Reconsolidation of traumatic memories protocol compared to trauma-focussed cognitive behaviour therapy for post-traumatic stress disorder in UK military veterans: a randomised controlled feasibility trial.

BACKGROUND: Post-traumatic stress disorder (PTSD) occurs more commonly in military veterans than the general population. Whilst current therapies are effective, up to half of veterans commencing treatment do not complete it. Reconsolidation of Traumatic Memories (RTM) protocol is a novel, easy to train, talking therapy with promising findings. We examine the feasibility of undertaking an efficacy trial of RTM in veterans. METHODS: A parallel group, single-centre randomised controlled feasibility trial with a post-completion qualitative interview study. Sixty military veterans were randomised 2:1 to RTM (n = 35) or Trauma Focussed Cognitive Behaviour Therapy (CBT) (n = 25). We aimed to determine the rate of recruitment and retention, understand reasons for attrition, determine data quality and size of efficacy signal. We explored veterans' perceptions of experiences of joining the trial, the research procedures and therapy, and design improvements for future veteran studies. Military veterans with a diagnosis of PTSD or complex PTSD, and clinically significant symptoms, were recruited between January 2020 and June 2021. Primary outcome was feasibility using pre-determined progression criteria alongside PTSD symptoms, with depression, recovery, and rehabilitation as secondary outcomes. Data were collected at baseline, 6, 12, and 20 weeks. Interviews (n = 15) were conducted after 20 weeks. Both therapies were delivered by trained charity sector provider therapists. RESULTS: Participants' mean age was 53 years, the mean baseline PTSD symptoms score assessed by the Post-traumatic Stress Checklist (PCL-5) was 57 (range 0-80). Fifty had complex PTSD and 39 had experienced ≥ 4 traumas. Data were analysed at 20 weeks for feasibility outcomes (n = 60) and mental health outcomes (n = 45). Seven of eight progression criteria were met. The RTM group experienced a mean 18-point reduction on the PCL-5. TFCBT group participants experienced a mean reduction of eight points. Forty-eight percent of the RTM group no longer met diagnostic criteria for PTSD compared to 16% in the TFCBT group. All veterans reported largely positive experiences of the therapy and research procedures and ways to improve them. CONCLUSION: RTM therapy remains a promising psychological intervention for the treatment of PTSD, including complex PTSD, in military veterans. With specific strengthening, the research protocol is fit for purpose in delivering an efficacy trial. TRIAL REGISTRATION: ISRCTN registration no 10314773 on 01.10.2019. Full trial protocol: available on request or downloadable at ISRCTN reg. no. 10314773.

IL-1 Signal Inhibition In Alcoholic Hepatitis (ISAIAH): a study protocol for a multicentre, randomised, placebo-controlled trial to explore the potential benefits of canakinumab in the treatment of alcoholic hepatitis.

BACKGROUND: Alcohol consumption causes a spectrum of liver abnormalities and leads to over 3 million deaths per year. Alcoholic hepatitis (AH) is a florid presentation of alcoholic liver disease characterized by liver failure in the context of recent and heavy alcohol consumption. The aim of this study is to explore the potential benefits of the IL-1ß antibody, canakinumab, in the treatment of AH. METHODS: This is a multicentre, double-blind, randomised placebo-controlled trial. Participants will be diagnosed with AH using clinical criteria. Liver biopsy will then confirm that all histological features of AH are present. Up to 58 participants will be recruited into two groups from 15 centres in the UK. Patients will receive an infusion of Canakinumab or matched placebo by random 1:1 allocation. The primary outcome is the difference between groups in the proportion of patients demonstrating histological improvement and will compare histological appearances at baseline with appearances at 28 days to assign a category of "improved" or "not improved". Patients with evidence of ongoing disease activity will receive a second infusion of canakinumab or placebo. Participants will be followed up for 90 days. Secondary outcomes include mortality and change in MELD score at 90 days. DISCUSSION: This phase II study will explore the benefits of the IL-1ß antibody, canakinumab, in the treatment of AH to provide proof of concept that inhibition of IL-1ß signalling may improve histology and survival for patients with AH. TRIAL REGISTRATION: EudraCT 2017-003724-79 . Prospectively registered on 13 April 2018.

Habitat suitability mapping of the black coral Leiopathes glaberrima to support conservation of vulnerable marine ecosystems.

