Kv3 channels in the murine lumbo-sacral spinal cord

Ion channels are important in a range of physiological processes and can be targeted pharmacologically and therapeutically. Kv3 channels are voltage-gated potassium ion channels important in neuronal firing and synaptic transmission and are highly expressed in the brain and spinal cord. The main aim of this thesis was to investigate the role of Kv3 channels in the spinal cord and we did this in three ways. Using fluorescence immunohistochemistry we identified, for the first time, expression of Kv3 subunits in the murine lumbosacral spinal cord, at the level of neuronal circuitry that regulates bladder function. Specifically, some of this expression could be attributed to both excitatory and inhibitory synaptic structures closely apposed to bladder motoneurones, the final output neurones in the control of bladder function. Kv3 expression at these locations was susceptible to ageing and was reduced in aged mice. Kv3 channels were functional in synapses as Kv3 blockade with TEA increased the amplitude of the post-synaptic response. To determine the role of Kv3 channels in a function of the spinal cord, specifically, control over bladder function, we used a modulator AUT1 (Autifony Therapeutics Ltd), which is selective for Kv3 channels, Treatment with AUT1 reduced bladder output in a dose-dependent manner, acutely in young mice and chronically in aged mice suggesting involvement of Kv3 channels in bladder output. The effect of AUT1 on specific Kv3 subunits was determined in HEK expression cell lines where it was found to modulate both a previously unexplored subunit (Kv3.4a) and a physiologically relevant heteromer. In lumbosacral spinal cord slices, AUT1 suppressed the excitability of interneurones, suggesting that the reduction in bladder output could be occurring at the level of interneurones in the lumbosacral spinal cord. Modulating Kv3 channels in this way may be a viable therapeutic strategy for conditions presenting with an overactive bladder

A Pharmacist-Assisted Initiative to Improve Chronic Pain Management and Reduce Opioid Use in Primary Care

Background– Since publication of the 2016 CDC Guideline for Prescribing Opioids for Chronic Pain, there have been growing concerns that providers, including those in primary care, are tapering opioids too quickly and without concomitant use of non-opioid strategies for pain, leading to inadequate pain management. As a result, in November 2022 the CDC published Clinical Practice Guidelines for Prescribing Opioids for Pain, emphasizing the importance of creating comprehensive care plans for pain management and developing a consensual plan between provider and patient when tapering opioids. Objective–Determine the impact of a pharmacist-assisted approach aimed at helping primary care providers minimize opioid use while improving management of chronic, non-malignant pain (CNMP).  Methods – This quality improvement project focused on one primary care provider partnering with a pharmacist to reassess the management of patients on long-term opioid therapy (LTOT) for CNMP. The intervention included a letter informing patients of the provider’s intent, pharmacist outreach to intervention patients, and pharmacist development of a patient registry, updated regularly with clinical data, recommendations, and outcomes for the provider to reference throughout the project. The intervention group was compared to patients prescribed opioids for CNMP by the remaining providers at the clinic who did not engage in the quality initiative.    Results – The intervention group had a mean effective daily morphine milligram equivalent (MME) reduction of 73.7% (17.2% control) after 18 months and 60% of patients discontinued opioids (14.3% control). In a subset of patients with functional assessment scores, 93.3% were either improved or unchanged, despite a 62.5% decrease in their mean effective daily MME. In both groups, one patient transferred care to a new provider.   Conclusions – With targeted recommendations and assistance from a pharmacist, a primary care provider can make significant progress in improving management of CNMP while reducing opioid prescribing

Induction of β-Lactamase Activity and Decreased β-Lactam Susceptibility by CO2 in Clinical Bacterial Isolates

