Effects of Adjunctive rh-transferrin on Susceptibility and Emergence of Resistance in Gram-negative Pathogens

Introduction: Human pathogens have experienced selective pressure from antibiotics for nearly 80 years. The high speed of antibiotic resistance formation in nosocomial bacteria together with overuse of antibiotics has promoted the current multidrug resistance crisis. The problem is especially important for Russian healthcare, where the majority of isolated clinical strains of A. baumannii are drug-resistant: 93% of them are resistant to Cefoperazone, 61,2% - to Amicacin, 51,9% - to Levofloxacin [1]. We attempted to decrease the emergence of resistant mutants using a novel combination of antibiotics with recombinant human transferrin (rh-transferrin). We hypothesized that rh- transferrin, which functions by passively starving the bacteria of iron needed for microbial replication [2], would exert less selective pressure as compared to traditional antibiotics. It has been reported in previous studies that transferrin has broad antimicrobial effects in vitro against Gram-positive and Gram-negative bacteria and fungal pathogens [3]. The main goal of this project is to study the in vitro and in vivo effect of adjunctive transferrin on susceptibility and emergence of resistance in the Gram-negative pathogens Acinetobacter baumannii and Klebsiella pneumoniae. Materials and Methods: Time-kill assays were done using ciprofloxacin or meropenem with and without transferrin. Viability was assessed at 1, 2, 4, 6, 8, and 24 hours for A. baumannii and at 1, 4, and 24 hours for K. pneumonia. The assay was done using either resazurin (cellular metabolic readout) or quantitative culturing. Antibiotic-resistant mutants were selected by passaging a high inoculum of bacteria in sub-lethal concentrations of antibiotic for 24 hours or by serial passaging lower inocula of bacteria for 20 days with or without rh-transferrin. C3HeB/FeJ mice were infected IV with 2x10^7 CFU of A. baumannii LAC-4 strain and mice were administered a sub-therapeutic dose of ciprofloxacin (50 mg/kg BID) with and without transferrin (100 mg/kg). Results: The time-kill assays for both bacterial species showed no interaction between the antibiotics and rh-transferrin in vitro for most strains. Mutant selection for 24 hours and 20 days demonstrated a decrease in mutant emergence in the group treated with a combination of rh-transferrin and antibiotics compared to antibiotics alone. The 20-day passage experiment selected for mutants with an extremely high level of resistance. LD100 for all strains in C3HeB/FeJ mice were defined. In vivo efficacy experiments will begin soon with combination therapy. Conclusions: We found that transferrin containing therapeutic regimens suppressed the emergence of resistance in vitro, and is promising as an adjunct to antibiotic therapy

ENIGMA and global neuroscience: A decade of large-scale studies of the brain in health and disease across more than 40 countries

This review summarizes the last decade of work by the ENIGMA (Enhancing NeuroImaging Genetics through Meta Analysis) Consortium, a global alliance of over 1400 scientists across 43 countries, studying the human brain in health and disease. Building on large-scale genetic studies that discovered the first robustly replicated genetic loci associated with brain metrics, ENIGMA has diversified into over 50 working groups (WGs), pooling worldwide data and expertise to answer fundamental questions in neuroscience, psychiatry, neurology, and genetics. Most ENIGMA WGs focus on specific psychiatric and neurological conditions, other WGs study normal variation due to sex and gender differences, or development and aging; still other WGs develop methodological pipelines and tools to facilitate harmonized analyses of "big data" (i.e., genetic and epigenetic data, multimodal MRI, and electroencephalography data). These international efforts have yielded the largest neuroimaging studies to date in schizophrenia, bipolar disorder, major depressive disorder, post-traumatic stress disorder, substance use disorders, obsessive-compulsive disorder, attention-deficit/hyperactivity disorder, autism spectrum disorders, epilepsy, and 22q11.2 deletion syndrome. More recent ENIGMA WGs have formed to study anxiety disorders, suicidal thoughts and behavior, sleep and insomnia, eating disorders, irritability, brain injury, antisocial personality and conduct disorder, and dissociative identity disorder. Here, we summarize the first decade of ENIGMA's activities and ongoing projects, and describe the successes and challenges encountered along the way. We highlight the advantages of collaborative large-scale coordinated data analyses for testing reproducibility and robustness of findings, offering the opportunity to identify brain systems involved in clinical syndromes across diverse samples and associated genetic, environmental, demographic, cognitive, and psychosocial factors

“Do-not-resuscitate orders: a clinical ethics perspective” medicolegal and bioethics

Closed chest cardiopulmonary resuscitation (CPR), having been so successful after its introduction in the operating room for saving lives of anesthetized patients, was adopted for use in the intensive care units, then hospital-wide, and finally to out of hospital patients. This has lead to ethical dilemmas involving patients who must themselves request discontinuation of artificial organ function devices and treatments, or placing family members in the difficult positions of having to make those decisions for their unconscious and suffering relatives. In this review, the Ethical principles on which physicians, hospitals, patients, and surrogate decision makers rely in order to apply their perceived moral obligations to provide patient safety, comfort, and treatment are examined with particular emphasis on do not resuscitate orders (DNR). It is clear that DNR does not equate with do not treat.Закрита серцево-легенева реанімація (СЛР), завдяки успіху, якого вона здобула післявпровадження її в операційних для рятування життів пацієнтів під час наркозу, булаприйнята у відділеннях інтенсивної терапії, потім поширилась до масштабів цілихлікарень, і нарешті вийшла за їх межі. Це призвело до етичної дилеми стосовнопацієнтів, які добровільно вимагають припинення штучних методів підтримкифункціонування їх органів, або ж стосовно тих тяжких ситуацій, коли члени родиниповинні прийняти подібне рішення щодо своїх родичів, які страждають, алеперебувають без свідомості. В цьому огляді було проаналізовано етичні принципи, наякі опираються лікарі, лікарні, пацієнти (або ж їх довірені особи) для втілення своїхсуб’єктивних моральних обов’язків забезпечення комфорту, захисту та лікуванняпацієнтів – з особливим акцентом на наказах «відмовитись від реанімації» (DNR, DoNot Resuscitate orders). Безсумнівно, «не реанімувати» не означає «не лікувати»

