The evolving field of Dermato-oncology and the role of dermatologists: Position Paper of the EADO, EADV and Task Forces, EDF, IDS, EBDV-UEMS and EORTC Cutaneous Lymphoma Task Force.

BACKGROUND The incidence of skin cancers has been increasing steadily over the last decades. Although there have been significant breakthroughs in the management of skin cancers with the introduction of novel diagnostic tools and innovative therapies, skin cancer mortality, morbidity and costs heavily burden the society. OBJECTIVE Members of the European Association of Dermato-Oncology, European Academy of Dermatology and Venereology, International Dermoscopy Society, European Dermatology Forum, European Board of Dermatovenereology of the European Union of Medical Specialists and EORTC Cutaneous Lymphoma Task Force have joined this effort to emphasize the fundamental role that the specialist in Dermatology-Venereology has in the diagnosis and management of different types of skin cancer. We review the role of dermatologists in the prevention, diagnosis, treatment and follow-up of patients with melanoma, non-melanoma skin cancers and cutaneous lymphomas, and discuss approaches to optimize their involvement in effectively addressing the current needs and priorities of dermato-oncology. DISCUSSION Dermatologists play a crucial role in virtually all aspects of skin cancer management including the implementation of primary and secondary prevention, the formation of standardized pathways of care for patients, the establishment of specialized skin cancer treatment centres, the coordination of an efficient multidisciplinary team and the setting up of specific follow-up plans for patients. CONCLUSION Skin cancers represent an important health issue for modern societies. The role of dermatologists is central to improving patient care and outcomes. In view of the emerging diagnostic methods and treatments for early and advanced skin cancer, and considering the increasingly diverse skills, knowledge and expertise needed for managing this heterogeneous group of diseases, dermato-oncology should be considered as a specific subspecialty of Dermatology-Venereology

Diverse Temperate Bacteriophage Carriage in Clostridium difficile 027 Strains

The hypervirulent Clostridium difficile ribotype 027 can be classified into subtypes, but it unknown if these differ in terms of severity of C. difficile infection (CDI). Genomic studies of C. difficile 027 strains have established that they are rich in mobile genetic elements including prophages. This study combined physiological studies, electron microscopy analysis and molecular biology to determine the potential role of temperate bacteriophages in disease and diversity of C. difficile 027.We induced prophages from 91 clinical C. difficile 027 isolates and used transmission electron microscopy and pulsed-field gel electrophoresis to characterise the bacteriophages present. We established a correlation between phage morphology and subtype. Morphologically distinct tailed bacteriophages belonging to Myoviridae and Siphoviridae were identified in 63 and three isolates, respectively. Dual phage carriage was observed in four isolates. In addition, there were inducible phage tail-like particles (PT-LPs) in all isolates. The capacity of two antibiotics mitomycin C and norfloxacin to induce prophages was compared and it was shown that they induced specific prophages from C. difficile isolates. A PCR assay targeting the capsid gene of the myoviruses was designed to examine molecular diversity of C. difficile myoviruses. Phylogenetic analysis of the capsid gene sequences from eight ribotypes showed that all sequences found in the ribotype 027 isolates were identical and distinct from other C. difficile ribotypes and other bacteria species.A diverse set of temperate bacteriophages are associated with C. difficile 027. The observed correlation between phage carriage and the subtypes suggests that temperate bacteriophages contribute to the diversity of C. difficile 027 and may play a role in severity of disease associated with this ribotype. The capsid gene can be used as a tool to identify C. difficile myoviruses present within bacterial genomes

Comparative genomic analysis of toxin-negative strains of Clostridium difficile from humans and animals with symptoms of gastrointestinal disease

Background: Clostridium difficile infections (CDI) are a significant health problem to humans and food animals. Clostridial toxins ToxA and ToxB encoded by genes tcdA and tcdB are located on a pathogenicity locus known as the PaLoc and are the major virulence factors of C. difficile. While toxin-negative strains of C. difficile are often isolated from faeces of animals and patients suffering from CDI, they are not considered to play a role in disease. Toxin-negative strains of C. difficile have been used successfully to treat recurring CDI but their propensity to acquire the PaLoc via lateral gene transfer and express clinically relevant levels of toxins has reinforced the need to characterise them genetically. In addition, further studies that examine the pathogenic potential of toxin-negative strains of C. difficile and the frequency by which toxin-negative strains may acquire the PaLoc are needed. Results: We undertook a comparative genomic analysis of five Australian toxin-negative isolates of C. difficile that lack tcdA, tcdB and both binary toxin genes cdtA and cdtB that were recovered from humans and farm animals with symptoms of gastrointestinal disease. Our analyses show that the five C. difficile isolates cluster closely with virulent toxigenic strains of C. difficile belonging to the same sequence type (ST) and have virulence gene profiles akin to those in toxigenic strains. Furthermore, phage acquisition appears to have played a key role in the evolution of C. difficile. Conclusions: Our results are consistent with the C. difficile global population structure comprising six clades each containing both toxin-positive and toxin-negative strains. Our data also suggests that toxin-negative strains of C. difficile encode a repertoire of putative virulence factors that are similar to those found in toxigenic strains of C. difficile, raising the possibility that acquisition of PaLoc by toxin-negative strains poses a threat to human health. Studies in appropriate animal models are needed to examine the pathogenic potential of toxin-negative strains of C. difficile and to determine the frequency by which toxin-negative strains may acquire the PaLoc

