Quantitative Analysis of Immune Infiltrates in Primary Melanoma.

Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3+CD8+ cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68+ macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68+HLA-DR+) macrophages than nonactivated (CD68+HLA-DR-) macrophages (P < 0.0001). CTLs were further in proximity from proliferating SOX10+ melanoma cells than nonproliferating ones (P < 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma (P = 0.0038 and P = 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor (P = 0.0147 and P = 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR+ CTLs (P = 0.0005). CTL distance to HLA-DR- macrophages associated with poor DSS (P = 0.0016), whereas distance to Ki67- tumor cells associated inversely with DSS (P = 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis (P = 0.009) and merits further development as a biomarker for clinical application

Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations

Background Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease affecting multiple body systems with wide variability in presentation. In 2013, Pediatric Neurology published articles outlining updated diagnostic criteria and recommendations for surveillance and management of disease manifestations. Advances in knowledge and approvals of new therapies necessitated a revision of those criteria and recommendations. Methods Chairs and working group cochairs from the 2012 International TSC Consensus Group were invited to meet face-to-face over two days at the 2018 World TSC Conference on July 25 and 26 in Dallas, TX, USA. Before the meeting, working group cochairs worked with group members via e-mail and telephone to (1) review TSC literature since the 2013 publication, (2) confirm or amend prior recommendations, and (3) provide new recommendations as required. Results Only two changes were made to clinical diagnostic criteria reported in 2013: “multiple cortical tubers and/or radial migration lines” replaced the more general term “cortical dysplasias,” and sclerotic bone lesions were reinstated as a minor criterion. Genetic diagnostic criteria were reaffirmed, including highlighting recent findings that some individuals with TSC are genetically mosaic for variants in TSC1 or TSC2. Changes to surveillance and management criteria largely reflected increased emphasis on early screening for electroencephalographic abnormalities, enhanced surveillance and management of TSC-associated neuropsychiatric disorders, and new medication approvals. Conclusions Updated TSC diagnostic criteria and surveillance and management recommendations presented here should provide an improved framework for optimal care of those living with TSC and their families

AVONET: morphological, ecological and geographical data for all birds

Functional traits offer a rich quantitative framework for developing and testing theories in evolutionary biology, ecology and ecosystem science. However, the potential of functional traits to drive theoretical advances and refine models of global change can only be fully realised when species‐level information is complete. Here we present the AVONET dataset containing comprehensive functional trait data for all birds, including six ecological variables, 11 continuous morphological traits, and information on range size and location. Raw morphological measurements are presented from 90,020 individuals of 11,009 extant bird species sampled from 181 countries. These data are also summarised as species averages in three taxonomic formats, allowing integration with a global phylogeny, geographical range maps, IUCN Red List data and the eBird citizen science database. The AVONET dataset provides the most detailed picture of continuous trait variation for any major radiation of organisms, offering a global template for testing hypotheses and exploring the evolutionary origins, structure and functioning of biodiversity

Antibiotic-resistant infections in primary care are symptomatic for longer and increase workload: outcomes for patients with E.coli UTIs

Background: Antimicrobial resistance is considered to be one of the major threats to public health. However, the practical implications for patients and workload in primary care are largely unknown. Aim: To determine outcomes for patients managed in primary care with an antibiotic resistant compared to an antibiotic sensitive Escherichia coli (E. coli) urinary tract infection (UTI). Design: Nested case control study with prospective measurement of outcomes. Setting: Ten general practices in South Wales. Method: Patients consulting with symptoms suggestive of UTI identified through systematic sampling, and with a laboratory proven E. coli infection, were followed up by interview 1 month after their consultations and by searching of their medical records. Results: Nine hundred and thirty-two patients were interviewed and had their medical records reviewed. The risk of patients reporting 'feeling poorly', 'frequency or pain on urinating' and being 'out of action' for more than 5 days after consulting was significantly increased for patients with resistant compared to sensitive infections. After adjusting for risk factors, there was an increased risk of 'frequency or pain on urinating' and 'being out of action' for those infected with a resistant E. coli. The median number of maximum reported days with at least one symptom was 12 days for patients with E. coli infections resistant to trimethoprim, 7 days for infections resistant to ampicillin, 7 days for infections resistant to any antibiotic, and 5 days for infections sensitive to all tested antibiotics. Even if treated with an appropriate antibiotic, infections caused by a resistant strain were symptomatic for longer. For those infected with an organism resistant to at least one antibiotic, the odds ratio (OR) for re-visiting their GP within the next 30 days for the UTI was 1.47 (95% confidence interval [CI] = 1.10 to 1.95). The OR was 1.49 (95% CI = 1.11 to 2.00) for ampicillin resistance and 2.48 (95% CI = 1.70 to 3.59) for trimethoprim resistance. Conclusions: Resistant E. coli UTIs are symptomatic for longer and cause increased work load in general practice

