations., (© 2022. The Author(s).)

Purpose: Cancer susceptibility and mortality are higher in males, and the mutational and transcriptomic landscape of cancer differs by sex. The current assumption is that men are at higher risk of epithelial cancers as they expose more to carcinogens and accumulate more damage than women. We present data showing women present with less aggressive primary cutaneous squamous cell carcinoma (cSCC) and early strong immune activation., Experimental Design: We explored clinical and molecular sexual disparity in immunocompetent and immunosuppressed patients with primary cSCC ( N = 738, N = 160), advanced-stage cSCC ( N = 63, N = 20) and FVB/N mice exposed to equal doses of DMBA, as well as in human keratinocytes by whole-exome, bulk, and single-cell RNA sequencing., Results: We show cSCC is more aggressive in men, and immunocompetent women develop mild cSCC, later in life. To test whether sex drives disparity, we exposed male and female mice to equal doses of carcinogen, and found males present with more aggressive, metastatic cSCC than females. Critically, females activate cancer immune-related expression pathways and CD4 and CD8 T-cell infiltration independently of mutations, a response that is absent in prednisolone-treated animals. In contrast, males increase the rate of mitosis and proliferation in response to carcinogen. Women's skin and keratinocytes also activate immune-cancer fighting pathways and immune cells at UV radiation-damaged sites. Critically, a compromised immune system leads to high-risk, aggressive cSCC specifically in women., Conclusions: This work shows the immune response is sex biased in cSCC and highlights female immunity offers greater protection than male immunity., (©2021 American Association for Cancer Research.)

Ultraviolet radiation (UVR) damages the dermis and fibroblasts; and increases melanoma incidence. Fibroblasts and their matrix contribute to cancer, so we studied how UVR modifies dermal fibroblast function, the extracellular matrix (ECM) and melanoma invasion. We confirmed UVR-damaged fibroblasts persistently upregulate collagen-cleaving matrix metalloprotein-1 (MMP1) expression, reducing local collagen (COL1A1), and COL1A1 degradation by MMP1 decreased melanoma invasion. Conversely, inhibiting ECM degradation and MMP1 expression restored melanoma invasion. Primary cutaneous melanomas of aged humans show more cancer cells invade as single cells at the invasive front of melanomas expressing and depositing more collagen, and collagen and single melanoma cell invasion are robust predictors of poor melanoma-specific survival. Thus, primary melanomas arising over collagen-degraded skin are less invasive, and reduced invasion improves survival. However, melanoma-associated fibroblasts can restore invasion by increasing collagen synthesis. Finally, high COL1A1 gene expression is a biomarker of poor outcome across a range of primary cancers.

Introduction: There is a recognised need to improve the quality of discharge documentation to facilitate the safe and effective ongoing care of patients once they leave hospital. Previous studies have focused on individual interventions, such as teaching or feedback. Our continuous quality improvement project aims to improve the quality of discharge documentation at our hospital by providing a comprehensive overhaul of the education and feedback around discharge documentation., Methods: We designed a comprehensive data analysis tool to analyse the performance of our discharge summaries. We presented at clinical governance sessions and arranged numerous teaching sessions for junior doctors. We developed a live-feedback system based on the content of a sample set of the previous month's summaries, which included poster-based feedback and group teaching., Results: Our interventions have significantly improved the quality of our discharge documentation across a broad range of categories, including the summary of the stay, actions for general practitioners and information given to patients in lay terminology., Conclusion: Our comprehensive quality improvement project has improved the quality of our discharge documentation. Further work aims to expand this project into a regional setting, as well as designing a strategy to maintain engagement of key stakeholders to ensure continued progress., (© Royal College of Physicians 2020. All rights reserved.)

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor and bi-functional lipid and protein phosphatase. We report that the metabolic regulator pyruvate dehydrogenase kinase1 (PDHK1) is a synthetic-essential gene in PTEN-deficient cancer and normal cells. The PTEN protein phosphatase dephosphorylates nuclear factor κB (NF-κB)-activating protein (NKAP) and limits NFκB activation to suppress expression of PDHK1, a NF-κB target gene. Loss of the PTEN protein phosphatase upregulates PDHK1 to induce aerobic glycolysis and PDHK1 cellular dependence. PTEN-deficient human tumors harbor increased PDHK1, a biomarker of decreased patient survival. This study uncovers a PTEN-regulated signaling pathway and reveals PDHK1 as a potential target in PTEN-deficient cancers., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims and methodAdmissions of patients to secure forensic hospitals are often lengthy. Previous research has examined factors associated with prolonged admission, but studies analysing admission data at a single medium secure unit (MSU) over a prolonged time period are lacking. We compared admission data for all patients admitted to a MSU in England during the years 1985, 1995, 2005 and 2012. RESULTS: The median length of admission increased from 167 days in 1985 to 580 days in 2012, though not in the intervening cohorts. There have been changes in the discharge destination of patients, away from independent accommodation in the community towards further care or supported accommodation.Clinical implicationsThe results suggest a change in the delivery of care. Further studies should be performed to assess whether the same trends exist at other sites. If these trends are also found elsewhere, this should trigger a specialty-wide discussion about admission length and its effects on bed availability.Declaration of interestNone.

