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Investigates the effect of age-related functional changes in temporal lobe epilepsy in rats. Determination of the changes in cerebral activity during epileptogenesis; Information on the different patterns of cerebral activity observed in 21-day old and adult rats; Reason for the resistance of 10-day old rats to neuronal damage and epileptogenesis; Role of the various brain structures in the process of epileptogenesis.

Objective: To evaluate the effect of a 2-hour, multicomponent educational intervention on provider skin cancer control practices.Design: Nonrandomized intervention study. The intervention was a 2-hour curriculum designed to augment provider skin cancer control practices through instruction in basic skin cancer triage (BSCT) and a brief summary of skin cancer epidemiology, prevention, and counseling.Setting: Five staff-model health maintenance organizations in southeastern New England.Participants: Convenience sample of primary care providers. Providers older than age 75, individuals in practice for less than 1 year, or individuals planning to retire in the next 2 years were excluded from the study. Twenty-two of 28 participants completed the study.Results: Providers completed preintervention and postintervention surveys asking them to rate their attitudes towards skin examination and skin cancer counseling and to rate the frequency of their skin cancer control practices, using 5-point Likert scales. We independently assessed provider behavior through surveys of their patients, eliciting information on provider practices before and after BSCT participation. Following participation in the curriculum, there was significant improvement in provider attitudes towards the total body skin examination but not towards skin cancer prevention counseling. Significant increases in provider self- reported skin cancer control practices during an initial visit with a new patient (2.17 to 3.21, P <.0001) and a routine visit with a patient at high risk for melanoma (2.15 to 3.00, P <.0001) were demonstrated. Analysis of the patient exit interviews independently confirmed these changes in practice patterns.Conclusions: The study results suggest that the BSCT curriculum may be a useful tool in increasing the practice of skin cancer control measures by primary care providers. [ABSTRACT FROM AUTHOR]

Abstract Background Colorectal cancer (CRC) represents a serious and growing health problem in Canada. Colonoscopy is used for screening and diagnosis of symptomatic or high CRC risk individuals. Although a number of countries are now implementing quality colonoscopy services, knowledge synthesis of barriers and facilitators perceived by healthcare professionals and patients during implementation has not been carried out. In addition, the perspectives of various stakeholders towards the implementation of quality colonoscopy services and the need of an efficient organisation of such services have been reported in the literature but have not been synthesised yet. The present study aims to produce a comprehensive synthesis of actual knowledge on the barriers and facilitators perceived by all stakeholders to the implementation of quality colonoscopy services in Canada. Methods First, we will conduct a comprehensive review of the scientific literature and other published documentation on the barriers and facilitators to implementing quality colonoscopy services. Standardised literature searches and data extraction methods will be used. The quality of the studies and their relevance to informing decisions on colonoscopy services implementation will be assessed. For each group of users identified, barriers and facilitators will be categorised and compiled using narrative synthesis and meta-analytical techniques. The principle factors identified for each group of users will then be validated for its applicability to various Canadian contexts using the Delphi study method. Following this study, a set of strategies will be identified to inform decision makers involved in the implementation of quality colonoscopy services across Canadian jurisdictions. Discussion This study will be the first to systematically summarise the barriers and facilitators to implementation of quality colonoscopy services perceived by different groups and to consider the local contexts in order to ensure the applicability of this knowledge to the particular realities of various Canadian jurisdictions. Linkages with strategic partners and decision makers in the realisation of this project will favour the utilisation of its results to support strategies for implementing quality colonoscopy services and CRC screening programs in the Canadian health system.

Abstract Background The insulin signaling pathway (ISP) has a key role in major physiological events like carbohydrate metabolism and growth regulation. The ISP has been well described in vertebrates and in a few invertebrate model organisms but remains largely unexplored in non-model invertebrates. This study is the first detailed genomic study of this pathway in a crustacean species, Daphnia pulex. Results The Daphnia pulex draft genome sequence assembly was scanned for major components of the ISP with a special attention to the insulin-like receptor. Twenty three putative genes are reported. The pathway appears to be generally well conserved as genes found in other invertebrates are present. Major findings include a lower number of insulin-like peptides in Daphnia as compared to other invertebrates and the presence of multiple insulin-like receptors (InR), with four genes as opposed to a single one in other invertebrates. Genes encoding for the Dappu_InR are likely the result of three duplication events and bear some unusual features. Dappu_InR-4 has undergone extensive evolutionary divergence and lacks the conserved site of the catalytic domain of the receptor tyrosine kinase. Dappu_InR-1 has a large insert and lacks the transmembranal domain in the β-subunit. This domain is also absent in Dappu_InR-3. Dappu_InR-2 is characterized by the absence of the cystein-rich region. Real-time q-PCR confirmed the expression of all four receptors. EST analyses of cDNA libraries revealed that the four receptors were differently expressed under various conditions. Conclusions Duplications of the insulin receptor genes might represent an important evolutionary innovation in Daphnia as they are known to exhibit extensive phenotypic plasticity in body size and in the size of defensive structures in response to predation.