The black coral Leiopathes glaberrima is an important habitat forming species that supports benthic biodiversity. Due to its high sensitivity to fishing activities, it has been classified as indicator of Vulnerable Marine Ecosystems (VMEs). However, the information on its habitat selection and large-scale spatial distribution in the Mediterranean Sea is poor. In this study a thorough literature review on the occurrence of L. glaberrima across the Mediterranean Sea was undertaken. Predictive modelling was carried out to produce the first continuous map of L. glaberrima suitable habitat in the central sector of the Mediterranean Sea. MaxEnt modeling was used to predict L. glaberrima probability of presence as a function of seven environmental predictors (bathymetry, slope, aspect North-South and East-West, kinetic energy due to currents at the seabed, seabed habitat types and sea bottom temperature). Our results show that bathymetry, slope and aspect are the most important factors driving L. glaberrima spatial distribution, while in less extent the other environmental variables. This study adds relevant information on the spatial distribution of vulnerable deep water corals in relation to the environmental factors in the Mediterranean Sea. It provides an important background for marine spatial planning especially for prioritizing areas for the conservation of VMEs.

PROState Pathway Embedded Comparative Trial: The IP3-PROSPECT study.

INTRODUCTION: The traditional double blind RCT is the 'gold standard' trial design. For a variety of reasons, these designs often fail to accrue enough participants to conclude. This is particularly challenging in localized prostate cancer. The cohort multiple randomised controlled trial (cmRCT) trial design may represent an alternative approach to delivering robust comparative data in prostate cancer. PATIENTS AND METHODS: IP3-PROSPECT is a cmRCT designed to test multiple prostate cancer interventions from eligible men in one cohort. Key to the design is two points of consent. First, at point of consent one, men referred for prostate cancer investigations are invited to join the cohort. They may then be randomly invited at a later date to consider an intervention at point of consent two. In the pilot phase we will test the acceptability and feasibility of developing the cohort. RESULTS: Acceptability and feasibility of the study will be measured by a combination of quantitative and qualitative methods. The primary outcome measure is the rate of consent to inclusion to the IP3-PROSPECT cohort. Secondary outcome measures include the completeness of data collection at sites and return rates of patient questionnaires. We will also interview patients and healthcare professionals to explore their thoughts on the implementation, practicality and efficiency of IP3-PROSPECT. CONCLUSION: The IP3-PROSPECT study will evaluate the cmRCT design in prostate cancer. Initially we will pilot the design, assessing for acceptability and feasibility. The cmRCT is an innovative design that offers potential for building a modern comparative evidence base for prostate cancer.

What is in our seas? Assessing anthropogenic litter on the seafloor of the central Mediterranean Sea.

Abundance, composition, and distribution of macro-litter found on the seafloor of the Strait of Sicily between 10 and 800 m depth has been studied using data collected by bottom trawl surveys MEDITS from 2015 to 2019. Three waste categories based on the items use were considered: single-use, fishing-related and generic-use. Over 600 sampling sites, just 14% of these were litter-free. The five-years average density of seafloor litter was 79.6 items/km2 and ranged between 46.8 in 2019 and 118.1 items/km2 in 2015. The predominant waste type was plastic (58% of all items). Regardless of material type, single-use items were a dominant (60% of items) and widespread (79% of hauls) fraction of litter with a mean density of 48.4 items/km2. Fishing-related items accounted for 12% of total litter items. Percentage of dirty hauls and litter density increased with depth. Analysis of the relation density-depth indicates a progressive increase of litter density beyond depth values situated within the interval 234-477 m depending on the litter category. A significant decrease in litter density by categories was observed over the period. Patterns of spatial distribution at the higher depths (200-80 0m) resulted stable over the years. Density hotspots of fishing-related items were found where the fishing activity that uses fish aggregating devices (FADs) is practised and in the proximity of rocky banks. Single-use and generic-use objects densities were greater on the seafloor along main maritime routes than other areas. Comparisons between the percentage of hauls littered with anthropic waste from the mid-1990s against those in 2018-19 highlighted an increase of about 10.8% and 15.3% for single-use items and fishing-related items respectively, and a decrease of 18.6% for generic-use items. This study provides a snapshot of the current situation of littering in the central Mediterranean Sea and represents a solid baseline against which the effectiveness of current and future mitigation strategies of the litter impact on marine environment can be measured.

