Ethanol Reversal of Oxycodone Tolerances

Oxycodone is a semi-synthetic opioid originally developed as a safer alternative to morphine. It is commonly prescribed for its pain-relieving effects, but has recently been implicated as a major underlying cause of the current opioid epidemic due to its clinical limitations that include tolerance, dependence and a high abuse liability. Simultaneous consumption of opioids and ethanol has been shown to increase the risk of overdose and death from opioids in opioid-tolerant individuals. We hypothesized that ethanol reversed opioid tolerance and previous studies showed that ethanol reversed morphine tolerance. This dissertation investigated whether ethanol reversed tolerance to other opioids in mice, primarily oxycodone. We found that tolerance developed to the antinociceptive effects of both oxycodone and hydrocodone, and that the same dose of ethanol (1 g/kg i.p.) reversed that tolerance. Oral ethanol (2 g/kg) also effectively reversed oxycodone tolerance. Ethanol did not significantly alter either acute or chronic oxycodone brain concentrations, suggesting that the reversal effect was mediated by neuronal mechanisms. DRG neurons were isolated from adult mice and the effects of oxycodone were assessed using whole-cell patch clamp electrophysiology experiments. Oxycodone [3µM] acutely reduced neuronal excitability as measured by a shift in threshold potentials to a more positive value. DRG neurons incubated overnight with 10µM oxycodone did not respond to the 3µM oxycodone challenge, indicating tolerance developed within these neurons. To test if ethanol was reversing tolerance through neuronal mechanisms, we incubated DRG neurons overnight with 10µM oxycodone and applied 20mM ethanol to the media prior to recording. Tolerance was robustly reversed in these neurons, as indicated by a response to 3µM oxycodone. The PKC inhibitor, Bis XI, also reversed oxycodone tolerance. In these studies we have clearly shown that tolerance develops to oxycodone in both the whole animal in an isolated neuronal preparation. In addition we have shown that the tolerance produced in these two preparations was reversed by ethanol at blood levels similar to those seen in humans. Further we have also included preliminary data that suggest that this reversal of oxycodone tolerance by ethanol may well be due to its actions on PKC

Diagnostic accuracy of qPCR and microscopy for cutaneous leishmaniasis in rural Ecuador: A Bayesian latent class analysis

Precisión diagnóstica; Leishmaniasis cutánea; Ecuador ruralPrecisió diagnòstica; Leishmaniosi cutània; Equador ruralDiagnostic accuracy; Cutaneous leishmaniasis; Rural EcuadorBackground Clinical and laboratory diagnosis of cutaneous leishmaniasis (CL) is hampered by under-ascertainment of direct microscopy. Methods This study compared the diagnostic accuracy of qPCR on DNA extracted from filter paper to the accuracy of direct smear slide microscopy in participants presenting with a cutaneous lesion suspected of leishmaniasis to 16 rural healthcare centers in the Ecuadorian Amazon and Pacific regions, from January 2019 to June 2021. We used Bayesian latent class analysis to estimate test sensitivity, specificity, likelihood ratios (LR), and predictive values (PV) with their 95% credible intervals (95%CrI). The impact of sociodemographic and clinical characteristics on predictive values was assessed as a secondary objective. Results Of 320 initially included participants, paired valid test results were available and included in the diagnostic accuracy analysis for 129 from the Amazon and 185 from the Pacific region. We estimated sensitivity of 68% (95%CrI 49% to 82%) and 73% (95%CrI 73% to 83%) for qPCR, and 51% (95%CrI 36% to 66%) and 76% (95%CrI 65% to 86%) for microscopy in the Amazon and Pacific region, respectively. In the Amazon, with an estimated disease prevalence among participants of 73%, negative PV for qPCR was 54% (95%CrI 5% to 77%) and 44% (95%CrI 4% to 65%) for microscopy. In the Pacific, (prevalence 88%) the negative PV was 34% (95%CrI 3% to 58%) and 37% (95%CrI 3% to 63%). The addition of qPCR parallel to microscopy in the Amazon increases the observed prevalence from 38% to 64% (+26 (95%CrI 19 to 34) percentage points). Conclusion The accuracy of either qPCR on DNA extracted from filter paper or microscopy for CL diagnosis as a stand-alone test seems to be unsatisfactory and region-dependent. We recommend further studies to confirm the clinically relevant increment found in the diagnostic yield due to the addition of qPCR