Abstract Background Unhealthy substance use is the spectrum from use that risks harm, to use associated with problems, to the diagnosable conditions of substance abuse and dependence, often referred to as substance abuse disorders. Despite the prevalence and impact of unhealthy substance use, medical education in this area remains lacking, not providing physicians with the necessary expertise to effectively address one of the most common and costly health conditions. Medical educators have begun to address the need for physician training in unhealthy substance use, and formal curricula have been developed and evaluated, though broad integration into busy residency curricula remains a challenge. Discussion We review the development of unhealthy substance use related competencies, and describe a curriculum in unhealthy substance use that integrates these competencies into internal medicine resident physician training. We outline strategies to facilitate adoption of such curricula by the residency programs. This paper provides an outline for the actual implementation of the curriculum within the structure of a training program, with examples using common teaching venues. We describe and link the content to the core competencies mandated by the Accreditation Council for Graduate Medical Education, the formal accrediting body for residency training programs in the United States. Specific topics are recommended, with suggestions on how to integrate such teaching into existing internal medicine residency training program curricula. Summary Given the burden of disease and effective interventions available that can be delivered by internal medicine physicians, teaching about unhealthy substance use must be incorporated into internal medicine residency training, and can be done within existing teaching venues.

Abstract Background Physicians receive little education about unhealthy alcohol use and as a result patients often do not receive efficacious interventions. The objective of this study is to evaluate whether a free web-based alcohol curriculum would be used by physician educators and whether in-person faculty development would increase its use, confidence in teaching and teaching itself. Methods Subjects were physician educators who applied to attend a workshop on the use of a web-based curriculum about alcohol screening and brief intervention and cross-cultural efficacy. All physicians were provided the curriculum web address. Intervention subjects attended a 3-hour workshop including demonstration of the website, modeling of teaching, and development of a plan for using the curriculum. All subjects completed a survey prior to and 3 months after the workshop. Results Of 20 intervention and 13 control subjects, 19 (95%) and 10 (77%), respectively, completed follow-up. Compared to controls, intervention subjects had greater increases in confidence in teaching alcohol screening, and in the frequency of two teaching practices – teaching about screening and eliciting patient health beliefs. Teaching confidence and teaching practices improved significantly in 9 of 10 comparisons for intervention, and in 0 comparisons for control subjects. At follow-up 79% of intervention but only 50% of control subjects reported using any part of the curriculum (p = 0.20). Conclusion In-person training for physician educators on the use of a web-based alcohol curriculum can increase teaching confidence and practices. Although the web is frequently used for disemination, in-person training may be preferable to effect widespread teaching of clinical skills like alcohol screening and brief intervention.

Transcribed Ultra-Conserved Regions (TUCRs) represent a severely understudied class of putative non-coding RNAs (ncRNAs) that are 100% conserved across multiple species. We performed the first-ever analysis of TUCRs in glioblastoma (GBM) and low-grade gliomas (LGG). We leveraged large human datasets to identify the genomic locations, chromatin accessibility, transcription, differential expression, correlation with survival, and predicted functions of all 481 TUCRs, and identified TUCRs that are relevant to glioma biology. Of these, we investigated the expression, function, and mechanism of action of the most highly upregulated intergenic TUCR, uc.110, identifying it as a new tumor enhancer. Uc.110 was highly overexpressed in GBM and LGG, where it promoted malignancy and tumor growth. Uc.110 activated the WNT pathway by upregulating the expression of membrane frizzled-related protein (MFRP), by sponging the tumor suppressor microRNA miR-544. This pioneering study shows important roles for TUCRs in gliomas and provides an extensive database and novel methods for future TUCR research.