Multi-omic analysis of the effects of low frequency ventilation during cardiopulmonary bypass surgery.

BACKGROUND: Heart surgery with cardio-pulmonary bypass (CPB) is associated with lung ischemia leading to injury and inflammation. It has been suggested this is a result of the lungs being kept deflated throughout the duration of CPB. Low frequency ventilation (LFV) during CPB has been proposed to reduce lung dysfunction. METHODS: We used a semi-biased multi-omic approach to analyse lung biopsies taken before and after CPB from 37 patients undergoing coronary artery bypass surgery randomised to both lungs left collapsed or using LFV for the duration of CPB. We also examined inflammatory and oxidative stress markers from blood samples from the same patients. RESULTS: 30 genes were induced when the lungs were left collapsed and 80 by LFV. Post-surgery 26 genes were significantly higher in the LFV vs. lungs left collapsed, including genes associated with inflammation (e.g. IL6 and IL8) and hypoxia/ischemia (e.g. HIF1A, IER3 and FOS). Relatively few changes in protein levels were detected, perhaps reflecting the early time point or the importance of post-translational modifications. However, pathway analysis of proteomic data indicated that LFV was associated with increased "cellular component morphogenesis" and a decrease in "blood circulation". Lipidomic analysis did not identify any lipids significantly altered by either intervention. DISCUSSION: Taken together these data indicate the keeping both lungs collapsed during CPB significantly induces lung damage, oxidative stress and inflammation. LFV during CPB increases these deleterious effects, potentially through prolonged surgery time, further decreasing blood flow to the lungs and enhancing hypoxia/ischemia.

Isotopic biomonitoring of N pollution in rivers embedded in complex human landscapes.

The dynamic and hierarchical structure of rivers, together with disruption of the natural river continuum by human activities, makes it difficult to identify and locate sources of nutrient pollution affecting receiving waters and observe its dispersion, thus impairing monitoring efforts. The identification of reliable indicators of anthropogenic nitrogen inputs in catchments is therefore key to achieving effective management of polluted rivers. We tested the capacity of N isotopic signatures (δ15N) of epilithon and snails to provide useful indications of organic and inorganic anthropogenic N inputs in three Mediterranean rivers differing in terms of surrounding land use and physicochemical conditions. We used a combined approach based on (i) analysis of nutrient concentrations in water, (ii) CORINE land cover classification and drainage patterns in catchments and (iii) isotopic analysis of river biota to verify whether isotopic variations were indicative of anthropic activities in the watershed, the associated alteration of water quality, and the consequent impact on snail abundance and diversity. Variation in the δ15N of epilithon within and between rivers reflected localised and diffuse N inputs from inorganic and organic sources. Negative epilithon δ15N values (<0‰) indicated inorganic pollution from agriculture. Values between 4‰ and 8‰ and those above 8‰ respectively indicated moderate organic pollution from urban areas, and high organic pollution, mostly from waste waters. The diversity and abundance of snails decreased with increasing water pollution. While their isotopic variations reflected between-river differences, they failed to indicate within-river variations in anthropogenic N inputs, since the proportion of epilithon in their diet varied along the rivers. Concluding, epilithon was a reliable indicator of anthropogenic N sources across a wide range of nutrient concentrations and anthropogenic inputs, and the proposed approach allowed us to determine the nature of nitrogen pollutants, their sources, location and dispersion along rivers embedded in complex human landscapes.

Rummaging through the bin: Modelling marine litter distribution using Artificial Neural Networks.

Marine litter has significant ecological, social and economic impacts, ultimately raising welfare and conservation concerns. Assessing marine litter hotspots or inferring potential areas of accumulation are challenging topics of marine research. Nevertheless, models able to predict the distribution of marine litter on the seabed are still limited. In this work, a set of Artificial Neural Networks were trained to both model the effect of environmental descriptors on litter distribution and estimate the amount of marine litter in the Central Mediterranean Sea. The first goal involved the use of self-organizing maps in order to highlight the importance of environmental descriptors in affecting marine litter density. The second goal was achieved by developing a multilayer perceptron model, which proved to be an efficient method to estimate the regional quantity of seabed marine litter. Results demonstrated that machine learning could be a suitable approach in the assessment of the marine litter issues.

