DNA methylation clocks for dogs and humans

DNA methylation profiles have been used to develop biomarkers of aging known as epigenetic clocks, which predict chronological age with remarkable accuracy and show promise for inferring health status as an indicator of biological age. Epigenetic clocks were first built to monitor human aging, but their underlying principles appear to be evolutionarily conserved, as they have now been successfully developed for many mammalian species. Here, we describe reliable and highly accurate epigenetic clocks shown to apply to 93 domestic dog breeds. The methylation profiles were generated using the mammalian methylation array, which utilizes DNA sequences that are conserved across all mammalian species. Canine epigenetic clocks were constructed to estimate age and also average time to death. We also present two highly accurate human–dog dual species epigenetic clocks (R = 0.97), which may facilitate the ready translation from canine to human use (or vice versa) of antiaging treatments being developed for longevity and preventive medicine. Finally, epigenome-wide association studies here reveal individual methylation sites that may underlie the inverse relationship between breed weight and lifespan. Overall, we describe robust biomarkers to measure aging and, potentially, health status in canines.

Ideally, model species for antiaging research should be representative of human characteristics such as size and genetic diversity, as well as shared environment. Domestic dogs (Canis lupus familiaris) fulfill most of these criteria, offering a unique opportunity to evaluate the effectiveness of emerging antiaging interventions (1–5). There is also a significant need to develop health-monitoring tools for dogs, as there are more than 76 million companion dogs in the United States alone (6).Over 340 dog breeds are recognized worldwide, which are each a closed breeding population under strong selection for morphologic and behavioral traits. As a result, dogs share extensive phenotypic and genetic homogeneity within breeds and increased heterogeneity between breeds (7). Small breeds live considerably longer than large breeds (8), offering the rare chance to understand the relationship between size and lifespan within a single mammalian species. Dogs also share a similar yet accelerated trajectory of development as humans including infancy, puberty, adulthood, and senescence in about 20% of the human lifespan (5, 9). As a result, dogs represent an ideal system for studies of comparative aging, where intrabreed studies can be conducted on a background of limited diversity.Our previous work on DNA-methylation-based age estimators (i.e., epigenetic clocks) for dogs and wolves (10) described one of the first nonhuman epigenetic clocks. We determined that the age dependence of DNA methylation (DNAm) is conserved at syntenic sites in the genomes of multiple mammalian species including humans. However, a small sample size (n < 150) and technical limitations associated with the measurement platform (reduced representation bisulfite sequencing) limited the generalizability of the results. Furthermore, our initial study utilized only a few canine breeds, which prevented testing the relationship between epigenetic aging and breed lifespan. Here, we report the development of a canine epigenetic clock based on 93 recognized dog breeds (11) using a mammalian array (HorvathMammalMethylChip40) that profiles highly conserved cytosines across mammalian species (12).In this study, we present dual-species epigenetic clocks that apply to both humans and dogs. We test whether short-lived breeds exhibit faster epigenetic aging than long-lived breeds and develop epigenetic predictors of the average time to death. Finally, we investigate the relationship between breed size and lifespan and characterize 5''-C-phosphate-G-3'' regions (CpGs) that are correlated with age or breed characteristics such as median lifespan or average adult weight.     

Electrocardiographic Characteristics and Associated Outcomes in Patients with Takotsubo Syndrome. Insights from the RETAKO Registry

Electrocardiographic disturbances in Takotsubo syndrome have been previously partially described but their consequences remain mostly unknown. Our aim was to describe the prevalence and prognostic significance of different electrocardiographic features in patients with Takotsubo syndrome. Our data come from the Spanish multicenter REgistry of TAKOtsubo syndrome (RETAKO). All patients with an available 12-lead surface electrocardiogram at admission and 48 hours post-admission were included. A total of 246 patients were studied, mean age was 71.3 ± 11.5 and 215 (87.4%) were women. ST-segment elevation was seen in 143 patients (59.1%) and was present in ≥2 wall leads in 97 (39.8%). Exclusive elevation in inferior leads was infrequent (5% - 2.0%). After 48 hours, 198 patients (88.0%) developed negative T waves in a median of 8 leads with a mean amplitude of 0.7 ± 0.5 mV and 137 (60.9%) had pathological Q waves. The mean corrected QT interval was 520 ± 72 ms. Corrected QT interval was independently associated with the primary endpoint of all-cause death and nonfatal cardiovascular events (P = 0.002) and all-cause death (P = 0.008). A higher heart rate at admission was an independent predictor of the primary endpoint (P = 0.001) and of acute pulmonary edema (P = 0.04). ST-segment elevation with reciprocal depression was an independent predictor of all-cause death (P = 0.04). Absence of ST-segment deviation was a protective factor (P = 0.005) for the primary endpoint. Tachyarrhythmias were independently associated with cardiogenic shock (P< 0.001). Takotsubo syndrome patients present with distinct electrocardiographic features. Prolonged corrected QT interval, tachyarrhythmias, heart rate at admission, and more extensive repolarization alterations are associated with poor outcomes.     