Antimicrobial susceptibility testing of clinical isolates is a crucial step toward appropriate treatment of infectious diseases. The clinical isolate Francisella philomiragia 14IUHPL001, recently isolated from a 63-year-old woman with atypical pneumonia, featured decreased susceptibility to β-lactam antibiotics when cultivated in 5% CO2. Quantitative β-lactamase assays demonstrated a significant (P < 0.0001) increase in enzymatic activity between bacteria cultivated in 5% CO2 over those incubated in ambient air. The presence of β-lactamase genes blaTEM and blaSHV was detected in the clinical isolate F. philomiragia 14IUHPL001 by PCR, and the genes were positively identified by nucleotide sequencing. Expression of blaTEM and blaSHV was detected by reverse transcription-PCR during growth at 5% CO2 but not during growth in ambient air. A statistically significant alkaline shift was observed following cultivation of F. philomiragia 14IUHPL001 in both ambient air and 5% CO2, allowing desegregation of the previously reported effects of acidic pH from the currently reported effect of 5% CO2 on blaTEM and blaSHV β-lactamases. To ensure that the observed phenomenon was not unique to F. philomiragia, we evaluated a clinical isolate of blaTEM-carrying Haemophilus influenzae and found parallel induction of blaTEM gene expression and β-lactamase activity at 5% CO2 relative to ambient air. IMPORTANCE β-Lactamase induction and concurrent β-lactam resistance in respiratory tract pathogens as a consequence of growth in a physiologically relevant level of CO2 are of clinical significance, particularly given the ubiquity of TEM and SHV β-lactamase genes in diverse bacterial pathogens. This is the first report of β-lactamase induction by 5% CO2

Power Electronics High Performance Air-Cooled Heat Sinks IntegratingGraphite Based Materials

The thermal management of the power electronics cooling in the aircraft is getting more attention in the recent years due to the progressive implementation of electrical systems, especially in the framework of the more electrical aircraft, one of Clean Sky framework research activities to allow Europe to lead the transition to more environmental friendly aircraft in the future. The reference innovative trend in the cooling of power electronics and other semiconductor devices has been to migrate from air cooled solutions to liquid cooled or two-phase flow solutions, as these being able to reach higher levels of heat transfer density and keep electronics temperatures within the required limits. However, in the context of new wide-bandgap semiconductor materials (GaN, SiC) that withstand higher operating temperatures with reduced losses, the use of air cooling is attracting again interest, as a potential candidate to reduce the complexity of thermal management systems, and indirectly their weight and cost. In this regard, the consortium of the Clean Sky 2 project ICOPE has been working in the development of new concepts of air cooled heat sinks that incorporate advanced thermal materials such as Annealed Pyrolytic Graphite (APG) and Metal Matrix Composites (MMC) (Aluminium Graphite (ALG)).The project has evolved from pre-design steps to identify potential design candidates towards a final design with the support of CFD simulations and engineering assessment. Different versions of heat sink incorporating different combinations of the referred materials have been manufactured and successfully tested. A first loop of prototypes, called Stage A, implement APG, while a second loop of prototypes (Stage B) integrate APG and MMC in different interactions. This paper is conceived as a summary of the project developments and results at heat sink level, presenting the overall concept, the materials involved, and the experimental and numerical results obtained, which achieve the expected performances in terms of heat transfer, pressure drop and weight. The outcome of these results can suggest to reconsider the power electronics cooling design in other applications outside the aircraft sector, for example within Power Conversion applications or automotive field

Rifaximin Treatment in Hepatic Encephalopathy

Background Hepatic encephalopathy is a chronically debilitating complication of hepatic cirrhosis. The efficacy of rifaximin, a minimally absorbed antibiotic, is well documented in the treatment of acute hepatic encephalopathy, but its efficacy for prevention of the disease has not been established. Methods In this randomized, double-blind, placebo-controlled trial, we randomly assigned 299 patients who were in remission from recurrent hepatic encephalopathy resulting from chronic liver disease to receive either rifaximin, at a dose of 550 mg twice daily (140 patients), or placebo (159 patients) for 6 months. The primary efficacy end point was the time to the first breakthrough episode of hepatic encephalopathy. The key secondary end point was the time to the first hospitalization involving hepatic encephalopathy. Results Rifaximin significantly reduced the risk of an episode of hepatic encephalopathy, as compared with placebo, over a 6-month period (hazard ratio with rifaximin, 0.42; 95% confidence interval [CI], 0.28 to 0.64; P Conclusions Over a 6-month period, treatment with rifaximin maintained remission from hepatic encephalopathy more effectively than did placebo. Rifaximin treatment also significantly reduced the risk of hospitalization involving hepatic encephalopathy. (ClinicalTrials.gov number, NCT00298038.