Truncal varicose vein diameter and patient-reported outcome measures.

BACKGROUND: Varicose veins and chronic venous disease are common, and some funding bodies ration treatment based on a minimum diameter of the incompetent truncal vein. This study assessed the effect of maximum vein diameter on clinical status and patient symptoms. METHODS: A prospective observational cohort study of patients presenting with symptomatic varicose veins to a tertiary referral public hospital vascular clinic between January 2011 and July 2012. Patients underwent standardized assessment with venous duplex ultrasonography, and completed questionnaires assessing quality of life (QoL) and symptoms (Aberdeen Varicose Vein Questionnaire, EuroQol Five Domain QoL assessment and EuroQol visual analogue scale). Clinical scores (Venous Clinical Severity Score (VCSS) and Clinical Etiologic Anatomic Pathophysiologic (CEAP) class) were also calculated. Regression analysis was used to investigate the relationship between QoL, symptoms and vein diameter. RESULTS: Some 330 patients were assessed before surgery. The median maximum vein diameter was 7·0 (i.q.r. 5·3-9·2) mm overall, 7·9 (6·0-9·8) mm for great saphenous vein and 6·0 (5·2-8·9) mm for small saphenous vein. In linear regression analysis, vein diameter was shown to have a significant association with VCSS (P = 0·041). For every 1-mm increase in vein diameter, there was a 2·75-fold increase in risk of being in CEAP class C4 compared with C2. No other QoL or symptom measures were related to vein diameter. CONCLUSION: Incompetent truncal vein diameter was associated with increasing VCSS, but not a variety of other varicose vein disease-specific and generic patient-reported outcome measures.

Species distribution models of two critically endangered deep-sea octocorals reveal fishing impacts on vulnerable marine ecosystems in central Mediterranean Sea.

Deep-sea coral assemblages are key components of marine ecosystems that generate habitats for fish and invertebrate communities and act as marine biodiversity hot spots. Because of their life history traits, deep-sea corals are highly vulnerable to human impacts such as fishing. They are an indicator of vulnerable marine ecosystems (VMEs), therefore their conservation is essential to preserve marine biodiversity. In the Mediterranean Sea deep-sea coral habitats are associated with commercially important crustaceans, consequently their abundance has dramatically declined due to the effects of trawling. Marine spatial planning is required to ensure that the conservation of these habitats is achieved. Species distribution models were used to investigate the distribution of two critically endangered octocorals (Funiculina quadrangularis and Isidella elongata) in the central Mediterranean as a function of environmental and fisheries variables. Results show that both species exhibit species-specific habitat preferences and spatial patterns in response to environmental variables, but the impact of trawling on their distribution differed. In particular F. quadrangularis can overlap with fishing activities, whereas I. elongata occurs exclusively where fishing is low or absent. This study represents the first attempt to identify key areas for the protection of soft and compact mud VMEs in the central Mediterranean Sea.

Meta-analysis of colorectal cancer follow-up after potentially curative resection.

BACKGROUND: After potentially curative resection of primary colorectal cancer, patients may be monitored by measurement of carcinoembryonic antigen and/or CT to detect asymptomatic metastatic disease earlier. METHODS: A systematic review and meta-analysis was conducted to find evidence for the clinical effectiveness of monitoring in advancing the diagnosis of recurrence and its effect on survival. MEDLINE (Ovid), Embase, the Cochrane Library, Web of Science and other databases were searched for randomized comparisons of increased intensity monitoring compared with a contemporary standard policy after resection of primary colorectal cancer. RESULTS: There were 16 randomized comparisons, 11 with published survival data. More intensive monitoring advanced the diagnosis of recurrence by a median of 10 (i.q.r. 5-24) months. In ten of 11 studies the authors reported no demonstrable difference in overall survival. Seven RCTs, published from 1995 to 2016, randomly assigned 3325 patients to a monitoring protocol made more intensive by introducing new methods or increasing the frequency of existing follow-up protocols versus less invasive monitoring. No detectable difference in overall survival was associated with more intensive monitoring protocols (hazard ratio 0·98, 95 per cent c.i. 0·87 to 1·11). CONCLUSION: Based on pooled data from randomized trials published from 1995 to 2016, the anticipated survival benefit from surgical treatment resulting from earlier detection of metastases has not been achieved.