Fostering engagement with health and housing innovation : development of participant personas in a social housing cohort

Funding: European Regional Development Fund (ERDF) and the South West Academic Health Sciences Network.Background : Personas, based on customer or population data, are widely used to inform design decisions in the Commercial Sector. The variety of methods available mean that personas can be produced from various sizes and types of project. Objective : To experiment with the use of personas that bring together survey, household air measurements and electricity-usage sensor, and interview data within a research and innovation project, with the aim of supporting eHealth and eWellbeing product, process and service development through broadening the engagement with and understanding of the data about the local community. Methods : The project participants were social housing residents (adults only) living in central Cornwall, a rural unitary authority in the United Kingdom. A total of 329 households were recruited between September 2017 and November 2018, with 235 (71.4%) providing complete baseline survey data on demographics, socioeconomic position, household composition, home environment, technology ownership, pet ownership, smoking, social cohesion, volunteering, caring, mental wellbeing, physical and mental health-related quality of life and activity. K-prototype cluster analysis was used to identify eight clusters among the baseline survey responses. The sensor and interview data were subsequently analysed by cluster and the insights from all three of the data sources brough together to produce the personas, known as the Smartline Archetypes. Results : The Smartline Archetypes proved to be an engaging way of presenting data, accessible to a broader group of stakeholders than those who accessed the raw anonymised data, thereby providing a vehicle for greater research engagement, innovation and impact. Conclusions : Through the adoption of a tool widely used in practice, research projects could generate greater policy and practical impact, while also becoming more transparent and open to the public.Publisher PDFPeer reviewe

Containing antibiotic resistance: decreased antibiotic-resistant coliform urinary tract infections with reduction in antibiotic prescribing by general practices

BACKGROUND: GPs are urged to prescribe antibiotics less frequently, despite lack of evidence linking reduced antibiotic prescribing with reductions in resistance at a local level. AIM: To investigate associations between changes in antibiotic dispensing and changes in antibiotic resistance at general-practice level. DESIGN OF STUDY: Seven-year study of dispensed antibiotics and antibiotic resistance in coliform isolates from urine samples routinely submitted from general practice. SETTING: General practices in Wales. METHOD: Multilevel modelling of trends in resistance to ampicillin and trimethoprim, and changes in practice total antibiotic dispensing and amoxicillin and trimethoprim dispensing. RESULTS: The primary analysis included data on 164 225 coliform isolates from urine samples submitted from 240 general practices over the 7-year study period. These practices served a population of 1.7 million patients. The quartile of practices that had the greatest decrease in total antibiotic dispensing demonstrated a 5.2% reduction in ampicillin resistance over the 7-year period with changes of 0.4%, 2.4%, and -0.3% in the other three quartiles. There was a statistically significant overall decrease in ampicillin resistance of 1.03% (95% confidence interval [CI] = 0.37 to 1.67%) per decrease of 50 amoxicillin items dispensed per 1000 patients per annum. There were also significant reductions in trimethoprim resistance in the two quartiles of practices that reduced total antibiotic dispensing most compared with those that reduced it least, with an overall decrease in trimethoprim resistance of 1.08% (95% CI = 0.065 to 2.10%) per decrease of 20 trimethoprim items dispensed per 1000 patients per annum. Main findings were confirmed by secondary analyses of 256 370 isolates from 527 practices that contributed data at some point during the study period. CONCLUSION: Reducing antibiotic dispensing at general-practice level is associated with reduced local antibiotic resistance. These findings should further encourage clinicians and patients to use antibiotics conservatively