Interstitial lung disease:A review of classification, aetiology, epidemiology, clinical diagnosis, pharmacological and non-pharmacological treatment

Interstitial lung diseases (ILDs) refer to a heterogeneous and complex group of conditions characterized by inflammation, fibrosis, or both, in the interstitium of the lungs. This results in impaired gas exchange, leading to a worsening of respiratory symptoms and a decline in lung function. While the etiology of some ILDs is unclear, most cases can be traced back to factors such as genetic predispositions, environmental exposures (including allergens, toxins, and air pollution), underlying autoimmune diseases, or the use of certain medications. There has been an increase in research and evidence aimed at identifying etiology, understanding epidemiology, improving clinical diagnosis, and developing both pharmacological and non-pharmacological treatments. This review provides a comprehensive overview of the current state of knowledge in the field of interstitial lung diseases

Evaluating a Remote Monitoring Program for Respiratory Diseases: Prospective Observational Study

BACKGROUND: Patients with chronic respiratory diseases and those in the postdischarge period following hospitalization because of COVID-19 are particularly vulnerable, and little is known about the changes in their symptoms and physiological parameters. Continuous remote monitoring of physiological parameters and symptom changes offers the potential for timely intervention, improved patient outcomes, and reduced health care costs. OBJECTIVE: This study investigated whether a real-time multimodal program using commercially available wearable technology, home-based Bluetooth-enabled spirometers, finger pulse oximeters, and smartphone apps is feasible and acceptable for patients with chronic respiratory diseases, as well as the value of low-burden, long-term passive data collection. METHODS: In a 3-arm prospective observational cohort feasibility study, we recruited 60 patients from the Royal Free Hospital and University College Hospital. These patients had been diagnosed with interstitial lung disease, chronic obstructive pulmonary disease, or post-COVID-19 condition (n=20 per group) and were followed for 180 days. This study used a comprehensive remote monitoring system designed to provide real-time and relevant data for both patients and clinicians. Data were collected using REDCap (Research Electronic Data Capture; Vanderbilt University) periodic surveys, Remote Assessment of Disease and Relapses-base active app questionnaires, wearables, finger pulse oximeters, smartphone apps, and Bluetooth home-based spirometry. The feasibility of remote monitoring was measured through adherence to the protocol, engagement during the follow-up period, retention rate, acceptability, and data integrity. RESULTS: Lowest-burden passive data collection methods, via wearables, demonstrated superior adherence, engagement, and retention compared with active data collection methods, with an average wearable use of 18.66 (SD 4.69) hours daily (77.8% of the day), 123.91 (SD 33.73) hours weekly (72.6% of the week), and 463.82 (SD 156.70) hours monthly (64.4% of the month). Highest-burden spirometry tasks and high-burden active app tasks had the lowest adherence, engagement, and retention, followed by low-burden questionnaires. Spirometry and active questionnaires had the lowest retention at 0.5 survival probability, indicating that they were the most burdensome. Adherence to and quality of home spirometry were analyzed; of the 7200 sessions requested, 4248 (59%) were performed. Of these, 90.3% (3836/4248) were of acceptable quality according to American Thoracic Society grading. Inclusion of protocol holidays improved retention measures. The technologies used were generally well received. CONCLUSIONS: Our findings provide evidence supporting the feasibility and acceptability of remote monitoring for capturing both subjective and objective data from various sources for respiratory diseases. The high engagement level observed with passively collected data suggests the potential of wearables for long-term, user-friendly remote monitoring in respiratory disease management. The unique piloting of certain features such as protocol holidays, alert notifications for missing data, and flexible support from the study team provides a reference for future studies in this field. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.2196/28873

Iron-catalyzed stereoselective C–H alkylation for simultaneous construction of C–N axial and C -central chirality