Contrasting habitat selection amongst cephalopods in the Mediterranean Sea: When the environment makes the difference.

Conservation of fish habitat requires a deeper knowledge of how species distribution patterns are related to environmental factors. Habitat suitability modelling is an essential tool to quantify species' realised niches and understand species-environment relationships. Cephalopods are important players in the marine food web and a significant resource for fisheries; they are also very sensitive to environmental changes. Here a time series of fishery-independent data (1998-2011) was used to construct habitat suitability models and investigate the influence of environmental variables on four commercial cephalopods: Todaropsis eblanae, Illex coindetii, Eledone moschata and Eledone cirrhosa, in the central Mediterranean Sea. The main environmental predictors of cephalopod habitat suitability were depth, seafloor morphology, chlorophyll-a concentration, sea surface temperature and surface salinity. Predictive maps highlighted contrasting habitat selection amongst species. This study identifies areas where the important commercial species of cephalopods are concentrated and provides significant information for a future spatial based approach to fisheries management in the Mediterranean Sea.

Predictive habitat suitability models to aid conservation of elasmobranch diversity in the central Mediterranean Sea.

Commercial fisheries have dramatically impacted elasmobranch populations worldwide. With high capture and bycatch rates, the abundance of many species is rapidly declining and around a quarter of the world's sharks and rays are threatened with extinction. At a regional scale this negative trend has also been evidenced in the central Mediterranean Sea, where bottom-trawl fisheries have affected the biomass of certain rays (e.g. Raja clavata) and sharks (e.g. Mustelus spp.). Detailed knowledge of elasmobranch habitat requirements is essential for biodiversity conservation and fisheries management, but this is often hampered by a poor understanding of their spatial ecology. Habitat suitability models were used to investigate the habitat preference of nine elasmobranch species and their overall diversity (number of species) in relation to five environmental predictors (i.e. depth, sea surface temperature, surface salinity, slope and rugosity) in the central Mediterranean Sea. Results showed that depth, seafloor morphology and sea surface temperature were the main drivers for elasmobranch habitat suitability. Predictive distribution maps revealed different species-specific patterns of suitable habitat while high assemblage diversity was predicted in deeper offshore waters (400-800 m depth). This study helps to identify priority conservation areas and diversity hot-spots for rare and endangered elasmobranchs in the Mediterranean Sea.

Validation of a semiconductor next-generation sequencing-based protocol for preimplantation genetic diagnosis of reciprocal translocations.

OBJECTIVE: We aim to validate a semiconductor next-generation sequencing (NGS)-based method to detect unbalanced chromosome translocation in preimplantation embryos. METHODS: The study consisted of a blinded retrospective evaluation with NGS of 145 whole-genome amplification products obtained from biopsy of cleavage-stage embryos or blastocysts, derived from 33 couples carrying different balanced translocations. Consistency of NGS-based copy number assignments was evaluated and compared with the results obtained by array-comparative genomic hybridization. RESULTS: Reliably identified with the NGS-based protocol were 162 segmental imbalances derived from 33 different chromosomal translocations, with the smallest detectable chromosomal segment being 5 Mb in size. Of the 145 embryos analysed, 20 (13.8%) were balanced, 43 (29.6%) were unbalanced, 53 (36.5%) were unbalanced and aneuploid, and 29 (20%) were balanced but aneuploid. NGS sensitivity for unbalanced/aneuploid chromosomal call (consistency of chromosome copy number assignment) was 99.75% (402/403), with a specificity of 100% (3077/3077). NGS specificity and sensitivity for unbalanced/aneuploid embryo call were 100%. CONCLUSIONS: Next-generation sequencing can detect chromosome imbalances in embryos with the added benefit of simultaneous comprehensive aneuploidy screening. Given the high level of consistency with array-comparative genomic hybridization, NGS has been demonstrated to be a robust high-throughput technique ready for clinical application in preimplantation genetic diagnosis for chromosomal translocations, with potential advantages of automation, increased throughput and reduced cost.

Remote ischaemic preconditioning: is it a flag on the field?