Modern Achievements in Neuroscience and Brain-Computer Interfaces

Nowadays is a unique time in the history of humankind because the accumulation of fundamental scientific knowledge is going faster and faster. The knowledge is doubled every 6 years. However, only 10% of this is utilized by people. From this perspective, the important scientific problem now is the study of human brain and preservation of its functions over time. The latter is especially relevant in anesthesia where the physician manipulates his patient’s brain functions every day. In 1953 this idea was proposed by Dr. V. Negovsky, the founder of Russian reanimatology. He believed that the study of brain functions in critically ill patients and the restoration of such functions after the intensive care period is the main function of an anesthesiologist. In 1990 the international project «The Decade of the Brain» was started. It contributed significantly to the understanding of emotions and consciousness, mapping and studying brain networks. Another project “The Human Genome” which revolutionized medicine, was successfully completed in 2003. The scientific achievements from both projects made the ground for personalized medicine. It is believed that future research in neuroscience will mainly go in a few directions. One of them would be the development of a genetic atlas of brain architecture, which will reveal the set of activated genes for each period of human ontogenesis and the mechanisms of this process. The scientific team from USC and UC Davis captured on video the process of synapsis formation and traced the development of intercellular connections between neural cells. It gave a ground for a new research project “Connectome”. The project is supposed to create a 4-D map of all neurons and all 100 trillion of their connections in the brain. The understanding of brain chains and networks will improve the diagnostics of brain diseases. The mapping of brain activity will create a “functional connectome”, which could shed light on human behavior and mental disorders. The other breakthrough achievement was brain pacemaker for patients with Alzheimer disease. The scientists from USC and Wake Forest University found a way to upload the memories from the brain to the digital source. “ENIGMA” is an international consortium in genetic neuroscience, which aims to study predisposition to brain diseases. The project has been ongoing since 2009 and for now, it is the largest neuroimaging research team in the world. By 2015 the data from more than 55,000 people have been analyzed. The main focus is on the most complicated disorders like Alzheimer disease. It was shown for this particular disease that 5-years delay in the onset of the disease (from 76 to 81 years of age) will result in 50% decrease in the number of affected people worldwide. The development of new therapeutic approaches in neuroscience will certainly rely on brain genetic structure, functional connections, and features of brain evolution. By developing the information technologies we are getting closer to the breakthrough in neuroscience in the near future

Implementing an infection control and prevention program decreases the incidence of healthcare-associated infections and antibiotic resistance in a Russian neuro-ICU

Abstract Background The impact of infection prevention and control (IPC) programs in limited resource countries such as Russia are largely unknown due to a lack of reliable data. The aim of this study is to evaluate the effect of an IPC program with respect to healthcare associated infection (HAI) prevention and to define the incidence of HAIs in a Russian ICU. Methods A pioneering IPC program was implemented in a neuro-ICU at Burdenko Neurosurgery Institute in 2010 and included hand hygiene, surveillance, contact precautions, patient isolation, and environmental cleaning measures. This prospective observational cohort study lasted from 2011 to 2016, included high-risk ICU patients, and evaluated the dynamics of incidence, etiological spectrum, and resistance profile of four types of HAIs, including subgroup analysis of device-associated infections. Survival analysis compared patients with and without HAIs. Results We included 2038 high-risk patients. By 2016, HAI cumulative incidence decreased significantly for respiratory HAIs (36.1% vs. 24.5%, p-value = 0.0003), urinary-tract HAIs (29.1% vs. 21.3%, p-value = 0.0006), and healthcare-associated ventriculitis and meningitis (HAVM) (16% vs. 7.8%, p-value = 0.004). The incidence rate of EVD-related HAVM dropped from 22.2 to 13.5 cases per 1000 EVD-days. The proportion of invasive isolates of Klebsiella pneumoniae and Acinetobacter baumannii resistant to carbapenems decreased 1.7 and 2 fold, respectively. HAVM significantly impaired survival and independently increasing the probability of death by 1.43. Conclusions The implementation of an evidence-based IPC program in a middle-income country (Russia) was highly effective in HAI prevention with meaningful reductions in antibiotic resistance

Emerg Infect Dis

Shiga toxin-producing Escherichia coli (STEC) is a pathogen that causes gastroenteritis and bloody diarrhea but can lead to severe disease, such as hemolytic uremic syndrome (HUS). STEC serotype O78:H(-) is rare among humans, and infections are often asymptomatic. We detected a sorbitol-fermenting STEC O78:H(-):stx(1c):hlyA in blood and fecal samples of a 2-week-old boy who had bacteremia and HUS and in fecal samples of his asymptomatic family members. The phenotypic and genotypic characteristics and the virulence properties of this invasive STEC were investigated. Our findings demonstrate that contrary to earlier suggestions, STEC under certain conditions can invade the human bloodstream. Moreover, this study highlights the need to implement appropriate diagnostic methods for identifying the whole spectrum of STEC strains associated with HUS

Risk Factors of Healthcare- Associated Infections in ICU Are Effectively Identified by Machine Learning

<p>Poster #404 at SHEA 2018.</p

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