Background and Purpose: Inhibitors of voltage-gated sodium channels (Na V s) are important anti-epileptic drugs, but the contribution of specific channel isoforms is unknown since available inhibitors are non-selective. We aimed to create novel, isoform selective inhibitors of Na v channels as a means of informing the development of improved antiseizure drugs., Experimental Approach: We created a series of compounds with diverse selectivity profiles enabling block of Na V 1.6 alone or together with Na V 1.2. These novel Na V inhibitors were evaluated for their ability to inhibit electrically evoked seizures in mice with a heterozygous gain-of-function mutation (N1768D/+) in Scn8a (encoding Na V 1.6) and in wild-type mice., Key Results: Pharmacologic inhibition of Na V 1.6 in Scn8a N1768D/+ mice prevented seizures evoked by a 6-Hz shock. Inhibitors were also effective in a direct current maximal electroshock seizure assay in wild-type mice. Na V 1.6 inhibition correlated with efficacy in both models, even without inhibition of other CNS Na V isoforms., Conclusions and Implications: Our data suggest Na V 1.6 inhibition is a driver of efficacy for Na V inhibitor anti-seizure medicines. Sparing the Na V 1.1 channels of inhibitory interneurons did not compromise efficacy. Selective Na V 1.6 inhibitors may provide targeted therapies for human Scn8a developmental and epileptic encephalopathies and improved treatments for idiopathic epilepsies., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction/methods: EPOCH-US is an ongoing, retrospective, observational cohort study among individuals identified in the Healthcare Integrated Research Database (HIRD ® ) with ≥ 12 months of continuous health plan enrollment. Data were collected for the HIRD population (containing immunocompetent and immunocompromised [IC] individuals), individual IC cohorts (non-mutually exclusive cohorts based on immunocompromising condition and/or immunosuppressive [IS] treatment), and the composite IC population (all unique IC individuals). This study updates previous results with addition of the general population cohort and data specifically for the year of 2022 (i.e., Omicron wave period). To provide healthcare decision-makers the most recent trends, this study reports incidence rates (IR) and severity of first SARS-CoV-2 infection; and relative risk, healthcare utilization, and costs related to first COVID-19 hospitalizations in the full year of 2022 and overall between April 2020 and December 2022., Results: These updated results showed a 2.9% prevalence of immune compromise in the population. From April 2020 through December 2022, the overall IR of COVID-19 was 115.7 per 1000 patient-years in the composite IC cohort and 77.8 per 1000 patient-years in the HIRD cohort. The composite IC cohort had a 15.4% hospitalization rate with an average cost of $42,719 for first COVID-19 hospitalization. Comparatively, the HIRD cohort had a 3.7% hospitalization rate with an average cost of $28,848 for first COVID-19 hospitalization. Compared to the general population, IC individuals had 4.3 to 23 times greater risk of hospitalization with first diagnosis of COVID-19. Between January and December 2022, hospitalizations associated with first COVID-19 diagnosis cost over $1 billion, with IC individuals (~ 3% of the population) generating $310 million (31%) of these costs., Conclusion: While only 2.9% of the population, IC individuals had a higher risk of COVID-19 hospitalization and incurred higher healthcare costs across variants. They also disproportionately accounted for over 30% of total costs for first COVID-19 hospitalization in 2022, amounting to ~ $310 million. These data highlight the need for additional preventive measures to decrease the risk of developing severe COVID-19 outcomes in vulnerable IC populations., (© 2024. The Author(s).)

The aim of this study was to investigate the comparative antiseizure activity of the l -enantiomers of d , l -fenfluramine and d , l -norfenfluramine and to evaluate the relationship between their concentration in plasma and brain and anticonvulsant activity. d , l -Fenfluramine, d , l -norfenfluramine and their individual enantiomers were evaluated in the mouse maximal electroshock seizure (MES) test. d , l -Fenfluramine, d , l -norfenfluramine and their individual l -enantiomers were also assessed in the DBA/2 mouse audiogenic seizure model. All compounds were administered intraperitoneally. Brain and plasma concentrations of the test compounds in DBA/2 mice were quantified and correlated with anticonvulsant activity. In the MES test, fenfluramine, norfenfluramine and their enantiomers showed comparable anticonvulsant activity, with ED 50 values between 5.1 and 14.8 mg/kg. In the audiogenic seizure model, l -norfenfluramine was 9 times more potent than d , l -fenfluramine and 15 times more potent than l -fenfluramine based on ED 50 (1.2 vs. 10.2 and 17.7 mg/kg, respectively). Brain concentrations of all compounds were about 20-fold higher than in plasma. Based on brain EC 50 values, l -norfenfluramine was 7 times more potent than d , l -fenfluramine and 13 times more potent than l -fenfluramine (1940 vs. 13,200 and 25,400 ng/g, respectively). EC 50 values for metabolically formed d , l -norfenfluramine and l -norfenfluramine were similar to brain EC 50 values of the same compounds administered as such, suggesting that, in the audiogenic seizure model, the metabolites were responsible for the antiseizure activity of the parent compounds. Because of the evidence linking d -norfenfluramine to d , l -fenfluramine to cardiovascular and metabolic adverse effects, their l -enantiomers could potentially be safer follow-up compounds to d , l -fenfluramine. We found that, in the models tested, the activity of l -fenfluramine and l -norfenfluramine was comparable to that of the corresponding racemates. Based on the results in DBA/2 mice and other considerations, l -norfenfluramine appears to be a particularly attractive candidate for further evaluation as a novel, enantiomerically pure antiseizure medication.