Automatic Extraction of Vehicle, Bicycle, and Pedestrian Traffic From Video Data

SPR No. 742This project investigated the use of traffic cameras to count and classify vehicles. The intent is to provide an alternative approach to pneumatic tubes for collecting traffic data at high volume locations and to eliminate safety risks to SCDOT personnel and contractors. The objective is to develop algorithms to post-process the 48-hour videos to determine the number of vehicles in each one of four categories: motorcycles, passenger cars and light trucks, buses/campers/tow trucks, and small to large trucks. To this end, background subtraction and foreground detection algorithms were implemented to detect moving vehicles, and a Convolutional Neural Network (CNN) model was developed to classify vehicles using thermal images obtained from a custom-built thermal camera and solar-powered trailer. Additionally, to overcome false detection of vehicles due to either camera motion or erratic light reflection from the pavement surface, an algorithm was developed to keep track of each vehicle\u2019s trajectory and the vehicle trajectories were used to determine the presence of an actual vehicle. The developed algorithms and CNN model were incorporated into a Windows-based application, named DECAF (detection and classification by functional class) to enable users to easily specify the folder that contains the video files to be processed, specify the region for which traffic should be analyzed, specify the time interval for which the data should be aggregated, and view the detection and classification results in two report formats: 1) a spreadsheet with vehicle-by-vehicle information, and 2) a PDF summary report with totals aggregated for the user-specified interval. DECAF was tested using videos collected from five different sites in Columbia, SC, and the overall detection and classification accuracy for the hours evaluated was found to be 95% or higher

The Great Escape: The Role of Self-esteem and Self-related Cognition in Terror Management

Integrating terror management theory and objective self-awareness theory, we propose the existential escape hypothesis, which states that people with low self-esteem should be especially prone to escaping self-awareness as a distal response to thoughts of death. This is because they lack the means to bolster the self as a defense, and the propensity to bolster the self reduces the motivation to escape from self-awareness. Five studies supported this hypothesis. Individuals low, but not high, in self-esteem scored lower on a measure of private self-awareness (Study 1), showed less implicit self-activation (Studies 2 & 3), were more likely to choose to write about others than themselves (Study 4), and consumed more alcohol in a field study at a nightclub (Study 5) in response to mortality reminders. Implications for terror management theory (highlighting an additional route to defend against mortality awareness), self-regulation, physical health and well-being are discussed

Plasma Metabolomics Identifies Lipid and Amino Acid Markers of Weight Loss in Patients with Upper Gastrointestinal Cancer

Cachexia is a multifactorial wasting syndrome associated with high morbidity and mortality in patients with cancer. Diagnosis can be difficult and, in the clinical situation, usually relies upon reported weight loss. The 'omics' technologies allow us the opportunity to study the end points of many biological processes. Among these, blood-based metabolomics is a promising method to investigate the pathophysiology of human cancer cachexia and identify candidate biomarkers. In this study, we performed liquid chromatography mass spectrometry (LC/MS)-based metabolomics to investigate the metabolic profile of cancer-associated weight loss. Non-selected patients undergoing surgery with curative intent for upper gastrointestinal cancer were recruited. Fasting plasma samples were taken at induction of anaesthesia. LC/MS analysis showed that 6 metabolites were highly discriminative of weight loss. Specifically, a combination profile of LysoPC 18.2, L-Proline, Hexadecanoic acid, Octadecanoic acid, Phenylalanine and LysoPC 16:1 showed close correlation for eight weight-losing samples (≥5% weight loss) and nine weight-stable samples (<5%weight loss) between predicted and actual weight change (r = 0.976, p = 0.0014). Overall, 40 metabolites were associated with ≥5% weight loss. This study provides biological validation of the consensus definition of cancer cachexia (Fearon et al.) and provides feasible candidate markers for further investigation in early diagnosis and the assessment of therapeutic intervention

The Predictive Nature of Individual Differences in Early Associative Learning and Emerging Social Behavior

Across the first year of life, infants achieve remarkable success in their ability to interact in the social world. The hierarchical nature of circuit and skill development predicts that the emergence of social behaviors may depend upon an infant's early abilities to detect contingencies, particularly socially-relevant associations. Here, we examined whether individual differences in the rate of associative learning at one month of age is an enduring predictor of social, imitative, and discriminative behaviors measured across the human infant's first year. One-month learning rate was predictive of social behaviors at 5, 9, and 12 months of age as well as face-evoked discriminative neural activity at 9 months of age. Learning was not related to general cognitive abilities. These results underscore the importance of early contingency learning and suggest the presence of a basic mechanism underlying the ontogeny of social behaviors