What do firefighters desire from the next generation of personal protective equipment? Outcomes from an international survey

The purpose of this study was to investigate smart features required for the next generation of personal protective equipment (PPE) for firefighters in Australia, Korea, Japan, and the USA. Questionnaire responses were obtained from 167 Australian, 351 Japanese, 413 Korean, and 763 U.S. firefighters (1,611 males and 61 females). Preferences concerning smart features varied among countries, with 27% of Korean and 30% of U.S. firefighters identifying ‘a location monitoring system’ as the most important element. On the other hand, 43% of Japanese firefighters preferred ‘an automatic body cooling system’ while 21% of the Australian firefighters selected equally ‘an automatic body cooling system’ and ‘a wireless communication system’. When asked to rank these elements in descending priority, responses across these countries were very similar with the following items ranked highest: ‘a location monitoring system’, ‘an automatic body cooling system’, ‘a wireless communication system’, and ‘a vision support system’. The least preferred elements were ‘an automatic body warming system’ and ‘a voice recording system’. No preferential relationship was apparent for age, work experience, gender or anthropometric characteristics. These results have implications for the development of the next generation of PPE along with the international standardisation of the smart PPE.     

Surgical approach to the locoregional recurrence of cancer of the rectum

A literature review has been made on the pelvic recurrence of rectal cancer using the MedLine, Ovid, EMBASE, Cochrane and Cinahl data bases. Assessment of the locoregional recurrence must be made using imaging tests in order to rule out the presence of metastasis, as well as for locating its exact location within the pelvis. As the only curative treatment should be complete resection of the recurrence with negative margins, a pre-operative CT, NMR, endorectal ultrasound and PET-CT must be performed to determine its resectability. For a potential cure, radical resections must be made, with the technique varying according to whether the location is central (axial), posterior (presacral) or lateral, as well as treatment directed at the primary tumour. Neoadjuvant treatments, brachiterapy and intra-operative radiotherapy improve the local control results and survival in these patients.     

A fungicidal monoclonal antibody protects against murine invasive candidiasis

Mice infected by Candida albicans and treated with monoclonal antibody C7 survived longer than saline-treated animals. A prozone-like effect was observed. The in vitro candidacidal activity of macrophages was strongly enhanced when C. albicans was opsonized by C7 and complete murine serum was present.     

Influence of antipseudomonal agents on Pseudomonas aeruginosa colonization and acquisition of resistance in critically ill medical patients

Objective  To assess the role of antipseudomonal agents on Pseudomonas aeruginosa colonization and acquisition of resistance. Design  Prospective cohort study. Setting  Two medical intensive care units. Patients and participants  346 patients admitted for ≥ 48 h. Intervention  Analysis of data from an 8-month study comparing a mixing versus a cycling strategy of antibiotic use. Measurements and results  Surveillance cultures from nares, pharynx, rectum, and respiratory secretions were obtained thrice weekly. Acquisition of resistance was defined as the isolation, after 48 h of ICU stay, of an isolate resistant to a given antibiotic if culture of admission samples were either negative or positive for a susceptible isolate. Emergence of resistance refers to the conversion of a defined pulsotype from susceptible to non-susceptible. Forty-four (13%) patients acquired 52 strains of P. aeruginosa. Administration of piperacillin-tazobactam for ≥ 3 days (OR 2.6, 95% CI 1.09–6.27) and use of amikacin for ≥ 3 days (OR 2.6, 95% CI 1.04–6.7) were positively associated with acquisition of P. aeruginosa, whereas use of quinolones (OR 0.27, 95% CI 0.1–0.7) and antipseudomonal cephalosporins (OR 0.27, 95% CI 0.08–0.9) was protective. Exposure to quinolones and cephalosporins was not associated with the acquisition of resistance, whereas it was linked with usage of all other agents. Neither quinolones nor cephalosporins were a major determinant on the emergence of resistance to themselves, as resistance to these antibiotics developed at a similar frequency in non-exposed patients. Conclusions  In critically ill patients, quinolones and antipseudomonal cephalosporins may prevent the acquisition of P. aeruginosa and may have a negligible influence on the acquisition and emergence of resistance.