Ischaemic preconditioning is one of several different techniques that have been proposed to render the heart more resistant to ischaemia/reperfusion injuries. A significant reduction of troponin release is 'proof of concept', however, whether ischaemic preconditioning leads to improved clinical outcomes is still to be proven. Moreover, the exact mechanism of action still remains unknown since very few studies have investigated the signal transmission in humans.

Microbial contamination of domiciliary nebulisers and clinical implications in chronic obstructive pulmonary disease.

BACKGROUND AND PURPOSE: Domiciliary nebulisers are widely used in chronic obstructive pulmonary disease (COPD) but nebuliser cleaning practice has not been assessed in patients with COPD who are often elderly and may have severe disease and multiple comorbidities. We aimed to evaluate microbial contamination of home nebulisers used by patients with COPD. METHODS: Random microbiological assessment of domiciliary nebulisers was undertaken together with an enquiry into cleaning practices. We also examined the effectiveness of the trust-wide cleaning instructions in eradicating isolated microorganisms in a laboratory setting. RESULTS: The mean age of patients in this study was 71 (range 40-93) years, and in 68% of patients a large number of significant comorbidities were present. Forty-four nebuliser sets were obtained and 73% were contaminated with microorganisms at >100 colony forming units/plate. Potentially pathogenic bacteria colonised 13 of the 44 nebulisers (30%) and organisms isolated included Pseudomonas aeroginosa, Staphylococcus aureus, multidrug resistant Serratia marcesans, Escherichia coli and multiresistant Klebsiella spp, Enterobacteriaceae and fungus Fusarium oxysporum. Washing of nebuliser masks, chambers and mouthpieces achieved complete eradication of Gram-positive bacterial and fungal flora. Gram-negative organisms were incompletely eradicated, which may be attributed to the presence of biofilms. We also found that in patients with pathogenic organisms cultured on the nebuliser sets, there was a higher probability of occurrence of a COPD exacerbation with a mean number of exacerbations of 3.3 (SD=1) per year in the group in whom pathogens were isolated compared with 1.7 (SD=1.2) exacerbations per year in those whose sets grew non-pathogenic flora (p=0.02). CONCLUSIONS: Nebulisers contaminated with microorganisms are potential reservoirs delivering serious pathogens to the lung. Relationships between nebuliser contamination, clinical infection and exacerbations require further examination, but is a potential concern in elderly patients with COPD with comorbidities who fail to effectively maintain reasonable standards of nebuliser cleanliness.

Pulmonary metastasectomy in colorectal cancer: a prospective study of demography and clinical characteristics of 543 patients in the Spanish colorectal metastasectomy registry (GECMP-CCR).

OBJECTIVES: To capture an accurate contemporary description of the practice of pulmonary metastasectomy for colorectal carcinoma in one national healthcare system. DESIGN: A national registry set up in Spain by Grupo Español de Cirugía Metástasis Pulmonares de Carcinoma Colo-Rectal (GECMP-CCR). SETTING: 32 Spanish thoracic units. PARTICIPANTS: All patients with one or more histologically proven lung metastasis removed by surgery between March 2008 and February 2010. INTERVENTIONS: Pulmonary metastasectomy for one or more pulmonary nodules proven to be metastatic colorectal carcinoma. PRIMARY AND SECONDARY OUTCOME MEASURES: The age and sex of the patients having this surgery were recorded with the number of metastases removed, the interval between the primary colorectal cancer operation and the pulmonary metastasectomy, and the carcinoembryonic antigen level. Also recorded were the practices with respect to mediastinal lymphadenopathy and coexisting liver metastases. RESULTS: Data were available on 543 patients from 32 units (6-43/unit). They were aged 32-88 (mean 65) years, and 65% were men. In 55% of patients, there was a solitary metastasis. The median interval between the primary cancer resection and metastasectomy was 28 months and the serum carcinoembryonic antigen was low/normal in the majority. Liver metastatic disease was present in 29% of patients at some point prior to pulmonary metastasectomy. Mediastinal lymphadenectomy varied from 9% to 100% of patients. CONCLUSIONS: The data represent a prospective comprehensive national data collection on pulmonary metastasectomy. The practice is more conservative than the impression gained when members of the European Society of Thoracic Surgeons were surveyed in 2006/2007 but is more inclusive than would be recommended on the basis of recent outcome analyses. Further analyses on the morbidity associated with this surgery and the correlation between imaging studies and pathological findings are being published separately by GECMP-CCR.