Epigenomic characterization of Clostridioides difficile finds a conserved DNA methyltransferase that mediates sporulation and pathogenesis

Clostridioides (formerly Clostridium) difficile is a leading cause of healthcare-associated infections. Although considerable progress has been made in the understanding of its genome, the epigenome of C. difficile and its functional impact has not been systematically explored. Here, we perform a comprehensive DNA methylome analysis of C. difficile using 36 human isolates and observe a high level of epigenomic diversity. We discovered an orphan DNA methyltransferase with a well-defined specificity, the corresponding gene of which is highly conserved across our dataset and in all of the approximately 300 global C. difficile genomes examined. Inactivation of the methyltransferase gene negatively impacts sporulation, a key step in C. difficile disease transmission, and these results are consistently supported by multiomics data, genetic experiments and a mouse colonization model. Further experimental and transcriptomic analyses suggest that epigenetic regulation is associated with cell length, biofilm formation and host colonization. These findings provide a unique epigenetic dimension to characterize medically relevant biological processes in this important pathogen. This study also provides a set of methods for comparative epigenomics and integrative analysis, which we expect to be broadly applicable to bacterial epigenomic studies

Parental Decisional Regret after Primary Distal Hypospadias Repair: Family and Surgery Variables, and Repair Outcomes

Purpose Decisional regret is defined as distress after making a health care choice and can be an issue for parents electing distal hypospadias repair for their sons. We assessed the influence on decisional regret of variables related to the family, surgery and outcomes. Materials and Methods Charts for 372 patients undergoing primary distal hypospadias repair between 2005 and 2012 were reviewed, and validated questionnaires, including the Decisional Regret Scale, Pediatric Penile Perception Score and Dysfunctional Voiding and Incontinence Scoring System, were administered to parents. Results Data were available for 172 of 372 families (response rate 46.2%). Of 323 parents 128 (39.6%) presented with moderately strong decisional regret, with good agreement within couples. Predictors of decisional regret included intermediate parental educational level (OR 3.19, 95% CI 1.52\u20136.69), patient not being the first born (OR 2.01, 95% CI 1.07\u20133.78), family history of hypospadias (OR 4.42, 95% CI 1.96\u20139.97), initial desire to avoid surgery (OR 2.07, 95% CI\ua01.04\u20134.12), younger age at followup (OR 0.81, 95% CI 0.72\u20130.91), presence of lower urinary tract symptoms (OR 4.92, 95% CI 1.53\u201315.81) and lower Pediatric Penile Perception Score (OR 0.86, 95% CI 0.75\u20130.99). Decisional regret was unrelated to parental desire to avoid circumcision, surgical variables, development of complications and duration of followup. Conclusions Decisional regret is a problem in a significant proportion of parents electing distal hypospadias repair for their sons. In our experience family variables seemed to be predictors of decisional regret, while surgical variables did not. Predictors of decisional regret included worse parental perception of penile appearance and the presence of lower urinary tract symptoms. However, the latter could be unrelated to surgery. Irrespective of the duration of followup, decisional regret seems decreased in parents of older patients

Performance Analysis of Microcellular Mobile Radio Systems with Selection Combining in the Presence of Arbitrary Number of Cochannel Interferences

In this paper, the performance of dual selection combining (SC) receiver in communications systems with a Rician desired signal affected by multiple Nakagami-m cochannel interferences (CCIs) is studied. This investigation is important since such environment seems to be the most realistic in microcellular radio communications systems. The performance analysis includes the channel correlation effect since in practice diversity is usually applied in small terminals so antenna elements can not be placed sufficiently apart to achieve independent fading channels. With assumption that CCIs are mutually independent and identically distributed, analytical expressions for the probability density function (PDF) and cumulative distribution function (CDF) of dual SC output signal-to-interference ratio (SIR) are derived and used to investigate important system performance measures, such as the average bit error probability (ABEP), channel capacity and outage probability. The proposed mathematical analysis is complemented by various graphically presented numerical results to show the effects of various system's parameters. In addition, the impact of diversity to the microcellular system's performance is also explored