Background: There are high rates of computed tomography (CT) utilization in the emergency department (ED) for patients with inflammatory bowel disease (IBD), despite guidelines recommending judicious use. We performed a national survey to better understand perceptions and practice patterns of Canadian physicians related to CT imaging in the ED., Methods: Our survey was developed by a multistep iterative process with input from key stakeholders between 2021 and 2022. It evaluated Canadian gastroenterologists', surgeons', and emergency physicians' (1) perceived rates of IBD findings detected by CT, (2) likelihood of performing CT for specific presentations and (3) comfort in diagnosing IBD phenotypes/complications without CT., Results: A total of 208 physicians responded to our survey: median age 44 years (IQR, 37-50), 63% male, 68% academic, 44% emergency physicians, 39% gastroenterologists, and 17% surgeons. Compared with emergency physicians and surgeons, gastroenterologists more often perceived that CT would detect inflammation alone and less often IBD complications. Based on established rates in the literature, 13 (16%) gastroenterologists, 33 (40%) emergency physicians, and 21 (60%) surgeons overestimated the rates of at least one IBD complication. Although most physicians were more comfortable diagnosing inflammation compared to IBD complications without CT, gastroenterologists were significantly less likely to recommend CT imaging for non-obstructive/penetrating presentations compared with emergency physicians and surgeons with results that varied by IBD subtype., Conclusion: This national survey demonstrates differences in physician perceptions and practices regarding CT utilization in the ED and can be used as a framework for educational initiatives regarding appropriate usage of this modality., Competing Interests: Jeffrey D. McCurdy has received speaker fees, consulting fees, payment for expert testimony, or participated in advisory board meetings from the following companies: Janssen, AbbVie, Amgen, BMS, Takeda, Pfizer, Fresenius Kabi, Celltrion, and Amgen. All other authors had no conflict of interest to disclose., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Canadian Association of Gastroenterology.)

Brain metastasis (BM) is the most common type of brain tumor and frequently foreshadows disease progression and poor overall survival with patients having a median survival of 6 months. 70,000 new cases of BM are diagnosed each year in the United States (US) and the incidence rate for BM is increasing with improved detection. MicroRNAs (miRNAs) are small non-coding RNAs that serve as critical regulators of gene expression and can act as powerful oncogenes and tumor suppressors. MiRNAs have been heavily implicated in cancer and proposed as biomarkers or therapeutic targets or agents. In this review, we summarize an extensive body of scientific work investigating the role of microRNAs in BM. We discuss miRNA dysregulation, functions, targets, and mechanisms of action in BM and present the current standing of miRNAs as biomarkers and potential therapeutics for BM. We conclude with future directions of miRNA basic and clinical research in BM., (© 2024. The Author(s).)

Objective: To estimate the prevalence of patients with an immunocompromising condition at risk for COVID-19, estimate COVID-19 prevalence rate (PR) and incidence rate (IR) by immunocompromising condition, and describe COVID-19-related healthcare resource utilization (HCRU) and costs., Methods: Using the Healthcare Integrated Research Database (HIRD), patients with ≥1 claim for an immunocompromising condition of interest or ≥2 claims for an immunosuppressive (IS) treatment and COVID-19 diagnosis during the infection period (1 April 2020-31 March 2022) and had ≥12 months baseline data were included. Cohorts (other than the composite cohort) were not mutually exclusive and were defined by each immunocompromising condition. Analyses were descriptive in nature., Results: Of the 16,873,161 patients in the source population, 2.7% ( n  = 458,049) were immunocompromised (IC). The COVID-19 IR for the composite IC cohort during the study period was 101.3 per 1000 person-years and the PR was 13.5%. The highest IR (195.0 per 1000 person-years) and PR (20.1%) were seen in the end-stage renal disease (ESRD) cohort; the lowest IR (68.3 per 1000 person-years) and PR (9.4%) were seen in the hematologic or solid tumor malignancy cohort. Mean costs for hospitalizations associated with the first COVID-19 diagnosis were estimated at nearly $1 billion (2021 United States dollars [USD]) for 14,516 IC patients, with a mean cost of $64,029 per patient., Conclusions: Immunocompromised populations appear to be at substantial risk of severe COVID-19 outcomes, leading to increased costs and HCRU. Effective prophylactic options are still needed for these high-risk populations as the COVID-19 landscape evolves.