Melanoma is a clinically heterogeneous disease, and current strategies for treatment of the primary tumour are based on pathological criteria alone. In the recent past, several DNA-sequencing and RNA-sequencing studies of primary and advanced melanoma samples have identified unique relationships between somatic mutations, genomic aberrations, and the genetic fingerprint of ultraviolet radiation (UVR). The recurrent patterns of genomic alterations reveal different disease pathways, drug targets and mechanisms limiting drug response. Here, we examine the known associations between the molecular categories of melanoma and the multidimensional UVR damage. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd., (Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.)

Objectives: The fate of all manuscripts rejected from the journal Clinical Otolaryngology (CO) over a three-year period was investigated. The aim was to review publication rate, delay and the impact factors of the journals that the papers went on to be published in., Design: In total, 917 papers were rejected from CO between 2011 and 2013. The fate of these manuscripts was determined by searching for the corresponding author's surname, and if necessary keywords from the manuscript title, in both PubMed and Google Scholar., Main Outcome Measures: The main outcome measures recorded were as follows: the subsequent publication of the article, delay to publication and journal of publication., Results: In all, 511 papers were subsequently published in journals, representing 55.7% of all rejected manuscripts. The average delay was 15.1 months (standard deviation [sd] = 8.8). The impact factor of CO was found to be higher than the average of the journals that accepted the rejected manuscripts in all 3 years. Only 41 (8%) papers were published in journals with a higher impact factor than CO. Of all subsequently accepted manuscripts, 60 (11.7%) were found only on Google Scholar (and not on PubMed)., Conclusions: Rejection from CO certainly does not prevent subsequent publication, although the papers tend to be published after a lengthy delay and in journals with a lower impact factor than CO. When performing literature searches, it is important to search more than one database to ensure as many of the relevant articles are found as possible., (© 2016 John Wiley & Sons Ltd.)

A Caucasian male in his early twenties suffering from treatment resistant schizophrenia was started on clozapine. After three days he developed tachycardia, a common side effect of clozapine induction. He had one temperature spike (38.9°C) on day ten after induction but remained clinically well. An ECG and blood tests were normal. Due to persistent tachycardia and an episode of collapse whilst seated on day 12, he was admitted to hospital for further investigation. A diagnosis of myocarditis was confirmed as a result of elevated cardiac enzyme levels and an echocardiogram. Following withdrawal of clozapine, supportive management, and initiation of cardiac medication, the patient made a successful recovery. He will be followed up with the cardiology team to ensure that his heart function returns to normal. Given the incidence of clozapine-induced myocarditis, the associated mortality risk, and diagnostic difficulties, this case raises questions about whether a formal system for identifying myocarditis should be adopted.

The centrosome is essential for cytotoxic T lymphocyte (CTL) function, contacting the plasma membrane and directing cytotoxic granules for secretion at the immunological synapse. Centrosome docking at the plasma membrane also occurs during cilia formation. The primary cilium, formed in nonhematopoietic cells, is essential for vertebrate Hedgehog (Hh) signaling. Lymphocytes do not form primary cilia, but we found and describe here that Hh signaling played an important role in CTL killing. T cell receptor activation, which "prearms" CTLs with cytotoxic granules, also initiated Hh signaling. Hh pathway activation occurred intracellularly and triggered Rac1 synthesis. These events "prearmed" CTLs for action by promoting the actin remodeling required for centrosome polarization and granule release. Thus, Hh signaling plays a role in CTL function, and the immunological synapse may represent a modified cilium.

This study characterized the acoustic properties of an International Electromechanical Commission (IEC) agar-based tissue mimicking material (TMM) at ultrasound frequencies in the range 10-47 MHz. A broadband reflection substitution technique was employed using two independent systems at 21°C ± 1°C. Using a commercially available preclinical ultrasound scanner and a scanning acoustic macroscope, the measured speeds of sound were 1547.4 ± 1.4 m∙s(-1) and 1548.0 ± 6.1 m∙s(-1), respectively, and were approximately constant over the frequency range. The measured attenuation (dB∙cm(-1)) was found to vary with frequency f (MHz) as 0.40f + 0.0076f(2). Using this polynomial equation and extrapolating to lower frequencies give values comparable to those published at lower frequencies and can estimate the attenuation of this TMM in the frequency range up to 47 MHz. This characterisation enhances understanding in the use of this TMM as a tissue equivalent material for high frequency ultrasound applications., (Copyright © 2012 World Federation for Ultrasound in Medicine & Biology. All rights reserved.)