The assembly of chiral molecules with multiple stereogenic elements is challenging, and, despite of indisputable advances, largely limited to toxic, cost-intensive and precious metal catalysts. In sharp contrast, we herein disclose a versatile C–H alkylation using a non-toxic, low-cost iron catalyst for the synthesis of substituted indoles with two chiral elements. The key for achieving excellent diastereo- and enantioselectivity was substitution on a chiral N-heterocyclic carbene ligand providing steric hindrance and extra represented by noncovalent interaction for the concomitant generation of C–N axial chirality and C-stereogenic center. Experimental and computational mechanistic studies have unraveled the origin of the catalytic efficacy and stereoselectivity

DNA barcodes reveal species-specific mercury levels in tuna sushi that pose a health risk to consumers

Excessive ingestion of mercury—a health hazard associated with consuming predatory fishes—damages neurological, sensory-motor and cardiovascular functioning. The mercury levels found in Bigeye Tuna (Thunnus obesus) and bluefin tuna species (Thunnus maccoyii, Thunnus orientalis, and Thunnus thynnus), exceed or approach levels permissible by Canada, the European Union, Japan, the US, and the World Health Organization. We used DNA barcodes to identify tuna sushi samples analysed for mercury and demonstrate that the ability to identify cryptic samples in the market place allows regulatory agencies to more accurately measure the risk faced by fish consumers and enact policies that better safeguard their health

Longitudinal cytokine profiling identifies GRO-α and EGF as potential biomarkers of disease progression in Essential Thrombocythemia

Myeloproliferative neoplasms (MPNs) are characterized by deregulation of mature blood cell production and increased risk of myelofibrosis (MF) and leukemic transformation. Numerous driver mutations have been identified but substantial disease heterogeneity remains unexplained, implying the involvement of additional as yet unidentified factors. The inflammatory microenvironment has recently attracted attention as a crucial factor in MPN biology, in particular whether inflammatory cytokines and chemokines contribute to disease establishment or progression. Here we present a large-scale study of serum cytokine profiles in more than 400 MPN patients and identify an essential thrombocythemia (ET)-specific inflammatory cytokine signature consisting of Eotaxin, GRO-α, and EGF. Levels of 2 of these markers (GRO-α and EGF) in ET patients were associated with disease transformation in initial sample collection (GRO-α) or longitudinal sampling (EGF). In ET patients with extensive genomic profiling data (n = 183) cytokine levels added significant prognostic value for predicting transformation from ET to MF. Furthermore, CD56+CD14+ pro-inflammatory monocytes were identified as a novel source of increased GRO-α levels. These data implicate the immune cell microenvironment as a significant player in ET disease evolution and illustrate the utility of cytokines as potential biomarkers for reaching beyond genomic classification for disease stratification and monitoring.The serum cytokine studies were supported by a research grant from the Rosetrees Trust. NFØ was supported by grants from the Danish Lundbeck Foundation and Danish Cancer Society, J.G. was supported by fellowships from Bloodwise and the Kay Kendall Leukaemia Fund; and M.S.S. is the recipient of a Biotechnology and Biological Sciences Research Council Industrial Collaborative Awards in Science and Engineering PhD Studentship. Work in the R.C.S. laboratory was supported by grants from the Stiftung Blutspendezentrum SRK beider Basel, the Swiss National Science Foundation (31003A-147016/1 and 31003A_166613), and the Swiss Cancer League (KLS-2950-02-2012 and KFS-3655-02-2015). A.K. was supported by the Else Kröner-Fresenius Foundation. Work in the A.R.G. laboratory is supported by the Wellcome Trust, Bloodwise, Cancer Research UK, the Kay Kendall Leukaemia Fund, and the Leukemia and Lymphoma Society of America. Work in the D.G.K. laboratory is supported by a Bloodwise Bennett Fellowship (15008), a European Hematology Association Non-Clinical Advanced Research Fellowship, and an ERC Starting Grant (ERC-2016-STG–715371). D.G.K. and A.R.G. are supported by a core support grant from the Wellcome Trust and Medical Research Council to the Wellcome MRC Cambridge Stem Cell Institute, the National Institute for Health Research Cambridge Biomedical Research Centre, and the CRUK Cambridge Cancer Centre